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Wilson disease protein (WND), also known as ATP7B protein, is a copper-transporting P-type ATPase which is encoded by the ATP7B gene. The ATP7B protein is located in the trans-Golgi network of the liver and brain and balances the copper level in the body by excreting excess copper into bile and plasma. Genetic disorder of the ATP7B gene may cause Wilson's disease, a disease in which copper accumulates in tissues, leading to neurological or psychiatric issues and liver diseases.
== Gene ==
Wilson disease protein is associated with ATP7B gene, approximately 80 Kb, located on human chromosome 13 and consists of 21 exons. The mRNA transcribed by ATP7B gene has a size of 7.5 Kb, and which encodes a protein of 1465 amino acids.
The gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites. This protein functions as a monomer, exporting copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Wilson's disease is caused by various mutations. One of the common mutations is single base pair mutation, H1069Q.
== Structure ==
ATP7B protein is a copper-transporting P-type ATPase, synthesized as a membrane protein of 165 KDa in human hepatoma cell line, and which is 57% homologous to Menkes disease-associated protein ATP7A.
ATP7B consists of several domains:
Phosphatase domain (TGEA motif Thr-Gly-Glu-Ala)
Phosphorylation domain (DKTGT motif Asp-Lys-Thr-Gly-Thr)
ATP binding domain (TGDN motif)
Metal binding domain (six copper binding motifs at the N-terminus in the cytosol)
Eight transmembrane segments
The CPC motif (Cys-Pro-Cys) in transmembrane segment 6 characterizes the protein as a heavy metal transporting ATPase.
The copper binding motif also shows a high affinity to other transition metal ions such as zinc Zn(II), cadmium Cd(II), gold Au(III), and mercury Hg(II). However, copper is able to decrease the zinc binding affinity at low concentration and increase copper binding affinity dramatically with increasing concentration to ensure a strong binding between the motif and copper.
As a P-type ATPases, ATP7B undergoes auto-phosphorylation of a key conserved aspartic acid (D) residue in the DKTGT motif. The ATP binding to the protein initiates the reaction and copper binds to the transmembrane region. Then phosphorylation occurs at the aspartic acid residue in the DKTGT motif with Cu release. Then dephosphorylation of the aspartic acid residue recovers the protein to ready for the next transport.
== Function ==
Most of ATP7B protein is located in the trans-Golgi network (TGN) of hepatocytes, which is different from its homologous protein ATP7A. Small amount of ATP7B is located in the brain.
As a copper-transporting protein, one major function is delivering copper to copper dependent enzymes in Golgi apparatus (e.g. ceruloplasmin (CPN)).
In the human body, the liver plays an important role in copper regulation including removal of extra copper. ATP7B participates in the physiological pathway in the copper removal process in two ways: secreting copper into plasma and excreting copper into bile.
== Interactions ==
=== ATOX1 ===
ATP7B receives copper from cytosolic protein antioxidant 1 copper chaperone (ATOX1). This protein targets ATP7B directly in liver in order to transport copper. ATOX1 transfers copper from cytosol to the metal binding domain of ATP7B which control the catalytic activity of ATP7B.
Several mutations in ATOX1 can block the copper pathways and cause Wilson disease.
=== GLRX ===
ATP7B interacts with glutaredoxin-1 (GLRX). Subsequent transport is promoted through the reduction of intramolecular disulfide bonds by GLRX catalysis.
== Associations with Wilson's disease ==
Wilson disease happens when accumulation of copper inside the liver causes mitochondrial damage and cell destruction and shows symptoms of hepatic disease. Then, the loss of excretion of copper in bile leads to an increasing concentration of copper level in urine and causes kidney problems. Therefore, symptoms of Wilson's disease could be various including kidney disease and neurological disease. The major cause is the malfunction of ATP7B by single base pair mutations, deletions, frame-shifts, splice errors in ATP7B gene.
== See also ==
ATP7A and Menkes disease
ATOX1
== References ==
== Further reading ==
== External links ==
GeneReviews/NIH/NCBI/UW entry on Wilson Disease or Hepatolenticular Degeneration
Wilson+disease+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Wilson_disease_protein |
Polycystin-2 (PC2) is a protein that in humans is encoded by the PKD2 gene.
The gene PKD2 also known as TRPP2, encodes a member of the polycystin protein family, called TRPP, and contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. TRPP2 may function in renal tubular development, morphology, and function, and may modulate intracellular calcium homeostasis and other signal transduction pathways. This protein interacts with polycystin 1 (TRPP1) to produce cation-permeable currents. It was discovered by Stefan Somlo at Yale University.
== Clinical significance ==
Mutations in this gene have been associated with autosomal dominant polycystic kidney disease.
== Interactions ==
Polycystin 2 has been shown to interact with the proteins TRPC1, PKD1 and TNNI3.
== See also ==
HAX1
TRPP
== References ==
== Further reading ==
== External links ==
GeneReviews/NIH/NCBI/UW entry on Polycystic Kidney Disease, Autosomal Dominant
"Transient Receptor Potential Channels: TRPP1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. | Wikipedia/Polycystic_kidney_disease_2 |
Odorant-binding proteins (OBPs) are small (10 to 30 kDa) soluble proteins secreted by auxiliary cells surrounding olfactory receptor neurons, including the nasal mucus of many vertebrate species and in the sensillar lymph of chemosensory sensilla of insects. OBPs are characterized by a specific protein domain that comprises six α-helices joined by three disulfide bonds. Although the function of the OBPs as a whole is not well established, it is believed that they act as odorant transporters, delivering the odorant molecules to olfactory receptors in the cell membrane of sensory neurons.
The olfactory receptors of terrestrial animals exist in an aqueous environment, yet detect odorants that are primarily hydrophobic. The aqueous solubility of hydrophobic odorants is greatly enhanced via odorant-binding proteins, which exist in the extracellular fluid surrounding the odorant receptors. This family is composed of pheromone binding proteins (PBP), which are male-specific and associate with pheromone-sensitive neurons and general-odorant-binding proteins (GOBP).
These proteins were initially identified on the basis of their ability to bind with moderate-affinity radioactively labeled odorants.
== Structure ==
OBPs are small proteins on the order of 14 kDa in size. All odorant binding proteins are believed to have a common structure despite their genetic diversity and highly variable primary structures. In vertebrates, OBPs are a part of the lipocalin family. They are structurally characterized by a β-barrel motif composed of antiparallel β-sheets. Insect OBPs share very little amino acid sequence similarity to vertebrate OBPs as they mainly contain α-helical domains. OBPs are divergent across and within species. The percentage of conserved residues between species has been shown to be as low as 8%. OBPs' have a characteristic signature that is recognized by a conserved pattern of six cysteines that are connected in the protein by three disulfide bridges. Their structures have been investigated to explore new bio-inspired repellents against mosquitoes, with potentially improved OBP binding affinity, selectivity, and reduced volatility.
== Function ==
The functions of odorant binding proteins as a whole is not well understood. They are generally believed to increase the solubility of hydrophobic odorants by binding them and transporting them across the aqueous sensillum lymph to receptors in the dendrites, and several studies support a role for OBPs in olfactory perception in vivo. Some odorant binding proteins are hypothesized to hasten odor response termination by extracting odorant molecules from the sensillar lymph or from receptors themselves. Presently, just one OBP, Obp76a, has been thoroughly investigated in the olfactory system of Drosophila and has a known physiological role. Obp76a, better known as LUSH, is located trichoid sensilla and is necessary for normal response of the odor receptor Or67d to its pheromone ligand cis-vaccenyl acetate (cVA), although responses of Or67d to cVA have been detected in the absence of Obp76a LUSH has also been found to bind cVA in vitro and is known to bind other insect pheromones, short-chain alcohols, and phthalates.
In 2016, Larter et al. found that the deletion of the sole abundant OBP, Obp28a, in ab8 sensilla of Drosophila does not reduce the magnitude of their olfactory responses, suggesting that Obp28a is not required for odorant transport and that ab8 sensilla do not require an abundant OBP. Their results further suggest Obp28a may be buffering changes in the odor environment, possibly as molecular gain control, which has not been previously reported for OBPs.
OBPs are thought to have multiple roles besides olfaction, including reproduction, egg laying and antiinflammatory responses.
== Expression ==
OBPs are numerous and diverse. In Drosophila, they are encoded by 52 genes of the same family yet only share 20% amino acid similarity between themselves. Some are encoded by the most abundant mRNAs of the antennae. Within and between species, OBPs are expressed in several different tissues, including the antennal sensilla, the taste system, and chemosensory organs. They are also known to be ectopically expressed in tissues such as the gut.
Genomic analysis of Drosophila and other insect species (Anopheles gambiae, Apis mellifera, Bombyx mori, and Triboliumcastaneum) has revealed that the OBP genes significantly differ between species. The OBP family contains 21 (in A. mellifera) to 66 genes (in A. gambiae), whereas it ranges from 52 members in Drosophila to 20 in T. castaneum. Generally these genes are irregularly scattered across the genome. Most (69% of the OBP genes in Drosophila) are arranged in small clusters from 2 to 6 OBP genes. The Drosophila OBP gene family has been classified into several subfamilies based on structural features, functional information, and phylogenetic relationships: the Classic, Minus-C, Plus-C, Dimer, PBP/GOBP, ABPI and ABPII, CRLBP, and D7 subfamilies. These subfamilies are unequally distributed across arthropods, even among the dipterans and are totally absent in some species.
== See also ==
Insect pheromone-binding protein
Odorant
Olfactory receptor
Olfactory receptor neuron
== References == | Wikipedia/Odorant_binding_protein |
Photosynthetic reaction centre proteins are main protein components of photosynthetic reaction centres (RCs) of bacteria and plants. They are transmembrane proteins embedded in the chloroplast thylakoid or bacterial cell membrane.
Plants, algae, and cyanobacteria have one type of PRC for each of its two photosystems. Non-oxygenic bacteria, on the other hand, have an RC resembling either the Photosystem I centre (Type I) or the Photosystem II centre (Type II). In either case, PRCs have two related proteins (L/M; D1/D2; PsaA/PsaB) making up a quasi-symmetrical 5-helical core complex with pockets for pigment binding. The two types are structurally related and share a common ancestor. Each type have different pockets for ligands to accommodate their specific reactions: while Type I RCs use iron sulfur clusters to accept electrons, Type II RCs use quinones. The centre units of Type I RCs also have six extra transmembrane helices for gathering energy.
== In bacteria ==
The Type II photosynthetic apparatus in non-oxygenic bacteria consists of light-harvesting protein-pigment complexes LH1 and LH2, which use carotenoid and bacteriochlorophyll as primary donors. LH1 acts as the energy collection hub, temporarily storing it before its transfer to the photosynthetic reaction centre (RC). Electrons are transferred from the primary donor via an intermediate acceptor (bacteriophaeophytin) to the primary acceptor (quinone Qa), and finally to the secondary acceptor (quinone Qb), resulting in the formation of ubiquinol QbH2. RC uses the excitation energy to shuffle electrons across the membrane, transferring them via ubiquinol to the cytochrome bc1 complex in order to establish a proton gradient across the membrane, which is used by ATP synthetase to form ATP.
The core complex is anchored in the cell membrane, consisting of one unit of RC surrounded by LH1; in some species there may be additional subunits. A type II RC consists of three subunits: L (light), M (medium), and H (heavy; InterPro: IPR005652). Subunits L and M provide the scaffolding for the chromophore, while subunit H contains a cytoplasmic domain. In Rhodopseudomonas viridis, there is also a non-membranous tetrahaem cytochrome (4Hcyt) subunit on the periplasmic surface.
The structure for a type I system in the anaerobe Heliobacterium modesticaldum was resolved in 2017 (PDB: 5V8K). As a homodimer consisting of only one type of protein in the core complex, it is considered a closer example to what an ancestral unit before the Type I/II split is like compared to all heterodimeric systems.
== Oxygenic systems ==
The D1 (PsbA) and D2 (PsbD) photosystem II (PSII) reaction centre proteins from cyanobacteria, algae and plants only show approximately 15% sequence homology with the L and M subunits, however the conserved amino acids correspond to the binding sites of the photochemically active cofactors. As a result, the reaction centres (RCs) of purple photosynthetic bacteria and PSII display considerable structural similarity in terms of cofactor organisation.
The D1 and D2 proteins occur as a heterodimer that form the reaction core of PSII, a multisubunit protein-pigment complex containing over forty different cofactors, which are anchored in the cell membrane in cyanobacteria, and in the thylakoid membrane in algae and plants. Upon absorption of light energy, the D1/D2 heterodimer undergoes charge separation, and the electrons are transferred from the primary donor (chlorophyll a) via phaeophytin to the primary acceptor quinone Qa, then to the secondary acceptor Qb, which like the bacterial system, culminates in the production of ATP. However, PSII has an additional function over the bacterial system. At the oxidising side of PSII, a redox-active residue in the D1 protein reduces P680, the oxidised tyrosine then withdrawing electrons from a manganese cluster, which in turn withdraw electrons from water, leading to the splitting of water and the formation of molecular oxygen. PSII thus provides a source of electrons that can be used by photosystem I to produce the reducing power (NADPH) required to convert CO2 to glucose.
Instead of assigning specialized roles to quinones, the PsaA-PsaB photosystem I centre evolved to make both quinones immobile. It also recruited the iron-sulphur PsaC subunit to further mitigate the risk of oxidative stress.
== In viruses ==
Photosynthetic reaction centre genes from PSII (PsbA, PsbD) have been discovered within marine bacteriophage. Though it is widely accepted dogma that arbitrary pieces of DNA can be borne by phage between hosts (transduction), one would hardly expect to find transduced DNA within a large number of viruses. Transduction is presumed to be common in general, but for any single piece of DNA to be routinely transduced would be highly unexpected. Instead, conceptually, a gene routinely found in surveys of viral DNA would have to be a functional element of the virus itself (this does not imply that the gene would not be transferred among hosts - which the photosystem within viruses is - but instead that there is a viral function for the gene, that it is not merely hitchhiking with the virus). However, free viruses lack the machinery needed to support metabolism, let alone photosynthesis. As a result, photosystem genes are not likely to be a functional component of the virus like a capsid protein or tail fibre. Instead, it is expressed within an infected host cell. Most virus genes that are expressed in the host context are useful for hijacking the host machinery to produce viruses or for replication of the viral genome. These can include reverse transcriptases, integrases, nucleases or other enzymes. Photosystem components do not fit this mould either.
The production of an active photosystem during viral infection provides active photosynthesis to dying cells. This is not viral altruism towards the host, however. The problem with viral infections tends to be that they disable the host relatively rapidly. As protein expression is shunted from the host genome to the viral genome, the photosystem degrades relatively rapidly (due in part to the interaction with light, which is highly corrosive), cutting off the supply of nutrients to the replicating virus. A solution to this problem is to add rapidly degraded photosystem genes to the virus, such that the nutrient flow is uninhibited and more viruses are produced. One would expect that this discovery will lead to other discoveries of a similar nature; that elements of the host metabolism key to viral production and easily damaged during infection are actively replaced or supported by the virus during infection. Indeed, recently, PSI gene cassettes containing whole gene suites [(psaJF, C, A, B, K, E and D) and (psaD, C, A and B)] were also reported to exist in marine cyanophages from the Pacific and Indian Oceans
== Subfamilies ==
Photosynthetic reaction centre, M subunit InterPro: IPR005781
Photosystem II reaction centre protein PsbA/D1 InterPro: IPR005867
Photosystem II reaction centre protein PsbD/D2 InterPro: IPR005868
Photosynthetic reaction centre, L subunit InterPro: IPR005871
== See also ==
C-terminal processing peptidase, also known as photosystem II D1 protein processing peptidase
== Notes ==
== References ==
Deisenhofer J, Epp O, Miki K, Huber R, Michel H (December 1984). "X-ray structure analysis of a membrane protein complex. Electron density map at 3 A resolution and a model of the chromophores of the photosynthetic reaction center from Rhodopseudomonas viridis". Journal of Molecular Biology. 180 (2): 385–98. doi:10.1016/s0022-2836(84)80011-x. PMID 6392571. | Wikipedia/Photosynthetic_reaction_centre_protein_family |
Calcium-binding proteins are proteins that participate in calcium cell signaling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to calcium and are known to be heterogeneous.
One of the functions of calcium binding proteins is to regulate the amount of free (unbound) Ca2+ in the cytosol of the cell. The cellular regulation of calcium is known as calcium homeostasis.
== Types ==
Many different calcium-binding proteins exist, with different cellular and tissue distribution and involvement in specific functions. Calcium binding proteins also serve an important physiological role for cells. The most ubiquitous Ca2+-sensing protein, found in all eukaryotic organisms including yeasts, is calmodulin. Intracellular storage and release of Ca2+ from the sarcoplasmic reticulum is associated with the high-capacity, low-affinity calcium-binding protein calsequestrin. Calretinin is another type of Calcium binding protein weighing 29kD. It is involved in cell signaling and shown to exist in neurons. This type of protein is also found in large quantities in malignant mesothelial cells, which can be easily differentiated from carcinomas. This differentiation is later applied for a diagnosis on ovarian stromal tumors. Also, another member of the EF-hand superfamily is the S100B protein, which regulates p53. P53 is known as a tumor suppressor protein and in this case acts as a transcriptional activator or repressor of numerous genes. S100B proteins are abundantly found in cancerous tumor cells causing them to be overexpressed, therefore making these proteins useful for classifying tumors. In addition, this explains why this protein can easily interact with p53 when transcriptional regulation takes place.
Calcium-binding proteins can be either intracellular and extracellular. Those that are intracellular can contain or lack a structural EF-hand domain. Extracellular calcium-binding proteins are classified into six groups. Since Ca (2+) is an important second messenger, it can act as an activator or inhibitor in gene transcription. Those that belong to the EF-hand superfamily such as Calmodulin and Calcineurin have been linked to transcription regulation. When levels of Ca(2+) increase in the cell, these members of the EF-hand superfamily regulate transcription indirectly by phosphorylating/dephosphorylating transcription factors.
=== Secretory calcium-binding phosphoprotein ===
The secretory calcium-binding phosphoprotein (SCPP) gene family consists of an ancient group of genes emerging around the same time as bony fish. SCPP genes are roughly divided into acidic and P/Q-rich types: the former mostly participates in bone and dentin formation, while the latter usually participate in enamel/enameloid formation. In mammals, P/Q-rich SCPP is also found in saliva and milk and includes unorthodox members such as MUC7 (a mucin) and casein. SCPP genes are recognized by exon structure rather than protein sequence.
== Functions ==
With their role in signal transduction, calcium-binding proteins contribute to all aspects of the cell's functioning, from homeostasis to learning and memory. For example, the neuron-specific calexcitin has been found to have an excitatory effect on neurons, and interacts with proteins that control the firing state of neurons, such as the voltage-dependent potassium channel.
Compartmentalization of calcium binding proteins such as calretinin and calbindin-28 kDa has been noted within cells, suggesting that these proteins perform distinct functions in localized calcium signaling. It also indicates that in addition to freely diffusing through the cytoplasm to attain a homogeneous distribution, calcium binding proteins can bind to cellular structures through interactions that are likely important for their functions.
== See also ==
Calbindin
Calmodulin
Calsequestrin
Troponin
== References ==
== External links ==
Calcium-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Calcium-binding_protein |
The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).
== Function ==
Approximately 98% of IGF-1 is always bound to one of six binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio. IGF-BP also binds to IGF-1 inside the liver, allowing growth hormone to continuously act upon the liver to produce more IGF-1.
IGF binding proteins (IGFBPs) are proteins of 24 to 45 kDa. All six IGFBPs share 50% homology with each other and have binding affinities for IGF-I and IGF-II at the same order of magnitude as the ligands have for the IGF-IR.
The IGFBPs help to lengthen the half-life of circulating IGFs in all tissues, including the prostate. Individual IGFBPs may act to enhance or attenuate IGF signaling depending on their physiological context (i.e. cell type). Even with these similarities, some characteristics are different: chromosomal location, heparin binding domains, RGD recognition site, preference for binding IGF-I or IGF-II, and glycosylation and phosphorylation differences. These structural differences can have a tremendous impact on how the IGFBPs interact with cellular basement membranes.
== Family members ==
In humans, IGFBPs are transcribed from the following seven genes:
IGFBP1
IGFBP2
IGFBP3
IGFBP4
IGFBP5
IGFBP6
IGFBP7
== See also ==
Insulin-like growth factor receptor
== References ==
== External links ==
Insulin-like+growth+factor+binding+proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Insulin-like_growth_factor-binding_protein |
Porins are beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse. Unlike other membrane transport proteins, porins are large enough to allow passive diffusion, i.e., they act as channels that are specific to different types of molecules. They are present in the outer membrane of gram-negative bacteria and some gram-positive mycobacteria (mycolic acid-containing actinomycetes), the outer membrane of mitochondria, and the outer chloroplast membrane (outer plastid membrane).
== Structure ==
Porins are composed of beta sheets (β sheets) made up of beta strands (β strands) which are linked together by beta turns (β turns) on the cytoplasmic side and long loops of amino acids on the other. The β strands lie in an antiparallel fashion and form a cylindrical tube, called a beta barrel (β barrel). The amino acid composition of the porin β strands are unique in that polar and nonpolar residues alternate along them. This means that the nonpolar residues face outward so as to interact with the nonpolar lipids of outer membrane, whereas the polar residues face inwards into the center of the beta barrel to create the aqueous channel. The specific amino acids in the channel determine the specificity of the porin to different molecules.
The β barrels that make up a porin are composed of as few as eight β strands to as many as twenty-two β strands. The individual strands are joined together by loops and turns. The majority of porins are monomers; however, some dimeric porins have been discovered, as well as an octameric porin. Depending on the size of the porin, the interior of the protein may either be filled with water, have up to two β strands folded back into the interior, or contain a "stopper" segment composed of β strands.
All porins form homotrimers in the outer membrane, meaning that three identical porin subunits associate together to form a porin super-structure with three channels. Hydrogen bonding and dipole-dipole interactions between each monomer in the homotrimer ensure that they do not dissociate, and remain together in the outer membrane.
Several parameters have been used to describe the structure of a porin protein. They include the tilting angle (α), shear number (S), strand number (n), and barrel radius (R). The tilting angle refers to the angle relative to the membrane. The shear number (S) is the number of amino acid residues found in each β strands. Strand number (n) is the amount of β strands in the porin, and barrel radius (R) refers to the radius of the opening of the porin. These parameters are related via the following formulas:
2
π
R
=
n
b
2
cos
(
α
)
{\displaystyle 2\pi R={\frac {nb}{2\cos(\alpha )}}}
and,
tan
(
α
)
=
S
a
n
b
{\displaystyle \tan(\alpha )={\frac {Sa}{nb}}}
Using these formulas, the structure of a porin can be determined by knowing only a few of the available parameters. While the structure of many porins have been determined using X-ray crystallography, the alternative method of sequencing protein primary structure may also be used instead.
== Cellular roles ==
Porins are water-filled pores and channels found in the membranes of bacteria and eukaryotes. Porin-like channels have also been discovered in archaea. Note that the term "nucleoporin" refers to unrelated proteins that facilitate transport through nuclear pores in the nuclear envelope.
Porins are primarily involved in passively transporting hydrophilic molecules of various sizes and charges across the membrane. For survival, certain required nutrients and substrates must be transported into the cells. Likewise, toxins and wastes must be transported out to avoid toxic accumulation. Additionally, porins can regulate permeability and prevent lysis by limiting the entry of detergents into the cell.
Two types of porins exist to transport different materials– general and selective. General porins have no substrate specificities, though some exhibit slight preferences for anions or cations. Selective porins are smaller than general porins, and have specificities for chemical species. These specificities are determined by the threshold sizes of the porins, and the amino acid residues lining them.
In gram-negative bacteria, the inner membrane is the major permeability barrier. The outer membrane is more permeable to hydrophilic substances, due to the presence of porins. Porins have threshold sizes of transportable molecules that depend on the type of bacteria and porin. Generally, only substances less than 600 daltons in size can diffuse through.
== Diversity ==
Porins were first discovered in gram-negative bacteria, but gram-positive bacteria with both types of porins have been found. They exhibit similar transport functions but have a more limited variety of porins, compared to the distribution found in gram-negative bacteria. Gram-positive bacteria lack outer membranes, so these porin channels are instead bound to specific lipids within the cell walls.
Porins are also found in eukaryotes, specifically in the outer membranes of mitochondria and chloroplasts. The organelles contain general porins that are structurally and functionally similar to bacterial ones. These similarities have supported the Endosymbiotic theory, through which eukaryotic organelles arose from gram-negative bacteria. However, eukaryotic porins exhibit the same limited diversity as gram-positive porins, and also display a greater voltage-dependent role during metabolism.
Archaea also contain ion channels that have originated from general porins. The channels are found in the cell envelope and help facilitate solute transfer. They have similar characteristics as bacterial and mitochondrial porins, indicating physiological overlaps over all three domains of life.
== Antibiotic resistance ==
Many porins are targets for host immune cells, resulting in signaling pathways that lead to bacterial degradation. Therapeutic treatments, like vaccinations and antibiotics, are used to supplement this immune response. Specific antibiotics have been designed to travel through porins in order to inhibit cellular processes.
However, due to selective pressure, bacteria can develop resistance through mutations in the porin gene. The mutations may lead to a loss of porins, resulting in the antibiotics having a lower permeability or being completely excluded from transport. These changes have contributed to the global emergence of antibiotic resistance, and an increase in mortality rates from infections.
== Discovery ==
The discovery of porins has been attributed to Hiroshi Nikaido, nicknamed "the porinologist."
== Classification ==
According to TCDB, there are five evolutionarily independent superfamilies of porins. Porin superfamily I includes 47 families of porins with a range of numbers of trans-membrane β-strands (β-TMS). These include the GBP, SP and RPP porin families. While PSF I includes 47 families, PSF II-V each contain only 2 families. While PSF I derives members from gram-negative bacteria primarily one family of eukaryotic mitochondrial porins, PSF II and V porins are derived from Actinomycetota. PSF III and V are derived from eukaryotic organelle.
=== Porin Superfamily I ===
1.B.1 - The General bacterial porin family
1.B.2 - The Chlamydial Porin (CP) Family
1.B.3 - The Sugar porin (SP) Family
1.B.4 - The Brucella-Rhizobium porin (BRP) Family
1.B.5 - The Pseudomonas OprP Porin (POP) Family
1.B.6 - OmpA-OmpF porin (OOP) family
1.B.7 Rhodobacter PorCa porin (RPP) family
1.B.8 Mitochondrial and plastid porin (MPP) family
1.B.9 FadL outer membrane protein (FadL) family
1.B.10 Nucleoside-specific channel-forming outer membrane porin (Tsx) family
1.B.11 Outer membrane fimbrial usher porin (FUP) family
1.B.12 Autotransporter-1 (AT-1) family
1.B.13 Alginate export porin (AEP) family
1.B.14 Outer membrane receptor (OMR) family
1.B.15 Raffinose porin (RafY) family
1.B.16 Short chain amide and urea porin (SAP) family
1.B.17 Outer membrane factor (OMF) family
1.B.18 Outer membrane auxiliary (OMA) protein family
1.B.19 Glucose-selective OprB porin (OprB) family
1.B.20 Two-partner secretion (TPS) family
1.B.21 OmpG porin (OmpG) family
1.B.22 Outer bacterial membrane secretin (secretin) family
1.B.23 Cyanobacterial porin (CBP) family
1.B.24 Mycobacterial porin
1.B.25 Outer membrane porin (Opr) family
1.B.26 Cyclodextrin porin (CDP) family
1.B.31 Campylobacter jejuni major outer membrane porin (MomP) family
1.B.32 Fusobacterial outer membrane porin (FomP) family
1.B.33 Outer membrane protein insertion porin (Bam complex) (OmpIP) family
1.B.34 Corynebacterial porins
1.B.35 Oligogalacturonate-specific porin (KdgM) family
1.B.39 Bacterial porin, OmpW (OmpW) family
1.B.42 - The Outer Membrane Lipopolysaccharide Export Porin (LPS-EP) Family
1.B.43 - The Coxiella Porin P1 (CPP1) Family
1.B.44 - The Probable Protein Translocating Porphyromonas gingivalis Porin (PorT) Family
1.B.49 - The Anaplasma P44 (A-P44) Porin Family
1.B.54 - Intimin/Invasin (Int/Inv) or Autotransporter-3 family
1.B.55 - The Poly Acetyl Glucosamine Porin (PgaA) Family
1.B.57 - The Legionella Major-Outer Membrane Protein (LM-OMP) Family
1.B.60 - The Omp50 Porin (Omp50 Porin) Family
1.B.61 - The Delta-Proteobacterial Porin (Delta-Porin) Family
1.B.62 - The Putative Bacterial Porin (PBP) Family
1.B.66 - The Putative Beta-Barrel Porin-2 (BBP2) Family
1.B.67 - The Putative Beta Barrel Porin-4 (BBP4) Family
1.B.68 - The Putative Beta Barrel Porin-5 (BBP5) Superfamily
1.B.70 - The Outer Membrane Channel (OMC) Family
1.B.71 - The Proteobacterial/Verrucomicrobial Porin (PVP) Family
1.B.72 - The Protochlamydial Outer Membrane Porin (PomS/T) Family
1.B.73 - The Capsule Biogenesis/Assembly (CBA) Family
1.B.78 - The DUF3374 Electron Transport-associated Porin (ETPorin) Family
=== Porin Superfamily II (MspA Superfamily) ===
1.B.24 - Mycobacterial porin
1.B.58 - Nocardial Hetero-oligomeric Cell Wall Channel (NfpA/B) Family
=== Porin Superfamily III ===
1.B.28 - The Plastid Outer Envelope Porin of 24 kDa (OEP24) Family
1.B.47 - The Plastid Outer Envelope Porin of 37 kDa (OEP37) Family
=== Porin Superfamily IV (Tim17/OEP16/PxMPL (TOP) Superfamily) ===
This superfamily includes protein that comprise pores in multicomponent protein translocases as follows: 3.A.8 - [Tim17 (P39515) Tim22 (Q12328) Tim23 (P32897)]; 1.B.69 - [PXMP4 (Q9Y6I8) PMP24 (A2R8R0)]; 3.D.9 - [NDH 21.3 kDa component (P25710)]
1.B.30 - The Plastid Outer Envelope Porin of 16 kDa (OEP16) Family
1.B.69 - The Peroxysomal Membrane Porin 4 (PxMP4) Family
3.A.8 - The Mitochondrial Protein Translocase (MPT) Family
=== Porin Superfamily V (Corynebacterial PorA/PorH Superfamily) ===
1.B.34 - The Corynebacterial Porin A (PorA) Family
1.B.59 - The Outer Membrane Porin, PorH (PorH) Family
== See also ==
Voltage-dependent anion channel
Aquaporin
== References == | Wikipedia/Porin_(protein) |
Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined. However, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.
== Expression ==
In humans, GHBP is formed by post-translational modification after the complete transcription and translation of the growth hormone receptor (GHR) gene into the cell-surface receptor protein. The gene that codes for GHR (and inherently GHBP) is on Chromosome 5. A precursor messenger RNA (mRNA) from the complete gene first is transcribed and then spliced to encode the full receptor protein. This mature mRNA is composed of exons. Exons are peptide encoding regions of DNA genes that remain in the transcript after splicing and during the maturation of mRNA. The mRNA transcript encodes for a receptor protein that is made up of three distinct parts: an intracellular domain, a transmembrane domain, and an extracellular domain. Specifically, part of exon 2 and exons 3-7 of the GHR gene will translate to amino acids that make up the extracellular domain of GHR. This extracellular domain physically binds GH in the receptor-ligand interaction.
In rodents and in humans the concentration GHR mRNA and the concentration of GHBP in the maternal circulation are dramatically increased during pregnancy. This is considered likely to control the availability of GH for binding to GH receptors in the maternal tissues during pregnancy.
=== Receptor ectodomain shedding ===
When the extracellular domain of GHR is proteolytically cleaved (see: proteolytic cleavage) from the rest of the receptor protein, the extracellular domain is released as the water-soluble, carrier protein GHBP. As the extracellular domain alone, the polypeptide consists of 246 amino acids and is roughly 60 kDA in size. This cleaving process is called “receptor ectodomain shedding. In humans and rabbits, tumor-necrosis factor alpha converting enzyme (T.A.C.E.) is postulated to play a significant role in the post-translational processing activity that sheds GHBP from GHR. Studies show that this activity primarily occurs in the liver. When growth hormone is bound to two dimerized GH receptors, the shedding activity is inhibited. This occurs because when the ligand binds to the receptors, a conformational change occurs in them that potentially blocks the proteolytic activity of T.A.C.E.
=== Alternative splicing ===
In humans, studies have shown that alternative splicing of the GHR gene can lead to increased rates of proteolysis. For example, a deletion within the mRNA that encodes part of the transmembrane domain of the protein effectively leads to non-translation of the intracellular domain due to the presence of a stop codon. This truncated version of GHR is cleaved more frequently into GHBP and may potentially explain the reasoning behind increased concentrations of GHBP present in some tissues.
In mouse and rat models, the extracellular domain is formed primarily through alternative splicing of the precursor GHR mRNA to form a mature transcript that translate GHBP alone. These animals can potentially shed GHBP via post-translational modification as well, although this activity is minimal.
== Function ==
The full range of physiological consequences of GHBP binding GH is not known , however literature provides evidence that the carrier-protein prolongs the half-life of growth hormone through its binding with the ligand.
=== Binding stoichiometry ===
Growth hormone binds to GHBP and GHR via an interactive region of helices 1 and 4 of GH. Two receptor molecules are pre-dimerized upon GH binding, so it always binds in a 1:2 ratio. Assays estimate that growth hormone and growth hormone binding protein form a natural complex at a 1:1 ratio for transport and preservation of the ligand through the bloodstream. However, some sources have shown that high physiological concentration of GHBP will result in a 1:2 ratio. When the cysteine amino acids in GHBP are mutated and the disulfide bridges are disrupted, the ability of the ligand to bind to the active site of the GHBP is significantly lessened.
=== Activation ===
The clearance rate, or the rate at which the carrier protein is broken down, for GHBP alone is much faster than when it is bound to its ligand. Additionally, current literature provides evidence that the carrier-protein prolongs the half-life of growth hormone through its binding with the ligand. One purpose of GHBP can be inferred: to maintain the level of GH in the blood, as roughly half of its concentration is complexed with GHBP. Yet this could be confounded by the fact that GH binding to GHBP prevents the ligand from binding to GHR and ultimately proteolytic activity. Another function is that GHBP displays competitive inhibition for GH against the GHR receptor.
Studies elucidate another aspect of GHBP physiological role: The proteolytic cleavage activity that forms GHBP ultimately regulates GHR production in humans as well as rats. If there is low GHBP concentration then there are high levels of GHR expression. Conversely, high levels of GHBP protein show negative correlation with levels of growth hormone receptor expression.
== Isoforms ==
=== Exon 3 ===
Studies have identified a GHBP isoform that exists due to gene polymorphism, or variable expression of the allele. These isoforms differ based on whether or not the extracellular domain of GHR includes the amino acids encoded by exon 3 - exon 3 is either kept (dominant) or spliced out (recessive). As human are diploid, they may genotype as homozygous dominant (two copies of the allele retain exon 3), heterozygous (one copy with Exon 3, and one without), or homozygous recessive (two copies of the allele without exon 3). Studies have shown that the two isoforms can co-exist as dimerized GH receptors, as E3+/E3+, E3+/E3-, or E3-/E3-.
Furthermore, the two isoforms both exist in the blood as GHBP. However, they may have separate functions that are poorly understood. The presence or absence of exon 3 in humans is individual-specific, but one study suggests that gender may play a role in this variable splicing, as females were shown to express higher levels of deleted-exon 3 GHBP in their blood. The evolutionary reason for exon-3 variable GHBP expression has not clearly be defined, and the isoforms in the blood have not been shown to differ with respect to GH affinity, which is unusual for an isoform that is missing an entire exon.
== References ==
== External links ==
somatotropin-binding+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Baumann G, Shaw MA, Winter RJ (Oct 1987). "Absence of the plasma growth hormone-binding protein in Laron-type dwarfism". The Journal of Clinical Endocrinology and Metabolism. 65 (4): 814–6. doi:10.1210/jcem-65-4-814. PMID 3654924. | Wikipedia/Growth_hormone-binding_protein |
Retinol binding protein 4, also known as RBP4, is a transporter protein for retinol (vitamin A alcohol). RBP4 has a molecular weight of approximately 21 kDa and is encoded by the RBP4 gene in humans. It is mainly, though not exclusively, synthesized in the liver and circulates in the bloodstream as a hepatokine bound to retinol in a complex with transthyretin. RBP4 has been a drug target for ophthalmology research due to its role in vision. RBP4 may also be involved in metabolic diseases as suggested by recent studies.
== Function ==
This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin, which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells.
== Structure ==
RBP4 is a single polypeptide chain with a hydrophobic pocket where retinol binds. The RBP4-retinol complex then binds transthyretin in circulation to prevent renal filtration of RBP4.
In serum, TTR and RBP4 bind in a 1 to 1 stoichiometry (two molecules of TTR combine with two molecules of RBP4 to form a complex with a total molecular weight of approximately 80,000 daltons).
== Clinical significance ==
Retinol-binding protein 4 has been a drug target for eye diseases as RBP4 is the sole carrier for retinol, which is an essential nutrient for the visual cycle. Animal studies using RBP4-antagonists showed that lowering RBP4 can lead to reduction in the accumulation of lipofuscin that leads to vision loss in eye diseases like Stargardt's disease and macular degeneration. An animal study using ABCA4 knockout mouse proved that reduction in serum RBP4 level could inhibit lipofuscin without inhibiting the visual cycle.[ref] One clinical study in age-related macular degeneration (AMD) was conducted using Fenretinide. The study showed trends in reducing lesion growth rate in AMD and rate of conversion from early stage AMD (dry AMD) to late stage AMD (wet AMD) without serious side effects.
RBP4 has recently been described as an adipokine that contributes to insulin resistance and diabetes in the AG4KO mouse model. In addition to the liver, RBP4 is also secreted by adipocytes of the fat tissue in a smaller portion and acts as a signal to surrounding cells, when there is a decrease in plasma glucose concentration. It is suspected that an elevated level of RBP4 attracts macrophages to the fat tissue, causes local inflammation, and leads to insulin resistance.
Mutations in the RBP4 gene have recently been linked to a form of autosomal dominant microphthalmia, anophthalmia, and coloboma (MAC) disease. A unique feature of this disease is the maternal inheritance effect, when a fetus inherits a mutated copy of the RBP4 gene from its mother, but not from its father. The physiologic basis lies in pregnancy whereby the mutated gene product, retinol binding protein (RBP), has negative effects in transferring vitamin A from maternal liver storage sites to the placenta, and then again on the fetal circulation side when delivering vitamin A from the placenta to developing fetal tissues, most notably the developing eye. This 'double whammy' effect does not exist when the mutant RBP4 gene is inherited from the father. The above mechanism is separate from previously known types of maternal inheritance effects such as genomic imprinting, mitochondrial inheritance, or maternal oocyte mRNA transfer. The authors of the above study cite the potential of vitamin A supplementation in pregnant females who are known to carry an RBP4 mutation with retinyl ester which utilizes an RBP-independent pathway to deliver retinoids from the maternal intestines directly to the placenta and ultimately is uptaken by the fetus. The key would be to supplement during the first several months of life when the eye begins to develop, as supplementing later in pregnancy would be too late to avoid any potential MAC disease.
== See also ==
Retinol
Adipokine
Transthyretin (TTR)
== References ==
== Further reading ==
== External links ==
RBP4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P02753 (Retinol-binding protein 4) at the PDBe-KB. | Wikipedia/Retinol_binding_protein_4 |
The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide biosynthesis machinery. It is one of the most abundant proteins in cells of E. coli. In both cases, the growing chain is bound to the ACP via a thioester derived from the distal thiol of a 4'-phosphopantetheine moiety.
== Structure ==
The ACPs are small negatively charged α-helical bundle proteins with a high degree of structural and amino acid similarity. The structures of a number of acyl carrier proteins have been solved using various NMR and crystallography techniques. The ACPs are related in structure and mechanism to the peptidyl carrier proteins (PCP) from nonribosomal peptide synthases.
== Biosynthesis ==
Subsequent to the expression of the inactive apo ACP, the 4'-phosphopantetheine moiety is attached to a serine residue. This coupling is mediated by acyl carrier protein synthase (ACPS), a 4'-phosphopantetheinyl transferase. 4'-Phosphopantetheine is a prosthetic group of several acyl carrier proteins including the acyl carrier proteins (ACP) of fatty acid synthases, ACPs of polyketide synthases, the peptidyl carrier proteins (PCP), as well as aryl carrier proteins (ArCP) of nonribosomal peptide synthetases (NRPS).
== References ==
== External links ==
Acyl Carrier Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Acyl_carrier_protein |
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer can be assembled as dimer of dimers with two homodimer subunits (such as sorbitol dehydrogenase), or two heterodimer subunits (such as hemoglobin).
== Subunit interactions in tetramers ==
The interactions between subunits forming a tetramer is primarily determined by non covalent interaction. Hydrophobic effects, hydrogen bonds and electrostatic interactions are the primary sources for this binding process between subunits. For homotetrameric proteins such as sorbitol dehydrogenase (SDH), the structure is believed to have evolved going from a monomeric to a dimeric and finally a tetrameric structure in evolution. The binding process in SDH and many other tetrameric enzymes can be described by the gain in free energy which can be determined from the rate of association and dissociation.
The above image shows the assembly of the four subunits (A,B,C and D) in SDH.
== Hydrogen bonds between subunits ==
Hydrogen bonding networks between subunits has been shown to be important for the stability of the tetrameric quaternary protein structure. For example, a study of SDH which used diverse methods such as protein sequence alignments, structural comparisons, energy calculations, gel filtration experiments and enzyme kinetics experiments, could reveal an important hydrogen bonding network which stabilizes the tetrameric quaternary structure in mammalian SDH.
== Tetramers in immunology ==
In immunology, MHC tetramers can be used in tetramer assays, to quantify numbers of antigen-specific T cells (especially CD8+ T cells). MHC tetramers are based on recombinant class I molecules that, through the action of bacterial BirA, have been biotinylated. These molecules are folded with the peptide of interest and β2M and tetramerized by a fluorescently labeled streptavidin. (Streptavidin binds to four biotins per molecule.) This tetramer reagent will specifically label T cells that express T cell receptors that are specific for a given peptide-MHC complex. For example, a Kb/FAPGNYPAL tetramer will specifically bind to Sendai virus specific cytotoxic T cell in a C57BL/6 mouse. Antigen specific responses can be measured as CD8+, tetramer+ T cells as a fraction of all CD8+ lymphocytes.
The reason for using a tetramer, as opposed to a single labeled MHC class I molecule is that the tetrahedral tetramers can bind to three TCRs at once, allowing specific binding in spite of the low (1 micromolar) affinity of the typical class I-peptide-TCR interaction.
MHC class II tetramers can also be made, although these are more difficult to work with practically.
== Homotetramers and heterotetramers ==
A homotetramer is a protein complex made up of four identical subunits which are associated but not covalently bound. Conversely, a heterotetramer is a 4-subunit complex where one or more subunits differ.
Examples of homotetramers include:
enzymes like beta-glucuronidase (pictured)
export factors such as SecB from Escherichia coli
magnesium ion transporters such as CorA.
lectins such as Concanavalin A
IMPDH and IMPDH2
Examples of heterotetramers include haemoglobin (pictured), the NMDA receptor, some aquaporins, some AMPA receptors, as well as some enzymes.
=== Purification of heterotetramers ===
Ion-exchange chromatography is useful for isolating specific heterotetrameric protein assemblies, allowing purification of specific complexes according to both the number and the position of charged peptide tags. Nickel affinity chromatography may also be employed for heterotetramer purification.
=== Intragenic complementation ===
Multiple copies of a polypeptide encoded by a gene often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to as intragenic complementation. In humans, argininosuccinate lyase (ASL) is a homotetrameric enzyme that can undergo intragenic complementation. An ASL disorder in humans can arise from mutations in the ASL gene, particularly mutations that affect the active site of the tetrameric enzyme. ASL disorder is associated with considerable clinical and genetic heterogeneity which is considered to reflect the extensive intragenic complementation occurring among different individual patients.
== References ==
== External links ==
T-cell Group - Cardiff University | Wikipedia/Tetrameric_protein |
Multi-antimicrobial extrusion protein (MATE) also known as multidrug and toxin extrusion or multidrug and toxic compound extrusion is a family of proteins which function as drug/sodium or proton antiporters.
== Function ==
The MATE proteins in bacteria, archaea and eukaryotes function as fundamental transporters of metabolic and xenobiotic organic cations.
== Structure ==
These proteins are predicted to have 12 alpha-helical transmembrane regions, some of the animal proteins may have an additional C-terminal helix. The X-ray structure of the NorM was determined to 3.65 Å, revealing an outward-facing conformation with two portals open to the outer leaflet of the membrane and a unique topology of the predicted 12 transmembrane helices distinct from any other known multidrug resistance transporter.
== Discovery ==
The multidrug efflux transporter NorM from V. parahaemolyticus which mediates resistance to multiple antimicrobial agents (norfloxacin, kanamycin, ethidium bromide etc.) and its homologue from E. coli were identified in 1998. NorM seems to function as drug/sodium antiporter which is the first example of Na+-coupled multidrug efflux transporter discovered. NorM is a prototype of a new transporter family and Brown et al. named it the multidrug and toxic compound extrusion family. NorM is nicknamed "Last of the multidrug transporters" because it is the last multidrug transporter discovered functionally as well as structurally.
== Genes ==
The following human genes encode MATE proteins:
SLC47A1
SLC47A2
== See also ==
Solute carrier family
Resistance-Nodulation-Cell Division Superfamily (RND)
== References == | Wikipedia/Multi-antimicrobial_extrusion_protein |
Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.
== Function ==
MRP2 is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). More specifically, this protein is a member of the MRP subfamily, which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells.
MRP2 is also expressed in the apical membrane of proximal renal tubule endothelial cells where they are involved in the excretion of small organic anions.
== MRP2 inhibitors ==
== Clinical significance ==
=== Dubin–Johnson syndrome ===
Several different mutations in this gene have been observed in patients with Dubin–Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia.
=== Iatrogenic Fanconi syndrome ===
Many negatively charged metabolic waste products are eliminated from the body by the kidneys. These organic anions are transported from the blood into the endothelial cells of the renal proximal tubules by the OAT1 transporter. From there, these waste molecules are transported into the lumen of the tubule by the MRP2 transporter. Many drugs are eliminated from the body by this mechanism. Some of these drugs pass through the MRP2 transporter slowly. This may cause a buildup of organic anions in the cytoplasm of the cells.
Drugs that inhibit the MRP2 transporter can cause a buildup of organic anions inside renal proximal tubule cells. If some of these organic anions inhibit mitochondrial DNA synthesis, it may cause iatrogenic Fanconi syndrome. The nucleoside phosphonate adefovir is a MRP2 inhibitor that has been linked to kidney disease. Tenofovir and cidofovir are also nucleoside phosphonates that inhibit MRP2 and have been associated with Fanconi syndrome.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== See also ==
ATP-binding cassette transporter
== References ==
== Further reading ==
== External links ==
ABCC2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Multidrug_resistance-associated_protein_2 |
Heart-type fatty acid binding protein (hFABP) also known as mammary-derived growth inhibitor is a protein that in humans is encoded by the FABP3 gene.
== Function ==
Heart-type Fatty Acid-Binding Protein (H-FABP) is a small cytoplasmic protein (15 kDa) released from cardiac myocytes following an ischemic episode. Like the nine other distinct FABPs that have been identified, H-FABP is involved in active fatty acid metabolism where it transports fatty acids from the cell membrane to mitochondria for oxidation. See FABP3 for biochemical details.
The intracellular fatty acid-binding proteins (FABPs) belongs to a multigene family. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of long-chain fatty acids. They may also be responsible in the modulation of cell growth and proliferation. Fatty acid-binding protein 3 gene contains four exons and its function is to arrest growth of mammary epithelial cells. This gene is also a candidate tumor suppressor gene for human breast cancer.
== Interactions ==
FABP3 is known to interact with TNNI3K in the context of interacting with cardiac troponin I. The protein also interacts with, VPS28, KIAA159, NUP62, PLK1, UBC, and Xpo1.
In HIV, a synthetic peptide corresponding to the immunosuppressive domain (amino acids 574-592) of HIV-1 gp41 downregulates the expression of fatty acid binding protein 3 (FABP3) in peptide-treated PBMCs.
== Clinical significance ==
=== Diagnostic potential ===
H-FABP is a sensitive biomarker for myocardial infarction and can be detected in the blood within one to three hours of the pain.
The diagnostic potential of the biomarker H-FABP for heart injury was discovered in 1988 by Professor Jan Glatz (Maastricht, Netherlands). H-FABP is 20 times more specific to cardiac muscle than myoglobin, it is found at 10-fold lower levels in skeletal muscle than heart muscle and the amounts in the kidney, liver and small intestine are even lower again.
H-FABP is recommended to be measured with troponin to identify myocardial infarction and acute coronary syndrome in patients presenting with chest pain. H-FABP measured with troponin shows increased sensitivity of 20.6% over troponin at 3–6 hours following chest pain onset. This sensitivity may be explained by the high concentration of H-FABP in myocardium compared to other tissues, the stability and solubility of H-FABP, its low molecular weight; 15kDa compared to 18, 80 and 37kDa for MYO, CK-MB and cTnT respectively, its rapid release into plasma after myocardial injury – 60 minutes after an ischemic episode, and its relative tissue specificity. Similarly this study showed that measuring H-FABP in combination with troponin increased the diagnostic accuracy and with a negative predictive value of 98% could be used to identify those not suffering from MI at the early time point of 3–6 hours post chest pain onset. The effectiveness of using the combination of H-FABP with troponin to diagnose MI within 6 hours is well reported.
=== Prognostic potential ===
In addition to its diagnostic potential, H-FABP also has prognostic value. Alongside D-dimer, NT-proBNP and peak troponin T, it was the only cardiac biomarker that proved to be a statistically significant predictor of death or MI at one year. This prognostic information was independent of troponin T, ECG and clinical examination. The risk associated with raised H-FABP is dependent upon its concentration. Patients who were TnI negative but H-FABP positive had 17% increased risk of all cause mortality within one year compared to those patients who were TnI positive but H-FABP negative. Currently these TnI positive patients are prioritised for angioplasty, and the TnI negative patients are considered to be of a lower priority, yet the addition of the H-FABP test helps identify patients who are currently slipping through the net and allows physicians to more appropriately manage this hidden high risk group. If both biomarkers were negative, there is 0% mortality at 6 months, in the authors own words this “represents a particularly worthwhile clinical outcome, especially because it was observed in patients admitted into hospital for suspected ACS.” H-FABP indicates risk across the ACS spectrum including UA, NSTEMI or STEMI where low H-FABP concentrations confer low risk whereas high H-FABP concentrations indicate patients who are at a much higher risk of future events.
=== H-FABP in other diseases ===
H-FABP has been proven to significantly predict 30-day mortality in acute pulmonary embolism. H-FABP is more effective than Troponin T in risk stratifying Chronic Heart Failure patients. H-FABP is beginning to create interest with researchers who have found emerging evidence that indicates a role in differentiating between different neurodegenerative diseases.
=== H-FABP Point of care testing ===
To obtain diagnostic and prognostic information a precise and fully quantitative measurement of H-FABP is required. Commercial tests include a Cardiac Array on Evidence MultiStat; and an automated biochemistry assay
== See also ==
Akash Manoj – Indian inventor who developed wearable device to detect h-FABP
== References ==
== Further reading == | Wikipedia/Heart-type_fatty_acid_binding_protein |
The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) are also discovered to bind human FABPs (1, 3, 5, and 7) that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.
Fatty Acid Binding Proteins (FABPs) represent a family of proteins that play a pivotal role in cellular lipid metabolism. These proteins act as intracellular carriers, facilitating the transport and utilization of fatty acids within cells. With their diverse tissue-specific distribution and involvement in various cellular processes, FABPs contribute significantly to energy homeostasis, lipid metabolism, and even cellular signaling. Fatty acid-binding proteins (FABPs) are members of the intracellular lipid-binding protein (iLBP) family and are involved in reversibly binding intracellular hydrophobic ligands and trafficking them throughout cellular compartments, including the peroxisomes, mitochondria, endoplasmic reticulum and nucleus. This comprehensive exploration aims to delve into the structure, function, types, and implications of FABPs in health and disease.
== Structure ==
FABPs are small, structurally conserved cytosolic proteins consisting of a water-filled, interior-binding pocket surrounded by ten anti-parallel beta sheets, forming a beta barrel. At the superior surface, two alpha-helices cap the pocket and are thought to regulate binding. FABPs have broad specificity, including the ability to bind long-chain (C16-C20) fatty acids, eicosanoids, bile salts and peroxisome proliferators. FABPs demonstrate strong evolutionary conservation and are present in a spectrum of species including Drosophila melanogaster, Caenorhabditis elegans, mouse and human. The human genome consists of nine putatively functional protein-coding FABP genes. The most recently identified family member, FABP12, has been less studied.
== Function ==
Dictated by the characteristic structure, the main function of the FABPs is to bind fatty acids, as well as the intake, transportation and consumption, despite their different selectivity, affinity, and binding mechanism. They enhance the solubility of hydrophobic fatty acids, allowing their efficient transport within the aqueous cytoplasm. FABPs also participate in the uptake of fatty acids from the extracellular environment and their subsequent delivery to specific cellular compartments, such as the nucleus, mitochondria, or endoplasmic reticulum. Research emerging in the last decade has suggested that FABPs have tissue-specific functions that reflect tissue-specific aspects of lipid and fatty acid metabolism. Proposed roles for FABPs include assimilation of dietary lipids in the intestine, targeting of liver lipids to catabolic and anabolic pathways, regulation of lipid storage and lipid-mediated gene expression in adipose tissue and macrophages, fatty acid targeting to β-oxidation pathways in muscle, and maintenance of phospholipid membranes in neural tissues.
FABPs facilitate the transport of fatty acids by forming a complex with them. This complex shields the hydrophobic fatty acids from the surrounding aqueous environment, enabling their transit through the cytoplasm. Different types of FABPs exhibit tissue-specific expression, ensuring the efficient transport of fatty acids to locations where they are needed most for various cellular processes. Studies have reported that the intracellular trafficking of fatty acids is a complicated and dynamic process that directly or indirectly influences multiple functions of the cell and especially regulates important biochemical processes in normal cells, including gene expression modulation, cell development, metabolism, and inflammatory response through enzymatic and transcriptional networks.
=== Cellular signaling ===
Beyond their role in fatty acid transport, FABPs also participate in cellular signaling pathways. By transporting fatty acids to the nucleus, FABPs can modulate the activity of nuclear receptors involved in transcriptional regulation. This interaction can influence gene expression, contributing to the overall regulation of cellular processes, including those related to lipid metabolism.
=== Role in metabolism ===
FABPs are integral to lipid metabolism, participating in various processes that contribute to energy homeostasis. These include fatty acid uptake, storage, and oxidation. In adipocytes, A-FABP is involved in the storage of fatty acids as triglycerides, while in the liver, L-FABP contributes to the regulation of lipid metabolism and cholesterol homeostasis. Metabolic syndromes such as obesity, high uric acid, high blood fat, hypertension, type II diabetes, and atherosclerosis, have received increasing attention due to the great changes that have occurred in eating habits and the general lifestyle. Accumulating evidence shows that the level of FABP5 may be closely associated with the pathogenesis of chronic metabolic diseases through its expression in adipocytes and macrophages.
== Types ==
Several distinct types of FABPs have been identified, each exhibiting a tissue-specific distribution. Some prominent examples include:
Liver-type FABP (L-FABP): Predominantly found in the liver, L-FABP is involved in the uptake and metabolism of fatty acids in hepatic cells.
Heart-type FABP (H-FABP): Abundant in cardiac muscle, H-FABP contributes to the transport and utilization of fatty acids for energy production in the heart.
Adipocyte FABP (A-FABP): Located in adipose tissue, A-FABP plays a crucial role in lipid metabolism, including the storage and release of fatty acids in adipocytes.
Intestinal FABP (I-FABP): Found in the intestine, I-FABP is essential for the absorption and transport of dietary fatty acids.
Each type of FABP has a specific role in the metabolism and utilization of fatty acids within its respective tissue, highlighting the functional diversity of this protein family.
== Clinical significance ==
Dysregulation of FABPs has been implicated in various metabolic disorders, providing insights into potential therapeutic targets. In obesity, for instance, there is often an altered expression of FABPs in adipose tissue, contributing to abnormal lipid metabolism. It has recently been suggested that macrophage accumulation in adipose tissue is a feature of adipose tissue inflammatory responses triggered by obesity and hence may contribute to the metabolic consequences such as insulin resistance. In diabetes, FABPs may influence insulin sensitivity and glucose metabolism. Additionally, in cardiovascular diseases, the dysregulation of FABPs in the heart and blood vessels may impact fatty acid utilization and contribute to pathological conditions.
Understanding the specific roles of FABPs in disease states is an active area of research, with potential implications for the development of targeted therapies. Modulating FABP activity or expression could offer new avenues for intervention in conditions associated with aberrant lipid metabolism. The creation of pharmacological agents to modify FABP function may therefore provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, thus offering a new class of multi-indication therapeutic agents.
== Medical applications ==
Fatty Acid Binding Proteins (FABPs) have shown significant promise in various medical applications due to their role in cellular lipid metabolism and their involvement in several physiological processes. Key medical applications of FABPs include:
=== Biomarkers for disease diagnosis and prognosis ===
Cardiovascular Diseases: Elevated levels of FABPs, particularly heart-type FABP (H-FABP), in blood plasma have been associated with acute myocardial infarction. Measurement of FABPs can aid in the early diagnosis and prognosis of cardiovascular events. Liver Diseases: Liver-type FABP (L-FABP) has been studied as a potential biomarker for liver diseases such as non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis. Monitoring L-FABP levels can provide insights into liver function and pathology.
=== Monitoring and predicting metabolic disorders ===
Obesity and Diabetes: FABPs, especially adipocyte FABP (A-FABP), are linked to obesity and insulin resistance. Monitoring FABP levels can provide information about the metabolic status of individuals, and targeting FABPs may offer therapeutic strategies for managing obesity-related complications. Type 2 Diabetes: FABPs are implicated in insulin resistance. Studying their expression and function can contribute to a better understanding of the mechanisms underlying type 2 diabetes, potentially leading to the development of targeted therapies.
=== Drug development and therapeutics ===
Target for Drug Intervention: FABPs are considered potential targets for drug development. Modulating FABP activity could be a strategy to regulate lipid metabolism and address conditions like atherosclerosis, metabolic syndrome, and other disorders associated with abnormal fatty acid handling. Anti-Inflammatory Therapies: FABPs are involved in inflammatory responses, and targeting them could be a therapeutic approach for inflammatory conditions. For example, inhibition of FABPs might attenuate inflammation associated with certain diseases.
=== Neurological disorders ===
Alzheimer's Disease: FABPs, particularly FABP7, have been implicated in neurodegenerative diseases such as Alzheimer's. Understanding their role in brain lipid metabolism may provide insights into disease mechanisms and potential therapeutic targets. Neuroprotection: Some studies suggest that FABPs, especially brain-type FABP (B-FABP), may play a neuroprotective role. Modulating their expression or activity could be explored as a strategy for neuroprotection in conditions like stroke.
=== Cancer research ===
Prognostic Markers: Altered expression of certain FABPs has been observed in various cancers. They may serve as prognostic markers, and understanding their role in cancer cell metabolism could open avenues for targeted therapies. Drug Delivery: FABPs have been explored for their potential in targeted drug delivery to cancer cells. Conjugating therapeutic agents with molecules that bind to FABPs may enhance drug delivery to cancer cells expressing these proteins.
=== Inflammatory bowel disease (IBD) ===
Biomarkers for IBD: FABPs, including intestinal FABP (I-FABP), have been investigated as potential biomarkers for inflammatory bowel diseases. Elevated levels in serum may indicate intestinal mucosal damage.
=== Wound Healing and Tissue Repair ===
Regeneration and Repair: FABPs, such as epidermal FABP (E-FABP), are expressed in skin cells and may play a role in skin regeneration and wound healing. Understanding their functions could contribute to strategies for enhancing tissue repair.
== Family members ==
Members of this family include:
=== Pseudogenes ===
== References ==
== External links ==
Fatty+Acid-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Fatty_acid-binding_protein |
Major urinary proteins (Mups), also known as α2u-globulins, are a subfamily of proteins found in abundance in the urine and other secretions of many animals. Mups provide a small range of identifying information about the donor animal, when detected by the vomeronasal organ of the receiving animal. They belong to a larger family of proteins known as lipocalins. Mups are encoded by a cluster of genes, located adjacent to each other on a single stretch of DNA, that varies greatly in number between species: from at least 21 functional genes in mice to none in humans. Mup proteins form a characteristic glove shape, encompassing a ligand-binding pocket that accommodates specific small organic chemicals.
Urinary proteins were first reported in rodents in 1932, during studies by Thomas Addis into the cause of proteinuria. They are potent human allergens and are largely responsible for a number of animal allergies, including to cats, horses and rodents. Their endogenous function within an animal is unknown but may involve regulating energy expenditure. However, as secreted proteins they play multiple roles in chemical communication between animals, functioning as pheromone transporters and stabilizers in rodents and pigs. Mups can also act as protein pheromones themselves. They have been demonstrated to promote aggression in male mice, and one specific Mup protein found in male mouse urine is sexually attractive to female mice. Mups can also function as signals between different species: mice display an instinctive fear response on the detection of Mups derived from predators such as cats and rats.
== Discovery ==
Humans in good health excrete urine that is largely free of protein. Therefore, since 1827 physicians and scientists have been interested in proteinuria, the excess of protein in human urine, as an indicator of kidney disease. To better understand the etiology of proteinuria, some scientists attempted to study the phenomenon in laboratory animals. Between 1932 and 1933 a number of scientists, including Thomas Addis, independently reported the surprising finding that some healthy rodents have protein in their urine. However, it was not until the 1960s that the major urinary proteins of mice and rats were first described in detail. It was found that the proteins are primarily made in the liver of males and secreted through the kidneys into the urine in large quantities (milligrams per day).
Since they were named, the proteins have been found to be differentially expressed in other glands that secrete products directly into the external environment. These include lacrimal, parotid, submaxillary, sublingual, preputial and mammary glands. In some species, such as cats and pigs, Mups appear not to be expressed in urine at all and are mainly found in saliva. Sometimes the term urinary Mups (uMups) is used to distinguish those Mups expressed in urine from those in other tissues.
== Mup genes ==
Between 1979 and 1981, it was estimated that Mups are encoded by a gene family of between 15 and 35 genes and pseudogenes in the mouse and by an estimated 20 genes in the rat. In 2008 a more precise number of Mup genes in a range of species was determined by analyzing the DNA sequence of whole genomes.
=== Rodents ===
The mouse reference genome has at least 21 distinct Mup genes (with open reading frames) and a further 21 Mup pseudogenes (with reading frames disrupted by a nonsense mutation or an incomplete gene duplication). They are all clustered together, arrayed side by side across 1.92 megabases of DNA on chromosome 4. The 21 functional genes have been divided into two sub-classes based on position and sequence similarity: 6 peripheral Class A Mups and 15 central Class B Mups. The central Class B Mup gene cluster formed through a number of sequential duplications from one of the Class A Mups. As all the Class B genes are almost identical to each other, researchers have concluded that these duplications occurred very recently in mouse evolution. Indeed, the repetitive structure of these central Mup genes means they are likely to be unstable and may vary in number among wild mice. The Class A Mups are more different from each other and are therefore likely to be more stable, older genes, but what, if any, functional differences the classes have are unknown. The similarity between the genes makes the region difficult to study using current DNA sequencing technology. Consequently, the Mup gene cluster is one of the few parts of the mouse whole genome sequence with gaps remaining, and further genes may remain undiscovered.
Rat urine also contains homologous urinary proteins; although they were originally given a different name, α2u-globulins, they have since become known as rat Mups. Rats have 9 distinct Mup genes and a further 13 pseudogenes clustered together across 1.1 megabases of DNA on chromosome 5. Like in mice, the cluster formed by multiple duplications. However, this occurred independently of the duplications in mice, meaning that both rodent species expanded their Mup gene families separately, but in parallel.
=== Nonrodents ===
Most other mammals studied, including the pig, cow, cat, dog, bushbaby, macaque, chimpanzee and orangutan, have a single Mup gene. Some, however, have an expanded number: horses have three Mup genes, and gray mouse lemurs have at least two. Insects, fish, amphibia, birds and marsupials appear to have disrupted synteny at the chromosomal position of the Mup gene cluster, suggesting the gene family may be specific to placental mammals. Humans are the only placental mammals found not to have any active Mup genes; instead, they have a single Mup pseudogene containing a mutation that causes missplicing, rendering it dysfunctional.
== Function ==
=== Transport proteins ===
Mups are members of a large family of low-molecular weight (~19 kDa) proteins known as lipocalins. They have a characteristic structure of eight beta sheets arranged in an anti-parallel beta barrel open on one face, with alpha helices at both ends. Consequently, they form a characteristic glove shape, encompassing a cup-like pocket that binds small organic chemicals with high affinity. A number of these ligands bind to mouse Mups, including 2-sec-butyl-4,5-dihydrothiazole (abbreviated as SBT or DHT), 6-hydroxy-6-methyl-3-heptanone (HMH) and 2,3 dihydro-exo-brevicomin (DHB). These are all urine-specific chemicals that have been shown to act as pheromones—molecular signals excreted by one individual that trigger an innate behavioural response in another member of the same species. Mouse Mups have also been shown to function as pheromone stabilizers, providing a slow release mechanism that extends the potency of volatile pheromones in male urine scent marks. Given the diversity of Mups in rodents, it was originally thought that different Mups may have differently shaped binding pockets and therefore bind different pheromones. However, detailed studies found that most variable sites are located on the surface of the proteins and appear to have little effect on ligand binding.
Rat Mups bind different small chemicals. The most common ligand is 1-Chlorodecane, with 2-methyl-N-phenyl-2-propenamide, hexadecane and 2,6,11-trimethyl decane found to be less prominent. Rat Mups also bind limonene-1,2-epoxide, resulting in a disease of the host's kidney, hyaline-droplet nephropathy, that progresses to cancer. Other species do not develop this disorder because their Mups do not bind that particular chemical. Accordingly, when transgenic mice were engineered to express the rat Mup, their kidneys developed the disease.
The Mup found in pigs, named salivary lipocalin (SAL), is expressed in the salivary gland of males where it tightly binds androstenone and androstenol, both pheromones that cause female pigs to assume a mating stance.
Isothermal titration calorimetry studies performed with Mups and associated ligands (pyrazines, alcohols, thiazolines, 6-hydroxy-6-methyl-3-heptanone, and N-phenylnapthylamine,) revealed an unusual binding phenomena. The active site has been found to be suboptimally hydrated, resulting in ligand binding being driven by enthalpic dispersion forces. This is contrary to most other proteins, which exhibit entropy-driven binding forces from the reorganisation of water molecules. This unusual process has been termed the nonclassical hydrophobic effect.
=== Pheromones ===
Studies have sought to find the precise function of Mups in pheromone communication. Mup proteins have been shown to promote puberty and accelerate the estrus cycle in female mice, inducing the Vandenbergh and Whitten effects. However, in both cases the Mups had to be presented to the female dissolved in male urine, indicating that the protein requires some urinary context to function. In 2007 Mups normally found in male mouse urine were made in transgenic bacteria, and therefore created devoid of the chemicals they normally bind. These Mups were shown to be sufficient to promote aggressive behaviour in males, even in the absence of urine. In addition, Mups made in bacteria were found to activate olfactory sensory neurons in the vomeronasal organ (VNO), a subsystem of the nose known to detect pheromones via specific sensory receptors, of mice and rats. Together, this demonstrated that Mup proteins can act as pheromones themselves, independent of their ligands.
Consistent with a role in male-male aggression, adult male mice secrete significantly more Mups into their urine than females, juveniles or castrated male mice. The precise mechanism driving this difference between the sexes is complex, but at least three hormones—testosterone, growth hormone and thyroxine—are known to positively influence the production of Mups in mice. Wild house mouse urine contains variable combinations of four to seven distinct Mup proteins per mouse. Some inbred laboratory mouse strains, such as BALB/c and C57BL/6, also have different proteins expressed in their urine. However, unlike wild mice, different individuals from the same strain express the same protein pattern, an artifact of many generations of inbreeding. One unusual Mup is less variable than the others: it is consistently produced by a high proportion of wild male mice and is almost never found in female urine. When this Mup was made in bacteria and used in behavioural testing, it was found to attract female mice. Other Mups were tested but did not have the same attractive qualities, suggesting the male-specific Mup acts as a sex pheromone. Scientists named this Mup darcin (Mup20, Q5FW60) as a humorous reference to Fitzwilliam Darcy, the romantic hero from Pride and Prejudice. Taken together, the complex patterns of Mups produced has the potential to provide a range of information about the donor animal, such as gender, fertility, social dominance, age, genetic diversity or kinship. Wild mice (unlike laboratory mice that are genetically identical and which therefore also have identical patterns of Mups in the urine) have individual patterns of Mup expression in their urine that act as a "barcode" to uniquely identify the owner of a scent mark.
In the house mouse, the major MUP gene cluster provides a highly polymorphic scent signal of genetic identity. Wild mice breeding freely in semi-natural enclosures showed inbreeding avoidance. This avoidance resulted from a strong deficit in successful matings between mice sharing both MUP haplotypes (complete match). In another study, using white-footed mice, it was found that when mice derived from wild populations were inbred, there was reduced survival when such mice were reintroduced into a natural habitat. These findings suggest that inbreeding reduces fitness, and that scent signal recognition has evolved in mice as a means of avoiding inbreeding depression.
=== Kairomones ===
In addition to serving as social cues between members of the same species, Mups can act as kairomones—chemical signals that transmit information between species. Mice are instinctively afraid of the smell of their natural predators, including cats and rats. This occurs even in laboratory mice that have been isolated from predators for hundreds of generations. When the chemical cues responsible for the fear response were purified from cat saliva and rat urine, two homologous protein signals were identified: Fel d 4 (Felis domesticus allergen 4; Q5VFH6), the product of the cat Mup gene, and Rat n 1 (Rattus norvegicus allergen 1; P02761), the product of the rat Mup13 gene. Mice are fearful of these Mups even when they are made in bacteria, but mutant animals that are unable to detect the Mups showed no fear of rats, demonstrating their importance in initiating fearful behaviour. It is not known exactly how Mups from different species initiate disparate behaviours, but mouse Mups and predator Mups have been shown to activate unique patterns of sensory neurons in the nose of recipient mice. This implies the mouse perceives them differently, via distinct neural circuits. The pheromone receptors responsible for Mup detection are also unknown, though they are thought be members of the V2R receptor class.
=== Allergens ===
Along with other members of the lipocalin protein family, major urinary proteins can be potent allergens to humans. The reason for this is not known; however, molecular mimicry between Mups and structurally similar human lipocalins has been proposed as a possible explanation. The protein product of the mouse Mup6 and Mup2 genes (previously mistaken as Mup17 due to the similarity among mouse MUPs), known as Mus m 1, Ag1 or MA1, accounts for much of the allergenic properties of mouse urine. The protein is extremely stable in the environment; studies have found 95% of inner city homes and 82% of all types of homes in the United States have detectable levels in at least one room. Similarly, Rat n 1 is a known human allergen. A US study found its presence in 33% of inner city homes, and 21% of occupants were sensitized to the allergen. Exposure and sensitization to rodent Mup proteins is considered a risk factor for childhood asthma and is a leading cause of laboratory animal allergy (LAA)—an occupational disease of laboratory animal technicians and scientists. One study found that two-thirds of laboratory workers who had developed asthmatic reactions to animals had antibodies to Rat n 1.
Mup genes from other mammals also encode allergenic proteins, for example Fel d 4 is primarily produced in the submandibular salivary gland and is deposited onto dander as the cat grooms itself. A study found that 63% of cat allergic people have antibodies against the protein. Most had higher titres of antibodies against Fel d 4 than against Fel d 1, another prominent cat allergen. Likewise, Equ c 1 (Equus caballus allergen 1; Q95182) is the protein product of a horse Mup gene that is found in the liver, sublingual and submaxillary salivary glands. It is responsible for about 80% of the antibody response in patients who are chronically exposed to horse allergens.
=== Metabolism ===
While the detection of Mups excreted by other animals has been well studied, the functional role in the producing animal is less clear. However, in 2009, Mups were shown to be associated with the regulation of energy expenditure in mice. Scientists found that genetically induced obese, diabetic mice produce thirty times less Mup RNA than their lean siblings. When they delivered Mup protein directly into the bloodstream of these mice, they observed an increase in energy expenditure, physical activity and body temperature and a corresponding decrease in glucose intolerance and insulin resistance. They propose that Mups' beneficial effects on energy metabolism occurs by enhancing mitochondrial function in skeletal muscle. Another study found Mups were reduced in diet-induced obese mice. In this case, the presence of Mups in the bloodstream of mice restricted glucose production by directly inhibiting the expression of genes in the liver.
== See also ==
Cis-vaccenyl acetate, an insect aggression pheromone
Major histocompatibility complex, peptides also implicated in individual recognition in mice
Proteins produced and secreted by the liver
== Notes ==
== References ==
== External links ==
Scent of a Rodent, The Why Files – The Science Behind The News
Fear Signals from Predators on YouTube, a video describing the research that determined Mups were kairomones | Wikipedia/Major_urinary_proteins |
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.
== Core components ==
F-box domain is a protein structural motif of about 50 amino acids that mediates protein–protein interactions. It has consensus sequence and varies in few positions. It was first identified in cyclin F. The F-box motif of Skp2, consisting of three alpha-helices, interacts directly with the SCF protein Skp1. F-box domains commonly exist in proteins in cancer with other protein–protein interaction motifs such as leucine-rich repeats (illustrated in the Figure) and WD repeats, which are thought to mediate interactions with SCF substrates.
== Function ==
F-box proteins have also been associated with cellular functions such as signal transduction and regulation of the cell cycle. In plants, many F-box proteins are represented in gene networks broadly regulated by microRNA-mediated gene silencing via RNA interference. F-box proteins are involved in many plant vegetative and reproduction growth and development. For example, F-box protein-FOA1 involved in abscisic acid (ABA) signaling to affect the seed germination. ACRE189/ACIF1 can regulate cell death and defense when the pathogen is recognized in the Tobacco and Tomato plant.
In human cells, under high-iron conditions, two iron atoms stabilise the F-Box FBXL5 and then the complex mediates the ubiquitination of IRP2.
== Regulation ==
F-box protein levels can be regulated by different mechanisms. The regulation can occur via protein degradation process and association with SCF complex . For example, in yeast, the F-box protein Met30 can be ubiquitinated in a cullin-dependent manner.[11]
== References ==
== Further reading ==
== External links ==
F-Box+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
F-box+motifs at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/F-box_protein |
Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST). They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT, via SGLT2). If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.
== Types ==
The sodium-glucose linked transporters (SGLTs) are responsible for the active transport of glucose across cell membranes. SGLT1 and SGLT2 are the most well-studied members of this family. Both SGLT1 and SGLT2 function as symporters, utilizing the energy from the sodium gradient created by the Na+/K+ ATPase to transport glucose against its concentration gradient.
SGLT2, encoded by the SLC5A2 gene, is predominantly expressed in the S1 and S2 segments of the proximal renal tubule and is responsible for approximately 97% of glucose reabsorption in the kidneys under normal conditions. SGLT1, encoded by the SLC5A1 gene, is primarily expressed in the late proximal tubule (S3 segment) and accounts for the remaining 3% of glucose reabsorption.
In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A.
SLC5A4, also known as SGLT3, is a member of the sodium-glucose cotransporter family. Unlike SGLT1 and SGLT2, which are efficient glucose transporters, SGLT3 functions primarily as a glucose sensor rather than a transporter. It has a low affinity for glucose and does not significantly contribute to glucose transport across cell membranes. Instead, SGLT3 acts as a glucose-gated ion channel, generating small depolarizing currents in response to extracellular glucose. This electrical signaling function suggests a role in glucose sensing and signaling pathways rather than in glucose transport.
The SLC5 family includes transporters for a diverse range of substrates beyond glucose. Specific members of this family are specialized for the transport of:
Mannose (SLC5A9, also known as SGLT4)
Myo-inositol (SLC5A3, also known as SMIT1)
Choline (SLC5A7, also known as CHT1)
Iodide (SLC5A5, also known as NIS)
Vitamins, specifically biotin and pantothenate (SLC5A6, also known as SMVT)
Short-chain fatty acids (SLC5A8 and SLC5A12, also known as SMCT1 and SMCT2 respectively)
Each of these transporters plays a specific role in cellular metabolism and homeostasis, often utilizing sodium gradients for substrate transport similar to the glucose transporters in this family.
== Mechanism ==
The transport of glucose across the proximal tubule cell membrane involves a complex process of secondary active transport (also known as co-transport). This process begins with the Na+/K+ ATPase on the basolateral membrane. This enzyme uses ATP to pump 3 sodium ions out of the cell into the blood while bringing 2 potassium ions into the cell. This action creates a sodium concentration gradient across the cell membrane, with a lower concentration inside the cell compared to both the blood and the tubular lumen.
SGLT proteins utilize this sodium gradient to transport glucose across the apical membrane into the cell, even against the glucose concentration gradient. This mechanism is an example of secondary active transport. Once inside the cell, glucose is then moved across the basolateral membrane into the peritubular capillaries by members of the GLUT family of glucose uniporters.
SGLT1 and SGLT2 are classified as symporters because they move sodium and glucose in the same direction across the membrane. To maintain this process, the Sodium–hydrogen antiporter plays a crucial role in replenishing intracellular sodium levels. Consequently, the net effect of glucose transport is coupled with the extrusion of protons from the cell, with sodium serving as an intermediate in this process.
== SGLT2 inhibitors for diabetes ==
SGLT2 inhibitors, also called gliflozins, are used in the treatment of type 2 diabetes. SGLT2 is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include dapagliflozin (Farxiga in US, Forxiga in EU), canagliflozin (Invokana) and empagliflozin (Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes. The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.
== History ==
In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption.
Crane's discovery of cotransport was the first-ever proposal of flux coupling in biology.
== See also ==
Cotransport
Cotransporter
Glucose-galactose malabsorption
Renal sodium reabsorption
Discovery and development of SGLT-2 inhibitors
== References ==
== External links ==
Sodium-Glucose+Transport+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Sodium-glucose_transport_proteins |
Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit", where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.
Examples include:
Gap-43 protein (presynaptic)
Neurogranin (postsynaptic)
Caldesmon
== Ca2+ Activation ==
A variety of different ions, including Calcium (Ca2+), play a vital role in the regulation of cellular functions. Calmodulin, a Calcium-binding protein, that mediates Ca2+ signaling is involved in all types of cellular mechanisms, including metabolism, synaptic plasticity, nerve growth, smooth muscle contraction, etc. Calmodulin allows for a number of proteins to aid in the progression of these pathways using their interactions with CaM in its Ca2+-free or Ca2+-bound state. Proteins each have their own unique affinities for calmodulin, that can be manipulated by Ca2+ concentrations to allow for the desired release or binding to calmodulin that determines its ability to carry out its cellular function. Proteins that get activated upon binding to Ca2+-bound state, include Myosin light-chain kinase, Phosphatase, Ca2+/calmodulin-dependent protein kinase II, etc. Proteins, such as neurogranin that plays a vital role in postsynaptic function, however, can bind to calmodulin in Ca2+-free or Ca2+-bound state via their IQ calmodulin-binding motifs. Since these interactions are exceptionally specific, they can be regulated through post-translational modifications by enzymes like kinases and phosphatases to affect their cellular functions. In the case of neurogranin, it's the synaptic function can be inhibited by the PKC-mediated phosphorylation of its IQ calmodulin-binding motif that impedes its interaction with calmodulin.
Cellular functions can be indirectly regulated by calmodulin, as it acts as a mediator for enzymes that require Ca2+ stimulation for activation. Studies have proven that calmodulin's affinity for Ca2+ increases when it is bound to a calmodulin-binding protein, which allows for it to take on its regulatory role for Ca2+-dependent reactions. Calmodulin, made up of two pairs of EF-hand motifs separated in different structural regions by an extended alpha helical region, that permits it to respond to the changes in the cytosolic concentration of the Ca2+ ions by taking on two distinct conformations, in the inactive Ca2+ unbound state and active Ca2+ bound state. Calmodulin binds to the targeted proteins via their short complementary peptide sequences, causing an “induced fit” conformational change that alters the calmodulin-binding proteins’ activity as desired in response to the second messenger Ca2+ signals that arise due to changes in the intracellular Ca2+ concentrations. These second messenger Ca2+ signals are transduced and integrated to maintain a homeostatic balance of the Ca2+ ions.
== GAP-43 Protein ==
Found in the nervous system, GAP-43 is a growth-associated protein (GAP) expressed in high levels during presynaptic developmental and regenerative axonal growth. As a major growth cone component, an increase in GAP-43 concentrations delays the process of axonal growth cones evolving into stable synaptic terminals. All GAP-43 proteins share a completely conserved amino acid sequence that contain a calmodulin-binding domain and a serine residue that can be used to inhibit calmodulin binding upon phosphorylation of Protein kinase C (PKC). By possessing these calmodulin-binding properties, GAP-43 is able to respond to PKC activation and release free calmodulin in desired areas. When there are low levels of Ca2+ concentrations, GAP-43 is able to bind and stabilize the inactive Ca2+-free state of calmodulin, this allows it to absorb and reversibly inactivate the CaM in the growth cones. This binding of the calmodulin to GAP-43 is allowed by the electrostatic interaction between the negatively-charged calmodulin and the positively-charged “pocket” formed in the GAP-43 molecule.
== References ==
== External links ==
Calmodulin-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Calmodulin-binding_proteins |
Riboflavin carrier proteins (RFCPs) together with human serum albumin transport flavin mononucleotide (FMN) in the blood circuit. RFCPs are important in pregnancy.
Studies from India have identified a riboflavin carrier protein (RCP) present in bird (e.g., chicken) eggs, which is considered to be specific for riboflavin, and is essential for normal embryological development. If this protein is rendered ineffective (e.g., by immuno-neutralization) by treatment of the bird with a specific antibody, then embryonic development ceases and the embryo dies. A genetic mutant lacking RCP is likewise infertile. A homologous protein, which can be rendered ineffective by the antibody to pure chicken riboflavin carrier protein, has been shown to occur in several mammalian species, including two species of monkeys, and also in humans. Very recent studies have suggested that circulating RCP levels and the immunohistochemical staining of RCP in biopsy specimens may provide new markers for breast cancer diagnosis and prognosis. Termination of pregnancy has been demonstrated by immuno-neutralization of RCP in monkeys. There remains some controversy over the roles of RCP, however, the other, less specific riboflavin binders in blood, including gamma-gobulins, also seem to play an important role. These studies have provided an intriguing example of the role of specific vitamin-transporting mechanisms, designed to ensure that the vitamin needs of the developing embryo will be efficiency met. Further evidence of the special needs of developing embryos has been provided by the demonstration that riboflavin analogs can cause teratogenic changes, even in the absence of any detectable damage to maternal tissues.
== Chicken Riboflavin carrier protein ==
RCP in chicken eggs is in both the yolk and whites. The RCP found in the yolk differs from that of the egg white. The difference in amino acid structure of RCP attributes to the cite of production and the destination of the RCP—the yolk-RCP (made in the liver) had 11-13 less amino acid compared to the whites-RCP (made in the oviducts).
The concentration of RCP in chickens depends on the concentration of estradiol injected and an increased production of RCP can be induced.
The dependence of RCP production on estrogen enables a potential role in the detection of breast cancer.
== References == | Wikipedia/Riboflavin_carrier_protein |
The anion exchanger family (TC# 2.A.31, also named bicarbonate transporter family) is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria (e.g., in Enterococcus faecium, 372 aas; gi 22992757; 29% identity in 90 residues). Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.
== Family overview ==
Bicarbonate (HCO3 −) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested different HCO3 − transport modes.
Anion exchanger proteins exchange HCO3 − for Cl− in a reversible, electroneutral manner.
Na+/HCO3 − co-transport proteins mediate the coupled movement of Na+ and HCO3 − across plasma membranes, often in an electrogenic manner.
Sequence analysis of the two families of HCO3 − transporters that have been cloned to date (the anion exchangers and Na+/HCO3 − co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO3 − and are inhibited by a class of pharmacological agents called disulphonic stilbenes. They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.
A conserved domain is found at the C terminus of many bicarbonate transport proteins. It is also found in some plant proteins responsible for boron transport. In these proteins it covers almost the entire length of the sequence.
The Band 3 anion exchange proteins that exchange bicarbonate are the most abundant polypeptide in the red blood cell membrane, comprising 25% of the total membrane protein. The cytoplasmic domain of band 3 functions primarily as an anchoring site for other membrane-associated proteins. Included among the protein ligands of this domain are ankyrin, protein 4.2, protein 4.1, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphofructokinase, aldolase, hemoglobin, hemichromes, and the protein tyrosine kinase (p72syk).
== Anion exchangers in humans ==
In humans, anion exchangers fall under the solute carrier family 4 (SLC4) family, which is composed of 10 paralogous members (SLC4A1-5; SLC4A7-11). Nine encode proteins that transport HCO−3. Functionally, eight of these proteins fall into two major groups: three Cl-HCO−3 exchangers (AE1-3) and five Na+-coupled HCO−3 transporters (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE). Two of the Na+-coupled transporters (NBCe1, NBCe2) are electrogenic; the other three Na+-coupled HCO−3 transporters and all three AEs are electroneutral. Two others (AE4, SLC4A9 and BTR1, SLC4A11) are not characterized. Most, though not all, are inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS). SLC4 proteins play roles in acid-base homeostasis, transport of H+ or HCO−3 by epithelia (e.g. absorption of HCO−3 in the renal proximal tubule, secretion of HCO−3 in the pancreatic duct), as well as the regulation of cell volume and intracellular pH.
Based on their hydropathy plots all SLC4 proteins are hypothesized to share a similar topology in the cell membrane. They have relatively long cytoplasmic N-terminal domains composed of a few hundred to several hundred residues, followed by 10-14 transmembrane (TM) domains, and end with relatively short cytoplasmic C-terminal domains composed of ~30 to ~90 residues. Although the C-terminal domain comprises a small percentage of the size of the protein, this domain in some cases, has (i) binding motifs that may be important for protein-protein interactions (e.g., AE1, AE2, and NBCn1), (ii) is important for trafficking to the cell membrane (e.g., AE1 and NBCe1), and (iii) may provide sites for regulation of transporter function via protein kinase A phosphorylation (e.g., NBCe1).
The SLC4 family comprises the following proteins.
SLC4A1
SLC4A2
SLC4A3
SLC4A4
SLC4A5
SLC4A7
SLC4A8
SLC4A9
SLC4A10
SLC4A11
=== Anion exchanger 1 ===
The human anion exchanger 1 (AE1 or Band 3) binds carbonic anhydrase II (CAII) forming a "transport metabolon" as CAII binding activates AE1 transport activity about 10 fold. AE1 is also activated by interaction with glycophorin, which also functions to target it to the plasma membrane. The membrane-embedded C-terminal domains may each span the membrane 13-16 times. According to the model of Zhu et al. (2003), AE1 in humans spans the membrane 16 times, 13 times as α-helix, and three times (TMSs 10, 11 and 14) possibly as β-strands. AE1 preferentially catalyzes anion exchange (antiport) reactions. Specific point mutations in human anion exchanger 1 (AE1) convert this electroneutral anion exchanger into a monovalent cation conductance. The same transport site within the AE1 spanning domain is involved in both anion exchange and cation transport.
AE1 in human red blood cells has been shown to transport a variety of inorganic and organic anions. Divalent anions may be symported with H+. Additionally, it catalyzes flipping of several anionic amphipathic molecules such as sodium dodecyl sulfate (SDS) and phosphatidic acid from one monolayer of the phospholipid bilayer to the other monolayer. The rate of flipping is sufficiently rapid to suggest that this AE1-catalyzed process is physiologically important in red blood cells and possibly in other animal tissues as well. Anionic phospholipids and fatty acids are likely to be natural substrates. However, the mere presence of TMSs enhances the rates of lipid flip-flop.
==== Structure ====
The crystal structure of AE1 (CTD) at 3.5 angstroms has been determined. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed identification of the likely anion-binding position in the AE1 (CTD), and led to proposal of a possible transport mechanism that could explain why selected mutations lead to disease. The 3-D structure confirmed that the AE family is a member of the APC superfamily.
There are several crystal structures available for the AE1 protein in RCSB (links are also available in TCDB).
AE1: 1BH7, 1BNX, 1BTQ, 1BTR, 1BTS, 1BTT, 1BZK, 2BTA, 1HYN, 2BTB, 3BTB, 2BTA, 2BTB, 3BTB, 4KY9, PDB: 4YZF, 1HYN, 5A16
=== Other members ===
Renal Na+:HCO−3 cotransporters have been found to be members of the AE family. They catalyze the reabsorption of HCO−3 in the renal proximal tubule in an electrogenic process that is inhibited by typical stilbene inhibitors of AE such as DIDS and SITS. They are also found in many other body tissues. At least two genes encode these symporters in any one mammal. A 10 TMS model has been presented, but this model conflicts with the 14 TMS model proposed for AE1. The transmembrane topology of the human pancreatic electrogenic Na+:HO−3 transporter, NBC1, has been studied. A TMS topology with N- and C-termini in the cytoplasm has been suggested. An extracellular loop determines the stoichiometry of Na+-HCO−3 cotransporters.
In addition to the Na+-independent anion exchangers (AE1-3) and the Na+:HCO−3 cotransporters (NBCs) (which may be either electroneutral or electrogenic), a Na+-driven HCO−3/Cl− exchanger (NCBE) has been sequenced and characterized. It transports Na+ + HCO−3 preferentially in the inward direction and H+ + Cl− in the outward direction. This NCBE is widespread in mammalian tissues where it plays an important role in cytoplasmic alkalinization. For example, in pancreatic β-cells, it mediates a glucose-dependent rise in pH related to insulin secretion.
Animal cells in tissue culture expressing the gene-encoding the ABC-type chloride channel protein CFTR (TC# 3.A.1.202.1) in the plasma membrane have been reported to exhibit cyclic AMP-dependent stimulation of AE activity. Regulation was independent of the Cl− conductance function of CFTR, and mutations in the nucleotide-binding domain #2 of CFTR altered regulation independently of their effects on chloride channel activity. These observations may explain impaired HCO−3 secretion in cystic fibrosis patients.
== Anion exchangers in plants and fungi ==
Plants and yeast have anion transporters that in both the pericycle cells of plants and the plasma membrane of yeast cells export borate or boric acid (pKa = 9.2). In A. thaliana, boron is exported from pericycle cells into the root stellar apoplasm against a concentration gradient for uptake into the shoots. In S. cerevisiae, export is also against a concentration gradient. The yeast transporter recognizes HCO−3, I−, Br−, NO−3 and Cl−, which may be substrates. Tolerance to boron toxicity in cereals is known to be associated with reduced tissue accumulation of boron. Expression of genes from roots of boron-tolerant wheat and barley with high similarity to efflux transporters from Arabidopsis and rice lowered boron concentrations due to an efflux mechanism. The mechanism of energy coupling is not known, nor is it known if borate or boric acid is the substrate. Several possibilities (uniport, anion:anion exchange and anion:cation exchange) can account for the data.
== Transport reactions ==
The physiologically relevant transport reaction catalyzed by anion exchangers of the AE family is:
Cl− (in) + HCO−3 (out) ⇌ Cl− (out) + HCO−3 (in).
That for the Na+:HCO3- cotransporters is:
Na+ (out) + nHCO−3 (out) → Na+ (in) + nHCO−3 (in).
That for the Na+/HCO−3:H+/Cl− exchanger is:
Na+ (out) + HCO−3 (out) + H+ (in) + Cl− (in) ⇌ Na+ (in) + HCO−3 (in) + H+ (out) + Cl− (out).
That for the boron efflux protein of plants and yeast is:
Boron (in) → Boron (out)
== See also ==
Solute carrier family
Transporter Classification Database
== References ==
As of 28 January 2016, this article is derived in whole or in part from Transporter Classification Database. The copyright holder has licensed the content in a manner that permits reuse under CC BY-SA 3.0 and GFDL. All relevant terms must be followed. The original text was at "2.A.31 The Anion Exchanger (AE) Family" | Wikipedia/Bicarbonate_transporter_protein |
aP2 (adipocyte Protein 2) is a carrier protein for fatty acids that is primarily expressed in adipocytes and macrophages. aP2 is also called fatty acid binding protein 4 (FABP4). Blocking this protein either through genetic engineering or drugs has the possibility of treating heart disease and the metabolic syndrome.
== See also ==
Fatty acid-binding protein
== References ==
== External links ==
FABP4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Human FABP4 genome location and FABP4 gene details page in the UCSC Genome Browser.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Fatty acid-binding protein, adipocyte
PDBe-KB provides an overview of all the structure information available in the PDB for Mouse Fatty acid-binding protein, adipocyte | Wikipedia/Adipocyte_protein_2 |
The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.
GIRK1 to GIRK3 are distributed broadly in the central nervous system, where their distributions overlap. GIRK4, instead, is found primarily in the heart.
== Subtypes ==
== Examples ==
A wide variety of G protein-coupled receptors activate GIRKs, including the M2-muscarinic, A1-adenosine, α2-adrenergic, D2-dopamine, μ- δ-, and κ-opioid, 5-HT1A serotonin, somatostatin, galanin, m-Glu, GABAB, TAAR1, CB1 and CB2, and sphingosine-1-phosphate receptors.
Examples of GIRKs include a subset of potassium channels in the heart, which, when activated by parasympathetic signals such as acetylcholine through M2 muscarinic receptors, causes an outward current of potassium, which slows down the heart rate. These are called muscarinic potassium channels (IKACh) and are heterotetramers composed of two GIRK1 and two GIRK4 subunits.
== References ==
== External links ==
G+Protein-Coupled+Inwardly-Rectifying+Potassium+Channels at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/G_protein-coupled_inwardly_rectifying_potassium_channel |
Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding protein (ABP).
Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin. SHBG is found in all vertebrates apart from birds.
== Function ==
Testosterone and estradiol circulate in the bloodstream, loosely bound mostly to serum albumin (~54%), and to a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1 to 2% is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. SHBG inhibits the function of these hormones. Thus, the local bioavailability of sex hormones is influenced by the level of SHBG. Because SHBG binds to testosterone (T) and dihydrotestosterone (DHT), these hormones are made less lipophilic and become concentrated within the luminal fluid of the seminiferous tubules. The higher levels of these hormones enable spermatogenesis in the seminiferous tubules and sperm maturation in the epididymis. SHBG’s production is regulated under the influence of FSH on Sertoli cells, enhanced by insulin, retinol, and testosterone.
The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone > androstenediol > estradiol > estrone. DHT binds to SHBG with about 5 times the affinity of testosterone and about 20 times the affinity of estradiol. Dehydroepiandrosterone (DHEA) is weakly bound to SHBG, but dehydroepiandrosterone sulfate is not bound to SHBG. Androstenedione is not bound to SHBG either, and is instead bound solely to albumin. Estrone sulfate and estriol are also poorly bound by SHBG. Less than 1% of progesterone is bound to SHBG.
SHBG levels are usually about twice as high in women as in men. In women, SHBG serves to limit exposure to both androgens and estrogens. Low SHBG levels in women have been associated with hyperandrogenism and endometrial cancer due to heightened exposure to androgens and estrogens, respectively. During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by five-fold to ten-fold. The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta. A case report of severe hyperandrogenism in a pregnant woman due to a rare instance of genetic SHBG deficiency illustrates this.
== Biochemistry ==
=== Biosynthesis ===
SHBG is produced mostly by the liver and is released into the bloodstream. Other sites that produce SHBG include the brain, uterus, testes, and placenta. Testes-produced SHBG is called androgen-binding protein.
== Gene ==
The gene for SHBG is called Shbg, located on chromosome 17 on the short arm between the bands 17p12→p13. Overlapping on the complementary DNA strand is the gene for spermidine/spermine N1-acetyltransferase family member 2 (SAT2). Nearby are the genes for p53 and ATP1B2, and fragile X mental retardation, autosomal homolog 2 (FXR2) on the complementary strand. There are eight exons, of which exon 1 has three variations called 1L, 1T and 1N which are triggered by three promoters: PL, PT and PN respectively. SHBG comes with the 1L, 2, 3, 4, 5, 6, 7, and 8 exons connected together. A variation includes SHBG-T which is missing exon 7 but with exon 1T promoted by promoter PT on the opposite strand, which shared with that for SAT2.
=== Polymorphisms ===
There are variations in the genetic material for this protein that have different effects.
In humans common polymorphisms include the following:
Rs6259, also called Asp327Asn location 7633209 on chromosome 17, results in there being an extra N-glycosylation site, and so an extra sugar can be attached. This results in a longer circulation half-life for the protein, and raised levels. Health effects include a lowered risk of endometrial cancer and an increased risk of systemic lupus erythematosus.
Rs6258 also called Ser156Pro is at position 7631360 on chromosome 17.
Rs727428 position 7634474 is in several percent of humans.
(TAAAA)(n) is five base pairs that repeats a variable number of times on the opposite DNA strand.
== Promoter activation ==
The mechanism of activating the promoter for SHBG in the liver involves hepatocyte nuclear factor 4 alpha (HNF4A) binding to a DR1-like cis-element which then stimulates production. Competing with HNF4A at a third site on the promoter is PPARG-2 which reduces copying the gene to RNA. If the HNF4A level is low, then COUP-TF binds to the first site and turns off production of SHBG.
== Protein ==
Sex hormone-binding globulin is homodimeric, meaning it has two identical peptide chains making up its structure. The amino acid sequence is the same as for androgen-binding protein produced in testes, but with different oligosaccharides attached.
SHBG has two laminin G-like domains which form pockets that bind hydrophobic molecules. The steroids are bound by the LG domain at the amino end of the protein. Inside the pocket of the domain is a serine residue that attracts the two different types of steroids at different points, thus changing their orientation. Androgens bind at the C3 functional groups on the A ring, and estrogens bind via a hydroxyl attached to C17 on the D ring. The two different orientations change a loop over the entrance to the pocket and the position of trp84 (in humans). Thus the whole protein signals what hormone it carries on its own surface. The steroid binding LG domain is coded by exons 2 to 5. A linker region joins the two LG domains together.
When first produced, the SHBG precursor has a leading signal peptide attached with 29 amino acids. The remaining peptide has 373 amino acids. There are two sulfur bridges.
The sugars are attached at two different N-glycosylation points on asparagine (351 and 367) and one O-glycosylation point (7) on threonine.
=== Metals ===
A calcium ion is needed to link the two elements of the dimer together. Also a zinc ion is used to orient an otherwise disorganised part of the peptide chain.
== Regulation ==
SHBG has both enhancing and inhibiting hormonal influences and thus can be viewed as a hepatokine. It decreases with high levels of insulin, growth hormone, insulin-like growth factor 1 (IGF-1), androgens, prolactin and transcortin. High estrogen and thyroxine levels cause it to increase.
In an effort to explain obesity-related reductions in SHBG, recent evidence suggests sugar or monosaccharide-induced hepatic lipogenesis, hepatic lipids in general, and cytokines like TNF-alpha and interleukins reduce SHBG, whereas insulin does not. For example, anti-psoriatic drugs that inhibit TNF-alpha cause an increase in SHBG. The common downstream mechanism for all of these, including the effect of thyroid hormones, was downregulation of hepatocyte nuclear factor 4 (HNF4).
== Blood values ==
Reference ranges for blood tests for SHBG have been developed:
== Clinical significance ==
=== High or low levels ===
SHBG levels are decreased by androgens, administration of anabolic steroids, polycystic ovary syndrome (PCOS), hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of type 2 diabetes. SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction increases SHBG in rodents and men, while lowering free and total testosterone and estradiol and having no effect on DHEA-S, which lacks affinity for SHBG. PCOS is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.
In utero, the human fetus has a low level of SHBG, allowing increased activity of sex hormones. After birth, the SHBG level rises and remains at a high level throughout childhood. At puberty the SHBG level halves in girls and goes down to a quarter in boys. The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In the third trimester of pregnancy, the SHBG level of the parent escalates to five to ten times the usual level for a woman. A hypothesis is that this protects against the effect of hormone produced by the fetus.
Obese girls are more likely to have an early menarche due to lower levels of SHBG. Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.
=== Type 2 diabetes ===
Reduced levels of SHBG and also certain polymorphisms of the SHBG gene are implicated in the development of insulin resistance and type 2 diabetes. Such effects apparently involve direct action at the cellular level where it became apparent that cell membranes of certain tissues contain specific high-affinity SHBG receptors.
=== Coagulation ===
SHBG is a useful correlate and indirect marker of estrogen-induced procoagulation and by extension thrombosis, for instance with birth control pills.
=== Medications ===
Oral contraceptives containing ethinylestradiol can increase SHBG levels 2- to 4-fold and decrease free testosterone concentrations by 40 to 80% in women. They can be used to treat symptoms of hyperandrogenism like acne and hirsutism. Some oral contraceptives, namely those containing high doses of ethinylestradiol (which have been discontinued and are no longer marketed), can increase SHBG levels as much as 5- to 10-fold.
Some medications, such as certain anabolic steroids like mesterolone and danazol and certain progestins like levonorgestrel and norethisterone, have high affinity for SHBG and can bind to it and displace endogenous steroids from it, thereby increasing free concentrations of these endogenous steroids. It has been estimated that therapeutic levels of danazol, methyltestosterone, fluoxymesterone, levonorgestrel, and norethisterone would respectively occupy or displace from testosterone 83–97%, 48–69%, 42–64%, 16–47%, and 4–39% of SHBG binding sites, while others with low affinity for SHBG such as ethinylestradiol, cyproterone acetate, and medroxyprogesterone acetate would occupy or displace from testosterone 1% or fewer SHBG binding sites.
Selective androgen receptor modulators (SARMs) also reduce SHBG.
== Endogenous steroids ==
=== Measurement ===
When checking serum estradiol or testosterone, a total level that includes free and bound fractions can be assayed, or the free portion may be measured alone. Sex hormone-binding globulin can be measured separately from the total fraction of testosterone.
A free androgen index expresses the ratio of testosterone to SHBG and can be used to summarize the activity of free testosterone.
=== Affinity and binding ===
== Synonyms ==
SHBG has been known under a variety of different names including:
Sex hormone-binding globulin (SHBG)
Sex steroid-binding globulin (SSBG, SBG)
Sex steroid-binding protein (SBP, SSBP)
Androgen-binding protein (ABP)
Estradiol-binding-protein (EBP)
Testosterone–estradiol binding globulin (TeBG, TEBG)
== References ==
== Further reading ==
== External links ==
Overview of all the structural information available in the PDB for UniProt: P04278 (Sex hormone-binding globulin) at the PDBe-KB.
Androgen-Binding+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Ensembl Gene ref Protein ref | Wikipedia/Androgen-binding_protein |
Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population, and application of this knowledge to prevent diseases.
It is a cornerstone of public health, and shapes policy decisions and evidence-based practice by identifying risk factors for disease and targets for preventive healthcare. Epidemiologists help with study design, collection, and statistical analysis of data, amend interpretation and dissemination of results (including peer review and occasional systematic review). Epidemiology has helped develop methodology used in clinical research, public health studies, and, to a lesser extent, basic research in the biological sciences.
Major areas of epidemiological study include disease causation, transmission, outbreak investigation, disease surveillance, environmental epidemiology, forensic epidemiology, occupational epidemiology, screening, biomonitoring, and comparisons of treatment effects such as in clinical trials. Epidemiologists rely on other scientific disciplines like biology to better understand disease processes, statistics to make efficient use of the data and draw appropriate conclusions, social sciences to better understand proximate and distal causes, and engineering for exposure assessment.
Epidemiology, literally meaning "the study of what is upon the people", is derived from Greek epi 'upon, among' demos 'people, district' and logos 'study, word, discourse', suggesting that it applies only to human populations. However, the term is widely used in studies of zoological populations (veterinary epidemiology), although the term "epizoology" is available, and it has also been applied to studies of plant populations (botanical or plant disease epidemiology).
The distinction between "epidemic" and "endemic" was first drawn by Hippocrates, to distinguish between diseases that are "visited upon" a population (epidemic) from those that "reside within" a population (endemic). The term "epidemiology" appears to have first been used to describe the study of epidemics in 1802 by the Spanish physician Joaquín de Villalba in Epidemiología Española. Epidemiologists also study the interaction of diseases in a population, a condition known as a syndemic.
The term epidemiology is now widely applied to cover the description and causation of not only epidemic, infectious disease, but of disease in general, including related conditions. Some examples of topics examined through epidemiology include as high blood pressure, mental illness and obesity. Therefore, this epidemiology is based upon how the pattern of the disease causes change in the function of human beings.
== History ==
The Greek physician Hippocrates, taught by Democritus, was known as the father of medicine, sought a logic to sickness; he is the first person known to have examined the relationships between the occurrence of disease and environmental influences. Hippocrates believed sickness of the human body to be caused by an imbalance of the four humors (black bile, yellow bile, blood, and phlegm). The cure to the sickness was to remove or add the humor in question to balance the body. This belief led to the application of bloodletting and dieting in medicine. He coined the terms endemic (for diseases usually found in some places but not in others) and epidemic (for diseases that are seen at some times but not others).
=== Modern era ===
In the middle of the 16th century, a doctor from Verona named Girolamo Fracastoro was the first to propose a theory that the very small, unseeable, particles that cause disease were alive. They were considered to be able to spread by air, multiply by themselves and to be destroyable by fire. In this way he refuted Galen's miasma theory (poison gas in sick people). In 1543 he wrote a book De contagione et contagiosis morbis, in which he was the first to promote personal and environmental hygiene to prevent disease. The development of a sufficiently powerful microscope by Antonie van Leeuwenhoek in 1675 provided visual evidence of living particles consistent with a germ theory of disease.
During the Ming dynasty, Wu Youke (1582–1652) developed the idea that some diseases were caused by transmissible agents, which he called Li Qi (戾气 or pestilential factors) when he observed various epidemics rage around him between 1641 and 1644. His book Wen Yi Lun (瘟疫论, Treatise on Pestilence/Treatise of Epidemic Diseases) can be regarded as the main etiological work that brought forward the concept. His concepts were still being considered in analysing SARS outbreak by WHO in 2004 in the context of traditional Chinese medicine.
Another pioneer, Thomas Sydenham (1624–1689), was the first to distinguish the fevers of Londoners in the later 1600s. His theories on cures of fevers met with much resistance from traditional physicians at the time. He was not able to find the initial cause of the smallpox fever he researched and treated.
John Graunt, a haberdasher and amateur statistician, published Natural and Political Observations ... upon the Bills of Mortality in 1662. In it, he analysed the mortality rolls in London before the Great Plague, presented one of the first life tables, and reported time trends for many diseases, new and old. He provided statistical evidence for many theories on disease, and also refuted some widespread ideas on them.
John Snow is famous for his investigations into the causes of the 19th-century cholera epidemics, and is also known as the father of (modern) Epidemiology. He began with noticing the significantly higher death rates in two areas supplied by Southwark Company. His identification of the Broad Street pump as the cause of the Soho epidemic is considered the classic example of epidemiology. Snow used chlorine in an attempt to clean the water and removed the handle; this ended the outbreak. This has been perceived as a major event in the history of public health and regarded as the founding event of the science of epidemiology, having helped shape public health policies around the world. However, Snow's research and preventive measures to avoid further outbreaks were not fully accepted or put into practice until after his death due to the prevailing Miasma Theory of the time, a model of disease in which poor air quality was blamed for illness. This was used to rationalize high rates of infection in impoverished areas instead of addressing the underlying issues of poor nutrition and sanitation, and was proven false by his work.
Other pioneers include Danish physician Peter Anton Schleisner, who in 1849 related his work on the prevention of the epidemic of neonatal tetanus on the Vestmanna Islands in Iceland. Another important pioneer was Hungarian physician Ignaz Semmelweis, who in 1847 brought down infant mortality at a Vienna hospital by instituting a disinfection procedure. His findings were published in 1850, but his work was ill-received by his colleagues, who discontinued the procedure. Disinfection did not become widely practiced until British surgeon Joseph Lister, aided by his college, chemist Thomas Anderson, was able to "discover" antiseptics in 1865 based on the earlier work of Louis Pasteur.
In the early 20th century, mathematical methods were introduced into epidemiology by Ronald Ross, Janet Lane-Claypon, Anderson Gray McKendrick, and others. In a parallel development during the 1920s, German-Swiss pathologist Max Askanazy and others founded the International Society for Geographical Pathology to systematically investigate the geographical pathology of cancer and other non-infectious diseases across populations in different regions. After World War II, Richard Doll and other non-pathologists joined the field and advanced methods to study cancer, a disease with patterns and mode of occurrences that could not be suitably studied with the methods developed for epidemics of infectious diseases. Geography pathology eventually combined with infectious disease epidemiology to make the field that is epidemiology today.
Another breakthrough was the 1954 publication of the results of a British Doctors Study, led by Richard Doll and Austin Bradford Hill, which lent very strong statistical support to the link between tobacco smoking and lung cancer.
In the late 20th century, with the advancement of biomedical sciences, a number of molecular markers in blood, other biospecimens and environment were identified as predictors of development or risk of a certain disease. Epidemiology research to examine the relationship between these biomarkers analyzed at the molecular level and disease was broadly named "molecular epidemiology". Specifically, "genetic epidemiology" has been used for epidemiology of germline genetic variation and disease. Genetic variation is typically determined using DNA from peripheral blood leukocytes.
=== 21st century ===
Since the 2000s, genome-wide association studies (GWAS) have been commonly performed to identify genetic risk factors for many diseases and health conditions.
While most molecular epidemiology studies are still using conventional disease diagnosis and classification systems, it is increasingly recognized that disease progression represents inherently heterogeneous processes differing from person to person. Conceptually, each individual has a unique disease process different from any other individual ("the unique disease principle"), considering uniqueness of the exposome (a totality of endogenous and exogenous / environmental exposures) and its unique influence on molecular pathologic process in each individual. Studies to examine the relationship between an exposure and molecular pathologic signature of disease (particularly cancer) became increasingly common throughout the 2000s. However, the use of molecular pathology in epidemiology posed unique challenges, including lack of research guidelines and standardized statistical methodologies, and paucity of interdisciplinary experts and training programs. Furthermore, the concept of disease heterogeneity appears to conflict with the long-standing premise in epidemiology that individuals with the same disease name have similar etiologies and disease processes. To resolve these issues and advance population health science in the era of molecular precision medicine, "molecular pathology" and "epidemiology" was integrated to create a new interdisciplinary field of "molecular pathological epidemiology" (MPE), defined as "epidemiology of molecular pathology and heterogeneity of disease". In MPE, investigators analyze the relationships between (A) environmental, dietary, lifestyle and genetic factors; (B) alterations in cellular or extracellular molecules; and (C) evolution and progression of disease. A better understanding of heterogeneity of disease pathogenesis will further contribute to elucidate etiologies of disease. The MPE approach can be applied to not only neoplastic diseases but also non-neoplastic diseases. The concept and paradigm of MPE have become widespread in the 2010s.
By 2012, it was recognized that many pathogens' evolution is rapid enough to be highly relevant to epidemiology, and that therefore much could be gained from an interdisciplinary approach to infectious disease integrating epidemiology and molecular evolution to "inform control strategies, or even patient treatment." Modern epidemiological studies can use advanced statistics and machine learning to create predictive models as well as to define treatment effects. There is increasing recognition that a wide range of modern data sources, many not originating from healthcare or epidemiology, can be used for epidemiological study. Such digital epidemiology can include data from internet searching, mobile phone records and retail sales of drugs.
== Types of studies ==
Epidemiologists employ a range of study designs from the observational to experimental and generally categorized as descriptive (involving the assessment of data covering time, place, and person), analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions). In observational studies, nature is allowed to "take its course", as epidemiologists observe from the sidelines. Conversely, in experimental studies, the epidemiologist is the one in control of all of the factors entering a certain case study. Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. The identification of causal relationships between these exposures and outcomes is an important aspect of epidemiology. Modern epidemiologists use informatics and infodemiology as tools.
Observational studies have two components, descriptive and analytical. Descriptive observations pertain to the "who, what, where and when of health-related state occurrence". However, analytical observations deal more with the 'how' of a health-related event. Experimental epidemiology contains three case types: randomized controlled trials (often used for a new medicine or drug testing), field trials (conducted on those at a high risk of contracting a disease), and community trials (research on social originating diseases).
The term 'epidemiologic triad' is used to describe the intersection of Host, Agent, and Environment in analyzing an outbreak.
=== Case series ===
Case-series may refer to the qualitative study of the experience of a single patient, or small group of patients with a similar diagnosis, or to a statistical factor with the potential to produce illness with periods when they are unexposed.
The former type of study is purely descriptive and cannot be used to make inferences about the general population of patients with that disease. These types of studies, in which an astute clinician identifies an unusual feature of a disease or a patient's history, may lead to a formulation of a new hypothesis. Using the data from the series, analytic studies could be done to investigate possible causal factors. These can include case-control studies or prospective studies. A case-control study would involve matching comparable controls without the disease to the cases in the series. A prospective study would involve following the case series over time to evaluate the disease's natural history.
The latter type, more formally described as self-controlled case-series studies, divide individual patient follow-up time into exposed and unexposed periods and use fixed-effects Poisson regression processes to compare the incidence rate of a given outcome between exposed and unexposed periods. This technique has been extensively used in the study of adverse reactions to vaccination and has been shown in some circumstances to provide statistical power comparable to that available in cohort studies.
=== Case-control studies ===
Case-control studies select subjects based on their disease status. It is a retrospective study. A group of individuals that are disease positive (the "case" group) is compared with a group of disease negative individuals (the "control" group). The control group should ideally come from the same population that gave rise to the cases. The case-control study looks back through time at potential exposures that both groups (cases and controls) may have encountered. A 2×2 table is constructed, displaying exposed cases (A), exposed controls (B), unexposed cases (C) and unexposed controls (D). The statistic generated to measure association is the odds ratio (OR), which is the ratio of the odds of exposure in the cases (A/C) to the odds of exposure in the controls (B/D), i.e. OR = (AD/BC).
If the OR is significantly greater than 1, then the conclusion is "those with the disease are more likely to have been exposed", whereas if it is close to 1 then the exposure and disease are not likely associated. If the OR is far less than one, then this suggests that the exposure is a protective factor in the causation of the disease.
Case-control studies are usually faster and more cost-effective than cohort studies but are sensitive to bias (such as recall bias and selection bias). The main challenge is to identify the appropriate control group; the distribution of exposure among the control group should be representative of the distribution in the population that gave rise to the cases. This can be achieved by drawing a random sample from the original population at risk. This has as a consequence that the control group can contain people with the disease under study when the disease has a high attack rate in a population.
A major drawback for case control studies is that, in order to be considered to be statistically significant, the minimum number of cases required at the 95% confidence interval is related to the odds ratio by the equation:
total cases
=
A
+
C
=
1.96
2
(
1
+
N
)
(
1
ln
(
O
R
)
)
2
(
O
R
+
2
O
R
+
1
O
R
)
≈
15.5
(
1
+
N
)
(
1
ln
(
O
R
)
)
2
{\displaystyle {\text{total cases}}=A+C=1.96^{2}(1+N)\left({\frac {1}{\ln(OR)}}\right)^{2}\left({\frac {OR+2{\sqrt {OR}}+1}{\sqrt {OR}}}\right)\approx 15.5(1+N)\left({\frac {1}{\ln(OR)}}\right)^{2}}
where N is the ratio of cases to controls.
As the odds ratio approaches 1, the number of cases required for statistical significance grows towards infinity; rendering case-control studies all but useless for low odds ratios. For instance, for an odds ratio of 1.5 and cases = controls, the table shown above would look like this:
For an odds ratio of 1.1:
=== Cohort studies ===
Cohort studies select subjects based on their exposure status. The study subjects should be at risk of the outcome under investigation at the beginning of the cohort study; this usually means that they should be disease free when the cohort study starts. The cohort is followed through time to assess their later outcome status. An example of a cohort study would be the investigation of a cohort of smokers and non-smokers over time to estimate the incidence of lung cancer. The same 2×2 table is constructed as with the case control study. However, the point estimate generated is the relative risk (RR), which is the probability of disease for a person in the exposed group, Pe = A / (A + B) over the probability of disease for a person in the unexposed group, Pu = C / (C + D), i.e. RR = Pe / Pu.
As with the OR, a RR greater than 1 shows association, where the conclusion can be read "those with the exposure were more likely to develop the disease."
Prospective studies have many benefits over case control studies. The RR is a more powerful effect measure than the OR, as the OR is just an estimation of the RR, since true incidence cannot be calculated in a case control study where subjects are selected based on disease status. Temporality can be established in a prospective study, and confounders are more easily controlled for. However, they are more costly, and there is a greater chance of losing subjects to follow-up based on the long time period over which the cohort is followed.
Cohort studies also are limited by the same equation for number of cases as for cohort studies, but, if the base incidence rate in the study population is very low, the number of cases required is reduced by 1⁄2.
== Causal inference ==
Although epidemiology is sometimes viewed as a collection of statistical tools used to elucidate the associations of exposures to health outcomes, a deeper understanding of this science is that of discovering causal relationships.
"Correlation does not imply causation" is a common theme for much of the epidemiological literature. For epidemiologists, the key is in the term inference. Correlation, or at least association between two variables, is a necessary but not sufficient criterion for the inference that one variable causes the other. Epidemiologists use gathered data and a broad range of biomedical and psychosocial theories in an iterative way to generate or expand theory, to test hypotheses, and to make educated, informed assertions about which relationships are causal, and about exactly how they are causal.
Epidemiologists emphasize that the "one cause – one effect" understanding is a simplistic mis-belief. Most outcomes, whether disease or death, are caused by a chain or web consisting of many component causes. Causes can be distinguished as necessary, sufficient or probabilistic conditions. If a necessary condition can be identified and controlled (e.g., antibodies to a disease agent, energy in an injury), the harmful outcome can be avoided (Robertson, 2015). One tool regularly used to conceptualize the multicausality associated with disease is the causal pie model.
=== Bradford Hill criteria ===
In 1965, Austin Bradford Hill proposed a series of considerations to help assess evidence of causation, which have come to be commonly known as the "Bradford Hill criteria". In contrast to the explicit intentions of their author, Hill's considerations are now sometimes taught as a checklist to be implemented for assessing causality. Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non."
Strength of Association: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal.
Consistency of Data: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect.
Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.
Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).
Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.
Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge).
Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations".
Experiment: "Occasionally it is possible to appeal to experimental evidence".
Analogy: The effect of similar factors may be considered.
=== Legal interpretation ===
Epidemiological studies can only go to prove that an agent could have caused, but not that it did cause, an effect in any particular case:
Epidemiology is concerned with the incidence of disease in populations and does not address the question of the cause of an individual's disease. This question, sometimes referred to as specific causation, is beyond the domain of the science of epidemiology. Epidemiology has its limits at the point where an inference is made that the relationship between an agent and a disease is causal (general causation) and where the magnitude of excess risk attributed to the agent has been determined; that is, epidemiology addresses whether an agent can cause disease, not whether an agent did cause a specific plaintiff's disease.
In United States law, epidemiology alone cannot prove that a causal association does not exist in general. Conversely, it can be (and is in some circumstances) taken by US courts, in an individual case, to justify an inference that a causal association does exist, based upon a balance of probability.
The subdiscipline of forensic epidemiology is directed at the investigation of specific causation of disease or injury in individuals or groups of individuals in instances in which causation is disputed or is unclear, for presentation in legal settings.
== Population-based health management ==
Epidemiological practice and the results of epidemiological analysis make a significant contribution to emerging population-based health management frameworks.
Population-based health management encompasses the ability to:
Assess the health states and health needs of a target population;
Implement and evaluate interventions that are designed to improve the health of that population; and
Efficiently and effectively provide care for members of that population in a way that is consistent with the community's cultural, policy and health resource values.
Modern population-based health management is complex, requiring a multiple set of skills (medical, political, technological, mathematical, etc.) of which epidemiological practice and analysis is a core component, that is unified with management science to provide efficient and effective health care and health guidance to a population. This task requires the forward-looking ability of modern risk management approaches that transform health risk factors, incidence, prevalence and mortality statistics (derived from epidemiological analysis) into management metrics that not only guide how a health system responds to current population health issues but also how a health system can be managed to better respond to future potential population health issues.
Examples of organizations that use population-based health management that leverage the work and results of epidemiological practice include Canadian Strategy for Cancer Control, Health Canada Tobacco Control Programs, Rick Hansen Foundation, Canadian Tobacco Control Research Initiative.
Each of these organizations uses a population-based health management framework called Life at Risk that combines epidemiological quantitative analysis with demographics, health agency operational research and economics to perform:
Population Life Impacts Simulations: Measurement of the future potential impact of disease upon the population with respect to new disease cases, prevalence, premature death as well as potential years of life lost from disability and death;
Labour Force Life Impacts Simulations: Measurement of the future potential impact of disease upon the labour force with respect to new disease cases, prevalence, premature death and potential years of life lost from disability and death;
Economic Impacts of Disease Simulations: Measurement of the future potential impact of disease upon private sector disposable income impacts (wages, corporate profits, private health care costs) and public sector disposable income impacts (personal income tax, corporate income tax, consumption taxes, publicly funded health care costs).
== Applied field epidemiology ==
Applied epidemiology is the practice of using epidemiological methods to protect or improve the health of a population. Applied field epidemiology can include investigating communicable and non-communicable disease outbreaks, mortality and morbidity rates, and nutritional status, among other indicators of health, with the purpose of communicating the results to those who can implement appropriate policies or disease control measures.
=== Humanitarian context ===
As the surveillance and reporting of diseases and other health factors become increasingly difficult in humanitarian crisis situations, the methodologies used to report the data are compromised. One study found that less than half (42.4%) of nutrition surveys sampled from humanitarian contexts correctly calculated the prevalence of malnutrition and only one-third (35.3%) of the surveys met the criteria for quality. Among the mortality surveys, only 3.2% met the criteria for quality. As nutritional status and mortality rates help indicate the severity of a crisis, the tracking and reporting of these health factors is crucial.
Vital registries are usually the most effective ways to collect data, but in humanitarian contexts these registries can be non-existent, unreliable, or inaccessible. As such, mortality is often inaccurately measured using either prospective demographic surveillance or retrospective mortality surveys. Prospective demographic surveillance requires much manpower and is difficult to implement in a spread-out population. Retrospective mortality surveys are prone to selection and reporting biases. Other methods are being developed, but are not common practice yet.
== Characterization, validity, and bias ==
=== Epidemic wave ===
The concept of waves in epidemics has implications especially for communicable diseases. A working definition for the term "epidemic wave" is based on two key features: 1) it comprises periods of upward or downward trends, and 2) these increases or decreases must be substantial and sustained over a period of time, in order to distinguish them from minor fluctuations or reporting errors. The use of a consistent scientific definition is to provide a consistent language that can be used to communicate about and understand the progression of the COVID-19 pandemic, which would aid healthcare organizations and policymakers in resource planning and allocation.
=== Validities ===
Different fields in epidemiology have different levels of validity. One way to assess the validity of findings is the ratio of false-positives (claimed effects that are not correct) to false-negatives (studies which fail to support a true effect). In genetic epidemiology, candidate-gene studies may produce over 100 false-positive findings for each false-negative. By contrast genome-wide association appear close to the reverse, with only one false positive for every 100 or more false-negatives. This ratio has improved over time in genetic epidemiology, as the field has adopted stringent criteria. By contrast, other epidemiological fields have not required such rigorous reporting and are much less reliable as a result.
=== Random error ===
Random error is the result of fluctuations around a true value because of sampling variability. Random error is just that: random. It can occur during data collection, coding, transfer, or analysis. Examples of random errors include poorly worded questions, a misunderstanding in interpreting an individual answer from a particular respondent, or a typographical error during coding. Random error affects measurement in a transient, inconsistent manner and it is impossible to correct for random error. There is a random error in all sampling procedures – sampling error.
Precision in epidemiological variables is a measure of random error. Precision is also inversely related to random error, so that to reduce random error is to increase precision. Confidence intervals are computed to demonstrate the precision of relative risk estimates. The narrower the confidence interval, the more precise the relative risk estimate.
There are two basic ways to reduce random error in an epidemiological study. The first is to increase the sample size of the study. In other words, add more subjects to your study. The second is to reduce the variability in measurement in the study. This might be accomplished by using a more precise measuring device or by increasing the number of measurements.
Note, that if sample size or number of measurements are increased, or a more precise measuring tool is purchased, the costs of the study are usually increased. There is usually an uneasy balance between the need for adequate precision and the practical issue of study cost.
=== Systematic error ===
A systematic error or bias occurs when there is a difference between the true value (in the population) and the observed value (in the study) from any cause other than sampling variability. An example of systematic error is if, unknown to you, the pulse oximeter you are using is set incorrectly and adds two points to the true value each time a measurement is taken. The measuring device could be precise but not accurate. Because the error happens in every instance, it is systematic. Conclusions you draw based on that data will still be incorrect. But the error can be reproduced in the future (e.g., by using the same mis-set instrument).
A mistake in coding that affects all responses for that particular question is another example of a systematic error.
The validity of a study is dependent on the degree of systematic error. Validity is usually separated into two components:
Internal validity is dependent on the amount of error in measurements, including exposure, disease, and the associations between these variables. Good internal validity implies a lack of error in measurement and suggests that inferences may be drawn at least as they pertain to the subjects under study.
External validity pertains to the process of generalizing the findings of the study to the population from which the sample was drawn (or even beyond that population to a more universal statement). This requires an understanding of which conditions are relevant (or irrelevant) to the generalization. Internal validity is clearly a prerequisite for external validity.
==== Selection bias ====
Selection bias occurs when study subjects are selected or become part of the study as a result of a third, unmeasured variable which is associated with both the exposure and outcome of interest. For instance, it has repeatedly been noted that cigarette smokers and non smokers tend to differ in their study participation rates. (Sackett D cites the example of Seltzer et al., in which 85% of non smokers and 67% of smokers returned mailed questionnaires.) Such a difference in response will not lead to bias if it is not also associated with a systematic difference in outcome between the two response groups.
==== Information bias ====
Information bias is bias arising from systematic error in the assessment of a variable. An example of this is recall bias. A typical example is again provided by Sackett in his discussion of a study examining the effect of specific exposures on fetal health: "in questioning mothers whose recent pregnancies had ended in fetal death or malformation (cases) and a matched group of mothers whose pregnancies ended normally (controls) it was found that 28% of the former, but only 20% of the latter, reported exposure to drugs which could not be substantiated either in earlier prospective interviews or in other health records". In this example, recall bias probably occurred as a result of women who had had miscarriages having an apparent tendency to better recall and therefore report previous exposures.
==== Design-related bias ====
Next to sample- and variable-related bias, bias can also arise from an imperfect study design. One example is immortal time bias, where during study period, there is some interval during which the outcome event cannot occur (making these individual "immortal").
==== Confounding ====
Confounding has traditionally been defined as bias arising from the co-occurrence or mixing of effects of extraneous factors, referred to as confounders, with the main effect(s) of interest. A more recent definition of confounding invokes the notion of counterfactual effects. According to this view, when one observes an outcome of interest, say Y=1 (as opposed to Y=0), in a given population A which is entirely exposed (i.e. exposure X = 1 for every unit of the population) the risk of this event will be RA1. The counterfactual or unobserved risk RA0 corresponds to the risk which would have been observed if these same individuals had been unexposed (i.e. X = 0 for every unit of the population). The true effect of exposure therefore is: RA1 − RA0 (if one is interested in risk differences) or RA1/RA0 (if one is interested in relative risk). Since the counterfactual risk RA0 is unobservable we approximate it using a second population B and we actually measure the following relations: RA1 − RB0 or RA1/RB0. In this situation, confounding occurs when RA0 ≠ RB0. (NB: Example assumes binary outcome and exposure variables.)
Some epidemiologists prefer to think of confounding separately from common categorizations of bias since, unlike selection and information bias, confounding stems from real causal effects.
== The profession ==
Few universities have offered epidemiology as a course of study at the undergraduate level. An undergraduate program exists at Johns Hopkins University in which students who major in public health can take graduate-level courses—including epidemiology—during their senior year at the Bloomberg School of Public Health. In addition to its master's and doctoral degrees in epidemiology, the University of Michigan School of Public Health has offered undergraduate degree programs since 2017 that include coursework in epidemiology.
Although epidemiologic research is conducted by individuals from diverse disciplines, variable levels of training in epidemiologic methods are provided during pharmacy, medical, veterinary, social work, podiatry, nursing, physical therapy, and clinical psychology doctoral programs in addition to the formal training master's and doctoral students in public health fields receive.
As public health practitioners, epidemiologists work in a number of different settings. Some epidemiologists work "in the field" (i.e., in the community; commonly in a public health service), and are often at the forefront of investigating and combating disease outbreaks. Others work for non-profit organizations, universities, hospitals, or larger government entities (e.g., state and local health departments in the United States), ministries of health, Doctors without Borders, the Centers for Disease Control and Prevention (CDC), the Health Protection Agency, the World Health Organization (WHO), or the Public Health Agency of Canada. Epidemiologists can also work in for-profit organizations (e.g., pharmaceutical and medical device companies) in groups such as market research or clinical development.
=== COVID-19 ===
An April 2020 University of Southern California article noted that, "The coronavirus epidemic... thrust epidemiology – the study of the incidence, distribution and control of disease in a population – to the forefront of scientific disciplines across the globe and even made temporary celebrities out of some of its practitioners."
== See also ==
== References ==
=== Citations ===
=== Sources ===
== External links == | Wikipedia/epidemiology |
The Journal of Clinical Epidemiology is a peer-reviewed journal of epidemiology. The journal was originally established as the Journal of Chronic Diseases in 1955 as a follow-up to Harry S. Truman's 1951 Presidential Task Force on national health concerns and the subsequently written Magnuson Report.
Under the editorial leadership of Alvan Feinstein and Walter O. Spitzer, the title of the journal was changed to the Journal of Clinical Epidemiology with the January 1988 issue. The current editors are André Knottnerus (Netherlands School of Primary Care Research) and Peter Tugwell (University of Ottawa).
According to the Journal Citation Reports, the journal has a 2020 Impact Factor of 6.437, ranking it 5th out of 108 journals in the category "Health Care Sciences & Services".
== References ==
== External links ==
Main Site | Wikipedia/Journal_of_Clinical_Epidemiology |
The Caerphilly Heart Disease Study, also known as the Caerphilly Prospective Study (CaPS), is an epidemiological prospective cohort, set up in 1979 in a representative population sample drawn from Caerphilly, a typical small town in South Wales, UK.
The initial aim was to examine relationships between a wide range of social, lifestyle, dietary and other factors with incident vascular disease. Opportunity was also taken, in collaboration with a range of clinical and laboratory colleagues, to collect data on a wide range of factors with possible relevance to diseases other than vascular, and at the same time to collect clinical information on incident disease events.
The study was initiated by Professor Peter Elwood, Director of the Medical Research Council (MRC) Epidemiology Unit for South Wales. The work has so far led to over 400 publications in the medical press.
== History ==
In 1948, an MRC epidemiological unit was set up in Cardiff, South Wales, under Professor Archie Cochrane. Peter Elwood joined Cochrane in 1963 and together they promoted long-term studies of representative population samples. They also conducted randomised controlled trials to test a variety of clinical hypotheses. Undoubtedly, the most important of their joint studies was a randomised controlled trial of aspirin showing a reduction of vascular mortality.
Reported in the British Medical Journal in 1974, this was the first study to demonstrate a protective role for aspirin in the reduction of death and reinfarction. The British Medical Journal recognised this article as one of the 50 most frequently cited papers published between 1945 and 1989.
Following this trial, Elwood and his research team set up the Caerphilly Heart Disease Study, with their primary focus on vascular disease, and the identification of predictors for platelet activity and thrombosis. Caerphilly was chosen for the work because the population was fairly stable, it had age and social class structures similar to that of the whole UK population, and there was a high incidence of ischaemic heart disease compared with the rest of the UK.
== Study design ==
In 1979, all men aged between 45 and 59 years, who were on the electoral registers and/or general practice lists for Caerphilly and the adjoining villages of Abertridwr, Senghenydd, Trethomas, Bedwas and Machen were invited to co-operate in a long-term health study. 2,512 subjects (89% of the total eligible population) agreed to participate and were examined in Phase 1 (baseline) between July 1979 and September 1983.
Since then, the men have been re-examined seven times (at five-year intervals) with approximately 95% of the surviving men co-operating in each re-examination. Many questions and tests have been repeated, but the opportunity has also been taken to include new questionnaires and tests. In the early phases of the study, samples of fasting blood were collected for extensive testing and long-term storage, and on occasions urine and other biological samples were also taken, and aliquots stored. Thus, while the initial aims of the study focused upon vascular disease, the wealth of data collected has enabled the testing of a large number of hypotheses relevant to other diseases too.
From the start of the study, the term 'Collaborative' was usually added to the title, paying tribute to the many physicians, laboratory technicians and other colleagues, expert in a wide range of clinical and metabolic disciplines, who were actively involved in the work.
Heart disease prevalence is far greater in men than women – therefore women were not included in the study. A far larger sample size would have been required if women had been the focus of the study, and unfortunately, the available resources were not sufficient for this.
The work in Caerphilly was often linked with the Speedwell Study, a similar study operating in nearby Bristol, 60 km away. The survey techniques were similar and a number of questionnaires and biological tests were used in both the studies. This enabled a number of joint reports on vascular disease, and in particular on the relevance of blood lipids, to be based on the five thousand subjects within the two cohorts together.
== Funding ==
Initially, the study was funded by the Medical Research Council and led by Peter Elwood. Following Elwood's retirement in 1995 the study continued under the leadership of Dr John Gallacher (Cardiff University) and Professor Yoav Ben-Shlomo (Bristol University), together with Dr John Yarnell (Queen's University) and Professor Tony Bayer (Cardiff University). Financial support was obtained from the British Heart Foundation and the Alzheimer's Society.
== Aims ==
The Caerphilly Study's research strategy was to identify factors showing an association with vascular disease (and other diseases), and then to test these associations in randomised controlled trials and statistical analysis.
The Framingham Heart Study, a much earlier cohort study in the US, had already shown that cholesterol is an important predictive factor for heart disease, and studies of US Veterans had shown that raised blood pressure is a major factor in stroke. The Caerphilly Study re-tested these predictors together with lipid fractions and high-density lipoproteins (total HDL, HDL2 and HDL3). More recently, arterial resistance and its contribution to blood pressure has also been studied within the cohort.
The randomised controlled trial of aspirin had shown that blood platelets play a key role in vascular disease. The Caerphilly Study focused on this by developing a large data-bank of platelet testing during the early phases of the study. Platelet collection and analysis was undertaken in close collaboration with Dr John O'Brien, Consultant Haematologist in St Mary's Hospital, Portsmouth, Professor Serge Renaud, a Director of Research in the French National Institute of Health and Medical Research in Lyon, and Professor Rod Flower FRS, then at the University of Bath. The work was done in a specially equipped mobile platelet laboratory, lent to the Caerphilly team by Serge Renaud, and towed by him from INSERM in Lyon, France, to the Miners' Hospital.
Detailed work was also completed on thrombosis and haemostatic factors with the active involvement of John O'Brien and in collaboration with Professor Gordon Lowe, in the Institute of Cardiovascular and Medical Sciences.
At baseline, a 1:3 sample (668 men) completed a 7-day weighed dietary intake record. Data on the dietary intake of each subject in the cohort was collected during each phase of the study.
Ten years into the study a detailed package of cognitive function tests were performed by each subject. These tests have been repeated several times and later enabled the evaluation of factors with possible relevance to cognitive decline and dementia.
== Major findings ==
=== Healthy lifestyles ===
The Caerphilly Study gave opportunity to study the relationship between lifestyle choices and health in a representative population sample drawn from a typical small town in the UK.
The participants were asked detailed questions at baseline and at subsequent examinations about lifestyle behaviours, enabling the men to be classified in terms of five healthy behaviours:
Non-smoking
A low body weight (BMI 18–25)
Regular exercise (30 minutes walking or equivalent, five days per week)
A low fat diet, combined with daily intake of five portions of fruit and vegetables.
An intake of alcohol within accepted guidelines (21 or less units of alcohol per week).
These healthy behaviours displayed significant negative associations with cognitive impairment and dementia, with participant disease outcomes falling as the number of healthy behaviours followed increased. Men who followed four or five of the healthy behaviours during 30 years of follow-up experienced on average a 73% reduction in diabetes, a 67% reduction in vascular disease, a 35% reduction in cancer (attributable to non-smoking alone) and a 64% reduction in cognitive impairment and dementia.
Healthy behaviours are the responsibility of each individual, and <1% of the men in the Caerphilly Study followed all five, with only 5% following four consistently. Comparisons with data collected in the 2009 Welsh Health Survey indicate that while the pattern of behaviours has changed, the proportions of subjects following four or five of the healthy behaviours has scarcely altered over the past 30 years.
The Caerphilly Study estimated the likely effect of increased healthy living within the community by supposing that each man in the Caerphilly cohort had each been urged at the start of the study in 1979 to adopt just one additional healthy behaviour. If only half of them had complied, then over the following 30 years 12% fewer would have developed diabetes; 6% fewer would have had a vascular disease event; 13% fewer would have developed dementia; and there would have been 5% fewer deaths. A video summarising this work is available on YouTube.
=== Cognitive function ===
Participants were asked to obtain from a close female relative the details of their own birth weight and how they had been fed as infants. Over half of the men obtained these details, and results showed that having been breast fed conferred some protection against the loss of cognitive function later in life, particularly in those whose birth weight had been low.
Smoking, alcohol intake and leisure activities are lifestyle factors which were found to be predictive of cognitive function. Significant associations were also between cognitive function and blood rheology and negative associations with both haematocrit and plasma viscosity, but not with the thrombotic potential of blood, as indicated by fibrinogen level. These relationships appear to be direct, and not through underlying long-term disease processes. Sleep pattern, and in particular severe daytime sleepiness, was also predictive of vascular dementia.
In diabetic subjects, it was found that poor control of blood sugar was associated with a lower cognitive function, and diabetes per se, but none of the components of metabolic syndrome, other than high blood pressure, were predictive of worse cognition. Hearing loss was also found to be predictive of later cognitive impairment and incident dementia.
=== Platelets and thrombosis ===
The main objective of the work on platelets was to identify an aspect of platelet morphology or activity with predictive power for incident vascular disease, which could be developed as a screening test to identify subjects at high risk of a vascular event. In addition to number and size of the platelets, three tests of platelet aggregation were performed, several being repeated after five years. A stressed template bleeding time test was also performed on each man.
No prediction for heart disease was shown by any aspect of platelet morphology nor any platelet test, nor by the bleeding time test. An unexpected finding was that the men who had had the most active platelets in two tests, based on platelet rich plasma and whole blood, had the lowest subsequent risk of an incident ischaemic stroke.
=== Diet and dietary items ===
Detailed analyses of the dietary data identified a number of food items related to vascular disease risk. The consumption of fatty fish was associated with lower levels of blood lipids, and a reduction in vascular disease mortality was confirmed in a randomised trial.
Milk consumption was found to be associated with a small reduction in the metabolic syndrome, and reductions in ischaemic heart disease, ischaemic stroke and diabetes, and these findings were confirmed in later overviews and meta-analyses. A reduction in blood pressure associated with milk consumption is well recognised, but new work in Caerphilly also identified a reduction in arterial stiffness associated with milk consumption.
The consumption of fruit and vegetables was shown to be positively associated with blood antioxidant levels. Detailed work with Serge Renaud on platelet activity showed a beneficial relationship between a low alcohol consumption and platelet aggregation, but an enhanced response to thrombin with binge drinking, confirming previous work in animals.
=== Sleep ===
A detailed questionnaire of sleep pattern was included in one of the re-examinations of the men. In addition to the association with cognitive function already mentioned, there was evidence of an increase in ischaemic stroke in men whose sleep is frequently disturbed, and an association between daytime sleepiness and a significant increase in ischaemic heart disease.
=== Other studies ===
Many analyses of foods and dietary factors were conducted, as well as an examination of Helicobacter pylori and other infections, and vascular disease risk. A reduction in vascular disease mortality was found in those subjects most sexually active. Relationships between vascular disease and psychiatric symptoms, noise exposure, and hearing loss were also identified.
== References == | Wikipedia/Caerphilly_Heart_Disease_Study |
Disease diffusion occurs when a disease is transmitted to a new location. It implies that a disease spreads, or pours out, from a central source. The idea of showing the spread of disease using a diffusion pattern is relatively modern, compared to earlier methods of mapping disease, which are still used today. According to Rytokonen, the goals of disease mapping are: 1) to describe the spatial variation in disease incidence to formulate an etiological hypothesis; 2) to identify areas of high risk in order to increase prevention; and 3) to provide a map of disease risk for a region for better risk preparedness.
Torsten Hägerstrand’s early work on “waves of innovation” is the basis that many medical cartographers and geographers use for mapping spatial diffusion (1968). The diffusion of disease can be described in four patterns: expansion diffusion, contagious diffusion, hierarchal diffusion and relocation diffusion. Cromley and McLafferty also mention network diffusion and mixed diffusion.
The diffusion of infectious disease tends to occur in a ‘wave’ fashion, spreading from a central source. Pyle mentions barriers that pose a resistance towards a wave of diffusion, which include but are not limited to: physiographic features (i.e. mountains, water bodies), political boundaries, linguistic barriers, and with diseases, a barrier could be differing control programs. The diffusion of disease can be identified as a normal distribution over time and translated into an S-shaped curve to show the phases of disease diffusion. The phases are: Infusion (25th percentile), Inflection (50th percentile), Saturation (75th percentile), and Waning to the upper limits.
== Disease diffusion types ==
Expansion diffusion occurs when the spreading phenomenon has a source and diffuses outwards into new areas, an example being a spreading wildfire.
Relocation diffusion occurs when the spreading phenomenon migrates into new areas, leaving behind its origin or source of the disease.
Contagious diffusion is the spread of an infectious disease through the direct contact of individuals with those infected.
Hierarchal diffusion occurs when a phenomenon spreads through an ordered sequence of classes or places.
Network diffusion occurs when a disease spreads via transportation and social networks, "reflecting the geographical and social structuring of human interactions".
Mixed diffusion is a combination of contagious diffusion and hierarchal diffusion. AIDS is a prominent example in modern-day society of a mixed diffusion disease, often spreading along the hierarchal, network, and contagious diffusion patterns.
The value of mapping and Geographic Information Systems (GIS) is becoming better known to public health professionals to help link disease control to prevention efforts, which can aid in developing better immunization programs. GIS is an excellent tool used to identify spatial patterns and core areas of disease transmission. Disease maps can distinguish the low and high risk areas, as well as highlight “physical and/or socio-cultural” factors that contribute to the causation of disease. Understanding how a disease spreads gives health officials a better understanding of how to better serve the public.
== References ==
4. Rytkönen, Mika JP. “Not All Maps are Equal: GIS and Spatial Analysis in Epidemiology.” International Journal of Circumpolar Health 63:1, 2004: pp. 11 Available: http://www.circumpolarhealthjournal.net/index.php/ijch/article/viewFile/17642/20108
== Further reading ==
Geographic Information Systems (GIS) at CDC, Centers for Disease Control and Prevention, US.
GIS in Public Health, Agency for Toxic Substances and Disease Registry (ATSDR), US.
Clarke, Keith C; Sara L. McLafferty; Barbara J. Tempalski (April–June 1996). "On Epidemiology and Geographic Information Systems: A Review and Discussion of Future Directions". Emerging Infectious Diseases. 2 (2): 85–92. doi:10.3201/eid0202.960202. PMC 2639830. PMID 8903207. Retrieved 2007-12-25.
Infectious diseases: How they spread, how to stop them, CNN.
Cashio, Cathy. Mapping infectious disease outbreaks, University of North Texas Resources Magazine 2004. | Wikipedia/Disease_diffusion_mapping |
Targeted immunization strategies are approaches designed to increase the immunization level of populations and decrease the chances of epidemic outbreaks. Though often in regards to use in healthcare practices and the administration of vaccines to prevent biological epidemic outbreaks, these strategies refer in general to immunization schemes in complex networks, biological, social or artificial in nature. Identification of at-risk groups and individuals with higher odds of spreading the disease often plays an important role in these strategies, since targeted immunization in high-risk groups is necessary for effective eradication efforts and has a higher return on investment than immunizing larger but lower-risk groups.
== Background ==
The success of vaccines in preventing major outbreaks relies on the mechanism of herd immunity, also known as community immunity, where the immunization of individuals provides protection for not only the individuals, but also the community at large. In cases of biological contagions such as influenza, measles, and chicken pox, immunizing a critical community size can provide protection against the disease for members who cannot be vaccinated themselves (infants, pregnant women, and immunocompromised individuals). Often however these vaccine programmes require the immunization of a large majority of the population to provide herd immunity. A few successful vaccine programmes have led to the eradication of infectious diseases like small pox and rinderpest, and the near eradication of polio, which plagued the world before the second half of the 20th century.
== Network-based strategies ==
More recently researchers have looked at exploiting network connectivity properties to better understand and design immunization strategies to prevent major epidemic outbreaks. Many real networks like the Internet, World Wide Web, and even sexual contact networks have been shown to be scale-free networks and as such exhibit a power-law distribution for the degree distribution. In large networks this results in the vast majority of nodes (individuals in social networks) having few connections or low degree k, while a few "hubs" have many more connections than the average <k>. This wide variability (heterogeneity) in degree offers immunization strategies based on targeting members of the network according to their connectivity rather than random immunization of the network. In epidemic modeling on scale-free networks, targeted immunization schemes can considerably lower the vulnerability of a network to epidemic outbreaks over random immunization schemes. Typically these strategies result in the need for far fewer nodes to be immunized in order to provide the same level of protection to the entire network as in random immunization. In circumstances where vaccines are scarce, efficient immunization strategies become necessary to preventing infectious outbreaks.
Examples
A common approach for targeted immunization studies in scale-free networks focuses on targeting the highest degree nodes for immunization. These nodes are the most highly connected in the network, making them more likely to spread the contagion if infected. Immunizing this segment of the network can drastically reduce the impact of the disease on the network and requires the immunization of far fewer nodes compared to randomly selecting nodes. However, this strategy relies on knowing the global structure of the network, which may not always be practical.
A recent centrality measure, Percolation Centrality, introduced by Piraveenan et al. is particularly useful in identifying nodes for vaccination based on the network topology. Unlike node degree which depends on topology alone, however, percolation centrality takes into account the topological importance of a node as well as its distance from infected nodes in deciding its overall importance. Piraveenan et al. has shown that percolation centrality-based vaccination is particularly effective when the proportion of people already infected is on the same order of magnitude as the number of people who could be vaccinated before the disease spreads much further. If infection spread is at its infancy, then ring-vaccination surrounding the source of infection is most effective, whereas if the proportion of people already infected is much higher than the number of people that could be vaccinated quickly, then vaccination will only help those who are vaccinated and herd immunity cannot be achieved. Percolation centrality-based vaccination is most effective in the critical scenario where the infection has already spread too far to be completely surrounded by ring-vaccination, yet not spread wide enough so that it cannot be contained by strategic vaccination. Nevertheless, Percolation Centrality also needs full network topology to be computed, and thus is more useful in higher levels of abstraction (for example, networks of townships rather than social networks of individuals), where the corresponding network topology can more readily be obtained.
== Increasing immunization coverage ==
Millions of children worldwide do not receive all of the routine vaccinations as per their national schedule. As immunization is a powerful public health strategy for improving child survival, it is important to determine what strategies work best to increase coverage. A Cochrane review assessed the effectiveness of intervention strategies to boost and sustain high childhood immunization coverage in low- and middle-income countries. Forty-one trials were included but most of the evidence was of low quality. Providing parents and other community members with information on immunization, health education at facilities in combination with redesigned immunization reminder cards, regular immunization outreach with and without household incentives, home visits, and integration of immunization with other services may improve childhood immunization coverage in low-and middle-income countries.
== See also ==
Influenza vaccine
Immunization
Vaccine-preventable diseases
Smallpox eradication
Poliomyelitis eradication
Infectious diseases
ILOVEYOU (computer worm epidemic in 2000)
Epidemiology
Epidemic model
Network Science
Critical community size
Scale-free network
Complex network
Percolation theory
Pandemic
== References == | Wikipedia/Targeted_immunization_strategies |
Public health surveillance (also epidemiological surveillance, clinical surveillance or syndromic surveillance) is, according to the World Health Organization (WHO), "the continuous, systematic collection, analysis and interpretation of health-related data needed for the planning, implementation, and evaluation of public health practice." Public health surveillance may be used to track emerging health-related issues at an early stage and find active solutions in a timely manner. Surveillance systems are generally called upon to provide information regarding when and where health problems are occurring and who is affected.
Public health surveillance systems can be passive or active. A passive surveillance system consists of the regular, ongoing reporting of diseases and conditions by all health facilities in a given territory. An active surveillance system is one where health facilities are visited and health care providers and medical records are reviewed in order to identify a specific disease or condition. Passive surveillance systems are less time-consuming and less expensive to run but risk under-reporting of some diseases. Active surveillance systems are most appropriate for epidemics or where a disease has been targeted for elimination.
Techniques of public health surveillance have been used in particular to study infectious diseases. Many large institutions, such as the WHO and the Centers for Disease Control and Prevention (CDC), have created databases and modern computer systems (public health informatics) that can track and monitor emerging outbreaks of illnesses such as influenza, SARS, HIV, and even bioterrorism, such as the 2001 anthrax attacks in the United States.
Many regions and countries have their own cancer registry, which is monitors the incidence of cancers to determine the prevalence and possible causes of these illnesses.
Other illnesses such as one-time events like stroke and chronic conditions such as diabetes, as well as social problems such as domestic violence, are increasingly being integrated into epidemiologic databases called disease registries. A cost-benefit analysis is conducted on these registries to determine governmental funding for research and prevention.
Systems that can automate the process of identifying adverse drug events, are currently being used, and are being compared to traditional written reports of such events. These systems intersect with the field of medical informatics, and are rapidly becoming adopted by hospitals and endorsed by institutions that oversee healthcare providers (such as JCAHO in the United States). Issues in regard to healthcare improvement are evolving around the surveillance of medication errors within institutions.
== Syndromic surveillance ==
Syndromic surveillance is the analysis of medical data to detect or anticipate disease outbreaks. According to a CDC definition, "the term 'syndromic surveillance' applies to surveillance using health-related data that precede diagnosis and signal a sufficient probability of a case or an outbreak to warrant further public health response. Though historically syndromic surveillance has been utilized to target investigation of potential cases, its utility for detecting outbreaks associated with bioterrorism is increasingly being explored by public health officials."
The first indications of disease outbreak or bioterrorist attack may not be the definitive diagnosis of a physician or a lab.
Using a normal influenza outbreak as an example, once the outbreak begins to affect the population, some people may call in sick for work/school, others may visit their drug store and purchase medicine over the counter, others will visit their doctor's office and other's may have symptoms severe enough that they call the emergency telephone number or go to an emergency department.
Syndromic surveillance systems monitor data from school absenteeism logs, emergency call systems, hospitals' over-the-counter drug sale records, Internet searches, and other data sources to detect unusual patterns. When a spike in activity is seen in any of the monitored systems disease epidemiologists and public health professionals are alerted that there may be an issue.
An early awareness and response to a bioterrorist attack could save many lives and potentially stop or slow the spread of the outbreak. The most effective syndromic surveillance systems automatically monitor these systems in real-time, do not require individuals to enter separate information (secondary data entry), include advanced analytical tools, aggregate data from multiple systems, across geo-political boundaries and include an automated alerting process.
A syndromic surveillance system based on search queries was first proposed by Gunther Eysenbach, who began work on such a system in 2004.
Inspired by these early, encouraging experiences, Google launched Google Flu Trends in 2008. More flu-related searches are taken to indicate higher flu activity. The results, which were published in Nature, closely matched CDC data, and led it by 1–2 weeks. However, it has been shown that the original approach behind Google Flu Trends had various modelling deficiencies leading to significant errors in its estimates. More recently, a series of more advanced linear and nonlinear approaches to influenza modeling from Google search queries have been proposed. Extending Google's work researchers from the Intelligent Systems Laboratory (University of Bristol, UK) created Flu Detector; an online tool which based on Information Retrieval and Statistical Analysis methods uses the content of Twitter to nowcast flu rates in the UK.
=== Digital methods ===
Digital surveillance of public health largely relies on a number of methods. The most important ones being the use of search-based trends on sites like Google and Wikipedia, social media posts on platforms like Facebook and Twitter, and participatory surveillance websites such as Flu Near You and Influenzanet. However the range of potential data sources suitable for disease surveillance has increased as different areas have become digitized; today school attendance records, hospital emergency admissions data and even sales data, can be used for syndromic surveillance purposes. Search trends provide indirect data on public health, while the latter two methods provide direct data.
==== Search aggregates ====
Search aggregates have been most frequently used to track and model influenza. A popular example is Google Flu Trends, which was first released in 2008. Wikipedia has also been used, though it is potentially prone to "noise", as it is a popular source of health information whether a user is ill or not. During the COVID-19 pandemic a new methodology has been developed to model COVID-19 prevalence based on web search activity. This methodology has also been used by Public Health England in the United Kingdom as one of their syndromic surveillance endpoints.
==== Social media ====
Examples of social media public health surveillance include HealthTweets, which gathers data from Twitter. Twitter data is considered highly useful for public health research, as its data policies allow public access to 1% samples of raw tweets. Tweets can also be geolocated, which can be used to model the spread of contagious disease. It is the most used social media platform for public health surveillance. During the COVID-19 pandemic, Facebook used aggregated, anonymized data collected from its platforms to provide human movement information to disease models. It also offered users a chance to participate in a disease symptom survey through Carnegie Mellon University.
==== Surveillance sites ====
Flu Near You and Influenzanet are two examples of crowd-sourced digital surveillance systems. Both sites recruit users to participate in surveys about influenza symptoms. Influenzanet was established in 2009, and operates in ten countries in Europe. Its predecessor was Grote Griepmeting, which was a Dutch/Belgian platform launched in 2003 and 2004. Flu Near You is used in the US. Another example of a surveillance sites is Dengue na Web, used to survey for dengue fever in Bahia, Brazil.
== Laboratory-based surveillance ==
Some conditions, especially chronic diseases such as diabetes mellitus, are supposed to be routinely managed with frequent laboratory measurements. Since many laboratory results, at least in Europe and the US, are automatically processed by computerized laboratory information systems, the results are relatively easy to inexpensively collate in special purpose databases or disease registries. Unlike most syndromic surveillance systems, in which each record is assumed to be independent of the others, laboratory data in chronic conditions can be theoretically linked together at the individual patient level. If patient identifiers can be matched, a chronological record of each patient's laboratory results can be analyzed as well as aggregated to the population level.
Laboratory registries allow for the analysis of the incidence and prevalence of the target condition as well as trends in the level of control. For instance, an NIH-funded program called the Vermedx Diabetes Information System maintained a registry of laboratory values of diabetic adults in Vermont and northern New York State in the US with several years of laboratory results on thousands of patients. The data included measures of blood sugar control (glycated hemoglobin A1c), cholesterol, and kidney function (serum creatinine and urine protein), and were used to monitor the quality of care at the patient, practice, and population levels. Since the data contained each patient's name and address, the system was also used to communicate directly with patients when the laboratory data indicated the need for attention. Out of control test results generated a letter to the patient suggesting they take action with their medical provider. Tests that were overdue generated reminders to have testing performed. The system also generated reminders and alerts with guideline-based advice for the practice as well as a periodic roster of each provider's patients and a report card summarizing the health status of the population. Clinical and economic evaluations of the system, including a large randomized clinical trial, demonstrated improvements in adherence to practice guidelines and reductions in the need for emergency department and hospital services as well as total costs per patient. The system has been commercialized and distributed to physicians, insurers, employers and others responsible for the care of chronically ill patients. It is now being expanded to other conditions such as chronic kidney disease.
A similar system, The New York City A1C Registry, is in used to monitor the estimated 600,000 diabetic patients in New York City, although unlike the Vermont Diabetes Information System, there are no provisions for patients to have their data excluded from the NYC database. The NYC Department of Health and Mental Hygiene has linked additional patient services to the registry such as health information and improved access to health care services. As of early 2012, the registry contains over 10 million test results on 3.6 million individuals. Although intended to improve health outcomes and reduce the incidence of the complications of diabetes, a formal evaluation has not yet been done.
In May 2008, the City Council of San Antonio, Texas approved the deployment of an A1C registry for Bexar County. Authorized by the Texas legislature and the state Health Department, the San Antonio Metropolitan Health District implemented the registry which drew results from all the major clinical laboratories in San Antonio. The program was discontinued in 2010 due to lack of funds.
Laboratory surveillance differs from population-wide surveillance because it can only monitor patients who are already receiving medical treatment and therefore having lab tests done. For this reason, it does not identify patients who have never been tested. Therefore, it is more suitable for quality management and care improvement than for epidemiological monitoring of an entire population or catchment area.
== See also ==
Contact tracing
Gamification#Health
Public health informatics
== References == | Wikipedia/Clinical_surveillance |
Sodium citrate may refer to any of the sodium salts of citric acid (though most commonly the third):
Monosodium citrate
Disodium citrate
Trisodium citrate
The three forms of salt are collectively known by the E number E331.
== Applications ==
=== Food ===
Sodium citrates are used as acidity regulators in food and drinks, and also as emulsifiers for oils. They enable cheeses to melt without becoming greasy and also reduce the acidity of food. They are generally considered safe and are designated GRAS by the FDA.
=== Blood clotting inhibitor ===
Sodium citrate is used to prevent donated blood from clotting in storage, and can also be used as an additive for apheresis to prevent clots forming in the tubes of the machine. By binding with calcium ions in the blood it prevents the process of coagulation. It is also used as an anticoagulant for laboratory testing, in that blood samples are collected into sodium citrate-containing tubes for tests such as the PT (INR), APTT, and fibrinogen levels. Sodium citrate is used in medical contexts as an alkalinizing agent in place of sodium bicarbonate, to neutralize excess acid in the blood and urine.
=== Metabolic acidosis ===
It has applications for the treatment of metabolic acidosis and chronic kidney disease.
=== Ferrous nanoparticles ===
Along with oleic acid, sodium citrate may be used in the synthesis of magnetic Fe3O4 nanoparticle coatings.
== References == | Wikipedia/Sodium_citrate |
DTaP-IPV vaccine is a combination vaccine whose full generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine (IPV).
It is also known as DTaP/IPV, dTaP/IPV, DTPa-IPV, or DPT-IPV. It protects against the infectious diseases diphtheria, tetanus, pertussis, and poliomyelitis.
Branded formulations marketed in the USA are Kinrix from GlaxoSmithKline and Quadracel from Sanofi Pasteur.
Repevax is available in the UK.
In Japan, the formulation is called 四種混合(shishukongou - "mixture of 4").
Astellas markets it under the クアトロバック ('Quattro-back') formulation, while another is available from Mitsubishi Tanabe Pharma named テトラビック ('Tetrabic').
A previous product by Takeda Pharmaceutical Company has been withdrawn by the company.
== References == | Wikipedia/DTaP-IPV_vaccine |
The Oxford Vaccine Group (OVG) is a vaccine research group within the Department of Paediatrics at the University of Oxford. It was founded in 1994 by Professor E. Richard Moxon, was initially based at the John Radcliffe Hospital, and moved in 2003 to its current location in the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM) at the Churchill Hospital in Oxford, England. The group, led by Professor Andrew Pollard since 2001, comprises around 75 members across a number of disciplines, including consultants in paediatrics and vaccinology, clinical research fellows, research nurses, statisticians, post-doctoral laboratory scientists, research assistants and DPhil students.
OVG came to public prominence in 2020 for the vaccine it created to combat COVID-19.
== Aims and background ==
OVG carries out research on vaccines to improve human health. It works to enhance the understanding of immunity, studies the epidemiology of infectious diseases, and conducts clinical trials into new and improved vaccines for children and adults.
Research by Richard Moxon into the public health impact of Haemophilus influenzae type b (Hib) invasive disease in the UK, and efficacy studies of the Hib conjugate vaccine in UK children, led to the founding of OVG in 1994. Since then OVG has particularly specialised in research into meningococcal disease and vaccines to prevent the disease. OVG has been involved with the development of the new vaccine against MenB which was licensed in Europe in 2013. The Group has also carried out research on pneumococcal vaccines, typhoid vaccines and, more recently, new vaccines against Ebola.
OVG is a research group within the Department of Paediatrics at the University of Oxford. It is a UK Clinical Research Collaboration (UKCRC) registered clinical trials unit working in collaboration with the Primary Care Unit Clinical Trials Unit (Nuffield Department of Primary Care Health Sciences) and the Jenner Institute at the University of Oxford. It is also a participant in the UK Paediatric Vaccine Group (UKPVG) and contributes to the Oxford University Hospitals NHS Trust’s tertiary Paediatric Infectious Disease and Immunology Service. All OVG trials are listed on the UK Clinical Trials Gateway. OVG supports the All Trials Campaign.
Professor Andrew Pollard, OVG’s Director, was appointed Chair of the Joint Committee on Vaccination and Immunisation (JCVI) in March 2014. Senior staff at OVG are periodically asked to give expert opinions on aspects of vaccines and infectious disease, especially meningococcal disease. For example the 2015 announcement that 14- to 18-year-olds in the UK are to be vaccinated against MenW disease, and the 2012 European Medicines Agency (EMA) recommendation for approval of a new meningitis B vaccine.
== Research activity ==
Since 2001, OVG has enrolled over 12,500 adults and children into clinical trials in the Thames Valley area of England. OVG research has included:
2003: a study looking at the mid- to long-term effectiveness of the Meningitis C vaccine. This research showed that immunity waned over time, and formed part of the evidence leading to the changes in the UK MenC vaccine schedule in 2013.
2005 onwards: collaborative projects with the paediatric department of Patan Hospital in Nepal, studying children admitted to the hospital with febrile illnesses and cases of typhoid, Haemophilus influenzae type b (Hib disease) and pneumonia, and evaluating carriage of Hib disease and Streptococcus pneumoniae.
2006: a study looking at the effectiveness of a new vaccine against the bird flu virus H5N1 in children and adults.
2006: a phase II trial of a new vaccine against MenB disease. This was the first time the vaccine had been used in babies. The trial results were successful and led to phase III trials and ultimately the licensing of the new vaccine, Bexsero, in 2013.
2009: a study comparing the effectiveness of two new vaccines against the swine flu virus H1N1 in children and adults.
2010: a study of a new quadrivalent meningococcal (MenACWY) vaccine.
2011 onwards: Ongoing participation in an EU Childhood Life-threatening Infectious Disease Study (EUCLIDS) work package looking at genetic responses to MenC and MenB vaccines.
2011 onwards: a series of challenge studies to test new vaccines against typhoid and paratyphoid fever.
2014-15: a phase 1 study into a new vaccine against Ebola. In January 2015 this trial was commended in the House of Commons by Nicola Blackwood MP and Prime Minister David Cameron.
2020 onwards: a vaccine against COVID-19, the Oxford–AstraZeneca COVID-19 vaccine, has been created and approved, and as of 2021 is in worldwide use along several other vaccines such as the Pfizer–BioNTech COVID-19 vaccine.
== Funding ==
The OVG is funded not only by its alma mater and UK government bodies such as the Medical Research Council (MRC), National Institute for Health and Care Research (NIHR) and UK Research and Innovation (UKRI), and Public Health England (PHE), but also private UK charities like the Wellcome Trust, Meningitis Research Foundation, Meningitis UK and Action Medical Research.
The group has earned attention from international funders like the Bill & Melinda Gates Foundation (BMGF), the Global Alliance for Vaccines and Immunization (GAVI), and the World Health Organization (WHO) as well as undisclosed vaccine manufacturers.
The probable commercial success of the ChAdOx1-based AZD1222 product led the BMGF to prod the OVG into a deal with AstraZeneca under which the financial reward would be split between partners, instead of "donat(ing) the rights to its promising coronavirus vaccine to any drugmaker" in a misguided effort "to provide medicines preventing or treating COVID-19 at a low cost or free of charge." Under the extant deal, the OVG (or the trustees of Oxford University) will have another revenue stream with which to finance its activities.
== Vaccine Knowledge Project ==
In 2011, the group launched the Vaccine Knowledge Project, funded by the Oxford Biomedical Research Centre. The project website aims to provide independent, evidence-based information about vaccines and infectious diseases. The NHS Choices website lists the Vaccine Knowledge website as a recommended external link on several of its pages. The website has also been referenced in the national media in the UK, particularly during the 2014-15 US measles outbreak originating in Disneyland California. The project is a member of the Vaccine Safety Net.
== Awards ==
In November 2021 the team were awarded a Pride of Britain Award for their work on the COVID-19 vaccine.
== References ==
== External links ==
Oxford Vaccine Group website
Vaccine Knowledge website
University of Oxford Department of Paediatrics website | Wikipedia/Oxford_Vaccine_Group |
The Pfizer–BioNTech COVID-19 vaccine, sold under the brand name Comirnaty, is an mRNA-based COVID-19 vaccine developed by the German biotechnology company BioNTech. For its development, BioNTech collaborated with the American company Pfizer to carry out clinical trials, logistics, and manufacturing. It is authorized for use in humans to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus. The vaccine is given by intramuscular injection. It is composed of nucleoside-modified mRNA (modRNA) that encodes a mutated form of the full-length spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. Initial guidance recommended a two-dose regimen, given 21 days apart; this interval was subsequently extended to up to 42 days in the United States, and up to four months in Canada.
Clinical trials began in April 2020; by November 2020, the vaccine had met the primary efficacy goals of the phase III clinical trial, with over 40,000 people participating. Interim analysis of study data showed a potential efficacy of 91.3% in preventing symptomatic infection within seven days of a second dose and no serious safety concerns. Most side effects are mild to moderate in severity and resolve within a few days. Common side effects include mild to moderate pain at the injection site, fatigue, and headaches. Reports of serious side effects, such as allergic reactions, remain very rare with no long-term complications documented.
The vaccine is the first COVID‑19 vaccine to be authorized by a stringent regulatory authority for emergency use and the first to be approved for regular use. In December 2020, the United Kingdom was the first country to authorize its use on an emergency basis. It is authorized for use at some level in the majority of countries. On 23 August 2021, the Pfizer–BioNTech vaccine became the first COVID-19 vaccine to be approved in the US by the Food and Drug Administration (FDA). The logistics of distributing and storing the vaccine present significant challenges due to the requirement for its storage at extremely low temperatures.
In August 2022, a bivalent version of the vaccine (Pfizer-BioNTech COVID-19 Vaccine, Bivalent) was authorized for use as a booster dose in individuals aged twelve and older in the US. The following month, the BA.1 version of the bivalent vaccine (Comirnaty Original/Omicron BA.1 or tozinameran/riltozinameran) was authorized as a booster for use in the UK. The same month, the European Union authorized both the BA.1 and the BA.4/BA.5 (tozinameran/famtozinameran) booster versions of the bivalent vaccine. In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula) was issued to Pfizer Inc.
== Medical uses ==
The Pfizer–BioNTech COVID-19 vaccine is used to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus, by eliciting an immune response to the S antigen. The vaccine is used to reduce morbidity and mortality from COVID-19.
The vaccine is supplied in a multidose vial as "a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection". It must be thawed to room temperature and diluted with normal saline before administration.
The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of three to four weeks between doses. Delaying the second dose by up to twelve weeks increases immunogenicity, even in older adults, against all variants of concern. Authors of the Pitch study think that the optimal interval against the Delta variant is around eight weeks, with longer intervals leaving receptors vulnerable between doses.
A third, fourth, or fifth dose can be added in some countries.
=== Effectiveness ===
A test-negative case-control study published in August 2021, found that two doses of the BNT162b2 (Pfizer) vaccine had 93.7% effectiveness against symptomatic disease caused by the alpha (B.1.1.7) variant and 88.0% effectiveness against symptomatic disease caused by the delta (B.1.617.2) variant. Notably, effectiveness after one dose of the Pfizer vaccine was 48.7% against alpha and 30.7% against delta, similar to effectiveness provided by one dose of the ChAdOx1 nCoV-19 vaccine.
In August 2021, the US Centers for Disease Control and Prevention (CDC) published a study reporting that the effectiveness against infection decreased from 91% (81–96%) to 66% (26–84%) when the Delta variant became predominant in the US, which may be due to unmeasured and residual confounding related to a decline in vaccine effectiveness over time.
Unless indicated otherwise, the following effectiveness ratings are indicative of clinical effectiveness two weeks after the second dose. A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.
In November 2021, Public Health England reported a possible but extremely small reduction in effectiveness against symptomatic disease from the Delta sublineage AY.4.2 at longer intervals after the second dose.
Preliminary data suggest that the effectiveness against the Omicron variant starts to decline in about 10 weeks, either after the initial two-dose regimen or after the booster dose. For other variants, the effectiveness of the initial doses starts to decline in about six months. A case-control study in Qatar from 1 January to 5 September 2021 found that effectiveness against infection peaked at 78% (95% CI, 76–79%) in the first month after the second dose, followed by a slow decline that accelerated after the fourth month, reaching 20% at months 5 to 7. A similar trajectory was observed against symptomatic disease and against specific variants. Effectiveness against severe disease, hospitalization and death was more robust, peaking at 96% (93–98%) in the second month and remaining almost stable through the sixth month, declining thereafter.
In October 2021, a phase III trial showed that a booster dose given approximately 11 months after the second dose restored the protective effect to the 96% (95% CI, 89–99%) efficacy level against symptomatic disease from the Delta variant.
In December 2021, Pfizer and BioNTech reported that preliminary data indicated that a third dose of the vaccine would provide a similar level of neutralizing antibodies against the Omicron variant as seen after two doses against other variants.
In December 2021, private health insurer Discovery Health, in collaboration with the South African Medical Research Council, reported that real-world data from more than 211,000 cases of COVID-19 in South Africa, of which 78,000 were of the Omicron variant, indicate that effectiveness against the variant after two doses is about 70% against hospital admission and 33% against symptomatic disease. Protection against hospital admission is maintained for all ages and groups with comorbidities.
A study of the bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022–January 2023, has shown that it reduced the risk of severe COVID-19 outcomes among the elderly. By contrast, among the chronically ill 18–64-year-olds the risk was similar among those who received bivalent vaccine and those who did not. Among the elderly a bivalent booster provided highest protection during the first two months after vaccination, but thereafter signs of waning were observed. The effectiveness among individuals aged 65–79 years and those aged 80 years or more was similar.
=== Specific populations ===
Based on the results of a preliminary study, the U.S. Centers for Disease Control and Prevention (CDC) recommends that pregnant women get vaccinated with the COVID‑19 vaccine.
A statement by the British Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) reported that the two agencies had reached a conclusion that the vaccine is safe and effective in children aged between 12 and 15 years.
In May 2021, experts commissioned by the Norwegian Medicines Agency concluded that the Pfizer-BioNTech vaccine is the likely cause of ten deaths of frail elderly patients in Norwegian nursing homes. They said that people with very short life expectancies have little to gain from vaccination, having a real risk of adverse reactions in the last days of life and of dying earlier.
A 2021 report by the New South Wales Government (NSW Health) in Australia found that the Pfizer-BioNTech vaccine is safe for those with various forms of immunodeficiency or immunosuppression, though it does note that the data on said groups is limited, due to their exclusion from many of the vaccine earlier trials held in 2020. It notes that the World Health Organization advises that the vaccine is among the three COVID-19 vaccines (alongside that of Moderna and AstraZeneca) it deems safe to give to immunocompromised individuals, and that expert consensus generally recommends their vaccination. The report states that the vaccines were able to generate an immune response in those individuals, though it does also note that this response is weaker than in those that are not immunocompromised. It recommends that specific patient groups, such as those with cancer, inflammatory bowel disease and various liver diseases be prioritised in the vaccination schedules over other patients that do not have said conditions.
In September 2021, Pfizer announced that a clinical trial conducted in more than 2,200 children aged 5–11 has generated a "robust" response and is safe.
== Adverse effects ==
In Phase III trials for the vaccine, there were no safety concerns and few adverse events.
Most side effects of the Pfizer–BioNTech COVID‑19 vaccine are mild to moderate in severity, and are gone within a few days. They are similar to other adult vaccines and are normal signs that the body is building protection to the virus. During clinical trials, the common side effects affecting more than one in 10 people are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, fever or diarrhea. Fever is more common after the second dose.
The European Medicines Agency (EMA) regularly reviews the data on the vaccine's safety. The safety report published on 8 September 2021 by the EMA was based on over 392 million doses administered in the European Union. According to the EMA "the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use of this vaccine." Rare side effects (that may affect up to one in 1,000 people) include temporary one sided facial drooping and allergic reactions, such as hives or swelling of the face.
=== Allergy ===
Documented hypersensitivity to polyethylene glycol (PEG) (a very rare allergy) is listed as a contraindication to the COVID-19 Pfizer vaccine. Severe allergic reaction has been observed in approximately eleven cases per million doses of vaccine administered. According to a report by the US Centers for Disease Control and Prevention, 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020 that people who have a history of "significant" allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine. On 12 December, the Canadian regulator followed suit, noting that: "Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered."
=== Myocarditis ===
In June 2021, the Israel's Ministry of Health announced a probable relationship between the second dose and myocarditis in a small group of 16–30-year-old men. Between December 2020 and May 2021, there were 55 cases of myocarditis per 1 million people vaccinated, 95% of which were classified as mild and most spent no more than four days in the hospital. Since April 2021, increasing number of cases of myocarditis and pericarditis have been reported in the United States in about 13 per 1 million young people, mostly male and over the age of 16, after vaccination with the Pfizer–BioNTech or the Moderna vaccine. Most affected individuals recover quickly with adequate treatment and rest. Since February 2022, the German Standing Committee on Vaccination recommends aspiration for COVID-19 vaccination as precautionary measure.
== Pharmacology ==
The BioNTech technology for the BNT162b2 vaccine is based on use of nucleoside-modified mRNA (modRNA) which encodes a mutated form of the full-length spike protein found on the surface of the SARS-CoV-2 virus, triggering an immune response against infection by the virus protein.
=== Sequence ===
The modRNA sequence of the vaccine is 4,284 nucleotides long. It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated "2P") that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies; a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284). The sequence contains no uridine residues; they are replaced by 1-methyl-3'-pseudouridylyl. The 2P proline substitutions in the spike proteins were originally developed for a Middle East respiratory syndrome (MERS) vaccine by researchers at the National Institute of Allergy and Infectious Diseases' Vaccine Research Center, Scripps Research, and Jason McLellan's team (at the University of Texas at Austin, previously at Dartmouth College).
== Chemistry ==
In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):
ALC-0315, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
ALC-0159, 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
cholesterol
dibasic sodium phosphate dihydrate
monobasic potassium phosphate
potassium chloride
sodium chloride
sucrose
water for injection
The first four of these are lipids. The lipids and modRNA together form nanoparticles that act not only as carriers to get the modRNA into the human cells, but also as adjuvants. ALC-0159 is a polyethylene glycol conjugate, i.e., a PEGylated lipid.
== Manufacturing ==
Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe. The license to distribute and manufacture the vaccine in China was purchased by Fosun, alongside its investment in BioNTech.
Manufacturing the vaccine requires a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. For all markets, this stage is conducted in the United States, at a small Pfizer pilot plant in Chesterfield, Missouri (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is bottled and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.
The second stage is being conducted at a Pfizer plant in Andover, Massachusetts, in the United States, and at BioNTech's plants in Germany. The DNA is used as a template to build the desired mRNA strands, which takes about four days. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 10 million doses. The bags are placed on trucks which take them to the next plant.
The third stage is being conducted at Pfizer plants in Portage, Michigan (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them. Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids. As of November 2020, the major bottleneck in the manufacturing process is combining mRNA with lipid nanoparticles. At this stage, it takes only four days to go from mRNA and lipids to finished vials, but each lot must then spend several weeks in deep-freeze storage while undergoing verification against 40 quality-control measures.
Before May 2021, the Pfizer plant in Puurs was responsible for all vials for destinations outside the United States. Therefore, all doses administered in the Americas outside of the United States before that point in time required at least two transatlantic flights (one to take DNA to Europe and one to bring back finished vaccine vials).
In February 2021, BioNTech announced it would increase production by more than 50% to manufacture 2 billion doses in 2021, raised again at the end of March to 2.5 billion doses in 2021.
In February 2021, Pfizer revealed that the entire sequence initially took about 110 days on average from start to finish, and that the company is making progress on reducing the time to 60 days. More than half the days in the production process are dedicated to rigorous testing and quality assurance at each of the three stages. Pfizer also revealed that the process requires 280 components and relies upon 25 suppliers located in 19 countries.
Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production. Due to the urgency presented by the COVID-19 pandemic, Pfizer and BioNTech began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.BioNTech announced in September 2020, that it had signed an agreement to acquire a manufacturing facility in Marburg, Germany, from Novartis to expand their vaccine production capacity. Once fully operational, the facility would produce up to 750 million doses per year, or more than 60 million doses per month. The site will be the third BioNTech facility in Europe that produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.
The Marburg facility had previously specialized in cancer immunotherapy for Novartis. By the end of March 2021, BioNTech had finished retrofitting the facility for mRNA vaccine production and retraining its 300 staff, and obtained approval to begin manufacturing. Besides making mRNA, the Marburg facility also performs the step of combining mRNA with lipids to form lipid nanoparticles, then ships the vaccine in bulk to other facilities for fill and finish (i.e., filling and boxing vials).
In April 2021, the EMA authorized an increase in batch size and associated process scale up at Pfizer's plant in Puurs. This increase is expected to have a significant impact on the supply of the vaccine in the European Union.
=== Logistics ===
The vaccine is delivered in vials that, once diluted, contain 2.25 mL of vaccine, comprising 0.45 mL frozen and 1.8 mL diluent. According to the vial labels, each vial contains five 0.3 mL doses, however excess vaccine may be used for one, or possibly two, additional doses. The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded. The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials. The Danish Health Authority allows mixing partial doses from two vials. As of 8 January 2021, each vial contains six doses. In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.The vaccine can be stored at 2 to 8 °C (36 to 46 °F) for thirty days before use and at 25 °C (77 °F) or 30 °C (86 °F) for up to two hours before use. During distribution the vaccine is stored in special containers that maintain temperatures between −80 and −60 °C (−112 and −76 °F).
Low-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine. The necessary storage temperatures for the vaccine are much lower than for the similar Moderna vaccine. The head of Indonesia's Bio Farma Honesti Basyir said purchasing the vaccine is out of the question for the world's fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India's existing cold chain network can handle only temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.
== History ==
Before COVID‑19 vaccines, creating a vaccine for an infectious disease from scratch had never before been produced in less than the five years it had taken in 1967 when Maurice Hilleman had set the modern record with a vaccine for mumps, followed by the vaccine for Ebola also taking five years.: 13
As of 2019 no vaccine existed for preventing a coronavirus infection in humans. The SARS-CoV-2 virus, which causes COVID‑19, was detected in December 2019,
The development of the Pfizer- BioNTech COVID‑19 vaccine began when BioNTech founder and CEO Uğur Şahin while at his home in Mainz on Friday 24 January 2020, was checking out his regular websites when he noted a report in the science section of Der Spiegel website about novel respiratory illness that had affected approximately 50 people in Wuhan.: 2
He then came across a submission from Hong Kong-based researchers on the website of the medical journal The Lancet in which they discussed a cluster of pneumonia associated with coronavirus and an indication of person-to-person transmission that had affected a family that had recently returned from Wuhan. The authors of the submission were of the opinion that they were observing the early stages of an epidemic,: 5–7
While no infectious disease expert Şahin did some quick calculations based on Wuhan's population and transport links and came to the conclusion that if this virus was possible of person-to-person transmission then it could cause a morality rate somewhere between 0.3 and 10 out of every 100 inflected people to give a best case scenario of two million deaths worldwide. This would expose him, his family, colleagues to danger. At the time there were 1,000 internationally confirmed cases of the virus.: 29 Later that day he sent an email to Helmut Jeggle, chairman of BioNTech to alert him of his conclusions.: 8 The next day he discussed it with his wife Özlem Türeci and his belief that once it reached Germany local schools would be closed by April.: 10 During a telephone call with Jeggle that same day he discussed potential impact of such a virus.: 11
Şahin and Türeci had previously identified that the mRNA vaccine technology that the company had been developing offered the possibly of being used to create a suitable vaccine.
While the company had a small team which had started developing vaccines for infectious disease and had collaborating with Pfizer on a flu vaccine BioNTech was after 11 years of financial losses totalling more than €400 million was concentrating its efforts on developing mRNA as a means of fighting cancer.: 25, 40
However, realizing the risk and believing that the company's proprietary mRNA technology at now at the stage where they had the tools to create a vaccine Şahin after discussing it with his wife, spent that weekend outlining the technical construction of eight possible vaccine candidates based on the company's mRNA platforms.: 29 He was assisted in his work by the SARS-CoV-2 genetic sequences having been previously published on 11 January 2020: 120 by Edward C. Holmes in association with Zhang Yongzhen, a professor at the Chinese Center for Disease Control and Prevention on open-source website Virological.org. This triggered an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.
On Monday 27 January Şahin had a series of meetings with the company's few infectious experts and the leaders of most of the departments to discuss his concerns about the virus and to announce his decision to establish a new project called 'Lightspeed' that would use all of the company's available resources to develop a vaccine. He also decided that rather than follow the traditional method of developing a single prototype and then discard it if it didn't work and then start again they would develop and test multiple vaccines in parallel. They would then discard the least promising.: 34–37
=== BioNTech approaches Pfizer about collaborating ===
At the board meeting the next day Şahin received permission to spend over the next weeks a limited amount of money that the company and its 1,300 personnel investigating the development of a vaccine, after which they would reevaluate whether to continue.: 41, 165 The board then considered whether to build up their capability to fully manufacture, document, sell and distribute any potential vaccine they decided that this would take too long and it would be better to partner with a pharma giant.: 43 Since the company had been collaborating with Pfizer since 2018 on developing a mRNA vaccine for influenza. Şahin called Pfizer's chief scientific officer, Phil Dormitzer later that Tuesday to tell them what they were doing and ask if they were interested in collaborating with BioNTech. Dormitzer was lukewarm as he felt that this new virus would be able to controlled and confined to China by public health measures and a few hours later confirmed on behalf of Pfizer that they were not interested.: 43–45, 156
=== Consulting the Paul Ehrlich Institute ===
Prior to contacting Pfizer, Şahin had contacted Klaus Cichutek at the Paul Ehrlich Institute (PEI) in Langen, which was Germany's drug regulator to ask for his assistance in arranging a meeting with a panel of experts to discuss a vaccine development strategy and to determine what needed to be done to receive authorisations to undertake a clinical trial.: 47 As it was taking the Wuhan developments very seriously PEI was more than willing to help and had already initiated a vaccine development programme and was providing emergency advice to other drug makers and waiving its administration fees. it was more than willing to assist BioNTech and came back two days later to say that provided a detailed briefing dossier could be delivered in time would meet with them the next week.: 48
Corinna Rosenbaum who was the lead project manager on the BioNTech flu project was asked to prepare what eventually was a 50-page dossier detailing how the company had the expertise and technology to create a safe vaccine.: 49–50 Crucial to the delivery of an mRNA vaccine to its cellular destination via an injection into a human muscle was the availability of a suitable wrapper made of lipid nano particles to protect it from the body's enzymes. The company had no experience in them they approached Acuitas Therapeutics whose proprietary wrapper technology was already being used in human trials and for which all of the necessary safety data was available. This would assist in gaining PEI approval. This small Canadian company of 25 staff was led by Tom Madden. An advantage of using Acuitas Therapeutics was that their ALC-0315 lipid formulation was already available at Polymun which was one of the only companies which had the expertise to immediately combine lipids with mRNA. Polymun was located near Vienna in Austria, an eight-hour drive from BioNTech's headquarters, which would be make it easier for material had to transported between the two companies.: 51–53 On Monday 3 February Acuitas Therapeutics agreed to assist.: 54 With Acuitas Therapeutics on board the briefing dossier was able to be completed and was sent to PEI late on Tuesday, 4 February, six days after work had commenced on compiling it.: 54
On 6 February Şahin, Türeci and Rosenbaum together with Tom Madden and Chris Barbosa from Acuitas Therapeutics met with PEI who were happy with what BioNTech proposed, with the only point of contention being PEI rejecting BioNTech proposal to either skip altogether or run toxicology studies in parallel with clinical trials before human trials could begin.: 54–56, 167
This was important as while the individual components had been shown by trials to not cause any significant issues in humans there was no safety data on the combination of mRNA and lipids. Toxicology studies on mice or rats normally took five months. At this point in time PEI main concerns were about whether there were any benefits in speeding up the normal process.: 56–60
For the vaccine to work it needed to deliver a stable accurate replica of the virus's spike protein so that the body's immune system could recognize and react to COVID‑19 if they became infected.: 72–75 In developing a stable replica, the team was assisted by advice from Barney S. Graham who had been studying the MERS virus, which was approximately 54% identical to the uploaded COVID-19 genetic code.: 74
There were two options, one was to reproduce a full likeness of entire spike protein which would contain approximately 1,200 amino acids (protein building blocks) increase the risk of antibody-dependent enhancement (ADE) complications. The other was to reproduce only the tip of the spike protein which was known as binding domain receptor (RBD). RDB was simpler as it would contain approximately 200 amino acids and risk of ADE would be reduced. Şahin decided that BioNTech would explore both methods.: 75–77
=== Development of parallel candidates ===
BioNTech decided to simultaneously develop in parallel in their laboratory in Mainz 20 possible COVID‑19 vaccine permutations in different doses based on all four versions of synthetic mRNA platforms that they had developed, modified mRNA (modRNA), uridine RNA (uRNA), self-amplifying mRNA (saRNA) and trans-amplifying mRNA (taRNA).: 118–119
Using the genetic sequences that were available on Virological.org a team at BioNTech led by Stephanie Hein used gene synthesis to create DNA hardcopies, which were to be used to create the templates to make the mRNA. These hardcopies each contained up to 4,000 nucleotides, which were assembled from 50 to 80 smaller building blocks.: 120
Once these DNA templates was produced another team created the actual mRNA vaccine candidates, the first batch of which was produced on 2 March. This was then poured into a 50 ml bag, frozen to minus 70 degrees Celsius and dispatched by a waiting car to Polymun to be combined with the lipids, a process that was to followed by the rest of the 20 candidates.: 122
Once the first vials containing the lipid wrapped mRNA candidates were revied back in Mainz on 9 March: 129 a team led by Annette Vogel began testing them to determine which using at various dosage amounts induced the best immune responses, first in glass dishes and then at a separate location, in mice. Each of the candidates was tested in three dosages, low, medium and high with each given to eight mice, with their blood then sampled and analyzed over the next six weeks.: 129 The blood was analyzed by a team led by Lena Kranz and Mathias Vormehr to check to see if the mice's T-cells reacted and carried out the required immune response.: 123 These tests showed that all 20 candidates produced an immune response in the mice.: 177
In parallel Annette Vogel was also using enzyme-linked immunosorbent assays (ELISA) to determine using a virus neutralisation test (VNT) if the candidates were inducing sufficient neutralising antibodies. Because of the risk that COVID‑19 posed this testing had to be done in a biosafety level three (BSL-3) laboratory, which BioNTech didn't have. Fortunately, they were able to get around this by creating a vesicular stomatitis virus (VSV) pseudovirus to replace the harmful elements with the isolated spike proteins from SARS-CoV-2. A working prototype pseudovirus test was ready by 10 March. This meant the laboratory security requirements could be downgraded to BSL-1, which the company had onsite.: 125–128
To obtain a return on its investment in 'Project Lightspeed Helmut' Jeggle was of the opinion that the company had to take advantage of the massive demand by being among the first three to the market with a vaccine. To do this BioNTech needed the evolvement of either GSK, Johnson & Johnston, Merck, Pfizer or Sanofi, who alone had the financial resources, manufacturing ability and territorial coverage to undertake the massive Phase 3 trials needed to prove to the regulators that the vaccine was safe.: 137
=== BioNTech reapproaches Pfizer about collaborating ===
Despite the earlier rebuff from Pfizer the company still preferred to partner with them. In the meantime they were able to reach what was in effect a licensing agreement on 16 March with Shanghai-based Fosun.
On 3 March Şahin was able to contact Kathrin Jansen, head of vaccine research and development at Pfizer that BioNTech who by now was of the opinion that mRNA was the best means of creating a COVID‑19 vaccine. She took the idea of a collaboration to Pfizer CEO Albert Bourla. While the two companies had been working together since 2018 on developing a mRNA vaccine for influenza, it was only now that their two chief executives became personally acquainted.
After a few phone calls, Bourla agreed that Pfizer would work with BioNTech on the development of BioNTech's COVID-19 vaccine. Since "time was of the essence," Bourla proposed that they commence work immediately and sort out the legal formalities later. Pfizer's lawyers were aghast when they realized what was going on. Although there was no formal legal agreement in place, BioNTech transferred its know-how to Pfizer the next day. Bouria agreed on the 50:50 partnership that Şahin proposed with each company equally sharing costs and any potential profits.: 158 Because of BioNTech's limited financial resources, Pfizer agreed to fund BioNTech's cost which was expected to be $190 million which would be paid back.: 162 As far as Bourla was concerned COVID‑19 was so important that he had told his staff that they had an "open cheque".: 159
On 13 March it was formally announced that BioNTech was collaborating with Pfizer with a letter of intent being signed on 17 March.: 135 However it wasn't until January 2021 that the formal commercial agreement between Pfizer and BioNTech for the COVID-19 vaccine was signed.
The release of news of the partnership bought BioNTech publicity that resulted the company receiving letters and telephone calls containing racists views and often death threats. Security was tightened and board members were offered personal protection.: 162–163
=== Funding ===
According to Pfizer, research and development for the vaccine cost close to US$1 billion.
BioNTech received a US$135 million investment from Fosun on 16 March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China and surrounding territories.: 161
In April 2020, BioNTech signed a partnership with Pfizer and received $185 million, including an equity investment of approximately $113 million.
In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank. The Bank's deal with BioNTech started early in the pandemic, when the Bank's staff reviewed its portfolio and came up with BioNTech as one of the companies capable of developing a COVID‑19 vaccine. The European Investment Bank had already signed a first transaction with BioNTech in 2019.
In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.
Pfizer CEO Albert Bourla said he decided against taking funding from the US government's Operation Warp Speed for the development of the vaccine "because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc." Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.
=== Clinical trials ===
Phase I–II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech. Before choosing BNT162b2, BioNTech and Pfizer had conducted phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China. In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.
The Pivotal Phase II–III Trial with the lead vaccine candidate "BNT162b2" began in July. Preliminary results from Phase I–II clinical trials on BNT162b2, published in October 2020, indicated potential for its safety and efficacy. During the same month, the European Medicines Agency (EMA) began a periodic review of BNT162b2.
The study of BNT162b2 is a continuous-phase trial in phase III as of November 2020. It is a "randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals". The study expanded during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.
The phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years. The Phase III results indicating a 95% efficacy of the developed vaccine were published on 18 November 2020. For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA. The EMA clarified that the second dose should be administered three weeks after the first dose.
At 14 days after dose 1, the cumulative incidence begins to diverge between the vaccinated group and the placebo group. The highest concentration of neutralizing antibodies is reached 7 days after dose 2 in younger adults and 14 days after dose 2 in older adults.
The ongoing phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.
High antibody activity persists for at least three months after the second dose, with an estimated antibody half-life of 55 days. From these data, one study suggested that antibodies might remain detectable for around 554 days.
==== Specific populations ====
Pfizer and BioNTech started a Phase II–III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594). The study will evaluate 30 mcg of BNT162b2 or placebo administered via intramuscular injection in two doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks' gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks' gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.
A study published in March 2021, in the American Journal of Obstetrics and Gynecology came to the conclusion that messenger RNA vaccines against the novel coronavirus, such as the Pfizer-BioNTech and Moderna vaccines were safe and effective at providing immunity against infection to pregnant and breastfeeding mothers. Furthermore, they found that naturally occurring antibodies created by the mother's immune system were passed on to their children via the placenta and/or breastmilk, thus resulting in passive immunity among the child, effectively giving the child protection against the disease. The study also found that vaccine-induced immunity among the study's participants was stronger in a statistically significant way over immunity gained through recovery from a natural COVID‑19 infection. In addition, the study reported that the occurrence and intensity of potential side effects in those undergoing pregnancy or lactating was very similar to those expected from non-pregnant populations, remaining generally very minor and well tolerated, mostly including injection site soreness, minor headaches, muscles aches or fatigue for a short period of time.
In January 2021, Pfizer said it had finished enrolling 2,259 children aged between 12 and 15 years to study the vaccine's safety and efficacy.
On 31 March 2021, Pfizer and BioNTech announced from initial Phase III trial data that the vaccine is 100% effective for those aged 12 to 15 years of age, with trials for those younger still in progress.
A research letter published in JAMA reported that the vaccines appeared to be safe for immunosuppressed organ transplant recipients, but that the resulting antibody response was considerably poorer than in the non-immunocompromised population after only one dose. The paper admitted the limitation of only reviewing the data following the first dose of a two-dose cycle vaccine.
In November 2021, journalist Paul D. Thacker alleged there has been "poor practice" at Ventavia, one of the companies involved in the phase III evaluation trials of the Pfizer vaccine. The report was enthusiastically embraced by anti-vaccination activists. David Gorski commented that Thacker's article presented facts without necessary context to misleading effect, playing up the seriousness of the noted problems.
=== Authorizations ===
Although jointly developed with Pfizer, Comirnaty is based on BioNTech's proprietary mRNA technology, and BioNTech holds the Marketing Authorization in the United States, the European Union, the UK, and Canada; expedited licenses such as the US emergency use authorization (EUA) are held jointly with Pfizer in many countries.
==== Expedited ====
The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine "rapid temporary regulatory approval to address significant public health issues such as a pandemic" on 2 December 2020, which it is permitted to do under the Medicines Act 1968. It is the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials, and the first mRNA vaccine to be authorized for use in humans. The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use, although the decision to fast-track the vaccine was criticized by some experts.
After the United Kingdom, the following countries and regions expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina, Australia, Bahrain, Canada, Chile, Costa Rica, Ecuador, Hong Kong, Iraq, Israel, Jordan, Kuwait, Malaysia, Mexico, Oman, Panama, the Philippines, Qatar, Saudi Arabia, Singapore, South Korea, the United Arab Emirates, the United States, and Vietnam.
The World Health Organization (WHO) authorized it for emergency use.
In the United States, an emergency use authorization (EUA) is "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic", according to the Food and Drug Administration (FDA). Pfizer applied for an EUA on 20 November 2020, and the FDA approved the application three weeks later on 11 December 2020. The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged sixteen years or older. Following the EUA issuance, BioNTech and Pfizer continued the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States. On 10 May 2021, the US FDA also authorized the vaccine for people aged 12 to 15 under an expanded EUA. The FDA recommendation was endorsed by the ACIP and adopted by the CDC on 12 May 2021. In October 2021, the EUA was expanded to include children aged 5 through 11 years of age. In June 2022, the EUA was expanded to include children aged six months through four years of age.
In February 2021, the South African Health Products Regulatory Authority (SAHPRA) in South Africa issued Section 21, Emergency Use Approval for the vaccine.
In May 2021, Health Canada authorized the vaccine for people aged 12 to 15. On 18 May 2021, Singapore's Health Sciences Authority authorized the vaccine for people aged 12 to 15. The European Medicines Agency (EMA) followed suit on 28 May 2021.
In June 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) came to a similar decision and approved the use of the vaccine for people twelve years of age and older.
==== Standard ====
In December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) granted temporary authorization for the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, saying the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.
In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the Pfizer–BioNTech COVID‑19 vaccine under the brand name Comirnaty. The recommendation was accepted by the European Commission the same day.
In February 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID‑19 vaccine under its standard marketing authorization procedure. In June 2021, the approval was extended to those aged twelve or over. Pfizer's negotiation process with Brazil (and other Latin American countries) was described as "bullying". The contract prohibits the state of Brazil from publicly discussing the existence or the terms of their agreement with Pfizer–BioNTech without the former's written consent. Brazil was also restricted from donating or receiving donations of vaccines.
In July 2021, the U.S. Food and Drug Administration (FDA) granted priority review designation for the biologics license application (BLA) for the Pfizer–BioNTech COVID-19 vaccine with a goal date for the decision in January 2022. On 23 August 2021, the FDA approved the vaccine for use for those aged sixteen years and older.
The Pfizer-BioNTech Comirnaty COVID-19 vaccine was authorized in Canada in September 2021, for people aged twelve and older.
In July 2022, the FDA approved the vaccine for use for those aged twelve years and older.
In September 2022, the CHMP of the EMA recommended converting the conditional marketing authorizations of the vaccine into standard marketing authorizations. The recommendation covers all existing and upcoming adapted Comirnaty vaccines, including the adapted Comirnaty Original/Omicron BA.1 (tozinameran/riltozinameran) and Comirnaty Original/Omicron BA.4/5 (tozinameran/famtozinameran).
=== Administering of the first non-clinical doses ===
The first dose administered outside of a clinical trial was given to 90-year-old Margaret Keenan in the outpatient ward at Coventry University Hospital on 8 December 2020.: xi The vial and syringe used for her injection was subsequently sent for display to the Science Museum in London. The first dose administered outside of a clinical trial in the United States was given to Sandra Lindsay on 14 December 2020.
=== Further development ===
==== Homologous prime-boost vaccination ====
In July 2021, Israel's Prime Minister announced that the country was rolling out a third dose of the Pfizer-BioNTech vaccine to people over the age of 60, based on data that suggested significant waning immunity from infection over time for those with two doses. The country expanded the availability to all Israelis over the age of 12, after five months since their second shot. On 29 August 2021, Israel's coronavirus czar announced that Israelis who had not received a booster shot within six months of their second dose would lose access to the country's green pass vaccine passport. Studies performed in Israel found that a third dose reduced the incidence of serious illness.
In August 2021, the United States Department of Health and Human Services (HHS) announced a plan to offer a booster dose eight months after the second dose, citing evidence of reduced protection against mild and moderate disease and the possibility of reduced protection against severe disease, hospitalization, and death. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of an additional mRNA vaccine dose for immunocompromised individuals at that time. Scientists and the WHO noted in August 2021, the lack of evidence on the need for a booster dose for healthy people and that the vaccine remains effective against severe disease months after administration. In a statement, the WHO and Strategic Advisory Group of Experts (SAGE) said that, while protection against infection may be diminished, protection against severe disease will likely be retained due to cell-mediated immunity. Research into optimal timing for boosters is ongoing, and a booster too early may lead to less robust protection.
In September 2021, the FDA and CDC authorizations were extended to provide a third shot for other specific groups.
In October 2021, the European Medicines Agency (EMA) stated that a booster shot of the vaccine could be given to healthy people, aged 18 years and older, at least six months after their second dose. It also stated that people with "severely weakened" immune systems can receive an extra dose of either the Pfizer-BioNTech vaccine or the Moderna vaccine starting at least 28 days after their second dose. The final approval to provide booster shots in the European Union will be decided by each national government.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
In October 2021, the Australian Therapeutic Goods Administration (TGA) provisionally approved a booster dose of Comirnaty for people 18 years of age and older.
In January 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 12 through 15 years of age, and it shortened the waiting period after primary vaccination to five months from six months.
In May 2022, the FDA expanded the emergency use authorization to provide for the use of a vaccine booster dose to those aged 5 through 11 years of age.
In August 2022, the FDA revoked the emergency use authorization for the monovalent vaccine booster for people aged twelve years of age and older and replaced it with an emergency use authorization for the bivalent vaccine booster dose for the same age group.
==== Heterologous prime-boost vaccination ====
In October 2021, the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of either homologous or heterologous vaccine booster doses. The authorization was expanded to include all adults in November 2021.
==== Bivalent booster vaccination ====
In August 2022, the "Pfizer-BioNTech COVID-19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5)" (in short: "COVID-19 Vaccine, Bivalent") received an emergency use authorization from the US Food and Drug Administration (FDA) for use as a booster dose in individuals aged twelve years of age and older. One dose contains 15 mcg of "a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2 Wuhan-Hu-1 strain (Original)" and 15 mcg "of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron variant lineages BA.4 and BA.5 (Omicron BA.4/BA.5)".
The bivalent vaccine authorized in the United States is different from the one that was authorized for use in the United Kingdom as the latter contains as second modRNA component 15 mcg of modRNA enocoding the S gylcoprotein of the earlier BA.1 variant.
In September 2022, the European Union authorized both the BA.1 and the BA.4/BA.5 booster versions of the bivalent vaccine for people aged twelve years of age and older.
While the Omicron BA.1 vaccine has been tested in a clinical study, the Omicron BA.4/BA.5 vaccine was only tested in pre-clinical studies. According to the published presentation, the neutralization responses of Omicron BA.4/BA.5 monovalent, Omicron BA.1 mononvalent, Omicron BA.4/BA.5 bivalent and the original BNT162b2 vaccine have been explored in a study with BALB/c-mice.
In October 2022, the FDA amended the authorization for the bivalent booster to cover people aged five years of age and older.
In December 2022, the FDA amended the authorization for the bivalent booster to be used as the third dose in people aged six months through four years of age.
==== XBB.1.5 monovalent vaccine ====
In September 2023, the FDA approved an updated monovalent (single) component Omicron variant XBB.1.5 version of the vaccine (Comirnaty 2023–2024 formula) as a single dose for individuals aged twelve years of age and older; and authorized the Pfizer-BioNTech COVID-19 Vaccine 2023–2024 formula under emergency use for individuals aged 6 months through 11 years of age. The approvals and emergency authorizations for the bivalent versions of the vaccine were revoked. Health Canada approved the Pfizer-BioNTech Comirnaty Omicron XBB.1.5 subvariant, monovalent COVID‑19 vaccine in September 2023. The UK Medicines and Healthcare products Regulatory Agency approved the used of the Comirnaty Omicron XBB.1.5 vaccine in September 2023.
==== JN.1 monovalent vaccine ====
Comirnaty JN.1 contains bretovameran, an mRNA molecule with instructions for producing a protein from the Omicron JN.1 subvariant of SARS-CoV-2. It is under evaluation in Australia.
==== KP.2 monovalent vaccine ====
In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Pfizer–BioNTech COVID-19 vaccine. In June 2024, the FDA advised manufacturers of licensed and authorized COVID-19 vaccines that the COVID-19 vaccines (2024-2025 formula) should be monovalent JN.1 vaccines. Based on the further evolution of SARS-CoV-2 and a rise in cases of COVID-19, the agency subsequently determined and advised manufacturers that the preferred JN.1-lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain. It was approved for use in the European Union.
== Society and culture ==
About 649 million doses of the Pfizer–BioNTech COVID-19 vaccine, including about 55 million doses in children and adolescents (below 18 years of age) were administered in the EU/EEA from authorization to 26 June 2022.
=== Brand names ===
BNT162b2 was the code name during development and testing, tozinameran is the international nonproprietary name (INN), and Comirnaty is the brand name. According to BioNTech, the name Comirnaty "represents a combination of the terms COVID‑19, mRNA, community, and immunity".
Famtozinameran is the INN for the BA.5 variant in the bivalent version of the vaccine.
Raxtozinameran is the INN for the XBB 1.5 variant version of the vaccine.
=== Economics ===
Pfizer reported revenue of US$154 million from the Pfizer–BioNTech COVID-19 vaccine in 2020, $36 billion in 2021, and $11.220 billion in 2023.
In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective. By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union, 120 million doses to Japan, 40 million doses (10 million before 2021) to the United Kingdom, 20 million doses to Canada, an unspecified number of doses to Singapore, and 34.4 million doses to Mexico. Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.
=== Pfizergate investigation ===
Accounts of how Pfizer's got its way into a large deal to provide 1.8 billion doses of its vaccine to the European Union were described by The New York Times as "a striking alignment of political survival and corporate hustle". Shots worth €4 billion were reportedly wasted before the deal was re-negotiated. In early 2023, Belgian prosecutors began investigating European Commission President Ursula von der Leyen and Pfizer CEO Albert Bourla. The case was taken over in 2024 by the European Public Prosecutor's Office citing "interference in public functions, destruction of SMS, corruption and conflict of interest."
=== Access ===
Pfizer has been accused of hindering vaccine equity. In 2021, Pfizer delivered only 39% of the contractually agreed doses to the COVAX programme, a number that equals 1.5% of all vaccines produced by Pfizer. The company sold 67% of their doses to high-income countries and sold none directly to low-income countries.
Pfizer actively lobbied against the temporary lift of intellectual property rights which would allow the vaccine to be produced by others without having to pay a royalty fee.
=== Misinformation ===
Videos on video-sharing platforms circulated around May 2021 showing people having magnets stick to their arms after receiving the vaccine, purportedly demonstrating the conspiracy theory that vaccines contain microchips, but these videos have been debunked.
== Notes ==
== References ==
== Further reading ==
== External links ==
Global Information About Pfizer–BioNTech COVID-19 Vaccine (also known as BNT162b2 or as Comirnaty) by Pfizer
Comirnaty Safety Updates from the European Medicines Agency
Product information from the Centers for Disease Control and Prevention | Wikipedia/Pfizer-BioNTech_COVID-19_vaccine |
Science Translational Medicine is an interdisciplinary biomedical journal established in October 2009 by the American Association for the Advancement of Science.
It publishes basic, biomedical, translational, and clinical research about human diseases. According to Web of Science, the journal has a 2023 impact factor of 15.8
The journal has published articles covering novel tools and technologies that aid in investigating the fundamental mechanisms underlying health and disease, as well as the variability of drug responses in humans, precision medicine, and regulatory science.
== Abstracting and indexing ==
The journal is abstracted and indexed by the major services with a focus on medicine and biology, including Science Citation Index
& Web of Science, Index Medicus/MEDLINE/PubMed, and Scopus
== Associated journals ==
Science Magazine
== See also ==
AAAS publications
== References ==
== External links ==
Official website | Wikipedia/Science_Translational_Medicine |
Circumsporozoite protein (CSP) is a secreted protein of the sporozoite stage of the malaria parasite (Plasmodium sp.) and is the antigenic target of RTS,S and other malaria vaccines. The amino-acid sequence of CSP consists of an immunodominant central repeat region flanked by conserved motifs at the N- and C- termini that are implicated in protein processing as the parasite travels from the mosquito to the mammalian vector. The amino acid sequence of CSP was determined in 1984.
The structure and function of CSP is highly conserved across the various strains of malaria that infect humans, non-human primates and rodents. It can first be detected in large quantities as sporozoites are forming within oocysts residing in the midgut walls of infected mosquitoes. Upon egression from mature oocysts, sporozoites begin migrating to the salivary glands, and CSP is known to be an important mediator of this process. Additionally, CSP is involved in hepatocyte binding in the mammalian host. Here, the N-terminus and central repeat region initially facilitate parasite binding. On the hepatocyte surface proteolytic cleavage at region 1 of the N-terminus exposes the adhesive domain of the C-terminus, thereby priming the parasites for invasion of the liver.
CSP is an approximately 58 kD protein, anchored to the parasite's cell surface via a GPI-anchor. The protein has been shown to possess mechanically pliable, structurally and conformationally disordered repeat region that could provide the parasite (sporozoite) with 'lubricating capacity' required during its navigation through the mosquito and vertebrate host tissues.
== References == | Wikipedia/Circumsporozoite_protein |
PfSPZ Vaccine is a metabolically active non-replicating whole sporozoite (SPZ) malaria vaccine being developed by Sanaria against Plasmodium falciparum (Pf) malaria. Clinical trials have been safe, extremely well tolerated and highly efficacious. The first generation PfSPZ product is attenuated by gamma irradiation; the second generation vaccines PfSPZ-CVac and PfSPZ LARC2 are, respectively, attenuated chemically and genetically. Multiple studies are ongoing with trials of the PfSPZ vaccines. All three products are produced using the same manufacturing process. These products are stored and distributed below -150 °C using liquid nitrogen (LN2) vapor phase (LNVP) freezers and cryoshippers.
== History ==
In the first half of the 20th century there were first attempts to protect people from malaria. At the beginning Pasteur's approach of developing bacterial vaccines was used as a big hope in eradication of this fatal disease. But inactivated malaria sporozoites (by formalin) were ineffective in inducing the protection.
In 1948 inactivated merozoites with an adjuvant were used for preventing lethal malaria to kill a group of monkeys. But the strong toxicity of the adjuvant and inability to obtain sufficient count of parasites from human blood stopped further efforts in this way.
In 1967 irradiated malaria sporozoites (extracted from salivary glands of infected mosquitos) induced immune response in mice without the need of the adjuvant and similar evidence obtained in human volunteer trials. The mice were exposed to irradiated mosquitos infected by malaria parasites. Mice and volunteers did not acquire malaria because mosquitos and the sporozoites were irradiated and their immune cells triggered response that could protect them from following infection. Yet this approach was not further developed due to problems with obtaining sufficient number of sporozoites and with the harvesting of parasites.
Later, modern adjuvants and the possibility of preparing of single parasite proteins provided another way to create a malaria vaccine. RTS,S is a subunit vaccine based on coat protein of sporozoites of the Plasmodium falciparum. The RTS,S vaccine was endorsed by the World Health Organization in October 2021 for broad use in children, making it the first malaria vaccine to receive this recommendation. As of April 2022, 1 million children in Ghana, Kenya and Malawi have received at least one shot of the vaccine, with more doses being provided as the vaccine production ramps up. RTS,S reduces hospital admissions from severe malaria by around 30%.
== PfSPZ development ==
In 2003 Sanaria ran trials in which falciparum sporozoites were manually dissected from salivary glands of mosquitos, irradiated and preserved before inoculation with one goal: to develop and commercialize a non-replicating, metabolically active PfSPZ vaccine.
In human volunteer trials PfSPZ was applied subcutaneously (SC) or intradermally (ID) and such as it showed only modest immune response. When PfSPZ Vaccine was injected intravenously (IV) to nonhuman primates or mice it finally triggers CD8+ T-cells producing IFNγ. These T cells are believed to be the main immunologic mechanism to fight malaria in liver.
Two first clinical trials of IV administration of PfSPZ were conducted in 2013. Previous ID or IC clinical trials didn't trigger adequate immune response. A 2014 phase 1 trial with the PfSPZ Vaccine found that more than half of the participants were protected from malaria infection for over a year after the trial.
In 2014 Sanaria promoted an Indiegogo campaign to develop a robot that could dissect salivary glands of mosquitos, to make preparation and further development of vaccine much faster and easier. The crowdfunding campaign ended, after being backed by $45,024 of the $250,000 goal.
The PfSPZ Vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.
A study published in 2017 reported complete protection after 10 weeks with three doses of PfSPZ-CVac. In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020. Another study of the PfSPZ vaccine was published in December 2022, reporting vaccine efficacy at up to 48% at 6 months follow up, and up to 46% efficacy at 18 months.
== Mechanism ==
CD8+ T cells play a key role in killing Plasmodium developing in the liver. Mice or monkeys which received monoclonal antibody to the CD8 lost protection by this type of vaccine. Once the antibody application was stopped, the protection was returned.
Plasmodium is injected by infected mosquito into the bloodstream of the host in the form of sporozoites, which travel to the liver and invade liver cells, where sporozoites divide and produce tens of thousands merozoites per one cell. RTS,S is prepared to stop malaria in the phase after the injection. The PfSPZ vaccine is made of attenuated sporozites, which are active and travel to liver cells, where CD8+ T cells producing IFNγ are activated. Frequencies of PfSPZ-specific CD3+CD4+, CD3+CD8+, CD3+γδ T cells are dose-dependent. PfSPZ-specific CD3+CD8+ T cells were found in 7 of 12 protected subjects in a human volunteer trial. These cells are required for protection in most individuals and are primarily situated in the liver because of the persistence of parasite antigens and retained as tissue memory cells.
== Distribution ==
PfSPZ vaccines are cryopreserved and stored in LNVP freezers below -150 °C and distributed using dry vapor cryoshippers that also maintain temperature below -150 °C. Cryoshippers are self-contained mobile storage units that have hold times of ~14 to 28 days or more depending on model and packaging and are highly suited for last-mile transportation, particularly in Africa. Cryoshippers are used extensively in the livestock breeding, CAR-T and cellular therapies industries. LNVP distribution uses a simple hub-and-spoke model and cryoshippers stay at the immunization sites as temporary storage units that may be recharged with LN2. Advantages of the LNVP cold chain are a) independence from electricity, b) no requirement for fridges, freezers or refrigerated transport, c) no narrow temperature requirements, d) reduced chances for temperature deviations, e) no moving parts, and f) energy efficiency. LN2 is widely available, including in African countries, making LNVP distribution easier than the 2-8 °C and the dry ice and ultralow freezer-based cold chains of Ervebo (vs ebola) and certain SARS-CoV-2 vaccines. Modeling LNVP distribution also indicated costs would be no different per 3-dose regimen than the 2-8 °C cold chain for lyophilized vaccines.
== References ==
== External links ==
https://sanaria.com | Wikipedia/PfSPZ_Vaccine |
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.
== Chemical activity ==
The chemical activity of a protein kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual-specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.
== Structure ==
Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core. The structures of over 280 human protein kinases have been determined.
There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conserved aspartic acid, which is important for the catalytic activity of the enzyme.
== Serine/threonine-specific protein kinases ==
Serine/threonine protein kinases (EC 2.7.11.1) phosphorylate the OH group of serine or threonine (which have similar side chains). Activity of these protein kinases can be regulated by specific events (e.g., DNA damage), as well as numerous chemical signals, including cAMP/cGMP, diacylglycerol, and Ca2+/calmodulin.
One very important group of protein kinases are the MAP kinases (acronym from: "mitogen-activated protein kinases"). Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation.
== Tyrosine-specific protein kinases ==
Tyrosine-specific protein kinases (EC 2.7.10.1 and EC 2.7.10.2) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors. Some examples include:
Platelet-derived growth factor receptor (PDGFR)
Epidermal growth factor receptor (EGFR)
Insulin receptor and insulin-like growth factor 1 receptor (IGF1R)
Stem cell factor (SCF) receptor (also called c-kit, see the article on gastrointestinal stromal tumor).
=== Receptor tyrosine kinases ===
These kinases consist of extracellular domains, a transmembrane spanning alpha helix, and an intracellular tyrosine kinase domain protruding into the cytoplasm. They play important roles in regulating cell division, cellular differentiation, and morphogenesis. More than 50 receptor tyrosine kinases are known in mammals.
==== Structure ====
The extracellular domains serve as the ligand-binding part of the molecule, often inducing the domains to form homo- or heterodimers. The transmembrane element is a single α helix. The intracellular or cytoplasmic Protein kinase domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.
==== Regulation ====
Ligand binding causes two reactions:
Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are multivalent. Some tyrosine receptor kinases (e.g., the platelet-derived growth factor receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal.
Trans-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase.
Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby".
==== Signal transduction ====
The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain.
=== Receptor-associated tyrosine kinases ===
Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a number of signaling cascades, in particular those involved in cytokine signaling (but also others, including growth hormone). One such receptor-associated tyrosine kinase is Janus kinase (JAK), many of whose effects are mediated by STAT proteins. (See JAK-STAT pathway.)
== Dual-specificity protein kinases ==
Some kinases have dual-specificity kinase activities. For example, MEK (MAPKK), which is involved in the MAP kinase cascade, is a both a serine/threonine and tyrosine kinase.
== Histidine-specific protein kinases ==
Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an aspartate residue on a 'receiver domain' on a different protein, or sometimes on the kinase itself. The aspartyl phosphate residue is then active in signaling.
Histidine kinases are found widely in prokaryotes, as well as in plants, fungi and eukaryotes. The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate.
== Aspartic acid/glutamic acid-specific protein kinases ==
== Inhibitors ==
Deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (imatinib) and Iressa (gefitinib).
Anthra(1,9-cd)pyrazol-6(2H)-one
Staurosporine
== Kinase assays and profiling ==
Drug developments for kinase inhibitors are started from kinase assays Archived 2014-11-26 at the Wayback Machine, the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays to radioisotope based detections, and competition binding assays.
== References ==
== External links ==
Human and mouse protein kinases in UniProt: classification and index
Kinase.Com: Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
KinMutBase: A registry of disease-causing mutations in protein kinase domains Archived 2022-06-15 at the Wayback Machine
KLIFS (Kinase-Ligand Interaction Fingerprints and Structures) Database -- analysis of kinase structures and kinase-inhibitor interactions
KinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny
Kinomer: A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases. | Wikipedia/Protein_kinases |
The mainstay of malaria diagnosis has been the microscopic examination of blood, utilizing blood films. Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens. More recently, modern techniques utilizing antigen tests or polymerase chain reaction have been discovered, though these are not widely implemented in malaria endemic regions. Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria.
== Blood films ==
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) as few as 5 parasites/μL blood. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look similar and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.
As malaria becomes less prevalent due to interventions such as bed nets, the importance of accurate diagnosis increases. This is because the assumption that any patient with a fever has malaria becomes less accurate. As such, significant research is being put into developing low cost microscopy solutions for the Global South.
Plasmodium malariae and P. knowlesi (which is the most common cause of malaria in Southeast Asia) look very similar under the microscope. However, P. knowlesi parasitemia increases very fast and causes more severe disease than P. malariae, so it is important to identify and treat infections quickly. Therefore, modern methods such as PCR (see "Molecular methods" below) or monoclonal antibody panels that can distinguish between the two should be used in this part of the world.
== Antigen tests ==
For areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are commercial antigen detection tests that require only a drop of blood. Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") have been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and the results are read visually as the presence or absence of colored stripes on the dipstick, so they are suitable for use in the field. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/μL of blood (commercial kits can range from about 0.002% to 0.1% parasitemia) compared to 5 by thick film microscopy. One disadvantage is that dipstick tests are qualitative but not quantitative – they can determine if parasites are present in the blood, but not how many.
The first rapid diagnostic tests were using Plasmodium glutamate dehydrogenase as antigen.
PGluDH was soon replaced by Plasmodium lactate dehydrogenase (pLDH). Depending on which monoclonal antibodies are used, this type of assay can distinguish between different species of human malaria parasites, because of antigenic differences between their pLDH isoenzymes. Antibody tests can also be directed against other malarial antigens such as the P. falciparum specific HPR2.
Modern rapid diagnostic tests for malaria often include a combination of two antigens such as a P. falciparum. specific antigen e.g. histidine-rich protein II (HRP II) and either a P. vivax specific antigen e.g. P. vivax LDH or an antigen sensitive to all plasmodium species which affect humans e.g. pLDH. Such tests do not have a sensitivity of 100% and where possible, microscopic examination of blood films should also be performed.
== Molecular methods ==
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction) are being developed with the hope of being able to deploy them in endemic areas.
PCR (and other molecular methods) is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore, more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitemia in the field.
Another approach is to detect the iron crystal byproduct of hemoglobin that is found in malaria parasites feasting on red blood cells, but not found in normal blood cells. It can be faster, simpler and precise than any other method.
Researchers at Rice University have published a preclinical study of their new tech that can detect even a single malaria-infected cell among a million normal cells. They claim it can be operated by nonmedical personal, produce zero false-positive readings, and it doesn't need a needle or any damage done.
== Over- and misdiagnosis ==
Multiple recent studies have documented malaria overdiagnosis as a persistent issue globally, but especially in African countries. Overdiagnosis results in over-inflation of actual malaria rates reported at the local and national levels. Health facilities tend to over-diagnose malaria in patients presenting with symptoms such as fever, due to traditional perceptions such as "any fever being equivalent to malaria" and issues related to laboratory testing (for example high false positivity rates of diagnosis by unqualified personnel ). Malaria overdiagnosis leads to under management of other fever-inducing conditions, over-prescription of antimalarial drugs and exaggerated perception of high malaria endemicity in regions which are no longer endemic for this infection.
== Subjective diagnosis ==
Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than using only a history of subjective fevers, a correct diagnosis increased from 2% to 41% of cases, and unnecessary treatment for malaria was significantly decreased.
== Differential ==
Fever and septic shock are commonly misdiagnosed as severe malaria in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria, because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.
== Quantitative buffy coat ==
Quantitative buffy coat (QBC) is a laboratory test to detect infection with malaria or other blood parasites. The blood is taken in a QBC capillary tube which is coated with acridine orange (a fluorescent dye) and centrifuged; the fluorescing parasites can then be observed under ultraviolet light at the interface between red blood cells and buffy coat. This test is more sensitive than the conventional thick smear, however it is unreliable for the differential diagnosis of species of parasite.
In cases of extremely low white blood cell count, it may be difficult to perform a manual differential of the various types of white cells, and it may be virtually impossible to obtain an automated differential. In such cases the medical technologist may obtain a buffy coat, from which a blood smear is made. This smear contains a much higher number of white blood cells than whole blood.
== References == | Wikipedia/Diagnosis_of_malaria |
Merozoite surface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan. Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria. These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.
== Forms ==
The most common form of MSPs are anchored to the merozoite surface with glycophosphatidylinositol, a short glycolipid often used for protein anchoring. Additional forms include integral membrane proteins and peripherally associated proteins, which are found to a lesser extent than glycophosphatidylinositol anchored proteins, or (GPI)-anchored proteins, on the merozoite surface. Merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) are the most abundant (GPI)-anchored proteins on the surface of Plasmodium merozoites.
== Function ==
MSP-1 is synthesized at the very beginning of schizogony, or asexual merozoite reproduction. The merozoite first attaches to a red blood cell using its MSP-1 complex. The MSP-1 complex targets spectrin, a complex on the internal surface of the cell membrane of a red blood cell. The majority of the MSP-1 complex is shed upon entry into the red blood cell, but a small portion of the C-terminus, called MSP-119, is conserved. The exact role of MSP-119 remains unknown, but it currently serves as a marker for the formation of the food vacuole.
The function of the MSP-2 complex is not concrete, but current research suggests it has a role in red blood cell invasion due to its degradation shortly after invasion. MSP- 3, 6, 7 and 9 are peripheral membrane proteins that have been shown to form a complex with MSP-1, but the functions of these proteins are largely unknown.
== Clinical significance ==
Due to their prevalence on the Plasmodium surface, MSPs have been a key target for vaccine development. Anti-malarial vaccines have been developed to target the merozoite at different stages in its life cycle. Vaccines that target the merozoite in its asexual erythrocytic stage utilize merozoite surface proteins, particularly MSP-1. In addition to vaccines, researchers are developing drugs that bind to MSPs in order to disrupt merozoite replication. Suramin, a drug used to treat African sleeping sickness, has shown moderate success with binding to MSP-1 and its derivatives such as MSP-119 to inhibit red blood cell invasion.
=== Challenges ===
The challenge faced when developing vaccines is the complexity and variation of these proteins. In merozoites of the same genus and species, the sequences encoding proteins such as MSP-1 vary depending on the region they are found. For example, the Combination B vaccine utilizes antigens of MSP-1 and MSP-2 but has limited efficacy based primarily on the MSP-2 alleles used. In an attempt to increase the efficiency of vaccines produced, constant regions such as MSP-119 which remain on the surface of the Plasmodium after the merozoite stage are becoming a key focus for vaccine studies. Additionally, synthetic glycophosphatidylinositol (GPI) molecules are candidates since they elicit a strong immune response while simultaneously remaining relatively consistent in structure over various malarial strains. Also MSP3 is being studied as a vaccine antigen.
== References == | Wikipedia/Merozoite_surface_protein |
Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. In the majority of circumstances, drugs have 3 types of names: chemical names, the most important of which is the IUPAC name; generic or nonproprietary names, the most important of which are international nonproprietary names (INNs); and trade names, which are brand names. Under the INN system, generic names for drugs are constructed out of affixes and stems that classify the drugs into useful categories while keeping related names distinguishable. A marketed drug might also have a company code or compound code.
== Legal regulation ==
Drug names are often subject to legal regulation, including approval for new drugs (to avoid confusion with existing drugs) and on packaging to establish clear rules about adulterants and fraudulent or misleading labeling. A national formulary is often designated to define drug names (and purity standards) for regulatory purposes. The legally approved names in various countries include:
Australian Approved Name
Brazilian Nonproprietary Name
British Approved Name
Dénomination Commune Française (France)
Denominazione Comune Italiana (Italy, generic name)
Japanese Accepted Name
United States Adopted Name
The World Health Organization administers the international nonproprietary name list.
A company or person developing a drug can apply for a generic (nonproprietary) name through their national formulary or directly to the WHO INN Programme. In order to minimize confusion, many of the national naming bodies have policies of maintaining harmony between national nonproprietary names and INNs. The European Union has mandated this harmonization for all member states In the United States, the developer applies to United States Adopted Name (USAN) Council, and a USAN negotiator applies to the INN on the developer's behalf.
== Chemical names ==
The chemical names are the scientific names, based on the molecular structure of the drug. There are various systems of chemical nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name. Chemical names are typically very long and too complex to be commonly used in referring to a drug in speech or in prose documents. For example, "1-(isopropylamino)-3-(1-naphthyloxy) propan-2-ol" is a chemical name for propranolol. Sometimes, a company that is developing a drug might give the drug a company code, which is used to identify the drug while it is in development. For example, CDP870 was UCB's company code for certolizumab pegol; UCB later chose "Cimzia" as its trade name. Many of these codes, although not all, have prefixes that correspond to the company name.
== Nonproprietary (generic) names ==
Generic names are used for a variety of reasons. They provide a clear and unique identifier for active chemical substances, appearing on all drug labels, advertising, and other information about the substance. Relatedly, they help maintain clear differentiation between proprietary and nonproprietary aspects of reality, which people trying to sell proprietary things have an incentive to obfuscate; they help people compare apples to oranges. They are used in scientific descriptions of the chemical, in discussions of the chemical in the scientific literature and descriptions of clinical trials. Generic names usually indicate via their stems what drug class the drug belongs to. For example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix.
=== History ===
The earliest roots of standardization of generic names for drugs began with city pharmacopoeias, such as the London, Edinburgh, Dublin, Hamburg, and Berlin Pharmacopoeias. The fundamental advances in chemistry during the 19th century made that era the first time in which what is now called chemical nomenclature, a huge profusion of names based on atoms, functional groups, and molecules, was necessary or conceivable. In the second half of the 19th century and the early 20th, city pharmacopoeias were unified into national pharmacopoeias (such as the British Pharmacopoeia, United States Pharmacopeia, Pharmacopoeia Germanica (PhG or PG), Italian Pharmacopeia, and Japanese Pharmacopoeia) and national formularies (such as the British National Formulary, the Australian Pharmaceutical Formulary, and the National Formulary of India). International pharmacopeias, such as the European Pharmacopoeia and the International Pharmacopoeia of the World Health Organization (WHO), have been the next level.
In 1953 the WHO created the International Nonproprietary Name (INN) system, which issues INNs in various languages, including Latin, English, French, Spanish, Russian, Chinese, and Arabic. Several countries also have national-level systems for creating generic drug names, including the British Approved Name (BAN) system, the Australian Approved Name (AAN) system, the United States Adopted Name (USAN) system (which is mostly the same as the United States Pharmacopeia (USP) system), and the Japanese Accepted Name (JAN) system. At least several of these national-level Approved Name/Adopted Name/Accepted Name systems were not created until the 1960s, after the INN system already existed. In the 21st century, increasing globalization is encouraging maximal rationalization for new generic names for drugs, and there is an increasing expectation that new USANs, BANs, and JANs will not differ from new INNs without special justification.
During the first half of the 20th century, generic names for drugs were often coined by contracting the chemical names into fewer syllables. Such contraction was partially, informally, locally standardized, but it was not universally consistent. In the second half of the 20th century, the nomenclatural systems moved away from such contraction toward the present system of stems and affixes that show chemical relationships.
Biopharmaceuticals have posed a challenge in nonproprietary naming because unlike smaller molecules made with total synthesis or semisynthesis, there is less assurance of complete fungibility between products from different manufacturers. Just as wine may vary by strain of yeast and year of grape harvest, so each product can be subtly different because living organisms are an integral part of production. The WHO MedNet community continually works to augment its system for biopharmaceuticals to ensure continued fulfillment of the goals served by having nonproprietary names. In recent years the development of the Biological Qualifier system has been an example.
The prefixes and interfixes have no pharmacological significance and are used to separate the drug from others in the same class. Suffixes or stems may be found in the middle or more often the end of the drug name, and normally suggest the action of the drug. Generic names often have suffixes that define what class the drug is.
=== List of stems and affixes ===
More comprehensive lists can be found in Appendix VII of the USP Dictionary or in the WHO INN stembook.
=== Example breakdown of a drug name ===
If the name of the drug solanezumab were to be broken down, it would be divided into two parts like this: solane-zumab. -Zumab is the suffix for humanized monoclonal antibody. Monoclonal antibodies by definition contain only a single antibody clone and have binding specificity for one particular epitope. In the case of solanezumab, the antibody is designed to bond to the amyloid-β peptides which make up protein plaques on the neurons of people with Alzheimer's disease.
See also Time release technology > List of abbreviations for formulation suffixes.
=== Combination drug products ===
For combination drug products—those with two or more drugs combined into a single dosage form—single nonproprietary names beginning with "co-" exist in both British Approved Name (BAN) form and in a formerly maintained USP name called the pharmacy equivalent name (PEN). Otherwise the two names are simply both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole. Similarly, co-codamol is codeine-paracetamol (acetaminophen), and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar "co"-prefixed BANs are still current.
=== Pronunciation ===
Most commonly, a nonproprietary drug name has one widely agreed pronunciation in each language. For example, doxorubicin is consistently in English. Trade names almost always have one accepted pronunciation, because the sponsoring company who coined the name has an intended pronunciation for it.
However, it is also common for a nonproprietary drug name to have two pronunciation variants, or sometimes three. For example, for paracetamol, both and are common, and one medical dictionary gives .
Some of the variation comes from the fact that some stems and affixes have pronunciation variants. For example, the aforementioned third (and least common) pronunciation for paracetamol reflects the treatment of the acet affix as rather than (both are accepted for acetyl).
The World Health Organization does not give suggested pronunciations for its INNs, but familiarity with the typical sounds and spellings of the stems and affixes often points to the widely accepted pronunciation of any given INN. For example, abciximab is predictably , because for INNs ending in -ciximab, the sound is familiar. The United States Pharmacopeia gives suggested pronunciations for most USANs in its USP Dictionary, which is published in annual editions. Medical dictionaries give pronunciations of many drugs that are both commonly used and have been commercially available for a decade or more, although many newer drugs or less common drugs are not entered. Pharmacists also have access to pronunciations from various clinical decision support systems such as Lexicomp.
== Drug brands ==
For drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name, which is a standard term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizer's trade name for atorvastatin, a cholesterol-lowering medication. Many drugs have multiple trade names, reflecting marketing in different countries, manufacture by different companies, or both. Thus the trade names for atorvastatin include not only Lipitor (in the U.S.) but also Atocor (in India).
== Publication policies for nonproprietary and proprietary names ==
In the scientific literature, there is a set of strong conventions for drug nomenclature regarding the letter case and placement of nonproprietary and proprietary names, as follows:
Nonproprietary names begin in lowercase; trade names begin with a capital.
Unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant (for example, "doxorubicin (Adriamycin)").
This pattern is important for the scientific literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug. They will often state which brand was used, for methodologic validity (fully disclosing all details that might possibly affect reproducibility), but they do so in a way that makes clear the absence of endorsement.
For example, the 2015 American Society of Hematology (ASH) publication policies say, "Non-proprietary (generic/scientific) names should be used and should be lowercase." ... "[T]he first letter of the name of a proprietary drug should be capitalized." ... "If necessary, you may include a proprietary name in parentheses directly following the generic name after its first mention."
Valid exceptions to the general pattern occur when a nonproprietary name starts a sentence (and thus takes a capital), when a proprietary name has intercapping (for example, GoLYTELY, MiraLAX), or when tall-man letters are used within nonproprietary names to prevent confusion of similar names (for example, predniSONE versus predniSOLONE).
=== Examples ===
== See also ==
Drug class
Drug development
Generic brand
Pharmaceutical code
Regulation of therapeutic goods
List of pharmaceutical compound number prefixes
== References == | Wikipedia/Drug_nomenclature |
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells (RBCs or erythrocytes) that are infected by the malarial parasite Plasmodium falciparum. PfEMP1 is synthesized during the parasite's blood stage (erythrocytic schizogony) inside the RBC, during which the clinical symptoms of falciparum malaria are manifested. Acting as both an antigen and adhesion protein, it is thought to play a key role in the high level of virulence associated with P. falciparum. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had antibody-binding (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called var. Each P. falciparum is able to switch on and off specific var genes to produce a functionally different protein, thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to endothelial cells, which facilitates further binding with uninfected RBCs (through the processes of sequestration and rosetting), ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of P. falciparum malaria.
== Introduction ==
Malaria is the deadliest among infectious diseases, accounting for approximately 429,000 human deaths in 2015 as of the latest estimate by the World Health Organization. In humans, malaria can be caused by five Plasmodium parasites, namely P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. P. falciparum is the most dangerous species, attributed to >99% of malaria's death toll, with 70% of these deaths occurring in children under the age of five years. The parasites are transmitted through the bites of female mosquitos (of the species of Anopheles). Before invading the RBCs and causing the symptoms of malaria, the parasites first multiply in the liver. The daughter parasites called merozoites then only infect the RBCs. They undergo structural development inside the RBCs, becoming trophozoites and schizonts. It is during this period that malarial symptoms are produced.
Unlike RBCs infected by other Plasmodium species, P. falciparum-infected RBCs had been known to spontaneously stick together. By the early 1980s, it was established that when the parasite (both the trophozoite and schizont forms) enters the blood stream and infects RBCs, the infected cells form knobs on their surface. Then they become sticky, and get attached to the walls (endothelium) of the blood vessels through a process called cytoadhesion, or cytoadherence. Such attachment favours binding with and accumulation of other RBCs. This process is known as sequestration. It is during this condition that the parasites induce an immune response (antigen-antibody reaction) and evade destruction in the spleen. Although the process and significance of sequestration were described in detail by two Italian physicians Amico Bignami and Ettore Marchiafava in the early 1890s, it took a century to discover the actual factor for the stickiness and virulence.
== Discovery ==
PfEMP1 was discovered by Russell J. Howard and his colleagues at the US National Institutes of Health in 1984. Using the techniques of radioiodination and immunoprecipitation, they found a unique but yet unknown antigen from P. falciparum-infected RBCs that appeared to cause binding with other cells. Since the antigenic protein could only be detected in infected cells, they asserted that the protein was produced by the malarial parasite, and not by RBCs. The antigen was large and appeared to be different in size in different strains of P. falciparum obtained from night monkey (Aotus). In one strain, called Camp (from Malaysia), the antigen was found to have a molecular size of approximately 285 kDa; while in the other, called St. Lucia (from El Salvador), it was approximately 260 kDa. Both antigens bind to cultured skin cancer (melanoma) cells. But the researchers failed to confirm whether or not the protein actually was an adhesion molecule to the wall of blood vessels. Later in the same year, they found out that the unknown antigen was associated only with RBCs having small lumps called knobs on their surface. The first human RBC antigen was reported in 1986. Howard's team found that the antigens from Gambian children, who were suffering from falciparum malaria, were similar to those from the RBCs of night monkey. They determined that the molecular sizes of the proteins ranged from 250 to 300 kDa.
In 1987, they discovered another type of surface antigen from the same Camp and St. Lucia strains of malarial parasites. This was also a large-sized protein of about 300 kDa, but quite different from the antigens reported in 1984. The new protein was unable to bind to melanoma cells and present only inside the cell. Hence, they named the earlier protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), to distinguish it from the newly identified Plasmodium falciparum erythrocyte membrane protein 2 (PfEMP2). The distinction was confirmed the next year, with an additional information that PfEMP1 is relatively less in number.
Although some of the properties of PfEMP1 were firmly established, the protein was difficult to isolate due to its low occurrence. Five years after its discovery, one of the original researchers Irwin Sherman began to doubt the existence of PfEMP1 as a unique protein. He argued that the antigen could be merely a surface protein of RBCs that changes upon infection with malarial parasites. A consensus was achieved in 1995 following the identification (by cloning) of the gene for PfEMP1. The discovery of the genes was independently reported by Howard's team and two other teams at NIH. Howard's team identified two genes for PfEMP1, and recombinant protein products of these genes were shown to have antigenic and adhesive properties. They further affirmed that PfEMP1 is the key molecule in the ability of P. falciparum to evade the host's immune system. Joseph D. Smith and others showed that PfEMP1 is actually a large family of proteins encoded by a multigene family called var. The gene products can bind to a variety of receptors including those on endothelial cells. Xin-Zhuan Su and others showed that there could be more than 50 var genes which are distributed on different chromosomes of the malarial parasite.
== Structure ==
PfEMP1 is a large family of proteins having high molecular weights ranging from 200 to 350 kDa. The wide range of molecular size reflects extreme variation in the amino acid composition of the proteins. But all the PfEMP1 proteins can be described as having three basic structural components, namely, an extracellular domain (ECD), a transmembrane domain (TMD) and an intracellular acidic terminal segment (ATS). The extracellular domain is fully exposed on the cell surface, and is the most variable region. It consists of a number of sub-domains, including a short and conserved N terminal segment (NTS) at the outermost region, followed by a highly variable Duffy-binding-like (DBL) domain, sometimes a Ca2+-binding C2 domain, and then one or two cysteine-rich interdomain regions (CIDRs).
Duffy-binding-like domains are so named because of their similarity to the Duffy binding proteins of P. vivax and P. knowlesi. There are six variant types of DBL, named DBLα, DBLβ, DBLγ, DBLδ, DBLε and DBLζ. CIDR is also divided into three classes: CIDRα, CIDRβ and CIDRγ. Both DBL and CIDR have an additional type called PAM, so named because of their specific involvement in pregnancy-associated malaria (PAM). In spite of the diverse DBL and CIDR proteins, the extracellular amino terminal region is partly conserved, consisting of about 60 amino acids of NTS, one each of DBLα and CIDR1 proteins in tandem. This semi-conserved DBLα-CIDR1 region is called the head structure. The last CIDR region joins the TMD, which is embedded in the cell membrane. The TMD and ATS are highly conserved among different PfEMP1s, and their structures have been solved using solution NMR (PDB: 2LKL).
The head structure is followed by a variable combination of diverse DBL and CIDR proteins, and in many cases along with C2. This variation gives rise to different types of PfEMP1. The DBL-CIDR combination in a particular type of PfEMP1 protein is never random, but organized into specific sequences known as domain cassettes. In some domain cassettes, there are only two or few DBL domains and CIDR domains, but in others they cover the entire length of the PfEMP1. These differences are responsible for different binding capacity among different PfEMP1s. For instance, among the most well-known types, VAR3 (earlier called type 3 PfEMP1) is the smallest, consisting of only NTS with DBL1α and DBL2ε domains in the ECD. Its molecular size is approximately 150 kDa. In domain cassette (DC) 4 type, the ECD is made up of three domains DBLα1.1/1.4, CIDRα1.6 and DBLβ3. The DBLβ3 domain contains a binding site for intercellular adhesion molecule 1 (ICAM1). This is particularly implicated with the development of brain infection. VAR2CSA is atypical in having a single domain cassette that consists of three N terminal DBLPAM domains followed by three DBLε domains and one CIDRPAM. The seven domains always occur together. The usual NTS is absent. The protein specifically binds to chondroitin sulphate A (CSA); hence the name VAR2CSA.
== Synthesis and transport ==
The PfEMP1 proteins are regulated and produced (encoded) by about 60 different var genes, but an individual P. falciparum would switch on only a single var gene at a time to produce only one type of PfEMP. The var genes are distributed in two exons. Exon 1 encodes amino acids of the highly variable ECD, while exon 2 encodes those of the conserved TMD and ATS. Based on their location in the chromosome and sequence, the var genes are generally classified into three major groups, A, B, and C, and two intermediate groups, B/A and B/C; or sometimes simply into five classes, upsA, upsB, upsC, upsD, and upsE respectively. Groups A and B are found towards the terminal end (subtelomeric) region of the chromosome, while group C is in the central (centromeric) region.
Once the PfEMP1 protein is fully synthesized (translated), it is carried to the cytoplasm towards the RBC membrane. The NTS is crucial for such directional movement. Within the cytoplasm, the newly synthesized protein is attached to a Golgi-like membranous vesicle called the Maurer's cleft. Inside the Maurer's clefts is a family of proteins called Plasmodium helical interspersed subtelomeric (PHIST) proteins. Of the PHIST proteins, PFI1780w and PFE1605w bind the intracellular ATS of PfEMP1 during transport to the RBC membrane.
The PfEMP1 molecule is deposited at the RBC membrane at the knobs. These knobs are easily identified as conspicuous bumps on the infected RBCs from the early trophozoite stage onward. The malarial parasite cannot induce its virulence on RBCs without knobs. As many as 10,000 knobs are distributed throughout the surface of a mature infected RBC, and each knob is 50-80 nm in diameter. The export of pfEMP1 from Maurer's cleft to RBC membrane is mediated by binding of another protein produced by the parasite called knob-associated histidine-rich protein (KAHRP). KAHRP enhances the structural rigidity of infected RBC and adhesion of PfEMP1 on the knobs. It is also directly responsible for forming knobs, as indicated by the fact that kahrp gene-deficient malarial parasites do not form knobs. To form a knob, KAHRP aggregates several membrane skeletal proteins of the host RBC, such as spectrin, actin, ankyrin R, and spectrin–actin band 4.1 complex. Upon arrival at the knob, PfEMP1 is attached to the spectrin network using the PHIST proteins.
== Function ==
The primary function of PfEMP1 is to bind and attach RBCs to the wall of the blood vessels. The most important binding properties of P. falciparum known to date are mediated by the head structure of PfEMP1, consisting of DBL domains and CIDRs. DBL domains can bind to a variety of cell receptors including thrombospondin (TSP), complement receptor 1 (CR1), chondroitin sulfate A (CSA), P-selectin, endothelial protein C receptor (EPCR), and heparan sulfate. The DBL domain adjacent to the head structure binds to ICAM-1. CIDRs mainly bind to a large variety of cluster determinant 36 (CD36). These bindings produce the pathogenic characteristics of the parasite, such as sequestration of infected cells in different tissues, invasion of RBCs, and clustering of infected cells by a process called rosetting.
CIDR1 protein in the semi-conserved head structure is the principal and best understood adhesion site of PfEMP1. It binds with CD36 on endothelial cells. Only group B and C proteins are able to bind, and that too with only those having CIDRα2-6 sequence types. On the other hand, group A proteins have either CIDRα1 or CIDRβ/γ/δ, and they are responsible for the most severe condition of malaria. Binding with ICAM-1 is achieved through the DBLβ domain adjacent to the head structure. However, many PfEMP1s having DBLβ domain do not bind to ICAM-1, and it appears that only the DBLβ paired with C2 domain can to bind to ICAM-1. The DBLα-CIDRγ tandem pair is the main factor for rosetting, sticking together the infected RBC with the uninfected cells, and thereby clogging of the blood vessels. This activity is performed through binding with CR1.
The most dangerous malarial infection is in the brain and is called cerebral malaria. In cerebral malaria, the PfEMP1 proteins involved are DC8 and DC13. They are named after the number of domain cassettes they contain, and are capable of binding not only endothelial cells of the brain, but also in different organs including brain, lung, heart, and bone marrow. Initially, it was assumed that PfEMP1 binds to ICAM-1 in the brain, but DC8 and DC13 were found incompatible with ICAM-1. Instead DC8 and DC13 specifically bind to EPCR using CIDRα sub-types such as CIDRα1.1, CIDRα1.4, CIDRα1.5 and CIDRα1.7. However, it was later shown that DC13 can bind to both ICAM-1 and EPCR. EPCR is thus a potential vaccine and drug target in cerebral malaria.
VAR2CSA is unique in that it is mostly produced by the placenta during pregnancy (the condition called pregnancy-associated malaria, PAM, or placental malaria). The majority of PAM is therefore due to VAR2SCA. Unlike other PfEMP1, VAR2CSA binds to chondroitin sulfate A present on the vascular endothelium of the placenta. Although its individual domains can bind to CSA, its entire structure is used for complete binding. The major complication in PAM is low-birth-weight babies. However, women who survived the first infection generally develop an effective immune response. In P. falciparum-prevalent regions in Africa, pregnant women are found to contain high levels of antibody (immunoglobulin G, or IgG) against VAR2CSA, which protect them the placenta-attacking malarial parasite. They are noted for giving birth to heavier babies.
== Clinical importance ==
In a normal human immune system, malarial parasite binding to RBCs stimulates the production of antibodies that attack the PfEMP1 molecules. Binding of antibody with PfEMP1 disables the binding properties of DBL domains, causing loss of cell adhesion, and the infected RBC is destroyed. In this scenario, malaria is avoided. However, to evade the host's immune response, different P. falciparum switch on and off different var genes to produce functionally different (antigenically distinct) PfEMP1s. Each variant type of PfEMP1 has different binding property, and thus, is not always recognized by antibodies.
By default, all the var genes in the malarial parasite are inactivated. Activation (gene expression) of var is initiated upon infection of the organs. Further, in each organ only specific var genes are activated. The severity of the infection is determined by the type of organ in which infection occurs, hence, the type of var gene activated. For examples, in the most severe cases of malaria, such as cerebral malaria, only the var genes for the PfEMP1 proteins DC8 and DC13 are switched on. Upon the synthesis of DC8 and DC13, their CIDRα1 domains bind to EPCR, which brings about the onset of severe malaria. The abundance of the gene products (transcripts) of these PfEMP1 proteins (specifically the CIDRα1 subtype transcripts) directly relates to the severity of the disease. This further indicates that preventing the interaction between CIDRα1 and EPCR would be good target for a potential vaccine. In pregnancy-associated malaria, another severe type of falciparum malaria, the gene for VAR2CSA (named var2csa) is activated in the placenta. Binding of VAR2CSA to CSA is the primary cause of premature delivery, death of the foetus and severe anaemia in the mother. This indicates that drugs targeting VAR2CSA will be able to prevent the effects of malaria, and for this reason VAR2CSA is the leading candidate for development of a PAM vaccine.
== References ==
This article was adapted from the following source under a CC BY 4.0 license (2017) (reviewer reports):
Kholhring Lalchhandama (2017). "Plasmodium falciparum erythrocyte membrane protein 1" (PDF). WikiJournal of Medicine. 4 (1). doi:10.15347/WJM/2017.004. ISSN 2002-4436. Wikidata Q43997683. | Wikipedia/Plasmodium_falciparum_erythrocyte_membrane_protein_1 |
Mosquito control manages the population of mosquitoes to reduce their damage to human health, economies, and enjoyment. Control strategies range from habitat modification and chemical insecticides to biological agents and mechanical traps. Climate change, artificial intelligence (AI), and community participation are increasingly shaping mosquito management today. Rising global temperatures have expanded mosquito habitats and disease risks, prompting new surveillance tools such as AI-enabled robots and community-led education programs to play key roles in reducing breeding grounds and tracking mosquito populations.
Mosquito-control operations are targeted to multiple problems:
Nuisance mosquitoes bother people around homes or in parks and recreational areas;
Economically important mosquitoes reduce real estate values, adversely affect tourism and related business interests, or negatively impact livestock or poultry production;
Public health is the focus when mosquitoes are vectors, or transmitters, of infectious disease.
Mosquito-borne diseases can threaten endangered species.
Disease organisms transmitted by mosquitoes include West Nile virus, Saint Louis encephalitis virus, Eastern equine encephalomyelitis virus, Everglades virus, Highlands J virus, La Crosse Encephalitis virus in the United States; dengue fever, yellow fever, Ilheus virus, malaria, Zika virus and filariasis in the American tropics; Rift Valley fever, Wuchereria bancrofti, Japanese encephalitis, chikungunya and filariasis in Africa and Asia; and Murray Valley encephalitis and Ross River fever in Australia. Vertical transmission from adult mosquitos to larvae is possible.
Depending on the situation, source reduction, biocontrol, larviciding (killing of larvae), or adulticiding (killing of adults) may be used to manage mosquito populations. These techniques are accomplished using habitat modification, pesticide, biological-control agents, and trapping. The advantage of non-toxic methods of control is they can be used in Conservation Areas.
Integrated pest management (IPM) is the use of the most environmentally appropriate method or combination of methods to control pest populations. Typical mosquito-control programs using IPM first conduct surveys, in order to determine the species composition, relative abundance and seasonal distribution of adult and larval mosquitoes, and only then is a control strategy defined.
== Monitoring mosquito populations ==
Adult mosquito populations may be monitored by landing rate counts, mechanical traps or by, lidar technology. For landing rate counts, an inspector visits a set number of sites every day, counting the number of adult female mosquitoes that land on a part of the body, such as an arm or both legs, within a given time interval. Mechanical traps use a fan to blow adult mosquitoes into a collection bag that is taken back to the laboratory for analysis of catch. The mechanical traps use visual cues (light, black/white contrasts) or chemical attractants that are normally given off by mosquito hosts (e.g., carbon dioxide, ammonia, lactic acid, octenol) to attract adult female mosquitoes. These cues are often used in combination. Entomology lidar detection has the possibility of showing the difference between male and female mosquitoes.
Monitoring larval mosquito populations involves collecting larvae from standing water with a dipper or a turkey baster. The habitat, approximate total number of larvae and pupae, and species are noted for each collection. An alternative method works by providing artificial breeding spots (ovitraps) and collecting and counting the developing larvae at fixed intervals. Monitoring these mosquito populations is crucial to see what species are present, if mosquito numbers are rising or falling, and detecting any diseases they carry.
Mosquito Alert is a cooperative citizen science project, currently run as a non-profit and coordinated by four public research centers in Spain. The aim of the project is to study, monitor, and fight the spread of invasive mosquitos. The project provided the first detection of the Asian bush mosquito Aedes japonicus in Spain in 2018, providing the first report of a population of mosquitos that were located 1,300 km from their previously nearest known location in Europe.
== Climate change and mosquito habitats ==
Climate change has enabled mosquitoes such as Aedes aegypti and Aedes albopictus to spread into new geographic regions, including temperate areas where they were previously unable to survive. Warmer temperatures accelerate mosquito development, shorten breeding cycles, and increase biting frequency, all of which enhance the potential for disease transmission. Shifts in rainfall patterns and the increased frequency of extreme weather events also create more stagnant water sources, which are ideal breeding grounds for mosquitoes. These ecological changes have contributed to the emergence or resurgence of mosquito-borne diseases such as dengue, Zika, and chikungunya in parts of Europe and North America. In response, public health organizations have begun integrating climate-based data, remote sensing, and predictive modeling into their surveillance systems to monitor habitat suitability and guide early warning efforts for mosquito population surges. Understanding the relationship between climate variables and mosquito ecology is now considered a key component of proactive vector control strategies.
== Community-based habitat reduction ==
A 2010 study in New Jersey evaluated how community participation can improve mosquito control through source reduction. AmeriCorps volunteers were trained to identify and explain mosquito breeding sites such as planters, rain barrels, and discarded containers. These peer educators visited over 750 homes, offering active, on-site education. Compared to control areas, the communities that received active outreach saw a 22.6% decrease in unmanaged container habitats. Additional events like tire disposal and trash can modification days encouraged long-term engagement. The study found that community-driven efforts led to measurable behavior change, particularly when residents had hands-on involvement.
== AI-enabled mosquito surveillance ==
Recent research has explored the use of robotics and artificial intelligence to improve mosquito surveillance. The "Dragonfly" robot, developed in Singapore, uses a deep learning algorithm called YOLO V4 (You Only Look Once version 4) to detect and classify mosquitoes. It can identify Aedes aegypti, Aedes albopictus, and Culex species from glue traps with an accuracy of up to 88% in offline tests and 82% in real-time field trials. The robot maps mosquito detections on a two-dimensional grid, helping researchers visualize population hotspots. This automated approach reduces the need for manual identification and supports faster response times in high-risk areas.
== Mechanical control ==
Mechanical control is the management and control using physical means.
=== Source reduction ===
Since many mosquitoes breed in standing water, source reduction can be as simple as emptying water from containers around the home. This is something that homeowners can accomplish. Mosquito breeding grounds can be eliminated at home by removing unused plastic pools, old tires, or buckets; by clearing clogged gutters and repairing leaks around faucets; by regularly (at most every 4 days) changing water in bird baths; and by filling or draining puddles, swampy areas, and tree stumps. Eliminating such mosquito breeding areas can be an extremely effective and permanent way to reduce mosquito populations without resorting to insecticides. However, this may not be possible in parts of the developing world where water cannot be readily replaced due to irregular water supply. Many individuals also believe mosquito control is the government's responsibility, so if these methods are not done regularly by homeowners then the effectiveness is reduced.
Open water marsh management (OWMM) involves the use of shallow ditches, to create a network of water flow within marshes and to connect the marsh to a pond or canal. The network of ditches drains the mosquito habitat and lets in fish which will feed on mosquito larvae. This reduces the need for other control methods such as pesticides. Simply giving the predators access to the mosquito larvae can result in long-term mosquito control. Open-water marsh management is used on both the eastern and western coasts of the United States.
Rotational impoundment management (RIM) involves the use of large pumps and culverts with gates to control the water level within an impounded marsh. RIM allows mosquito control to occur while still permitting the marsh to function in a state as close to its natural condition as possible. Water is pumped into the marsh in the late spring and summer to prevent the female mosquito from laying her eggs on the soil. The marsh is allowed to drain in the fall, winter, and early spring. Gates in the culverts are used to permit fish, crustaceans, and other marsh organisms to enter and exit the marsh. RIM allows the mosquito-control goals to be met while at the same time reducing the need for pesticide use within the marsh. Rotational impoundment management is used to a great extent on the east coast of Florida.
A 2019 study also explored the idea of using unmanned aerial vehicles as a valid strategy to identify and prioritize water bodies where disease vectors such as Ny. darlingi are most likely to breed.
=== Oil drip ===
An oil drip can or oil drip barrel was a common and nontoxic anti-mosquito measure. The thin layer of oil on top of the water prevents mosquito breeding in two ways: mosquito larvae in the water cannot penetrate the oil film with their breathing tube, and so drown and die; also adult mosquitoes do not lay eggs on the oiled water.
=== Mosquito traps ===
A traditional approach to controlling mosquito populations is the use of ovitraps or lethal ovitraps, which provide artificial breeding spots for mosquitoes to lay their eggs. While ovitraps only trap eggs, lethal ovitraps usually contain a chemical inside the trap that is used to kill the adult mosquito and/or the larvae in the trap. Studies have shown that with enough of these lethal ovitraps, Aedes mosquito populations can be controlled. A recent approach is the automatic lethal ovitrap, which works like a traditional ovitrap but automates all steps needed to provide the breeding spots and to destroy the developing larvae.
In 2016 researchers from Laurentian University released a design for a low cost trap called an Ovillanta which consists of attractant-laced water in a section of discarded rubber tire. At regular intervals the water is run through a filter to remove any deposited eggs and larva. The water, which then contains an 'oviposition' pheromone deposited during egg-laying, is reused to attract more mosquitoes. Two studies have shown that this type of trap can attract about seven times as many mosquito eggs as a conventional ovitrap.
Some newer mosquito traps or known mosquito attractants emit a plume of carbon dioxide together with other mosquito attractants such as sugary scents, lactic acid, octenol, warmth, water vapor and sounds. By mimicking a mammal's scent and outputs, the trap draws female mosquitoes toward it, where they are typically sucked into a net or holder by an electric fan where they are collected. According to the American Mosquito Control Association, the trap will kill some mosquitoes, but their effectiveness in any particular case will depend on a number of factors such as the size and species of the mosquito population and the type and location of the breeding habitat. They are useful in specimen collection studies to determine the types of mosquitoes prevalent in an area but are typically far too inefficient to be useful in reducing mosquito populations.
=== Trap larva ===
This is a process of achieving sustainable mosquito control in an eco friendly manner by providing artificial breeding grounds with an ovitrap or an ovillanta utilizing common household utensils and destroying larvae by non-hazardous natural means such as throwing them in dry places or feeding them to larvae eating fishes like Gambusia affinis, or suffocating them by spreading a thin plastic sheet over the entire water surface to block atmospheric air. Shifting the water with larvae to another vessel and pouring a few drops of kerosene oil or insecticide/larvicide in it is another option for killing wrigglers, but not preferred due to its environmental impact. Most of the ornamental fishes eat mosquito larvae.
== Chemical control ==
Chemical control is the management and control using chemical means.
=== Larviciding ===
Control of larvae can be accomplished through use of contact poisons, growth regulators, surface films, stomach poisons (including bacterial agents), and biological agents such as fungi, nematodes, copepods, and fish. A chemical commonly used in the United States is methoprene, considered slightly toxic to larger animals, which mimics and interferes with natural growth hormones in mosquito larvae, preventing development. Methoprene is frequently distributed in time-release briquette form in breeding areas. Another chemical is Temefos or temephos, a sand granular insecticide is used to treat water infected with disease carrying insects.
It is believed by some researchers that the larvae of Anopheles gambiae (important vectors of malaria) can survive for several days on moist mud, and that treatments should therefore include mud and soil several meters from puddles.
=== Adulticiding ===
Control of adult mosquitoes is the most familiar aspect of mosquito control to most of the public. It is accomplished by ground-based applications or via aerial application of residual chemical insecticides such as Duet. Generally modern mosquito-control programs in developed countries use low-volume applications of insecticides, although some programs may still use thermal fogging. Beside fogging there are some other insect repellents for indoors and outdoors. An example of a synthetic insect repellent is DEET. A naturally occurring repellent is citronella. Indoor Residual Spraying (IRS) is another method of adulticide. Walls of properties are sprayed with an insecticide, the mosquitoes die when they land on the surface covered in insecticide.
To control adult mosquitoes in India, van mounted fogging machines and hand fogging machines are used.
=== Use of DDT ===
DDT was formerly used throughout the world for large area mosquito control, but it is now banned in most developed countries.
Controversially, DDT remains in common use in many developing countries (14 countries were reported to be using it in 2009), which claim that the public-health cost of switching to other control methods would exceed the harm caused by using DDT. It is sometimes approved for use only in specific, limited circumstances where it is most effective, such as application to walls.
The role of DDT in combating mosquitoes has been the subject of considerable controversy. Although DDT has been proven to affect biodiversity and cause eggshell thinning in birds such as the bald eagle, some say that DDT is the most effective weapon in combating mosquitoes, and hence malaria. While some of this disagreement is based on differences in the extent to which disease control is valued as opposed to the value of biodiversity, there is also genuine disagreement amongst experts about the costs and benefits of using DDT.
Notwithstanding, DDT-resistant mosquitoes have started to increase in numbers, especially in tropics due to mutations, reducing the effectiveness of this chemical; these mutations can rapidly spread over vast areas if pesticides are applied indiscriminately (Chevillon et al. 1999). In areas where DDT resistance is encountered, malathion, propoxur or lindane is used.
== Chemicals from body odor that attract mosquitoes ==
Mosquitoes are highly adept at locating their human hosts, largely due to their ability to detect specific chemicals present in human body odor. Research has identified several compounds in human sweat and skin that are particularly attractive to mosquitoes. Understanding these attractants is crucial for developing more effective mosquito control methods, including targeted repellents and traps that mimic human odors to lure mosquitoes away from people.
=== Key Attractants ===
Carbon Dioxide (CO2): One of the most well-known attractants, carbon dioxide is exhaled by humans and detected by mosquitoes from a considerable distance. It is often the initial cue that mosquitoes use to locate potential hosts.
Lactic Acid: Found in human sweat, lactic acid is a significant attractant for many mosquito species, including those that transmit malaria and dengue fever. Its concentration can vary among individuals, partly explaining why mosquitoes are more attracted to some people than others.
Octenol: Also known as mushroom alcohol, octenol is present in human breath and sweat. It is particularly attractive to some mosquito species and is used in combination with carbon dioxide in mosquito traps.
Acetone and Sulcatone: These compounds are found in human breath and skin, and research has shown that they also play a role in attracting mosquitoes.
Ammonia: Released through the skin, especially with increased sweat production, ammonia is another compound that attracts mosquitoes. Moreover, recent studies have implicated other compounds such as fatty acids and certain volatile organic compounds (VOCs) in mosquito attraction, expanding the list of known attractants.
Among these attractants, CO2 and lactic acid are considered the most effective, with CO2 attracting mosquitoes from the longest distances and lactic acid influencing their preference for certain individuals.
=== Implications for Mosquito Control ===
Understanding the specific chemicals that attract mosquitoes facilitates the development of innovative control strategies. For example, mosquito traps that emit both CO2 and lactic acid have proven more effective in luring mosquitoes away from human populations, significantly reducing the risk of bites and the spread of diseases. Additionally, personal repellents engineered to mask or chemically alter these attractants can render individuals less detectable to mosquitoes. Integrating these repellents into daily personal care routines, especially in regions prone to mosquito-borne diseases, offers a proactive approach to disease prevention.
Research into the chemical properties of human body odor that attract mosquitoes reveals complex interactions between mosquito host-seeking behavior and human chemical signatures. By deciphering these mechanisms, scientists aim to devise solutions that could substantially reduce the incidence of mosquito-borne diseases. Advances in synthetic biology and nanotechnology are opening new avenues for creating targeted compounds and delivery systems that efficiently combat mosquitoes without harming the environment.
=== Enhancements and Future Directions ===
While existing repellents and traps offer temporary solutions, they frequently fall short due to their limited duration of effectiveness and inconsistent efficacy across different mosquito species. For example, many current repellents do not provide all-night protection, and traps might not attract all types of mosquitoes. Future research should prioritize the discovery of new attractant compounds through molecular biology and high-throughput screening methods, aiming to develop more universally effective and durable mosquito control solutions.
Addressing the ecological impacts of widespread use of chemical attractants and repellents is also essential. Careful evaluation is needed to ensure these methods do not harm non-target species or disrupt ecological balances. In practical scenarios, leveraging these insights could transform how we manage mosquito populations and reduce disease transmission. With ongoing technological advancements and deeper understanding of mosquito ecology, we can anticipate the development of next-generation repellents and attractant-based traps that provide robust and environmentally friendly protection against mosquitoes.
== Biological control ==
Biological control is the management and control using biological means.
=== Natural predation ===
Biological pest control, or "biocontrol", is the use of the natural enemies of pests like mosquitoes to manage the pest's populations. There are several types of biocontrol, including the direct introduction of parasites, pathogens, and predators to target mosquitoes. Effective biocontrol agents include predatory fish that feed on mosquito larvae such as mosquitofish (Gambusia affinis) and some cyprinids (carps and minnows) and killifish. Tilapia also consume mosquito larvae. Direct introduction of tilapia and mosquitofish into ecosystems around the world have had disastrous consequences. However, utilizing a controlled system via aquaponics provides the mosquito control without the adverse effects to the ecosystem.
Other predators include dragonfly (fly) naiads, which consume mosquito larvae in the breeding waters, adult dragonflies, which eat adult mosquitoes, and some species of lizard and gecko. Biocontrol agents that have had lesser degrees of success include the predator mosquito Toxorhynchites and predator crustaceans—Mesocyclops copepods, nematodes and fungi. Predators such as birds, bats, lizards, and frogs have been used, but their effectiveness is only anecdotal.
=== Biocides ===
Instead of chemical insecticides, some researchers are studying biocides. Like all animals, mosquitoes are subject to disease. Invertebrate pathologists study these diseases in the hope that some of them can be utilized for mosquito management. Microbial pathogens of mosquitoes include viruses, bacteria, fungi, protozoa, nematodes and microsporidia.
Most notably, scientists in Burkina Faso were studying the Metarhizium fungal species. This fungus in a high concentration can slowly kill mosquitoes. To increase the lethality of the fungus, a gene from a spider was inserted into the fungus causing it to produce a neurotoxin. The gene was regulated to only activate when in mosquito hemolymph. Research was done to show the fungi would not affect other insects or humans. Two other species of fungi that can kill adult mosquitoes are Metarhizium anisopliae and Beauveria bassiana.
Dead spores of the soil bacterium Bacillus thuringiensis, especially Bt israelensis (BTI) interfere with dipteran larval digestive systems. It can be dispersed by hand or dropped by helicopter in large areas. BTI loses effectiveness after the larvae turn into pupae, because they stop eating. BTI was reported to be widely applied in West Africa with limited adverse effects, and may pose lesser risk than chemical pesticides.
=== Wolbachia method ===
In the Wolbachia method, both male and female mosquitos that carry the Wolbachia bacterium are released into natural populations. Wolbachia boosts the natural immune response of the mosquito so that it does not easily get infected and become a host vector for mosquito-borne diseases. Therefore it is unable to easily transmit those viruses to people. This is known as replacement strategy as it aims to replace the natural population with Wolbachia-carrying ones. Since 2011, the World Mosquito Program has conducted several trials and projects, in 14 countries across Asia, Latin America and Oceania.
=== Incompatible Insect Technique (IIT) ===
This approach also uses Wolbachia but involves the release of only male mosquitos that carry the Wolbachia bacterium. When these male mosquitos mate with wild female mosquitos, her eggs do not hatch due to lack of biocompatibility. Wolbachia is not endemic to wild mosquito populations although it is endemic in 50% of all insect species. This is known as suppression strategy as it aims to suppress the natural reproduction cycle. Wolbachia-Aedes suppression has been piloted in various countries such as Myanmar (1967), French Polynesia (2009, 2012), USA (2014-2016, 2018), Thailand (2016), Australia (2017), Singapore (since 2016) and Puerto Rico (2020).
==== Projects ====
Maui and Kuai, Hawaii - A series of IIT projects were planned to protect endangered bird species from avian malaria. The projects involve the release of large numbers of male mosquitos infected with a strain of Wolbachia that is incompatible with the strain carried by resident females. These mosquitos would not be irradiated or subject to genetic modification.
=== Sterile Insect Technique (SIT) ===
Introducing large numbers of sterile males is another approach to reducing mosquito numbers. This is called Sterile Insect Technique (SIT). Radiation is used to disrupt DNA in the mosquitoes and randomly create mutations. Males with mutations that disrupt their fertility are selected and released in mass into the wild population. These sterile males mate with wild type females and no offspring is produced, reducing the population size.
==== Projects ====
Guangzhou, China - A combination of SIT with IIT, were used in a mosquito control program in Guangzhou, China. The pilot trial was carried out with the support of the IAEA in cooperation with the Food and Agriculture Organization of the United Nations (FAO). The pilot demonstrated the successful near-elimination of field populations of the world's most invasive mosquito species, Aedes albopictus (Asian tiger mosquito). The two-year trial (2016–2017) covered a 32.5-hectare area on two relatively isolated islands in the Pearl River in Guangzhou. It involved the release of about 200 million irradiated mass-reared adult male mosquitoes exposed to Wolbachia bacteria.
== Genetic modification ==
These techniques share the characteristic of introducing lethal genes and reducing the size of the mosquito population over time.
=== Growth inhibition ===
Another control approach under investigation for Aedes aegypti uses a strain that is genetically modified to require the antibiotic tetracycline to develop beyond the larval stage. Modified males develop normally in a nursery while they are supplied with this chemical and can be released into the wild. However, their subsequent offspring will lack tetracycline in the wild and never mature. Field trials were conducted in the Cayman Islands, Malaysia and Brazil to control the mosquitoes that cause dengue fever. In April 2014, Brazil's National Technical Commission for Biosecurity approved the commercial release of the modified mosquito. The FDA is the lead agency for regulating genetically-engineered mosquitoes in the United States.
In 2014 and 2018 research was reported into other genetic methods including cytoplasmic incompatibility, chromosomal translocations, sex distortion and gene replacement. Although several years away from the field trial stage, if successful these other methods have the potential to be cheaper and to eradicate the Aedes aegypti mosquito more efficiently.
A pioneering experimental demonstration of the gene drive method eradicated small populations of Anopheles gambiae.
In 2020, Oxitec's non-biting Friendly Aedes aegypti mosquito was approved for release by the US EPA and Florida state authorities.
==== Projects ====
Malaysia - In several experiments, researchers released batches of male adult Aedes mosquitos with genetic modifications to study the effects of dispersal and reproduction in natural populations. Mosquito traps were ultilized for the purpose of these studies. The process allowed for the opportunity to determine which mosquitoes were affected, and provided a group to be re-released with genetic modifications resulting in the OX513A variant to reduce reproduction. Adult mosquitoes are attracted inside the traps where they died of dehydration.
=== Factor EOF1 ===
Research is being conducted that indicates that dismantling a protein associated with eggshell organization, factor EOF1 (factor 1), which may be unique to mosquitoes, may be a means to hamper their reproduction effectively in the wild without creating a resistant population or affecting other animals.
== Legal measures ==
In Singapore, under the Control of Vectors and Pesticides Act there is a legal duty on occupants to prevent Aedes mosquitos from breeding in their homes. If breeding mosquitos are found by inspectors, occupiers are subject to a fine of 5,000 Singapore dollars or imprisonment for a term not exceeding 3 months or both.
== Proposals to eradicate mosquitoes ==
Some biologists have proposed the deliberate extinction of certain mosquito species. Biologist Olivia Judson has advocated "specicide" of thirty mosquito species by introducing a genetic element which can insert itself into another crucial gene, to create recessive "knockout genes". She says that the Anopheles mosquitoes (which spread malaria) and Aedes mosquitoes (which spread dengue fever, yellow fever, elephantiasis, zika, and other diseases) represent only 30 out of some 3,500 mosquito species; eradicating these would save at least one million human lives per year, at a cost of reducing the genetic diversity of the family Culicidae by 1%. She further argues that since species become extinct "all the time" the disappearance of a few more will not destroy the ecosystem: "We're not left with a wasteland every time a species vanishes. Removing one species sometimes causes shifts in the populations of other species — but different need not mean worse." In addition, anti-malarial and mosquito control programs offer little realistic hope to the 300 million people in developing nations who will be infected with acute illnesses each year. Although trials are ongoing, she writes that if they fail: "We should consider the ultimate swatting."
Biologist E. O. Wilson has advocated the extinction of several species of mosquito, including malaria vector Anopheles gambiae. Wilson stated, "I'm talking about a very small number of species that have co-evolved with us and are preying on humans, so it would certainly be acceptable to remove them. I believe it's just common sense."
Insect ecologist Steven Juliano has argued that "it's difficult to see what the downside would be to removal, except for collateral damage". Entomologist Joe Conlon stated that "If we eradicated them tomorrow, the ecosystems where they are active will hiccup and then get on with life. Something better or worse would take over."
However, David Quammen has pointed out that mosquitoes protect forests from human exploitation and may act as competitors for other insects. In terms of malaria control, if populations of mosquitoes were temporarily reduced to zero in a region, then this would exterminate malaria, and the mosquito population could then be allowed to rebound.
== See also ==
== Citations ==
== General references ==
Chevillon, Christine; Raymond, Michel; Guillemaud, Thomas; Lenormand, Thomas; Pasteur, Nicole (1999). "Population genetics of insecticide resistance in the mosquito Culex pipiens". Biol. J. Linn. Soc. 68 (1–2): 147–57. doi:10.1111/j.1095-8312.1999.tb01163.x.
Florida Coordinating Council on Mosquito Control (1998). Florida Mosquito Control: The State of the Mission as Defined by Mosquito Controllers, Regulators, and Environmental Managers (White Paper). University of Florida. Archived from the original on 20 June 2004.
Durden, Lance A.; Mullen, Gary L. (2002). Medical and veterinary entomology. Boston: Academic Press. ISBN 978-0-12-510451-7.
Service, M.W. (1993). Mosquito ecology: field sampling methods (2nd ed.). London: Elsevier Applied Science. ISBN 978-1-85166-798-7.
Ware, George Whitaker (1994). The pesticide book (4th ed.). Fresno, CA: Thomson Publications. ISBN 978-0-913702-58-1.
Walker, K. (April 2002). A review of control methods for African malaria vectors (PDF) (Activity Report). Vol. 108. U.S. Agency for International Development. Archived from the original (PDF) on 8 October 2006.
Martinez, Julien et al. “Differential attraction in mosquito-human interactions and implications for disease control.” Philosophical transactions of the Royal Society of London. Series B, Biological sciences vol. 376,1818 (2021): 20190811. doi:10.1098/rstb.2019.0811
Connelly, C Roxanne, and Jeff Borchert. “MOSQUITO CONTROL EMERGENCY PREPAREDNESS AND RESPONSE TO NATURAL DISASTERS.” Journal of the American Mosquito Control Association vol. 36,2 Suppl (2020): 2-4. doi:10.2987/8756- 971X-36.2S.2
Connelly, C. Roxanne; Borchert, Jeff (1 June 2020). "Mosquito Control Emergency Preparedness and Response to Natural Disasters". Journal of the American Mosquito Control Association. 36 (2s): 2–4. doi:10.2987/8756-971x-36.2s.2. ISSN 8756-971X. PMC 7871406. PMID 33575685.
Carlson, Douglas B et al. “Mosquito Control and Coastal Development: How they Have Coexisted and Matured in Florida and Australia.” Journal of the American Mosquito Control Association vol. 35,2 (2019): 123-134. doi:10.2987/18-6807.1 * Carlson, Douglas B.; Dale, Pat E. R.; Kurucz, Nina; Dwyer, Patrick G.; Knight, Jon M.; Whelan, Peter I.; Richards, D. Diane (1 June 2019). "Mosquito Control and Coastal Development: How they Have Coexisted and Matured in Florida and Australia". Journal of the American Mosquito Control Association. 35 (2): 123–134. doi:10.2987/18-6807.1. hdl:10072/396593. ISSN 8756-971X. PMID 31442134.
== External links ==
CDC info page on malaria vector control
Reducing mosquito population the environmental way | Wikipedia/Mosquito_control |
Vaccine refrigerators are designed to store vaccines and other medical products at a stable temperature to ensure they do not degrade. In developing countries with a sunny climate, solar-powered vaccine refrigerators are common.
== Requirements for vaccine refrigeration ==
Many vaccines must be stored at low temperatures, some below -15 °C, and others between 2 and 8 °C. as in an Ice Lined Refrigerator (ILR). If vaccines are not stored correctly they can lose their effectiveness.
According to the Center for Disease Control, failure to adhere to recommended specifications for storage and handling of immunobiologics can reduce or destroy their potency, resulting in inadequate or no immune response in the recipient. Maintenance of vaccine quality is the shared responsibility of all handlers of vaccines from the time a vaccine is manufactured until administration.
According to the Immunization Action Coalition, all vaccines should be stored in a refrigerator or freezer that is designed specifically for the storage of biologics or, alternatively, in a separate dedicated unit. A dorm-style combination refrigerator-freezer unit with just one exterior door has been shown to be unacceptable no matter where the vaccine was placed inside the unit. Stand-alone refrigerator or freezer units are best for storage needs. With retail pharmacies playing a major role in pneumonia, influenza and shingles immunization programs, the value of critical vaccines being stored in pharmacy refrigerators has increased. In 2022, it is not uncommon for many pharmacies to have over $100,000 of product in a single refrigerator during peak seasons.
It is estimated that $20 million is wasted annually from poor refrigeration, and up to 35% of vaccines are affected by improper storage. Accurate and uniform temperature in a refrigerator plays a key role in ensuring the life of vaccines, reagents and other biologicals. Research has shown that minor variances in temperature such as those in a household refrigerator can compromise the effectiveness of your biologicals, risking up to thousands of dollars in valuable contents.
Vaccines are also compromised through improper use of the door gasket to feed cables from data loggers and thermometers, allowing excess warm air in, and cold air out of the refrigerator or freezer. Over time this causes the compressor to work a longer duty cycle and eventually leads to failure. This can be remedied by using probe access ports, found on most clinical refrigerators and freezer. These are easy to open up and drastically reduce air intake and loss from inside the units.
== Solar powered vaccine refrigerators ==
In developing countries the electricity grid often does not reach rural areas, and is not always reliable. As keeping vaccines at the appropriate temperature is vital, Solar powered refrigerators are a cost-effective alternative that can be highly reliable. A typical system will use a solar photovoltaic panel to generate electricity from sunlight, and a deep cycle battery to store energy for operation overnight, although newer fridges which have revolutionary Sure Chill Technology or Direct Drive technology do not need batteries to maintain temperatures for many days without sunlight.
== WHO prequalified products ==
The World Health Organization Immunization Devices Prequalification (IMD-PQS) programme maintains a list of immunization cold chain equipment that it has prequalified for procurement and use by national immunization programmes of the WHOs Expanded Programme on Immunization (EPI), including refrigerators.
IMD-PQS prequalifies products based on rigorous performance specifications that it develops in collaboration with national immunization programmes and in consultation with product manufacturers, to ensure that products address the specific needs of immunization programmes’ operating environments.
== See also ==
Solar power
Vaccines
== References ==
== External links ==
Solar vaccine refrigerators in Nigeria Archived 2008-11-09 at the Wayback Machine
Roemer Industries Inc., Solar vaccine refrigerator manufacturer in California USA | Wikipedia/Vaccine_refrigerator |
Many vaccines require refrigeration to remain active, and the lack of infrastructure to maintain the cool chain to reliably bring vaccines into more remote areas of developing countries poses a serious challenge to national immunization programs. Portable vaccine cooler units have been proposed by several technologists. The WHO Performance, Quality and Safety (PQS) programme is a driver of the technology.
== Technology development ==
In 2005 Ian Tansley of Sure Chill designed an ice-chest vaccine cooler regulated by the density of water. Since water has greatest density at around 4 °C, putting the vaccine chamber at the bottom of a thermo-syphon regulates the temperature at between 2 °C and 8 °C, as long as there is ice and the heat-exchange capacity is not overloaded. Sure Chill claimed to be WHO approved and in use for vaccine storage in 46 countries.
A refrigeration device was shown for this purpose by Adam Grosser at a TED Talk in 2007, but had not been produced commercially as of 2020. Grosser's proposed device uses exposure to a cooking fire for 30 minutes to store heat. After a cooling period of an hour, the device is placed into a 15-litre container, which contains the vaccine. His concept calls for a 24-hour re-cycle period.
It was revealed in March 2008 that another class of long-term Vaccine Cooler is based around an Ice Box with separate Ice and Vaccine chambers. Using ice as the energy storage device allows the Vaccine Cooler to operate for long periods without power: separating the vaccine chamber from the ice chamber allows temperature regulation while avoiding the need for special packing and conditioning of the cold packs. Suggestions have included the use of a regulated heat pipe to connect the vaccine chamber and the ice chamber.
In September 2008 it was reported that Malcolm McCulloch of Oxford University was heading a three-year project to develop more robust appliances that could be used in locales lacking electricity, and that his team had completed a prototype of his renewal of the Einstein refrigerator. He was quoted as saying that improving the design and changing the types of gases used might allow the design's efficiency to be quadrupled. The three working fluids in this design are water, ammonia and butane.
The Free Piston Stirling Cooler, a type of mechanical refrigerator, was brought to market before 2010 by Twinbird Corporation of Japan. In 2016 Will Broadway won the James Dyson Award for a vaccine cooler based on a miniaturisation of the bi-fluid Icyball technology. Broadway's design uses electricity or propane as the heat source. As of August 2019, Broadway claimed an 88-hour cool-life under WHO PQS test conditions, whereas competitor products could only meet a nine-hour cool-life.
== References == | Wikipedia/Vaccine_cooler |
Cysteine-rich secretory proteins, often abbreviated as CRISPs, are a group of glycoproteins. They are a subgroup of the CRISP, antigen 5 and Pr-1 (CAP) protein superfamily and also contain a domain related to the ShK toxins. They are substantially implicated in the functioning of the mammalian reproductive system. CRISPs are also found in a variety of snake venoms where they inhibit both smooth muscle contraction and cyclic nucleotide-gated ion channels.
== Structure ==
CRISPs contain two domains joined by a hinge region. The larger domain is a CAP-like 'Pathogenesis-related 1' domain (PR-1), followed by the smaller ShK-like 'Cysteine-Rich Domain' (CRD).
CRISPs are glycoproteins, with a number of carbohydrate glycans covalently attached to amino acid side-chains on their surface via glycosylation. The primary structure is also rich in cysteine that form disulfide bonds, particularly in the hinge region and CRD.
== Mammalian reproduction ==
CRISPs are found in the testes and epididymis of mammals, and are also involved in the process of fertilisation. In the spermatogenesis process (development of the spermatozoa in the testis), the CRISP2 protein is incorporated into the acrosome where it is believed to be involved in the adhesion of germ cells with Sertoli cells. CRISP2 also forms part of the sperm tail where it is thought to be involved in regulating flagellar beating. Proteins CRISP1 and CRISP4 are both found in the epididymis where they are also incorporated within the spermatozoa as it matures. Protein CRISP3 is found in seminal fluid, excreted from the prostate although its function is unknown.
During capacitation, the penultimate stage of spermatozoa maturation, the acrosomal sperm head membrane is destabilised to allow greater binding between oocyte and sperm. CRISP1 binds to surface of the sperm leading to a quiescent state of storage prior to capacitation. The mechanism is believed to involve inhibition of ion channel activity, similar to the mechanism of action of the other major function of CRISPs in snake venom. Research also suggests that CRISPs are involved in the oocyte-sperm binding needed for fertilisation. Given the involvement of CRISPs in several stages of human reproduction, it is unsurprising that applications in treatment of infertility and as contraceptives are being actively investigated.
== Snake venom ==
CRISPs are found in the venom of a wide variety of snake species. Examples include ablomin from the Japanese Mamushi snake (Gloydius blomhoffii, formerly Agkistrodon blomhoffi), latisemin from the Erabu sea snake (Laticauda semifasciata), ophanin from the King Cobra (Ophiophagus hannah), piscivorin from the Eastern Cottonmouth (Agkistrodon piscivorus) and triflin from the Habu snake (Trimeresurus flavoviridis) – each of these proteins is named for the snake species in which it was discovered. These venoms are toxic due to their blocking of calcium channels and also because they reduce potassium-induced smooth muscle contraction. Among the four CRISPs isolated from the Monocled Cobra (Naja kaouthia) and the three from the Egyptian Cobra (Naja haje), ion channel activity occurred by blocking of cyclic nucleotide-gated ion channels. One of the N. haje CRISPs was the first example of an acidic CRISP in reptilian venom. The selective ion channel activity of snake CRISPs, coupled with the variety of CRISPs available as the pool of venom proteins appears highly variable between (at least) cobra species, provide a valuable tool for probing the mechanisms of ion channel activity.
== References == | Wikipedia/Cysteine-rich_secretory_protein |
An academic clinical trial is a clinical trial not funded by pharmaceutical or biotechnology company for commercial ends but by public-good agencies (usually universities or medical trusts) to advance medicine. These trials are a valuable component of the health care system; they benefit patients and help determine the safety and efficacy of drugs and devices, and play an important role in the checks and balances that regular commercially oriented clinical trials.
A typical area of academic clinical trials is the advancement and optimization of already existing therapies. Thus, academic clinical trials may for instance test how a combination of registered drugs may improve treatment outcomes; or they may apply registered treatments in additional, less frequent indications. Such research questions are not a primary focus of for-profit companies, and thus these trials are typically initiated by individual investigators or academic research organizations.
There are many different organizations which have an interest in academic clinical trials and facilitate or take part in their conduct. These organizations include:
Hospitals, universities, researchers and institutions who view trials as a source of income and prestige, and receive private, charitable and governmental funding.
Pharmaceutical or biotech companies who view the development and commercialization of treatments as their business.
Regulators who wish to ensure treatments are safe and work effectively.
Patients and patients' organizations and associations who want faster access to advanced treatments.
Academic clinical trials are run at academic sites, such as medical schools, academic hospitals, and universities; and non-academic sites which may be managed by so-called site management organizations (SMOs). Site management organizations are for-profit organizations which enlist and manage the physician practice sites that actually recruit and follow patients enrolled in clinical trials. In some cases, academic members participate in clinical trials as members of SMOs.
== See also ==
Clinical investigator
Clinical monitoring
Clinical research associate
Clinical site
Clinical trial protocol
Clinical trials publication
EORTC (European Organisation for Research and Treatment of Cancer)
== References == | Wikipedia/Academic_clinical_trial |
The DPT vaccine or DTP vaccine is a class of combination vaccines to protect
against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus (lockjaw). The vaccine components include diphtheria and tetanus toxoids, and either killed whole cells of the bacterium that causes pertussis or pertussis antigens. The term toxoid refers to vaccines which use an inactivated toxin produced by the pathogen which they are targeted against to generate an immune response. In this way, the toxoid vaccine generates an immune response which is targeted against the toxin which is produced by the pathogen and causes disease, rather than a vaccine which is targeted against the pathogen itself. The whole cells or antigens will be depicted as either "DTwP" or "DTaP", where the lower-case "w" indicates whole-cell inactivated pertussis and the lower-case "a" stands for "acellular". In comparison to alternative vaccine types, such as live attenuated vaccines, the DTP vaccine does not contain any live pathogen, but rather uses inactivated toxoid (and for pertussis, either a dead pathogen or pure antigens) to generate an immune response; therefore, there is not a risk of use in populations that are immune compromised since there is not any known risk of causing the disease itself. As a result, the DTP vaccine is considered a safe vaccine to use in anyone and it generates a much more targeted immune response specific for the pathogen of interest.
In the United States, the DPT (whole-cell) vaccine was administered as part of the childhood vaccines recommended by the Centers for Disease Control and Prevention (CDC) until 1996, when the acellular DTaP vaccine was licensed for use.
== History ==
Diphtheria and tetanus toxoids and whole-cell pertussis (DTP; now also "DTwP" to differentiate from the broader class of triple-combination vaccines) vaccination was licensed in 1949. Since the introduction of the combination vaccine, there has been an extensive decline in the incidence of pertussis, or whooping cough, the disease which the vaccine protects against. Additionally, the rates of disease have continued to decline as more extensive immunization strategies have been implemented, including booster doses and increased emphasis on increasing health literacy.
In the 20th century, the advancements in vaccinations helped to reduce the incidence of childhood pertussis and had a dramatically positive effect on the health of populations in the United States. However, in the early 21st century, reported instances of the disease increased 20-fold due to a downturn in the number of immunizations received and resulted in numerous fatalities. During the 21st century, many parents declined to vaccinate their children against pertussis for fear of perceived side effects, despite scientific evidence showing vaccines to be highly effective and safe. In 2009, the journal Pediatrics concluded the largest risk among unvaccinated children was not the contraction of side effects, but rather the disease that the vaccination aims to protect against.
DTP vaccines with acellular pertussis (DTaP; see below) were introduced in the 1990s. The reduced range of antigens causes fewer side effects, but results in a more expensive, shorter-lasting, and possibly less protective vaccine compared to DTwP. High-income countries have mostly switched to DTaP. As of 2023, global production of aP remains limited.
=== Vaccination rates ===
In 2016, the CDC reported that 80.4% of children in the US had received four or more DTaP vaccinations by 2 years of life. Vaccination rates for children aged 13–17 with one or more TDaP shots was 90.2% in 2019. Only 43.6% of adults (older than 18) have received a TDaP shot in the last 10 years. The CDC aimed to increase vaccination rate among 2-year-olds from 80.4% to 90.0%
The World Health Organization (WHO) estimated that 89% of people globally had received at least one dose of DTP vaccine and 84% had received three doses of the vaccine, completing the WHO-recommended primary series (DTP3). The WHO also tracks the DTP3 completion rate among one-year-olds on a yearly basis. Yearly DTP3 completion rate is considered a good proxy for the completeness of childhood vaccination in general.
== Combination vaccines with acellular pertussis ==
DTaP and Tdap are both combination vaccines against diphtheria, tetanus, and pertussis. The "a" indicates that the pertussis toxoids are acellular, while the lower-case "d" and "p" in "Tdap" indicate smaller concentrations of diphtheria toxoids and pertussis antigens.
=== DTaP ===
DTaP (also DTP and TDaP) is a combination vaccine against diphtheria, tetanus, and pertussis, in which the pertussis component is acellular. This is in contrast to whole-cell, inactivated DTP (or DTwP). The acellular vaccine uses selected antigens of the pertussis pathogen to induce immunity. Because it uses fewer antigens than the whole-cell vaccines, it is considered to cause fewer side effects, but it is also more expensive. Research suggests that the DTwP vaccine is more effective than DTaP in conferring immunity, because DTaP's narrower antigen base is less effective against current pathogen strains.
=== Tdap ===
Tdap (also TDP) is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine. It was licensed in the United States for use in adults and adolescents on 10 June 2005. Two Tdap vaccines are available in the US. In January 2011, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended the use of Tdap in adults of all ages, including those age 65 and above. In October 2011, in an effort to reduce the burden of pertussis in infants, the ACIP recommended that unvaccinated pregnant women receive a dose of Tdap. On 24 October 2012, the ACIP voted to recommend the use of Tdap during every pregnancy.
The ACIP and Canada's National Advisory Committee on Immunization (NACI) recommended that both adolescents and adults receive Tdap in place of their next Td booster (recommended to be given every ten years). Tdap and Td can be used as prophylaxis for tetanus in wound management. People who will be in contact with young infants are encouraged to get Tdap even if it has been less than five years since Td or TT to reduce the risk of infants being exposed to pertussis. NACI suggests intervals shorter than five years can be used for catch-up programs and other instances where programmatic concerns make five-year intervals difficult.
The WHO recommends a pentavalent vaccine, combining the DTP vaccine with vaccines against Haemophilus influenzae type B and hepatitis B. Evidence on how effective this pentavalent vaccine is compared to the individual vaccines has not yet been determined.
A 2019 study found that state requirements mandating the use of the Tdap vaccine "increased Tdap vaccine take-up and reduced pertussis (whooping cough) incidence by about 32%."
== Related combination vaccines ==
=== Excluding pertussis ===
DT and Td vaccines lack the pertussis component. The Td vaccine is administered to children over the age of seven as well as to adults. It is most commonly administered as a booster shot every 10 years. The Td booster shot may also be administered as protection from a severe burn or dirty wound. The DT vaccine is given to children under the age of seven who are unable to receive the pertussis antigen in the DTaP vaccine due to a contraindication.
=== Additional targets ===
In the United States, a combined inactivated polio (IPV), DTaP, and hepatitis B DTaP-IPV-HepB vaccine is available for children. In the UK, all babies born on or after 1 August 2017 are offered a hexavalent vaccine: DTaP, IPV, Haemophilus influenzae, and hepatitis B (DTaP-Hib-HepB-IPV in short).
As of 2023, most of the DTP vaccine procured by UNICEF is of the DTwP-HepB-Hib (pentavalent whole-cell) type. The UNICEF plans to procure the DTwP-HepB-Hib-IPV (hexavalent whole-cell) vaccine starting in 2024.
== Contraindications ==
The DPT vaccine should be avoided in persons who experienced a severe allergic reaction, such as anaphylaxis, to a past vaccine containing tetanus, diphtheria, or pertussis. It should also be avoided in persons with a known severe allergy to an ingredient in the vaccine. If the reaction was caused by tetanus toxoids, the CDC recommends considering a passive immunization with tetanus immune globulin (TIG) if a person has a large or unclean wound. The DPT vaccine should also be avoided if a person developed encephalopathy (seizures, coma, declined consciousness) within seven days of receiving any pertussis-containing vaccine and the encephalopathy cannot be traced to another cause. A DT vaccine is available for children under the ages of seven who have contraindications or precautions to pertussis-containing vaccines.
== Side effects ==
=== DTaP ===
Common side effects include soreness where the shot was given, fever, irritability, tenderness, loss of appetite, and vomiting. Most side effects are mild to moderate and may last from one to three days. More serious but rare reactions after a DTaP vaccination may include seizures, lowered consciousness, or a high fever over 105 °F (41 °C). Allergic reactions are uncommon, but are medical emergencies. Signs of an allergic reaction include hives, dyspnea, wheezing, swelling of face and throat, syncope, and tachycardia and the child should be rushed to the nearest hospital.
=== Tdap ===
Common side effects include pain or swelling where the shot was given, mild fever, headache, tiredness, nausea, vomiting, diarrhea, and stomach ache. Allergic reactions are possible and have the same presentation and indications as described above for allergic reactions in DTaP. Any individual who has experienced a life-threatening allergic reaction after receiving a previous dose of diphtheria, tetanus, or pertussis containing vaccine should not receive the Tdap vaccination.
In pregnant women, research suggests that Tdap administration may be associated with an increased risk of chorioamnionitis, a placental infection. Increased incidence of fever is also noted in pregnant women. Despite the observed increase in incidence of chorioamnionitis in pregnant women following Tdap administration, there has been no observed increase in the incidence of preterm birth, for which chorioamnionitis is a risk factor. Research has not discerned an association between Tdap administration during pregnancy and other serious pregnancy complications such as neonatal death and stillbirth. An association between Tdap administration during pregnancy and pregnancy-related hypertensive disorders (such as pre-eclampsia) has not been identified.
== Immunization schedules and requirements ==
=== Australia ===
In Australia, the DTP vaccine is part of the National Immunisation Program (NIP). The vaccine is administered to infants in a series of doses: the first three doses are given at 2, 4, and 6 months of age, followed by a fourth dose at 18 months and a fifth dose at 4 years. Adolescents receive a single booster dose at 12-13 years.
Adults are recommended to receive a dTpa booster every 10 years, especially those in close contact with infants. Pregnant women are advised to receive a dTpa booster during each pregnancy, ideally between 20-32 weeks of gestation, to protect newborns from pertussis.
=== France ===
In France, children are given DTaP-Hib-HepB-IPV vaccines at 2 months (first dose) and 4 months (second dose) with a booster at 11 months of age. A tetravalent booster for diphtheria, pertussis, tetanus and poliomyelitis is given at 6 years, at 11–13 years, then at 25, 45, 65 years of age, then every 10 years.
=== Netherlands ===
In the Netherlands, pertussis is known as kinkhoest and DKTP refers to the DTaP-IPV combination vaccine against diphtheria, kinkhoest, tetanus, and polio. DTaP is given as part of the National Immunisation Programme.
=== United Kingdom ===
In the United Kingdom, Td/IPV is called the "3-in-1 teenage booster" and protects against tetanus, diphtheria and polio. It is given by the NHS to all teenagers aged 14 (the hexavalent vaccine is given to infants and provides the first stage of protection against diphtheria, tetanus, and polio, as well as pertussis, Haemophilus influenzae type B and hepatitis B). Subsequent boosters are recommended for foreign travellers where more than 10 years has passed since their last booster. This is provided on the NHS free of charge due to the significant risk that an imported case of polio could pose to public health in Britain.
=== United States ===
The standard immunization regimen for children within the United States is five doses of DTaP between the ages of two months and fifteen years. To be considered fully vaccinated, the Centers for Disease Control and Prevention (CDC) typically requires five doses of Tdap. The CDC recommends that children receive their first dose at two months, the second dose at four months, the third dose at six months, the fourth dose between 15 and 18 months, and the fifth dose between 4–6 years. If the fourth dose of the DTaP immunization regimen falls on or subsequent to the recipient's fourth birthday, the CDC states that only four doses are required to be fully vaccinated. In the instance that an individual under 18 has not received the DTaP vaccine, individuals should be vaccinated on the schedule in accordance with the vaccination "catch up schedule" provided by the CDC.
Infants younger than twelve months of age, specifically less than three months of age, are at highest risk of acquiring pertussis. In U.S., there is no current tetanus-diphtheria-pertussis vaccination (whooping cough) recommended or licensed for new born infants. As a result, in their first few months of life, unprotected infants are at highest risk of life-threatening complications and infections from pertussis. Infants should not receive pertussis vaccination younger than six weeks of age. Ideally, Infants should receive DTaP (name of whooping cough vaccine for children from age 2 months through 6 years) at 2, 4, 6 months of age and they are not protected until the full series is completed. To protect infants younger than twelve months of age not vaccinated with Tdap against pertussis, ACIP also recommends adults (e.g., parents, siblings, grandparents, childcare providers, and healthcare personnel) and children to receive Tdap at least two weeks before being in contact with the infant.
The CDC recommends that adults who have received their childhood DTP series receive a Td or Tdap booster every ten years. For adults that have not received the DTP series, the CDC recommends a three-part vaccine series followed by a Td or Tdap booster every ten years.
==== In pregnancy ====
According to the CDC's Advisory Committee on Immunization Practices (ACIP) guidelines, one dose of Tdap is recommended during each pregnancy to ensure protection against pertussis in newborn infants. Optimal timing to administer a dose of Tdap during each pregnancy is between 27 through 36 weeks gestation. If Tdap is administered early in pregnancy, it is not recommended to administer again during the 27 through 36 weeks gestation period as only one dose is recommended during pregnancy. In October 2022, Boostrix (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed [Tdap]) was approved for immunization during the third trimester of pregnancy to prevent pertussis, commonly known as whooping cough, in infants younger than two months of age.
Pregnant women who have not previously vaccinated with Tdap (i.e., have never received DTP, DTaP, or DT as child or Td or TT as an adult) are recommended to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus. In such cases, administration of Tdap is recommended after 20 weeks' gestation, and in earlier pregnancy a single dose of Tdap can be substituted for one dose of Td, and then the series completed with Td. For pregnant women not previously vaccinated with Tdap, if Tdap is not administered during pregnancy, it should be administered immediately postpartum. Postpartum administration of TDaP is not equivalent to administration of the vaccination during pregnancy. Because the vaccine is administered postpartum, the mother is unable to develop antibodies that can be transferred to the infant in utero, consequently, leaving the infant vulnerable to the diseases preventable by the Tdap Vaccine. Postpartum administration of the TdaP vaccine to the mother seeks to reduce the likelihood that the mother will contract disease that can be subsequently passed on the infant, albeit there will still be a two-week period prior to the protective effects of the vaccine setting in. Postpartum administration is an extension of the concept of "cocooning", a term that refers to the full vaccination of all individuals that may come into direct contact with the infant. Cocooning, like postpartum Tdap administration, is not recommended by the CDC. Cocooning depends on ensuring full vaccination of all individuals that the infant may come into contact with, and there may be financial, administrative or personal barriers that preclude full and timely vaccination of all individuals within the "cocoon".
== Brand names ==
=== Australia ===
=== United Kingdom ===
Brand names in the United Kingdom include Revaxis (Sanofi Pasteur).
=== United States ===
As of January 2020, there are six DTaP vaccines and two Tdap vaccines licensed and available for use in the United States. All of them are indicated as childhood vaccinations with the schedules as follows:
== References ==
== Further reading ==
=== Diphtheria ===
World Health Organization (2009). The immunological basis for immunization : module 2: diphtheria — update 2009. World Health Organization (WHO). hdl:10665/44094. ISBN 9789241597869.
Ramsay M, ed. (2013). "Chapter 15: Diphtheria". Immunisation against infectious disease. Public Health England.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
=== Pertussis ===
World Health Organization (2017). The immunological basis for immunization series: module 4: pertussis, update 2017. World Health Organization (WHO). hdl:10665/259388. ISBN 9789241513173.
Ramsay M, ed. (2013). "Chapter 24: Pertussis". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 16: Pertussis". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 10: Pertussis". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
=== Tetanus ===
World Health Organization (2018). The immunological basis for immunization series: module 3: tetanus: update 2018. World Health Organization (WHO). hdl:10665/275340. ISBN 9789241513616.
Ramsay M, ed. (2013). "Chapter 30: Tetanus". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 21: Tetanus". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 16: Tetanus". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
"Tdap (Tetanus, Diphtheria, Pertussis) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 19 May 2023.
"DTaP (Diphtheria, Tetanus, Pertussis) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 21 July 2023.
"DTaP/Tdap/Td ACIP Vaccine Recommendations". U.S. Centers for Disease Control and Prevention (CDC). 24 September 2024.
Tetanus Toxoid at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-Pertussis Vaccine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-acellular Pertussis Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/DTaP_vaccine |
Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. Oral polio vaccines cause about three cases of vaccine-associated paralytic poliomyelitis per million doses given. This compares with 5,000 cases per million who are paralysed following a polio infection. Both types of vaccine are generally safe to give during pregnancy and in those who have HIV/AIDS, but are otherwise well. However, the emergence of circulating vaccine-derived poliovirus (cVDPV), a form of the vaccine virus that has reverted to causing poliomyelitis, has led to the development of novel oral polio vaccine type 2 (nOPV2), which aims to make the vaccine safer and thus stop further outbreaks of cVDPV.
The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus that people drank. The vaccine was not approved for use in the United States, but was used successfully elsewhere. The success of an inactivated (killed) polio vaccine, developed by Jonas Salk, was announced in 1955. Another attenuated live oral polio vaccine, developed by Albert Sabin, came into commercial use in 1961.
Polio vaccine is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Interruption of person-to-person transmission of the virus by vaccination is important in global polio eradication, since no long-term carrier state exists for poliovirus in individuals with normal immune function, polio viruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period appears to be remote. The two types of vaccine are inactivated polio vaccine (IPV) and oral polio vaccine (OPV).
=== Inactivated ===
When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of poliovirus after two doses, and at least 99% are immune following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to protect for many years. IPV replaced the oral vaccine in many developed countries in the 1990s mainly due to the (small) risk of vaccine-derived polio in the oral vaccine.
=== Attenuated ===
Oral polio vaccines were easier to administer than IPV, as they eliminated the need for sterile syringes, so were more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.
One dose of trivalent OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients. Three doses of live-attenuated OPV produce protective antibodies to all three poliovirus types in more than 95% of recipients. As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic. OPV does not require special medical equipment or extensive training. Attenuated poliovirus derived from the OPV is excreted for a few days after vaccination, potentially infecting and thus indirectly inducing immunity in unvaccinated individuals, thus amplifying the effects of the doses delivered. Taken together, these advantages have made it the favored vaccine of many countries, and it has long been preferred by the global eradication initiative.
The primary disadvantage of OPV derives from its inherent nature. As an attenuated but active virus, it can induce vaccine-associated paralytic poliomyelitis (VAPP) in roughly one individual per every 2.7 million doses administered. The live virus can circulate in under-vaccinated populations (termed either variant poliovirus or circulating vaccine-derived poliovirus, cVDPV), and over time can revert to a neurovirulent form causing paralytic polio. This genetic reversal of the pathogen to a virulent form takes a considerable time and does not affect the person who was originally vaccinated. With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus.
Until recent times, a trivalent OPV containing all three viral strains was used, and had nearly eradicated polio infection worldwide. With the complete eradication of wild poliovirus type 2 this was phased out in 2016 and replaced with bivalent vaccine containing just types 1 and 3, supplemented with monovalent type 2 OPV in regions where cVDPV type 2 was known to circulate. The switch to the bivalent vaccine and associated missing immunity against type 2 strains, among other factors, led to outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), which increased from two cases in 2016 to 1037 cases in 2020.
A novel OPV2 vaccine (nOPV2), which has been genetically modified to reduce the likelihood of disease-causing activating mutations, was granted emergency licencing in 2021, and subsequently full licensure in December 2023. This has greater genetic stability than the traditional oral vaccine and is less likely to revert to a virulent form. Genetically stabilised vaccines targeting poliovirus types 1 and 3 are in development, with the intention that these will eventually completely replace the Sabin vaccines.
=== Schedule ===
In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV doses and at least one IPV dose starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with more than 90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at two months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before two months of age.
== Side effects ==
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. They are generally safe to be given to pregnant women and those who have HIV/AIDS, but are otherwise well.
=== Allergic reaction to the vaccine ===
Inactivated polio vaccine can cause an allergic reaction in a few people, since the vaccine contains trace amounts of antibiotics, streptomycin, polymyxin B, and neomycin. It should not be given to anyone who has an allergic reaction to these medicines. Signs and symptoms of an allergic reaction, which usually appear within minutes or a few hours after receiving the injected vaccine, include breathing difficulties, weakness, hoarseness or wheezing, heart-rate fluctuations, skin rash, and dizziness.
=== Vaccine-associated paralytic polio ===
A potential adverse effect of the Sabin OPV is caused by its known potential to recombine to a form that causes neurological infection and paralysis. The Sabin OPV results in vaccine-associated paralytic poliomyelitis (VAPP) in around one individual per every 2.7 million doses administered, with symptoms identical to wild polio. Due to its improved genetic stability, the novel OPV (nOPV) has a reduced risk of this occurring.
=== Contamination concerns ===
In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40), which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents. More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma. However, SV40 has not been determined to cause these cancers.
SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963; it is not found in the OPV form. Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963, when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40. Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated, meaning hundreds of millions more may have been exposed to SV40.
In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40. Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not. The question of whether SV40 causes cancer in humans remains controversial, however, and the development of improved assays for detection of SV40 in human tissues will be needed to resolve the controversy.
During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains was the safest. Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi). The results of these human trials have been controversial, and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted. By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns has evolved due to lack of adequate information, often relating to fears that the vaccine might induce sterility. The disease has since resurged in Nigeria and several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.
== Manufacture ==
=== Inactivated ===
The Salk vaccine, IPV, is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin. The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome.
In the United States, the vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine. In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.
=== Attenuated ===
OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome. Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their attenuated vaccine strains. In 1958, the NIH created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in the late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated the safety and high efficacy of the vaccine. Based on these results, the Sabin strains were chosen for worldwide distribution. Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain. The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site, which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV (TOPV) was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine. A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.
OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.
== History ==
In a generic sense, vaccination works by priming the immune system with an "immunogen". Stimulating immune response, by use of an infectious agent, is known as immunization. The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.
The development of two polio vaccines led to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States occurred in 1979, with an outbreak among the Amish in several Midwest states.
=== 1930s ===
In the 1930s, poliovirus was perceived as especially terrifying, as little was known of how the disease was transmitted or how it could be prevented. This virus was also notable for primarily impacting affluent children, making it a prime target for vaccine development, despite its relatively low mortality and morbidity. Despite this, the community of researchers in the field thus far had largely observed an informal moratorium on any vaccine development, as it was perceived to present too high a risk for too little likelihood of success.
This shifted in the early 1930s, when American groups took up the challenge: Maurice Brodie led a team from the public health laboratory of the city of New York and John A. Kolmer collaborated with the Research Institute of Cutaneous Medicine in Philadelphia. The rivalry between these two researchers lent itself to a race-like mentality, which combined with a lack of oversight of medical studies, was reflected in the methodology and outcomes of each of these early vaccine-development ventures.
==== Kolmer's live vaccine ====
Kolmer began his vaccine development project in 1932 and ultimately focused on producing an attenuated or live virus vaccine. Inspired by the success of vaccines for rabies and yellow fever, he hoped to use a similar process to denature the polio virus. To go about attenuating his polio vaccine, he repeatedly passed the virus through monkeys. Using methods of production that were later described as "hair-raisingly amateurish, the therapeutic equivalent of bath-tub gin", Kolmer ground the spinal cords of his infected monkeys and soaked them in a salt solution. He then filtered the solution through mesh, treated it with ricinolate, and refrigerated the product for 14 days to ultimately create what would later be prominently critiqued as a "veritable witches brew".
In keeping with the norms of the time, Kolmer completed a relatively small animal trial with 42 monkeys before proceeding to self-experimentation in 1934. He tested his vaccine upon himself, his two children, and his assistant. He gave his vaccine to just 23 more children before declaring it safe and sending it out to doctors and health departments for a larger test of efficacy. By April 1935, he was able to report having tested the vaccine on 100 children without ill effect. Kolmer's first formal presentation of results did not come about until November 1935, when he presented the results of 446 children and adults he had vaccinated with his attenuated vaccine. He also reported that together the Research Institute of Cutaneous Medicine and the Merrell Company of Cincinnati (the manufacturer who held the patent for his ricinoleating process) had distributed 12,000 doses of vaccine to some 700 physicians across the United States and Canada. Kolmer did not describe any monitoring of this experimental vaccination program, nor did he provide these physicians with instructions in how to administer the vaccine or how to report side effects. Kolmer dedicated the bulk of his publications thereafter to explaining what he believed to be the cause of the 10+ reported cases of paralytic polio following vaccination, in many cases in towns where no polio outbreak had occurred. Six of these cases had been fatal. Kolmer had no control group, but asserted that many more children would have gotten sick.
==== Brodie's inactivated vaccine ====
At nearly the same time as Kolmer's project, Maurice Brodie had joined immunologist William H. Park at the New York City Health Department, where they worked together on poliovirus. With the aid of grant funding from the President's Birthday Ball Commission (a predecessor to what would become the March of Dimes), Brodie was able to pursue the development of an inactivated or "killed virus" vaccine. Brodie's process also began by grinding the spinal cords of infectious monkeys and then treating the cords with various germicides, ultimately finding a solution of formaldehyde to be the most effective. By 1 June 1934, Brodie was able to publish his first scholarly article describing his successful induction of immunity in three monkeys with inactivated poliovirus. Through continued study on an additional 26 monkeys, Brodie ultimately concluded that administration of live virus vaccine tended to result in humoral immunity, while administration of killed virus vaccine tended to result in tissue immunity.
Soon after, following a similar protocol to Kolmer's, Brodie proceeded with self-experimentation upon himself and his co-workers at the NYC Health Department laboratory. Brodie's progress was eagerly covered by popular press, as the public hoped for a successful vaccine to become available. Such reporting did not make mention of the 12 children in a New York City Asylum who were subjected to early safety trials. As none of the subjects experienced ill effects, Park, described by contemporaries as "never one to let grass grow under his feet", declared the vaccine safe. When a severe polio outbreak overwhelmed Kern County, California, it became the first trial site for the new vaccine on very short notice. Between November 1934 and May 1935, over 1,500 doses of the vaccine were administered in Kern County. While initial results were very promising, insufficient staffing and poor protocol design left Brodie open to criticism when he published the California results in August 1935. Through private physicians, Brodie also conducted a broader field study, including 9,000 children who received the vaccine and 4,500 age- and location-matched controls who did not receive a vaccine. Again, the results were promising. Of those who received the vaccine, only a few went on to develop polio. Most had been exposed before vaccination and none had received the full series of vaccine doses being studied. Additionally, a polio epidemic in Raleigh, North Carolina, provided an opportunity for the U.S. Public Health Service to conduct a highly structured trial of the Brodie vaccine using funding from the Birthday Ball Commission.
==== Academic reception ====
While their work was ongoing, the larger community of bacteriologists began to raise concerns regarding the safety and efficacy of the new poliovirus vaccines. At this time, very little oversight of medical studies occurred and the ethical treatment of study participants largely relied upon moral pressure from peer academic scientists. Brodie's inactivated vaccines faced scrutiny from many who felt killed virus vaccines could not be efficacious. While researchers were able to replicate the tissue immunity he had produced in his animal trials, the prevailing wisdom was that humoral immunity was essential for an efficacious vaccine. Kolmer directly questioned the killed virus approach in scholarly journals. Kolmer's studies, however, had raised even more concern with increasing reports of children becoming paralysed following vaccination with his live-virus vaccine and notably, with paralysis beginning at the arm rather than the foot in many cases. Both Kolmer and Brodie were called to present their research at the Annual Meeting of the American Public Health Association in Milwaukee, Wisconsin, in October 1935. Additionally, Thomas M. Rivers was asked to discuss each of the presented papers as a prominent critic of the vaccine development effort. This resulted in the APHA arranging a symposium on poliomyelitis to be delivered at the annual meeting of their southern branch the following month. During the discussion at this meeting, James Leake of the U.S. Public Health Service stood to immediately present clinical evidence that the Kolmer vaccine had caused several deaths and then allegedly accused Kolmer of being a murderer. As Rivers recalled in his oral history, "All hell broke loose, and it seemed as if everybody was trying to talk at the same time ... Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting." In response to the attacks from all sides, Brodie was reported to have stood up and stated, "It looks as though, according to Dr. Rivers, my vaccine is no good, and according to Dr. Leake, Dr Kolmer's is dangerous." Kolmer simply responded by stating, "Gentlemen, this is one time I wish the floor would open up and swallow me." Ultimately, Kolmer's live vaccine was undoubtedly shown to be dangerous and had already been withdrawn in September 1935 before the Milwaukee meeting. While the consensus of the symposium was largely skeptical of the efficacy of Brodie's vaccine, its safety was not in question and the recommendation was for a much larger, well-controlled trial. However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and another attempt would not be made for nearly 20 years.
While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, but the basic science and technology of the time were insufficient to understand and use this breakthrough. Brodie's work using formalin-inactivated virus later became the basis for the Salk vaccine, but he did not live to see this success. Brodie was fired from his position within three months of the symposium's publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors before he died in 1939. Kolmer, already an established and well-respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks until his retirement in 1957.
=== 1948 ===
A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that a few unused tubes. He retrieved a sample of mouse brain infected with poliovirus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized in 1954 for their efforts with a Nobel Prize in Physiology or Medicine. Other important advances that led to the development of polio vaccines included the identification of three poliovirus serotypes (poliovirus type 1 – PV1, or Mahoney; PV2, Lansing; and PV3, Leon), the finding that before paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma globulin protects against paralytic polio.
=== 1950–1955 ===
During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950. His vaccine, however, being a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use. On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for physically and mentally disabled people located in New York. After the child had no side effects, Koprowski enlarged his experiment to include 19 other children.
==== Jonas Salk ====
The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA. Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto. Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.
Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and eventually involved 1.8 million children, in 44 states from Maine to California. By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.
The results of the field trial were announced on 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). The Salk vaccine had been 60–70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio. Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S., following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957. By 1961 only 161 cases were recorded in the United States.
A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.
==== Safety incidents ====
In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with the Salk polio vaccine from the Cutter pharmaceutical company, with the paralysis starting in the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 409,000 children in the western and midwestern United States.
Later investigations showed that the Cutter vaccine had caused 260 cases of polio, killing 11. In response, the Surgeon General pulled all polio vaccines made by Cutter Laboratories from the market, but not before 260 cases of paralytic illness had occurred. Eli Lilly, Parke-Davis, Pitman-Moore, and Wyeth polio vaccines were also reported to have paralyzed numerous children. It was soon discovered that some lots of Salk polio vaccine made by Cutter, Wyeth, and the other labs had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in the polio vaccine, leading to a drop in vaccination rates.
=== 1961 ===
At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico and the Soviet Union, Koprowski in the Congo and Poland. In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus. In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship of Peoples, described as the Soviet Union's highest civilian honor. Sabin's oral vaccine using live virus came into commercial use in 1961.
Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.
=== 1987 ===
An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there. The first dose of the polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age. The timing of the third dose depends on the vaccine formulation but should be given between 6 and 18 months of age. A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry. In some countries, a fifth vaccination is given during adolescence. Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries. In 2002, a pentavalent (five-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States.
=== 1988 ===
A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF, and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).
=== After 1990 ===
Polio was eliminated in the Americas by 1994. The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000. Europe was declared polio-free in 2002. Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.
Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained. In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine. As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travellers.
Polio vaccination programs have been resisted by some people in Pakistan, Afghanistan, and Nigeria – the three countries as of 2017 with remaining polio cases. Almost all Muslim religious and political leaders have endorsed the vaccine, but a fringe minority believes that the vaccines are secretly being used for the sterilisation of Muslims. The fact that the CIA organized a fake vaccination program in 2011 to help find Osama bin Laden is an additional cause of distrust. In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control. However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the two remaining endemic countries.
== Travel requirements ==
Travellers who wish to enter or leave certain countries must be vaccinated against polio, usually at most 12 months and at least 4 weeks before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 25–27 Most requirements apply only to travel to or from so-called 'polio-endemic', 'polio-affected', 'polio-exporting', 'polio-transmission', or 'high-risk' countries. As of August 2020, Afghanistan and Pakistan are the only polio-endemic countries in the world (where wild polio has not yet been eradicated). Several countries have additional precautionary polio vaccination travel requirements, for example to and from 'key at-risk countries', which as of December 2020 include China, Indonesia, Mozambique, Myanmar, and Papua New Guinea.
== Society and culture ==
=== Cost ===
As of 2015, the Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.89) per dose in 10-dose vials.
=== Misconceptions ===
A misconception has been present in Pakistan that the polio vaccine contains haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.
== References ==
== Further reading ==
== External links ==
"Polio Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
History of Vaccines Website – History of Polio History of Vaccines, a project of the College of Physicians of Philadelphia
PBS.org – 'People and Discoveries: Salk Produces Polio Vaccine 1952', Public Broadcasting Service (PBS)
"IPOL – Poliovirus Vaccine Inactivated (Monkey Kidney Cell)". U.S. Food and Drug Administration (FDA). 11 December 2019. STN: 103930. Archived from the original on 23 December 2019.
Poliovirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Inactivated_poliovirus_vaccine |
Polio vaccines are vaccines used to prevent poliomyelitis (polio). Two types are used: an inactivated poliovirus given by injection (IPV) and a weakened poliovirus given by mouth (OPV). The World Health Organization (WHO) recommends all children be fully vaccinated against polio. The two vaccines have eliminated polio from most of the world, and reduced the number of cases reported each year from an estimated 350,000 in 1988 to 33 in 2018.
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. Oral polio vaccines cause about three cases of vaccine-associated paralytic poliomyelitis per million doses given. This compares with 5,000 cases per million who are paralysed following a polio infection. Both types of vaccine are generally safe to give during pregnancy and in those who have HIV/AIDS, but are otherwise well. However, the emergence of circulating vaccine-derived poliovirus (cVDPV), a form of the vaccine virus that has reverted to causing poliomyelitis, has led to the development of novel oral polio vaccine type 2 (nOPV2), which aims to make the vaccine safer and thus stop further outbreaks of cVDPV.
The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus that people drank. The vaccine was not approved for use in the United States, but was used successfully elsewhere. The success of an inactivated (killed) polio vaccine, developed by Jonas Salk, was announced in 1955. Another attenuated live oral polio vaccine, developed by Albert Sabin, came into commercial use in 1961.
Polio vaccine is on the World Health Organization's List of Essential Medicines.
== Medical uses ==
Interruption of person-to-person transmission of the virus by vaccination is important in global polio eradication, since no long-term carrier state exists for poliovirus in individuals with normal immune function, polio viruses have no non-primate reservoir in nature, and survival of the virus in the environment for an extended period appears to be remote. The two types of vaccine are inactivated polio vaccine (IPV) and oral polio vaccine (OPV).
=== Inactivated ===
When the IPV (injection) is used, 90% or more of individuals develop protective antibodies to all three serotypes of poliovirus after two doses, and at least 99% are immune following three doses. The duration of immunity induced by IPV is not known with certainty, although a complete series is thought to protect for many years. IPV replaced the oral vaccine in many developed countries in the 1990s mainly due to the (small) risk of vaccine-derived polio in the oral vaccine.
=== Attenuated ===
Oral polio vaccines were easier to administer than IPV, as they eliminated the need for sterile syringes, so were more suitable for mass vaccination campaigns. OPV also provided longer-lasting immunity than the Salk vaccine, as it provides both humoral immunity and cell-mediated immunity.
One dose of trivalent OPV produces immunity to all three poliovirus serotypes in roughly 50% of recipients. Three doses of live-attenuated OPV produce protective antibodies to all three poliovirus types in more than 95% of recipients. As with other live-virus vaccines, immunity initiated by OPV is probably lifelong. OPV produces excellent immunity in the intestine, the primary site of wild poliovirus entry, which helps prevent infection with wild virus in areas where the virus is endemic. OPV does not require special medical equipment or extensive training. Attenuated poliovirus derived from the OPV is excreted for a few days after vaccination, potentially infecting and thus indirectly inducing immunity in unvaccinated individuals, thus amplifying the effects of the doses delivered. Taken together, these advantages have made it the favored vaccine of many countries, and it has long been preferred by the global eradication initiative.
The primary disadvantage of OPV derives from its inherent nature. As an attenuated but active virus, it can induce vaccine-associated paralytic poliomyelitis (VAPP) in roughly one individual per every 2.7 million doses administered. The live virus can circulate in under-vaccinated populations (termed either variant poliovirus or circulating vaccine-derived poliovirus, cVDPV), and over time can revert to a neurovirulent form causing paralytic polio. This genetic reversal of the pathogen to a virulent form takes a considerable time and does not affect the person who was originally vaccinated. With wild polio cases at record lows, 2017 was the first year where more cases of cVDPV were recorded than the wild poliovirus.
Until recent times, a trivalent OPV containing all three viral strains was used, and had nearly eradicated polio infection worldwide. With the complete eradication of wild poliovirus type 2 this was phased out in 2016 and replaced with bivalent vaccine containing just types 1 and 3, supplemented with monovalent type 2 OPV in regions where cVDPV type 2 was known to circulate. The switch to the bivalent vaccine and associated missing immunity against type 2 strains, among other factors, led to outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), which increased from two cases in 2016 to 1037 cases in 2020.
A novel OPV2 vaccine (nOPV2), which has been genetically modified to reduce the likelihood of disease-causing activating mutations, was granted emergency licencing in 2021, and subsequently full licensure in December 2023. This has greater genetic stability than the traditional oral vaccine and is less likely to revert to a virulent form. Genetically stabilised vaccines targeting poliovirus types 1 and 3 are in development, with the intention that these will eventually completely replace the Sabin vaccines.
=== Schedule ===
In countries with endemic polio or where the risk of imported cases is high, the WHO recommends OPV vaccine at birth followed by a primary series of three OPV doses and at least one IPV dose starting at 6 weeks of age, with a minimum of 4 weeks between OPV doses. In countries with more than 90% immunization coverage and low risk of importation, the WHO recommends one or two IPV doses starting at two months of age followed by at least two OPV doses, with the doses separated by 4–8 weeks depending on the risk of exposure. In countries with the highest levels of coverage and the lowest risks of importation and transmission, the WHO recommends a primary series of three IPV injections, with a booster dose after an interval of six months or more if the first dose was administered before two months of age.
== Side effects ==
The inactivated polio vaccines are very safe. Mild redness or pain may occur at the site of injection. They are generally safe to be given to pregnant women and those who have HIV/AIDS, but are otherwise well.
=== Allergic reaction to the vaccine ===
Inactivated polio vaccine can cause an allergic reaction in a few people, since the vaccine contains trace amounts of antibiotics, streptomycin, polymyxin B, and neomycin. It should not be given to anyone who has an allergic reaction to these medicines. Signs and symptoms of an allergic reaction, which usually appear within minutes or a few hours after receiving the injected vaccine, include breathing difficulties, weakness, hoarseness or wheezing, heart-rate fluctuations, skin rash, and dizziness.
=== Vaccine-associated paralytic polio ===
A potential adverse effect of the Sabin OPV is caused by its known potential to recombine to a form that causes neurological infection and paralysis. The Sabin OPV results in vaccine-associated paralytic poliomyelitis (VAPP) in around one individual per every 2.7 million doses administered, with symptoms identical to wild polio. Due to its improved genetic stability, the novel OPV (nOPV) has a reduced risk of this occurring.
=== Contamination concerns ===
In 1960, the rhesus monkey kidney cells used to prepare the poliovirus vaccines were determined to be infected with the simian virus-40 (SV40), which was also discovered in 1960 and is a naturally occurring virus that infects monkeys. In 1961, SV40 was found to cause tumors in rodents. More recently, the virus was found in certain forms of cancer in humans, for instance brain and bone tumors, pleural and peritoneal mesothelioma, and some types of non-Hodgkin lymphoma. However, SV40 has not been determined to cause these cancers.
SV40 was found to be present in stocks of the injected form of the IPV in use between 1955 and 1963; it is not found in the OPV form. Over 98 million Americans received one or more doses of polio vaccine between 1955 and 1963, when a proportion of vaccine was contaminated with SV40; an estimated 10–30 million Americans may have received a dose of vaccine contaminated with SV40. Later analysis suggested that vaccines produced by the former Soviet bloc countries until 1980, and used in the USSR, China, Japan, and several African countries, may have been contaminated, meaning hundreds of millions more may have been exposed to SV40.
In 1998, the National Cancer Institute undertook a large study, using cancer case information from the institute's SEER database. The published findings from the study revealed no increased incidence of cancer in persons who may have received vaccine containing SV40. Another large study in Sweden examined cancer rates of 700,000 individuals who had received potentially contaminated polio vaccine as late as 1957; the study again revealed no increased cancer incidence between persons who received polio vaccines containing SV40 and those who did not. The question of whether SV40 causes cancer in humans remains controversial, however, and the development of improved assays for detection of SV40 in human tissues will be needed to resolve the controversy.
During the race to develop an oral polio vaccine, several large-scale human trials were undertaken. By 1958, the National Institutes of Health had determined that OPV produced using the Sabin strains was the safest. Between 1957 and 1960, however, Hilary Koprowski continued to administer his vaccine around the world. In Africa, the vaccines were administered to roughly one million people in the Belgian territories (now the Democratic Republic of the Congo, Rwanda, and Burundi). The results of these human trials have been controversial, and unfounded accusations in the 1990s arose that the vaccine had created the conditions necessary for transmission of simian immunodeficiency virus from chimpanzees to humans, causing HIV/AIDS. These hypotheses, however, have been conclusively refuted. By 2004, cases of poliomyelitis in Africa had been reduced to just a small number of isolated regions in the western portion of the continent, with sporadic cases elsewhere. Recent local opposition to vaccination campaigns has evolved due to lack of adequate information, often relating to fears that the vaccine might induce sterility. The disease has since resurged in Nigeria and several other African nations without necessary information, which epidemiologists believe is due to refusals by certain local populations to allow their children to receive the polio vaccine.
== Manufacture ==
=== Inactivated ===
The Salk vaccine, IPV, is based on three wild, virulent reference strains, Mahoney (type 1 poliovirus), MEF-1 (type 2 poliovirus), and Saukett (type 3 poliovirus), grown in a type of monkey kidney tissue culture (Vero cell line), which are then inactivated with formalin. The injected Salk vaccine confers IgG-mediated immunity in the bloodstream, which prevents polio infection from progressing to viremia and protects the motor neurons, thus eliminating the risk of bulbar polio and post-polio syndrome.
In the United States, the vaccine is administered along with the tetanus, diphtheria, and acellular pertussis vaccines (DTaP) and a pediatric dose of hepatitis B vaccine. In the UK, IPV is combined with tetanus, diphtheria, pertussis, and Haemophilus influenzae type b vaccines.
=== Attenuated ===
OPV is an attenuated vaccine, produced by the passage of the virus through nonhuman cells at a subphysiological temperature, which produces spontaneous mutations in the viral genome. Oral polio vaccines were developed by several groups, one of which was led by Albert Sabin. Other groups, led by Hilary Koprowski and H.R. Cox, developed their attenuated vaccine strains. In 1958, the NIH created a special committee on live polio vaccines. The various vaccines were carefully evaluated for their ability to induce immunity to polio while retaining a low incidence of neuropathogenicity in monkeys. Large-scale clinical trials performed in the Soviet Union in the late 1950s to early 1960s by Mikhail Chumakov and his colleagues demonstrated the safety and high efficacy of the vaccine. Based on these results, the Sabin strains were chosen for worldwide distribution. Fifty-seven nucleotide substitutions distinguish the attenuated Sabin 1 strain from its virulent parent (the Mahoney serotype), two nucleotide substitutions attenuate the Sabin 2 strain, and 10 substitutions are involved in attenuating the Sabin 3 strain. The primary attenuating factor common to all three Sabin vaccines is a mutation located in the virus's internal ribosome entry site, which alters stem-loop structures and reduces the ability of poliovirus to translate its RNA template within the host cell. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of infection and replication, but is unable to replicate efficiently within nervous system tissue. In 1961, type 1 and 2 monovalent oral poliovirus vaccine (MOPV) was licensed, and in 1962, type 3 MOPV was licensed. In 1963, trivalent OPV (TOPV) was licensed, and became the vaccine of choice in the United States and most other countries of the world, largely replacing the inactivated polio vaccine. A second wave of mass immunizations led to a further dramatic decline in the number of polio cases. Between 1962 and 1965, about 100 million Americans (roughly 56% of the population at that time) received the Sabin vaccine. The result was a substantial reduction in the number of poliomyelitis cases, even from the much-reduced levels following the introduction of the Salk vaccine.
OPV is usually provided in vials containing 10–20 doses of vaccine. A single dose of oral polio vaccine (usually two drops) contains 1,000,000 infectious units of Sabin 1 (effective against PV1), 100,000 infectious units of the Sabin 2 strain, and 600,000 infectious units of Sabin 3. The vaccine contains small traces of antibiotics—neomycin and streptomycin—but does not contain preservatives.
== History ==
In a generic sense, vaccination works by priming the immune system with an "immunogen". Stimulating immune response, by use of an infectious agent, is known as immunization. The development of immunity to polio efficiently blocks person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community.
The development of two polio vaccines led to the first modern mass inoculations. The last cases of paralytic poliomyelitis caused by endemic transmission of wild virus in the United States occurred in 1979, with an outbreak among the Amish in several Midwest states.
=== 1930s ===
In the 1930s, poliovirus was perceived as especially terrifying, as little was known of how the disease was transmitted or how it could be prevented. This virus was also notable for primarily impacting affluent children, making it a prime target for vaccine development, despite its relatively low mortality and morbidity. Despite this, the community of researchers in the field thus far had largely observed an informal moratorium on any vaccine development, as it was perceived to present too high a risk for too little likelihood of success.
This shifted in the early 1930s, when American groups took up the challenge: Maurice Brodie led a team from the public health laboratory of the city of New York and John A. Kolmer collaborated with the Research Institute of Cutaneous Medicine in Philadelphia. The rivalry between these two researchers lent itself to a race-like mentality, which combined with a lack of oversight of medical studies, was reflected in the methodology and outcomes of each of these early vaccine-development ventures.
==== Kolmer's live vaccine ====
Kolmer began his vaccine development project in 1932 and ultimately focused on producing an attenuated or live virus vaccine. Inspired by the success of vaccines for rabies and yellow fever, he hoped to use a similar process to denature the polio virus. To go about attenuating his polio vaccine, he repeatedly passed the virus through monkeys. Using methods of production that were later described as "hair-raisingly amateurish, the therapeutic equivalent of bath-tub gin", Kolmer ground the spinal cords of his infected monkeys and soaked them in a salt solution. He then filtered the solution through mesh, treated it with ricinolate, and refrigerated the product for 14 days to ultimately create what would later be prominently critiqued as a "veritable witches brew".
In keeping with the norms of the time, Kolmer completed a relatively small animal trial with 42 monkeys before proceeding to self-experimentation in 1934. He tested his vaccine upon himself, his two children, and his assistant. He gave his vaccine to just 23 more children before declaring it safe and sending it out to doctors and health departments for a larger test of efficacy. By April 1935, he was able to report having tested the vaccine on 100 children without ill effect. Kolmer's first formal presentation of results did not come about until November 1935, when he presented the results of 446 children and adults he had vaccinated with his attenuated vaccine. He also reported that together the Research Institute of Cutaneous Medicine and the Merrell Company of Cincinnati (the manufacturer who held the patent for his ricinoleating process) had distributed 12,000 doses of vaccine to some 700 physicians across the United States and Canada. Kolmer did not describe any monitoring of this experimental vaccination program, nor did he provide these physicians with instructions in how to administer the vaccine or how to report side effects. Kolmer dedicated the bulk of his publications thereafter to explaining what he believed to be the cause of the 10+ reported cases of paralytic polio following vaccination, in many cases in towns where no polio outbreak had occurred. Six of these cases had been fatal. Kolmer had no control group, but asserted that many more children would have gotten sick.
==== Brodie's inactivated vaccine ====
At nearly the same time as Kolmer's project, Maurice Brodie had joined immunologist William H. Park at the New York City Health Department, where they worked together on poliovirus. With the aid of grant funding from the President's Birthday Ball Commission (a predecessor to what would become the March of Dimes), Brodie was able to pursue the development of an inactivated or "killed virus" vaccine. Brodie's process also began by grinding the spinal cords of infectious monkeys and then treating the cords with various germicides, ultimately finding a solution of formaldehyde to be the most effective. By 1 June 1934, Brodie was able to publish his first scholarly article describing his successful induction of immunity in three monkeys with inactivated poliovirus. Through continued study on an additional 26 monkeys, Brodie ultimately concluded that administration of live virus vaccine tended to result in humoral immunity, while administration of killed virus vaccine tended to result in tissue immunity.
Soon after, following a similar protocol to Kolmer's, Brodie proceeded with self-experimentation upon himself and his co-workers at the NYC Health Department laboratory. Brodie's progress was eagerly covered by popular press, as the public hoped for a successful vaccine to become available. Such reporting did not make mention of the 12 children in a New York City Asylum who were subjected to early safety trials. As none of the subjects experienced ill effects, Park, described by contemporaries as "never one to let grass grow under his feet", declared the vaccine safe. When a severe polio outbreak overwhelmed Kern County, California, it became the first trial site for the new vaccine on very short notice. Between November 1934 and May 1935, over 1,500 doses of the vaccine were administered in Kern County. While initial results were very promising, insufficient staffing and poor protocol design left Brodie open to criticism when he published the California results in August 1935. Through private physicians, Brodie also conducted a broader field study, including 9,000 children who received the vaccine and 4,500 age- and location-matched controls who did not receive a vaccine. Again, the results were promising. Of those who received the vaccine, only a few went on to develop polio. Most had been exposed before vaccination and none had received the full series of vaccine doses being studied. Additionally, a polio epidemic in Raleigh, North Carolina, provided an opportunity for the U.S. Public Health Service to conduct a highly structured trial of the Brodie vaccine using funding from the Birthday Ball Commission.
==== Academic reception ====
While their work was ongoing, the larger community of bacteriologists began to raise concerns regarding the safety and efficacy of the new poliovirus vaccines. At this time, very little oversight of medical studies occurred and the ethical treatment of study participants largely relied upon moral pressure from peer academic scientists. Brodie's inactivated vaccines faced scrutiny from many who felt killed virus vaccines could not be efficacious. While researchers were able to replicate the tissue immunity he had produced in his animal trials, the prevailing wisdom was that humoral immunity was essential for an efficacious vaccine. Kolmer directly questioned the killed virus approach in scholarly journals. Kolmer's studies, however, had raised even more concern with increasing reports of children becoming paralysed following vaccination with his live-virus vaccine and notably, with paralysis beginning at the arm rather than the foot in many cases. Both Kolmer and Brodie were called to present their research at the Annual Meeting of the American Public Health Association in Milwaukee, Wisconsin, in October 1935. Additionally, Thomas M. Rivers was asked to discuss each of the presented papers as a prominent critic of the vaccine development effort. This resulted in the APHA arranging a symposium on poliomyelitis to be delivered at the annual meeting of their southern branch the following month. During the discussion at this meeting, James Leake of the U.S. Public Health Service stood to immediately present clinical evidence that the Kolmer vaccine had caused several deaths and then allegedly accused Kolmer of being a murderer. As Rivers recalled in his oral history, "All hell broke loose, and it seemed as if everybody was trying to talk at the same time ... Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting." In response to the attacks from all sides, Brodie was reported to have stood up and stated, "It looks as though, according to Dr. Rivers, my vaccine is no good, and according to Dr. Leake, Dr Kolmer's is dangerous." Kolmer simply responded by stating, "Gentlemen, this is one time I wish the floor would open up and swallow me." Ultimately, Kolmer's live vaccine was undoubtedly shown to be dangerous and had already been withdrawn in September 1935 before the Milwaukee meeting. While the consensus of the symposium was largely skeptical of the efficacy of Brodie's vaccine, its safety was not in question and the recommendation was for a much larger, well-controlled trial. However, when three children became ill with paralytic polio following a dose of the vaccine, the directors of the Warm Springs Foundation in Georgia (acting as the primary funders for the project) requested it be withdrawn in December 1935. Following its withdrawal, the previously observed moratorium on human poliomyelitis vaccine development resumed and another attempt would not be made for nearly 20 years.
While Brodie had arguably made the most progress in the pursuit of a poliovirus vaccine, he suffered the most significant career repercussions due to his status as a less widely known researcher. Modern researchers recognize that Brodie may well have developed an effective polio vaccine, but the basic science and technology of the time were insufficient to understand and use this breakthrough. Brodie's work using formalin-inactivated virus later became the basis for the Salk vaccine, but he did not live to see this success. Brodie was fired from his position within three months of the symposium's publication. While he was able to find another laboratory position, he died of a heart attack only three years later at age 36. By contrast, Park, who was believed in the community to be reaching senility at this point in his older age, was able to retire from his position with honors before he died in 1939. Kolmer, already an established and well-respected researcher, returned to Temple University as a professor of medicine. Kolmer had a very productive career, receiving multiple awards, and publishing countless papers, articles, and textbooks until his retirement in 1957.
=== 1948 ===
A breakthrough came in 1948 when a research group headed by John Enders at the Children's Hospital Boston successfully cultivated the poliovirus in human tissue in the laboratory. This group had recently successfully grown mumps in cell culture. In March 1948, Thomas H. Weller was attempting to grow varicella virus in embryonic lung tissue. He had inoculated the planned number of tubes when he noticed that a few unused tubes. He retrieved a sample of mouse brain infected with poliovirus and added it to the remaining test tubes, on the off chance that the virus might grow. The varicella cultures failed to grow, but the polio cultures were successful. This development greatly facilitated vaccine research and ultimately allowed for the development of vaccines against polio. Enders and his colleagues, Thomas H. Weller and Frederick C. Robbins, were recognized in 1954 for their efforts with a Nobel Prize in Physiology or Medicine. Other important advances that led to the development of polio vaccines included the identification of three poliovirus serotypes (poliovirus type 1 – PV1, or Mahoney; PV2, Lansing; and PV3, Leon), the finding that before paralysis, the virus must be present in the blood, and the demonstration that administration of antibodies in the form of gamma globulin protects against paralytic polio.
=== 1950–1955 ===
During the early 1950s, polio rates in the U.S. were above 25,000 annually; in 1952 and 1953, the U.S. experienced an outbreak of 58,000 and 35,000 polio cases, respectively, up from a typical number of some 20,000 a year, with deaths in those years numbering 3,200 and 1,400. Amid this U.S. polio epidemic, millions of dollars were invested in finding and marketing a polio vaccine by commercial interests, including Lederle Laboratories in New York under the direction of H. R. Cox. Also working at Lederle was Polish-born virologist and immunologist Hilary Koprowski of the Wistar Institute in Philadelphia, who tested the first successful polio vaccine, in 1950. His vaccine, however, being a live attenuated virus taken orally, was still in the research stage and would not be ready for use until five years after Jonas Salk's polio vaccine (a dead-virus injectable vaccine) had reached the market. Koprowski's attenuated vaccine was prepared by successive passages through the brains of Swiss albino mice. By the seventh passage, the vaccine strains could no longer infect nervous tissue or cause paralysis. After one to three further passages on rats, the vaccine was deemed safe for human use. On 27 February 1950, Koprowski's live, attenuated vaccine was tested for the first time on an 8-year-old boy living at Letchworth Village, an institution for physically and mentally disabled people located in New York. After the child had no side effects, Koprowski enlarged his experiment to include 19 other children.
==== Jonas Salk ====
The first effective polio vaccine was developed in 1952 by Jonas Salk and a team at the University of Pittsburgh that included Julius Youngner, Byron Bennett, L. James Lewis, and Lorraine Friedman, which required years of subsequent testing. Salk went on CBS radio to report a successful test on a small group of adults and children on 26 March 1953; two days later, the results were published in JAMA. Leone N. Farrell invented a key laboratory technique that enabled the mass production of the vaccine by a team she led in Toronto. Beginning 23 February 1954, the vaccine was tested at Arsenal Elementary School and the Watson Home for Children in Pittsburgh, Pennsylvania.
Salk's vaccine was then used in a test called the Francis Field Trial, led by Thomas Francis, the largest medical experiment in history at that time. The test began with about 4,000 children at Franklin Sherman Elementary School in McLean, Virginia, and eventually involved 1.8 million children, in 44 states from Maine to California. By the conclusion of the study, roughly 440,000 received one or more injections of the vaccine, about 210,000 children received a placebo, consisting of harmless culture media, and 1.2 million children received no vaccination and served as a control group, who would then be observed to see if any contracted polio.
The results of the field trial were announced on 12 April 1955 (the tenth anniversary of the death of President Franklin D. Roosevelt, whose paralytic illness was generally believed to have been caused by polio). The Salk vaccine had been 60–70% effective against PV1 (poliovirus type 1), over 90% effective against PV2 and PV3, and 94% effective against the development of bulbar polio. Soon after Salk's vaccine was licensed in 1955, children's vaccination campaigns were launched. In the U.S., following a mass immunization campaign promoted by the March of Dimes, the annual number of polio cases fell from 35,000 in 1953 to 5,600 by 1957. By 1961 only 161 cases were recorded in the United States.
A week before the announcement of the Francis Field Trial results in April 1955, Pierre Lépine at the Pasteur Institute in Paris had also announced an effective polio vaccine.
==== Safety incidents ====
In April 1955, soon after mass polio vaccination began in the US, the Surgeon General began to receive reports of patients who contracted paralytic polio about a week after being vaccinated with the Salk polio vaccine from the Cutter pharmaceutical company, with the paralysis starting in the limb the vaccine was injected into. The Cutter vaccine had been used in vaccinating 409,000 children in the western and midwestern United States.
Later investigations showed that the Cutter vaccine had caused 260 cases of polio, killing 11. In response, the Surgeon General pulled all polio vaccines made by Cutter Laboratories from the market, but not before 260 cases of paralytic illness had occurred. Eli Lilly, Parke-Davis, Pitman-Moore, and Wyeth polio vaccines were also reported to have paralyzed numerous children. It was soon discovered that some lots of Salk polio vaccine made by Cutter, Wyeth, and the other labs had not been properly inactivated, allowing live poliovirus into more than 100,000 doses of vaccine. In May 1955, the National Institutes of Health and Public Health Services established a Technical Committee on Poliomyelitis Vaccine to test and review all polio vaccine lots and advise the Public Health Service as to which lots should be released for public use. These incidents reduced public confidence in the polio vaccine, leading to a drop in vaccination rates.
=== 1961 ===
At the same time that Salk was testing his vaccine, both Albert Sabin and Hilary Koprowski continued working on developing a vaccine using live virus. During a meeting in Stockholm to discuss polio vaccines in November 1955, Sabin presented results obtained on a group of 80 volunteers, while Koprowski read a paper detailing the findings of a trial enrolling 150 people. Sabin and Koprowski both eventually succeeded in developing vaccines. Because of the commitment to the Salk vaccine in America, Sabin and Koprowski both did their testing outside the United States, Sabin in Mexico and the Soviet Union, Koprowski in the Congo and Poland. In 1957, Sabin developed a trivalent vaccine containing attenuated strains of all three types of poliovirus. In 1959, ten million children in the Soviet Union received the Sabin oral vaccine. For this work, Sabin was given the medal of the Order of Friendship of Peoples, described as the Soviet Union's highest civilian honor. Sabin's oral vaccine using live virus came into commercial use in 1961.
Once Sabin's oral vaccine became widely available, it supplanted Salk's injected vaccine, which had been tarnished in the public's opinion by the Cutter incident of 1955, in which Salk vaccines improperly prepared by one company resulted in several children dying or becoming paralyzed.
=== 1987 ===
An enhanced-potency IPV was licensed in the United States in November 1987, and is currently the vaccine of choice there. The first dose of the polio vaccine is given shortly after birth, usually between 1 and 2 months of age, and a second dose is given at 4 months of age. The timing of the third dose depends on the vaccine formulation but should be given between 6 and 18 months of age. A booster vaccination is given at 4 to 6 years of age, for a total of four doses at or before school entry. In some countries, a fifth vaccination is given during adolescence. Routine vaccination of adults (18 years of age and older) in developed countries is neither necessary nor recommended because most adults are already immune and have a very small risk of exposure to wild poliovirus in their home countries. In 2002, a pentavalent (five-component) combination vaccine (called Pediarix) containing IPV was approved for use in the United States.
=== 1988 ===
A global effort to eradicate polio, led by the World Health Organization (WHO), UNICEF, and the Rotary Foundation, began in 1988, and has relied largely on the oral polio vaccine developed by Albert Sabin and Mikhail Chumakov (Sabin-Chumakov vaccine).
=== After 1990 ===
Polio was eliminated in the Americas by 1994. The disease was officially eliminated in 36 Western Pacific countries, including China and Australia, in 2000. Europe was declared polio-free in 2002. Since January 2011, no cases of the disease have been reported in India, hence in February 2012, the country was taken off the WHO list of polio-endemic countries. In March 2014, India was declared a polio-free country.
Although poliovirus transmission has been interrupted in much of the world, transmission of wild poliovirus does continue and creates an ongoing risk for the importation of wild poliovirus into previously polio-free regions. If importations of poliovirus occur, outbreaks of poliomyelitis may develop, especially in areas with low vaccination coverage and poor sanitation. As a result, high levels of vaccination coverage must be maintained. In November 2013, the WHO announced a polio outbreak in Syria. In response, the Armenian government put out a notice asking Syrian Armenians under age 15 to get the polio vaccine. As of 2014, polio virus had spread to 10 countries, mainly in Africa, Asia, and the Middle East, with Pakistan, Syria, and Cameroon advising vaccinations to outbound travellers.
Polio vaccination programs have been resisted by some people in Pakistan, Afghanistan, and Nigeria – the three countries as of 2017 with remaining polio cases. Almost all Muslim religious and political leaders have endorsed the vaccine, but a fringe minority believes that the vaccines are secretly being used for the sterilisation of Muslims. The fact that the CIA organized a fake vaccination program in 2011 to help find Osama bin Laden is an additional cause of distrust. In 2015, the WHO announced a deal with the Taliban to encourage them to distribute the vaccine in areas they control. However, the Pakistani Taliban was not supportive. On 11 September 2016, two unidentified gunmen associated with the Pakistani Taliban, Jamaat-ul-Ahrar, shot Zakaullah Khan, a doctor who was administering polio vaccines in Pakistan. The leader of the Jamaat-ul-Ahrar claimed responsibility for the shooting and stated that the group would continue this type of attack. Such resistance to and skepticism of vaccinations has consequently slowed down the polio eradication process within the two remaining endemic countries.
== Travel requirements ==
Travellers who wish to enter or leave certain countries must be vaccinated against polio, usually at most 12 months and at least 4 weeks before crossing the border, and be able to present a vaccination record/certificate at the border checks.: 25–27 Most requirements apply only to travel to or from so-called 'polio-endemic', 'polio-affected', 'polio-exporting', 'polio-transmission', or 'high-risk' countries. As of August 2020, Afghanistan and Pakistan are the only polio-endemic countries in the world (where wild polio has not yet been eradicated). Several countries have additional precautionary polio vaccination travel requirements, for example to and from 'key at-risk countries', which as of December 2020 include China, Indonesia, Mozambique, Myanmar, and Papua New Guinea.
== Society and culture ==
=== Cost ===
As of 2015, the Global Alliance for Vaccines and Immunization supplies the inactivated vaccine to developing countries for as little as €0.75 (about US$0.89) per dose in 10-dose vials.
=== Misconceptions ===
A misconception has been present in Pakistan that the polio vaccine contains haram ingredients and could cause impotence and infertility in male children, leading some parents not to have their children vaccinated. This belief is most common in the Khyber Pakhtunkhwa province and the FATA region. Attacks on polio vaccination teams have also occurred, thereby hampering international efforts to eradicate polio in Pakistan and globally.
== References ==
== Further reading ==
== External links ==
"Polio Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). August 2021.
History of Vaccines Website – History of Polio History of Vaccines, a project of the College of Physicians of Philadelphia
PBS.org – 'People and Discoveries: Salk Produces Polio Vaccine 1952', Public Broadcasting Service (PBS)
"IPOL – Poliovirus Vaccine Inactivated (Monkey Kidney Cell)". U.S. Food and Drug Administration (FDA). 11 December 2019. STN: 103930. Archived from the original on 23 December 2019.
Poliovirus Vaccines at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Inactivated_polio_vaccine |
Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV, and Dengue virus and is monitored for in vaccine development.
== Technical description ==
In ADE, antiviral antibodies promote viral infection of target immune cells by exploiting the phagocytic FcγR or complement pathway. After interaction with a virus, the antibodies bind Fc receptors (FcR) expressed on certain immune cells or complement proteins. FcγRs bind antibodies via their fragment crystallizable region (Fc).
The process of phagocytosis is accompanied by virus degradation, but if the virus is not neutralized (either due to low-affinity binding or targeting to a non-neutralizing epitope), antibody binding may result in virus escape and, therefore, more severe infection. Thus, phagocytosis can cause viral replication and the subsequent death of immune cells. Essentially, the virus “deceives” the process of phagocytosis of immune cells and uses the host's antibodies as a Trojan horse.
ADE may occur because of the non-neutralizing characteristic of an antibody, which binds viral epitopes other than those involved in host-cell attachment and entry. It may also happen when antibodies are present at sub-neutralizing concentrations (yielding occupancies on viral epitopes below the threshold for neutralization), or when the strength of antibody-antigen interaction is below a certain threshold. This phenomenon can lead to increased viral infectivity and virulence.
ADE can occur during the development of a primary or secondary viral infection and with a virus challenge after vaccination. It has been observed mainly with positive-strand RNA viruses, including flaviviruses such as dengue, yellow fever, and Zika; alpha- and betacoronaviruses; orthomyxoviruses such as influenza; retroviruses such as HIV; and orthopneumoviruses such as RSV. The viruses that cause it frequently share common features such as antigenic diversity, replication ability, or ability to establish persistence in immune cells.
The mechanism that involves phagocytosis of immune complexes via the FcγRII/CD32 receptor is better understood compared to the complement receptor pathway. Cells that express this receptor are represented by monocytes, macrophages, and some categories of dendritic cells and B-cells. ADE is mainly mediated by IgG antibodies, but IgM and IgA antibodies have also been shown to trigger it.
== Coronavirus ==
=== COVID-19 ===
Prior to the COVID-19 pandemic, ADE was observed in animal studies of laboratory rodents with vaccines for SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). As of 27 January 2022, there have been no observed incidents with vaccines for COVID-19 in trials with nonhuman primates, in clinical trials with humans, or following the widespread use of approved vaccines.
== Influenza ==
Prior receipt of 2008–09 TIV (Trivalent Inactivated Influenza Vaccine) was associated with an increased risk of medically attended pH1N1 illness during the spring-summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.
Natural infection and the attenuated vaccine induce antibodies that enhance the update of the homologous virus and H1N1 virus isolated several years later, demonstrating that a primary influenza A virus infection results in the induction of infection enhancing antibodies.
ADE was suspected in infections with influenza A virus subtype H7N9, but knowledge is limited.
== Dengue ==
The most widely known ADE example occurs with dengue virus. Dengue is a single-stranded positive-polarity RNA virus of the family Flaviviridae. It causes disease of varying severity in humans, from dengue fever (DF), which is usually self-limited, to dengue hemorrhagic fever and dengue shock syndrome, either of which may be life-threatening. It is estimated that as many as 390 million individuals contract dengue annually.
ADE may follow when a person who has previously been infected with one serotype becomes infected months or years later with a different serotype, producing higher viremia than in first-time infections. Accordingly, while primary (first) infections cause mostly minor disease (dengue fever) in children, re-infection is more likely to be associated with dengue hemorrhagic fever and/or dengue shock syndrome in both children and adults.
Dengue encompasses four antigenically different serotypes (dengue virus 1–4). In 2013 a fifth serotype was reported. Infection induces the production of neutralizing homotypic immunoglobulin G (IgG) antibodies that provide lifelong immunity against the infecting serotype. Infection with dengue virus also produces some degree of cross-protective immunity against the other three serotypes. Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of months to a few years. These heterotypic titers decrease over long time periods (4 to 20 years). While heterotypic titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived memory B cells producing homotypic antibodies.
In addition to neutralizing heterotypic antibodies, an infection can also induce heterotypic antibodies that neutralize the virus only partially or not at all. The production of such cross-reactive, but non-neutralizing antibodies could enable severe secondary infections. By binding to but not neutralizing the virus, these antibodies cause it to behave as a "trojan horse", where it is delivered into the wrong compartment of dendritic cells that have ingested the virus for destruction. Once inside the white blood cell, the virus replicates undetected, eventually generating high virus titers and severe disease.
A study conducted by Modhiran et al. attempted to explain how non-neutralizing antibodies down-regulate the immune response in the host cell through the Toll-like receptor signaling pathway. Toll-like receptors are known to recognize extra- and intracellular viral particles and to be a major basis of the cytokines' production. In vitro experiments showed that the inflammatory cytokines and type 1 interferon production were reduced when the ADE-dengue virus complex bound to the Fc receptor of THP-1 cells. This can be explained by both a decrease of Toll-like receptor production and a modification of its signaling pathway. On the one hand, an unknown protein induced by the stimulated Fc receptor reduces Toll-like receptor transcription and translation, which reduces the capacity of the cell to detect viral proteins. On the other hand, many proteins (TRIF, TRAF6, TRAM, TIRAP, IKKα, TAB1, TAB2, NF-κB complex) involved in the Toll-like receptor signaling pathway are down-regulated, which led to a decrease in cytokine production. Two of them, TRIF and TRAF6, are respectively down-regulated by 2 proteins SARM and TANK up-regulated by the stimulated Fc receptors.
One example occurred in Cuba, lasting from 1977 to 1979. The infecting serotype was dengue virus-1. This epidemic was followed by outbreaks in 1981 and 1997. In those outbreaks; dengue virus-2 was the infecting serotype. 205 cases of dengue hemorrhagic fever and dengue shock syndrome occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by dengue virus-1 during the first outbreak. Furthermore, people with secondary infections with dengue virus-2 in 1997 had a 3-4 fold increased probability of developing severe disease than those with secondary infections with dengue virus-2 in 1981. This scenario can be explained by the presence of sufficient neutralizing heterotypic IgG antibodies in 1981, whose titers had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.
== HIV-1 ==
ADE of infection has also been reported in HIV. Like dengue virus, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of the complement system and receptors. The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like dengue virus. ADE in HIV can be complement-mediated or Fc receptor-mediated. Complements in the presence of HIV-1 positive sera have been found to enhance the infection of the MT-2 T-cell line. The Fc-receptor mediated enhancement was reported when HIV infection was enhanced by sera from HIV-1 positive guinea pig enhanced the infection of peripheral blood mononuclear cells without the presence of any complements. Complement component receptors CR2, CR3 and CR4 have been found to mediate this Complement-mediated enhancement of infection. The infection of HIV-1 leads to activation of complements. Fragments of these complements can assist viruses with infection by facilitating viral interactions with host cells that express complement receptors. The deposition of complement on the virus brings the gp120 protein close to CD4 molecules on the surface of the cells, thus leading to facilitated viral entry. Viruses pre-exposed to non-neutralizing complement system have also been found to enhance infections in interdigitating dendritic cells. Opsonized viruses have not only shown enhanced entry but also favorable signaling cascades for HIV replication in interdigitating dendritic cells.
HIV-1 has also shown enhancement of infection in HT-29 cells when the viruses were pre-opsonized with complements C3 and C9 in seminal fluid. This enhanced rate of infection was almost 2 times greater than infection of HT-29 cells with the virus alone. Subramanian et al., reported that almost 72% of serum samples out of 39 HIV-positive individuals contained complements that were known to enhance the infection. They also suggested that the presence of neutralizing antibody or antibody-dependent cellular cytotoxicity-mediating antibodies in the serum contains infection-enhancing antibodies. The balance between the neutralizing antibodies and infection-enhancing antibodies changes as the disease progresses. During advanced stages of the disease, the proportion of infection-enhancing antibodies are generally higher than neutralizing antibodies. Increase in viral protein synthesis and RNA production have been reported to occur during the complement-mediated enhancement of infection. Cells that are challenged with non-neutralizing levels of complements have been found to have accelerated release of reverse transcriptase and viral progeny. The interaction of anti-HIV antibodies with non-neutralizing complement exposed viruses also aid in binding of the virus and the erythrocytes which can lead to the more efficient delivery of viruses to the immune-compromised organs.
ADE in HIV has raised questions about the risk of infections to volunteers who have taken sub-neutralizing levels of vaccine just like any other viruses that exhibit ADE. Gilbert et al., in 2005 reported that there was no ADE of infection when they used the rgp120 vaccine in phase 1 and 2 trials. It has been emphasized that much research needs to be done in the field of the immune response to HIV-1, information from these studies can be used to produce a more effective vaccine.
== Mechanism ==
Interaction of a virus with antibodies must prevent the virus from attaching to the host cell entry receptors. However, instead of preventing infection of the host cell, this process can facilitate viral infection of immune cells, causing ADE. After binding the virus, the antibody interacts with Fc or complement receptors expressed on certain immune cells. These receptors promote virus-antibody internalization by the immune cells, which should be followed by the virus destruction. However, the virus might escape the antibody complex and start its replication cycle inside the immune cell, avoiding the degradation.
This happens if the virus is bound to a low-affinity antibody.
=== Different virus serotypes ===
There are several possibilities to explain the phenomenon of enhancing intracellular virus survival:
1) Antibodies against a virus of one serotype bind to a different serotype virus. The binding is meant to neutralize the virus from attaching to the host cell, but the virus-antibody complex also binds to the Fc-region antibody receptor (FcγR) on the immune cell. The cell internalizes the virus for programmed destruction, but the virus avoids it and starts its replication cycle instead.
2) Antibodies against a virus of one serotype bind to a virus of a different serotype, activating the classical pathway of the complement system. The complement cascade system binds C1Q complex attached to the virus surface protein via the antibodies, which in turn bind the C1q receptor found on cells, bringing the virus and the cell close enough for a specific virus receptor to bind the virus and begin infection. This mechanism has been shown for Ebola virus in vitro and some flaviviruses in vivo.
=== Conclusion ===
When an antibody to a virus cannot neutralize it, it forms sub-neutralizing virus-antibody complexes. Upon phagocytosis by macrophages or other immune cells, the complex may release the virus due to poor binding with the antibody. This happens during acidification and eventual fusion of the phagosome with lysosomes. The escaped virus begins its replication cycle within the cell, triggering ADE.
== See also ==
Original antigenic sin
Vaccine adverse event
Other ways in which antibodies can (unusually) make an infection worse instead of better
Blocking antibody, which can be either good or bad, depending on circumstances
Hook effect, most relevant to in vitro tests but known to have some in vivo relevances
== References == | Wikipedia/Antibody-dependent_enhancement |
The DrugBank database is a comprehensive, freely accessible, online database containing information on drugs and drug targets created and maintained by the University of Alberta and The Metabolomics Innovation Centre located in Alberta, Canada. As both a bioinformatics and a cheminformatics resource, DrugBank combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. DrugBank has used content from Wikipedia; Wikipedia also often links to Drugbank, posing potential circular reporting issues.
The DrugBank Online website is available to the public as a free-to-access resource. However, use and re-distribution of content from DrugBank Online or the underlying DrugBank Data, in whole or part, and for any purpose requires a license. Academic users can apply for a free license for certain use cases while all other users require a paid license.
The latest release of the database (version 5.0) contains 9591 drug entries including 2037 FDA-approved small molecule drugs, 241 FDA-approved biotech (protein/peptide) drugs, 96 nutraceuticals and over 6000 experimental drugs. Additionally, 4270 non-redundant protein (i.e. drug target/enzyme/transporter/carrier) sequences are linked to these drug entries. Each DrugCard entry (Fig. 1) contains more than 200 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data.
Four additional databases, HMDB, T3DB, SMPDB and FooDB are also part of a general suite of metabolomic/cheminformatic databases. HMDB contains equivalent information on more than 40,000 human metabolites, T3DB contains information on 3100 common toxins and environmental pollutants, SMPDB contains pathway diagrams for nearly 700 human metabolic pathways and disease pathways, while FooDB contains equivalent information on ~28,000 food components and food additives.
== Version history ==
The first version of DrugBank was released in 2006. This early release contained relatively modest information about 841 FDA-approved small molecule drugs and 113 biotech drugs. It also included information on 2133 drug targets. The second version of DrugBank was released in 2009. This greatly expanded and improved version of the database included 1344 approved small molecule drugs and 123 biotech drugs as well as 3037 unique drug targets. Version 2.0 also included, for the first time, withdrawn drugs and illicit drugs, extensive food-drug and drug-drug interactions as well as ADMET (absorption, distribution, metabolism, excretion and toxicity) parameters. Version 3.0 was released in 2011. This version contained 1424 approved small molecule drugs and 132 biotech drugs as well as >4000 unique drug targets. Version 3.0 also included drug transporter data, drug pathway data, drug pricing, patent and manufacturing data as well as data on >5000 experimental drugs. Version 4.0 was released in 2014. This version included 1558 FDA-approved small molecule drugs, 155 biotech drugs and 4200 unique drug targets. Version 4.0 also incorporated extensive information on drug metabolites (structures and reactions), drug taxonomy, drug spectra, drug binding constants and drug synthesis information. Table 1 provides a more complete statistical summary of the history of DrugBank's development.
== Scope and access ==
All data in DrugBank is derived from public non-proprietary sources. Nearly every data item is fully traceable and explicitly referenced to the original source. DrugBank data is available through a public web interface.
== See also ==
ChEMBL
Drug metabolism
HMDB
KEGG
List of biological databases
Pharmacology
SMPDB
T3DB
Therapeutic Targets Database
== References == | Wikipedia/DrugBank |
Whole-cell vaccines are a type of vaccine that has been prepared in the laboratory from entire cells. Such vaccines simultaneously contain multiple antigens to activate the immune system. They induce antigen-specific T-cell responses.
Whole-cell vaccines have been researched in the fields of bacterial infectious disease (as an inactivated vaccine) and cancer (as tumor cells modified to stimulate the immune system by secreting stimulatory molecules). One whole-cell vaccine that sees global use is the whole-cell pertussis vaccine.
== Against infectious disease ==
=== Pertussis ===
The causative organism of pertussis is Bordetella pertussis. The whole-cell pertussis vaccine is effective and safe in treating this disease but is also associated with short-term side effects. Depending upon the different B. pertussis antigens, the immune response produced by the whole-cell vaccine also varies. The pertussis whole-cell vaccine contains inactivated bacterial cells that contain antigens like pertussis toxin, adenylate cyclase toxin, lipooligosaccharides and agglutinogens. The whole-cell pertussis vaccine is prepared by growing Bordetella pertussis in a liquid medium. After the inactivation of the bacteria, a specific cellular concentration is aliquoted. The vaccine efficacy ranges between 36 and 98%.
==== Advantages over acellular pertussis vaccine ====
Whole-cell pertussis vaccine stimulates natural infection better than the acellular pertussis vaccine.
Even though cell-mediated immunity persists in patients received with the acellular pertussis vaccine, stronger lymphocytic proliferation, specifically memory T helper 1 cell and T helper 17 cells and cytokine responses are observed in patients received with the whole cell pertussis vaccine.
The vaccination with whole cell pertussis vaccine ensures the low risks of pulmonary infection and nasal colonization, due to the increased production of Tissue Resident Memory cells.
=== Pneumococcus ===
The whole-cell pneumococcal vaccine consisted of inactive Streptococcus pneumoniae RM200 cells and was the first whole-cell vaccine used against S. pneumoniae. In 2012, Phase-I studies were conducted by combining the whole-cell vaccine with alum. 1 out of 42 experienced adverse reactions which were not related to vaccination. The mild reactions experienced were similar to the control groups. Immunoglobulin G responses to the whole-cell vaccine was determined by pan proteome microassay and found that the whole-cell pneumococcal vaccine induced an increase in IgG response in a naturally immunogenic protein expressed by RM200 and also caused a reaction to PclA, PspC and ZmpB protein variants.
== Against cancer ==
The whole-cell tumour vaccine is based on the logic that tumour cells will contain proteins produced by cancer lesion and will provide multiple antigens for immune recognition. Whole-cell tumour vaccines represent one form of immunotherapy method undergoing clinical development.
To make a whole-cell tumor vaccine, tumor cells from the patient are transduced so that they produce costimulatory molecules such as cytokines, chemokines, and others. The cells are irradiated so they cannot grow like the parent tumor, but can still express the tumor antigens and the additional molecules.
Phase I & II clinical trials of various whole-cell tumour vaccines indicate this method is safe for cancer patients. The advantage of a whole-cell vaccine is that the cells provide a source of all potential antigens, eliminating the need to identify the most optimal antigen to target in a particular type of cancer. Multiple tumour antigens can be targeted simultaneously, generating an immune response to various tumour antigens.
=== Advantages ===
Whole tumour cell vaccines contain characterised and uncharacterised Tumour Antigen Associated Cells that can be processed Antigen Presenting Cells to stimulate the immune system; this makes the whole tumour cell vaccine different from other antigen-specific vaccines.
Antigen Presenting Cells can present Tumour Associated Antigens to CD8+ and CD4+ T cells via MHC I & II, respectively. The simultaneous presentation of MHC I & II leads to a robust immune response against tumours.
Induces immune response to multiple epitopes within an antigenic protein.
=== Disadvantages ===
The use of whole-tumour cells for vaccine preparation is not very specific because only a portion of the antigens expressed by tumour cells are specific to tumours, and the rest of the antigens are present in normal cells.
A tumour biopsy is needed to prepare autologous tumour cell vaccines. In some cases, the cells obtained through tumour biopsy may not be sufficient, or the tumour cells might have undergone necrosis.
The Tumour Associated Antigens present in whole tumour cell vaccines can release immunosuppressive cytokines like TGF-β, inhibiting the development of proper immune response.
The CD8+ T cell presented by MHC-I does not elicit a response against tumour antigens due to a lack of expression of costimulatory molecules like CD80 & CD86 in these cancer cells.
=== Mode of action ===
The whole tumour cell vaccine consists of the identified and unidentified tumour antigens. Antigen-presenting cells present these tumour antigens via Major Histocompatibility Complex Class I & II to CD8+ T lymphocytes and CD4+T lymphocytes, respectively. By interacting with the Fas ligand or secretion of lytic enzymes, cytotoxic T lymphocytes can lead to apoptosis. Active CD4+ T cells activate the Natural-killer cells, and also CD4+T cells activate the humoral immune response and also promote the activity of CD8+ T cells.
Vaccine-induced immune responses are measured by Delayed type Hypersensitivity responses to autologous tumour cells. The granulocyte-macrophage colony-stimulating factor (GM-CSF) is superior to other cytokines, and the addition of GM-CSF in whole-cell vaccine results in a better response against tumour cells. GM-CSF recruits dendritic cells to the site of irradiated cells and stimulates the antigen uptake, processing and presentation. These dendritic cells facilitate the T-cell response by combining with CD8+ T cells.
== See also ==
Pertussis vaccine
Pneumococcal vaccine
== References == | Wikipedia/Whole-cell_vaccine |
The Randomised Evaluation of COVID-19 Therapy (RECOVERY Trial) is a large-enrollment clinical trial of possible treatments for people in the United Kingdom admitted to hospital with severe COVID-19 infection. The trial was later expanded to Indonesia, Nepal and Vietnam. The trial has tested ten interventions on adults: eight repurposed drugs, one newly developed drug and convalescent plasma.
== Overview ==
The RECOVERY Trial is a large-scale, randomized controlled trial. It is an "open label" study: people receiving the treatment and the attending clinicians both know which treatment is being administered. It is a multi-arm adaptive clinical trial, meaning that new treatments can be added into the trial as it progresses, and other treatment "arms" closed to new enrolment when results have been produced.
The very fast setting up of the trial was crucial for the fast-developing COVID-19 pandemic.
Martin Landray, one of the trial's creators, said in March 2021 "I think it has set a new standard for what can be delivered and not just for pandemics. It would be a travesty if we went back to a situation where it takes years sometimes to get a trial off the ground."
=== Enrollment ===
When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive trial treatments. If any treatment is contra-indicated (or positively indicated) for that patient, or is not available, then that treatment is not included in the randomization process. The main randomization stage has three parts, so that patients might be allocated none, one, two or three of the trial treatments. If their disease progresses, there may also be a second randomization.
=== Goals ===
The primary objective of the trial is to "provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomization".
The trial protocol was developed in March 2020. The design minimizes the administrative load on hospital staff, who at the time were facing the prospect of overwhelming numbers of COVID-19 admissions.
== Treatments ==
As of 25 June 2021, the following treatments are allocated at random to hospitalized people with severe COVID-19 infection:
Baricitinib (an immunomodulatory drug used in rheumatoid arthritis)
Dimethyl fumarate (adults only, early phase assessment)
Infliximab (adults only)
High-dose dexamethasone (adults with hypoxia only)
Children with PIMS-TS may also be allocated the following:
Low-dose dexamethasone (a steroid, which reduces inflammation)
Intravenous immunoglobulin
Tocilizumab (an anti-inflammatory)
Anakinra (an anti-inflammatory)
The following treatments have previously been included in the trial and obtained positive results:
Low-dose dexamethasone
Tocilizumab
REGN-COV2 (a cocktail of two anti-viral monoclonal antibodies)
Baricitinib
The following treatments have previously been included in the trial and were closed to new entrants after being shown to be ineffective.:
Lopinavir-Ritonavir (an HIV medication)
Hydroxychloroquine (used to treat malaria and rheumatism)
Azithromycin (an antibiotic)
Convalescent plasma (blood plasma from people who have recovered from COVID-19 and which may contain antibodies against the SARS-CoV-2 virus)
Aspirin (a commonly used blood thinner)
Colchicine (a drug used for gout)
== Operations ==
The trial is run by the Nuffield Departments of Population Health and of Medicine at the University of Oxford and supported by the National Institute for Health Research (NIHR). The study is led by Peter Horby and Martin Landray who serve as Co-Chief Investigators of the trial. By July 2020, the trial was in progress at 176 NHS hospitals in the UK, involving many thousands of health professionals.
The trial began in March 2020. As of March 2021 the trial had enrolled more than 40,000 COVID-19 participants admitted to hospitals in the UK; the estimated primary completion date was December 2021, and the estimated study completion date was December 2031.
== Results ==
=== Dexamethasone ===
In June 2020, preliminary results were published in a preprint showing that low-dose dexamethasone treatment reduced the death rate by one third in hospitalized people needing ventilators due to severe COVID-19 infection, and by one fifth in people treated with oxygen therapy. There was no benefit (and the possibility of harm) among people who did not require oxygen. The preliminary report was subsequently published in The New England Journal of Medicine.
==== Impacts ====
Six days before the pre-print, these results had been announced in a news release. A UK Therapeutic Alert was issued the same day, and all the Chief Medical Officers in the United Kingdom exceptionally recommended an immediate change of UK-wide clinical practice, in advance of publication of any final paper.
Demand for dexamethasone surged after publication of the preprint.
Based on the preliminary, unpublished results of the RECOVERY trial, the US National Institutes of Health COVID-19 Treatment Guidelines Panel recommended dexamethasone in patients with COVID-19 who are on mechanical ventilation or those who require supplemental oxygen, and recommended against dexamethasone for those not requiring supplemental oxygen.
Other countries granted specific approval for the drug as part of standard medical care, among them Japan, Taiwan and South Africa.
A pre-print study, which was awarded Health Data Research UK Open Access Publication of the Month for August 2020, found that the discovery would save approximately 650,000 lives globally over the course of six months.
==== Limitations of dexamethasone result ====
John Fletcher, research editor at the BMJ, noted that there were "limitations and causes of concern" in the dexamethasone results.
Around a third of patients in the trial were still in hospital at the end of the 28-day trial period, so their final outcomes were not known.
As an immunosuppressive drug, there are fears that dexamethasone could make the illness worse, and prolong the infection in patients where the immune system has not yet overreacted and caused inflammation.
The preprint authors themselves warned that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment. The trial observed a 22% increase in mortality in these patients (rate ratio 1.22 [95% Confidence Interval 0.93 to 1.61]; p=0.14), though this observation may still be due to chance.
Responding to the publication, the WHO emphasized that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision, stating that "There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm."
==== Confirmation of dexamethasone result ====
The results of this initial finding were replicated in a systematic review published in September 2020 by the WHO's Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group.
=== Hydroxychloroquine ===
In June 2020, the trial determined that there was no clinical benefit from use of hydroxychloroquine in people hospitalized with COVID-19.
=== Lopinavir-ritonavir ===
In June 2020, chief investigators of the trial reported there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment. These results were published in The Lancet on 5 October 2020.
=== Azithromycin ===
In December 2020, the chief investigators announced that they had found no benefit from azithromycin in patients hospitalised with COVID-19. 2582 patients had received azithromycin, and 5182 were randomised to usual care alone. 28-day mortality in both cohorts was 19%. These preliminary results were released as a preprint on the same day.
=== Convalescent plasma ===
In January 2021, the chief investigators announced the closure of the convalescent plasma arm of the trial. Among 1873 reported deaths from 10,405 patients, the trial reported "no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34)". The article with full results was published on 14 May 2021.
=== Tocilizumab ===
Tocilizumab significantly reduces the risk of death when given to hospitalised patients with severe COVID-19. 2022 patients allocated to Tocilizumab were compared to 2094 who received standard hospital care. "596 (29%) of the patients in the tocilizumab group died within 28 days compared with 694 (33%) patients in the usual care group (rate ratio 0·86; [95% confidence interval [CI] 0·77 to 0·96]; p=0·007), an absolute difference of 4%." Receiving tocilizumab also increased the chance of discharge from hospital within 28 days.
This result supports the earlier findings of the Remap-Cap trial on the effectiveness of Tocilizumab for patients in intensive care, and extends those findings to a wider group of patients.
=== Dimethyl fumarate ===
A study published in January 2024 by the trial's chief investigators found that dimethyl fumarate did not significantly improve clinical outcomes in hospitalized COVID-19 patients.
== See also ==
Solidarity trial
PANORAMIC trial
AGILE trial
COVID-19 drug development
== References ==
== External links ==
Official website
Trial Protocol (v12.1) dated 2020-12-16 | Wikipedia/RECOVERY_Trial |
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.
Classically, for clinical indications of an approved drug, TI refers to the ratio of the dose of the drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.
In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). In modern settings, more sophisticated toxicity endpoints are used.
For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index is preferable instead of a lower one; an individual would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to induce the therapeutic effect of the drug. However, a lower efficacy-based therapeutic index is preferable instead of a higher one; an individual would have to take a higher dose of a drug to reach the toxic threshold than the dose taken to induce the therapeutic effect of the drug.
Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of its blood levels in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.
== Types ==
Based on efficacy and safety of drugs, there are two types of therapeutic index:
Safety-based therapeutic index
T
I
safety
=
L
D
50
E
D
50
{\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}}
It is desirous for the value of LD50 to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TIsafety increases as the difference between LD50 and ED50 increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vice versa.
Efficacy-based therapeutic index
T
I
efficacy
=
E
D
50
T
D
50
{\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}}
Ideally the ED50 is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD50 is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED50 and TD50, the greater the value of TIefficacy. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window.
Protective index
Similar to safety-based therapeutic index, the protective index uses TD50 (median toxic dose) in place of LD50.
Protective index
=
T
D
50
E
D
50
=
1
T
I
efficacy
{\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}}
For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index (
T
I
safety
{\displaystyle {TI_{\text{safety}}}}
) is still useful as it can be considered an upper bound of the protective index, and the former also has the advantages of objectivity and easier comprehension.
Since the protective index (PI) is calculated as TD50 divided by ED50, it can be mathematically expressed that:
T
I
efficacy
=
1
Protective index
{\displaystyle TI_{\text{efficacy}}={\frac {1}{\text{Protective index}}}}
which means that
T
I
efficacy
{\displaystyle TI_{\text{efficacy}}}
is a reciprocal of protective index.
All the above types of therapeutic index can be used in both pre-clinical trials and clinical trials.
== Drug development ==
A low efficacy-based therapeutic index (
T
I
efficacy
{\displaystyle TI_{\text{efficacy}}}
) and a high safety-based therapeutic index (
T
I
safety
{\displaystyle TI_{\text{safety}}}
) are preferable for a drug to have a favorable efficacy vs safety profile. At the early discovery/development stage, the clinical TI of a drug candidate is unknown. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of successful development. Recognizing drug candidates with potentially suboptimal TI at the earliest possible stage helps to initiate mitigation or potentially re-deploy resources.
TI is the quantitative relationship between pharmacological efficacy and toxicological safety of a drug, without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific efficacy vs safety profile.
In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose.
A review published by Muller PY and Milton MN in Nature Reviews Drug Discovery critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.
== Range of therapeutic indices ==
The therapeutic index varies widely among substances, even within a related group.
For instance, the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant, has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70.
Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (a sedative): the therapeutic indices for these substances are 15:1 and 10:1, respectively. Paracetamol, alternatively known by its trade names Tylenol or Panadol, also has a therapeutic index of 10.
Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1.
Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include dimercaprol, theophylline, warfarin and lithium carbonate.
Some antibiotics and antifungals require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed 'amphoterrible' for this very reason), and polymyxin B.
=== Cancer radiotherapy ===
Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from x-rays, gamma rays, or charged or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues. Both of these parameters have sigmoidal dose–response curves. Thus, a favorable outcome in dose–response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce DNA mutation or chromosomal rearrangement during its repair process. Direct radiation creates a DNA free radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA.
Cancer cells cause an imbalance of signals in the cell cycle. G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting it is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation. p53, a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of myeloid leukemia cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with Ataxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53. In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment.
Irradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a phenotype of enhanced genetic instability such as micronucleation. This suggests an effect on cell-to-cell communication such as paracrine and juxtacrine signaling. Normal cells do not lose their DNA repair mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of carcinogenesis. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as EGFR and insulin growth factor.
The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its desirable area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in peptide receptor radionuclide therapy for neuroendocrine tumors and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.
== Safety ratio ==
Sometimes the term safety ratio is used, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. In such cases, the effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose.
The Certain Safety Factor, also referred to as the Margin of Safety (MOS), is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99). This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another.
Certain safety factor
=
L
D
1
E
D
99
{\displaystyle {\text{Certain safety factor}}=\mathrm {\frac {LD_{1}}{ED_{99}}} }
== Synergistic effect ==
A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, depressants, opiates, or stimulants when compared with being taken alone. Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable.
== Therapeutic window ==
The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.
== Optimal biological dose ==
Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity.
== Maximum tolerated dose ==
The maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce the desired effect without unacceptable toxicity. The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects. The maximum dose is used, rather than a lower dose, to reduce the number of test subjects (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing chemical residue tolerances in foods. Maximum tolerated dose studies are also done in clinical trials.
MTD is an essential aspect of a drug's profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.
Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patient's health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional "blunting" with antidepressants, pruritus with opiates, and blurred vision with anticholinergics.
== See also ==
Drug titration – process of finding the correct dose of a drug
Effective dose
EC50
IC50
LD50
Hormesis
== References == | Wikipedia/Maximum_tolerated_dose |
The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness. The trial was announced 18 March 2020, and as of 6 August 2021, 12,000 patients in 30 countries had been recruited to participate in the trial.
In May, the WHO announced an international coalition for simultaneously developing several candidate vaccines to prevent COVID-19 disease, calling this effort the Solidarity trial for vaccines.
The treatments being investigated are remdesivir, lopinavir/ritonavir combined, lopinavir/ritonavir combined with interferon-beta, and hydroxychloroquine or chloroquine. Hydroxychloroquine or chloroquine investigation was discontinued in June 2020 due to concluding that it provided no benefit.
== Solidarity trial for treatment candidates ==
The trial intends to rapidly assess thousands of COVID-19 infected people for the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness, a process called "repurposing" or "repositioning" an already-approved drug for a different disease.
The Solidarity project is designed to give rapid insights to key clinical questions:
Do any of the drugs reduce mortality?
Do any of the drugs reduce the time a patient is hospitalized?
Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?
Enrolling people with COVID-19 infection is simplified by gathering informed consent, and capturing data on an online clinical trial platform (Castor EDC). After the trial staff determine the drugs available at the hospital, the platform randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the Castor EDC Platform. The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but WHO needed speed with quality for the trial across many hospitals and countries. A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France).
The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to John-Arne Røttingen, chief executive of the Research Council of Norway and chairman of the Solidarity trial international steering committee, the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems."
=== Adaptive design ===
According to the WHO Director General, the aim of the trial is to "dramatically cut down the time needed to generate robust evidence about what drugs work", a process using an "adaptive design". The Solidarity and European Discovery trials apply adaptive design to rapidly alter trial parameters when results from the four experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase III-IV clinical trials – such as the Solidarity and Discovery projects – may shorten the trial duration and use fewer subjects, possibly expediting decisions for early termination to save costs if interim results are negative. If the Solidarity project shows early evidence of success, design changes across the project's international locations can be made rapidly to enhance overall outcomes of affected people and hasten use of the therapeutic drug.
== Treatment candidates under study ==
The individual or combined drugs being studied in the Solidarity and Discovery projects are already approved for other diseases. They are:
Remdesivir
Lopinavir/ritonavir combined
Lopinavir/ritonavir combined with interferon-beta
Hydroxychloroquine or chloroquine (discontinued due to no benefit, June 2020)
Due to safety concerns and evidence of heart arrhythmias leading to higher death rates, the WHO suspended the hydroxychloroquine arm of the Solidarity trial in late May 2020, then reinstated it, then withdrew it again when an interim analysis in June showed that hydroxychloroquine provided no benefit to hospitalized people severely infected with COVID-19.
In October 2020, the World Health Organization Solidarity trial produced an interim report concluding that its "remdesivir, hydroxychloroquine, lopinavir and interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay." Gilead – the manufacturer of remdesivir – criticized the Solidarity trial methodology after it showed no benefit of the treatments, claiming that the international nature of the Solidarity trial was a weakness, whereas many experts regard the multinational study as a strength. Purchase agreements between the EU and Gilead for remdesivir and granting of its Emergency Use Authorization by the US FDA during October were questioned by Solidarity trial scientists as not based on positive clinical trial data, when the interim analysis of the Solidarity trial had found remdesivir to be ineffective.
In January 2022, the Canadian component of the Solidarity trial reported that in-hospital people with COVID-19 treated with remdesivir had lower death rates (by about 4%) and reduced need for oxygen (less by 5%) and mechanical ventilation (less by 7%) compared to people receiving standard-of-care treatments.
== Support and participation ==
During March, funding for the Solidarity trial reached US$108 million from 203,000 individual donations, charitable organizations and governments, with 45 countries involved in financing or trial management. As of 1 July 2020, nearly 5,500 patients in 21 countries of 39 that have approval to recruit were recruited to participate in the trial. More than 100 countries in all 6 WHO regions have expressed interest in participating.
== Solidarity trial for vaccine candidates ==
The WHO has developed a multinational coalition of vaccine scientists defining a Global Target Product Profile (TPP) for COVID-19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID-19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks. The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development; 3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international randomized controlled trial – the Solidarity trial for vaccines – to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID-19 disease, ensuring fast interpretation and sharing of results around the world. The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage.
== Solidarity Plus Trial ==
The WHO announced in August 2021 that it will roll out the next phase Solidarity trial under the name Solidarity PLUS trial in 52 countries. The trial will enroll hospitalized patients to test three new drugs for potential treatment of COVID-19. These drugs include artesunate, imatinib and infliximab. The selection of these therapies was done by an independent expert panel of WHO. These drugs are already used for other indications: artesunate is used for malaria, imatinib for cancers, and infliximab, an anti-TNF agent is used for Crohn's Disease and rheumatoid arthritis. The drugs will be donated for the purpose of trial by their manufacturers.
== See also ==
COVID-19 drug repurposing research
COVID-19 drug development#Phase III-IV trials
RECOVERY Trial
PANORAMIC trial
AGILE trial
== References ==
== External links ==
"'Solidarity' clinical trial for COVID-19 treatment by the World Health Organization
COVID-19 (Questions & Answers) by the World Health Organization
COVID-19 (Q&A) by the US Centers for Disease Control and Prevention (CDC)
Coronaviruses by US National Institute for Allergy and Infectious Diseases
COVID-19 (Q&A) by the European Centre for Disease Prevention and Control
COVID-19 by the China National Health Commission | Wikipedia/Solidarity_trial |
An ecosystem model is an abstract, usually mathematical, representation of an ecological system (ranging in scale from an individual population, to an ecological community, or even an entire biome), which is studied to better understand the real system.
Using data gathered from the field, ecological relationships—such as the relation of sunlight and water availability to photosynthetic rate, or that between predator and prey populations—are derived, and these are combined to form ecosystem models. These model systems are then studied in order to make predictions about the dynamics of the real system. Often, the study of inaccuracies in the model (when compared to empirical observations) will lead to the generation of hypotheses about possible ecological relations that are not yet known or well understood. Models enable researchers to simulate large-scale experiments that would be too costly or unethical to perform on a real ecosystem. They also enable the simulation of ecological processes over very long periods of time (i.e. simulating a process that takes centuries in reality, can be done in a matter of minutes in a computer model).
Ecosystem models have applications in a wide variety of disciplines, such as natural resource management, ecotoxicology and environmental health, agriculture, and wildlife conservation. Ecological modelling has even been applied to archaeology with varying degrees of success, for example, combining with archaeological models to explain the diversity and mobility of stone tools.
== Types of models ==
There are two major types of ecological models, which are generally applied to different types of problems: (1) analytic models and (2) simulation / computational models. Analytic models are typically relatively simple (often linear) systems, that can be accurately described by a set of mathematical equations whose behavior is well-known. Simulation models on the other hand, use numerical techniques to solve problems for which analytic solutions are impractical or impossible. Simulation models tend to be more widely used, and are generally considered more ecologically realistic, while analytic models are valued for their mathematical elegance and explanatory power. Ecopath is a powerful software system which uses simulation and computational methods to model marine ecosystems. It is widely used by marine and fisheries scientists as a tool for modelling and visualising the complex relationships that exist in real world marine ecosystems.
== Model design ==
The process of model design begins with a specification of the problem to be solved, and the objectives for the model.
Ecological systems are composed of an enormous number of biotic and abiotic factors that interact with each other in ways that are often unpredictable, or so complex as to be impossible to incorporate into a computable model. Because of this complexity, ecosystem models typically simplify the systems they are studying to a limited number of components that are well understood, and deemed relevant to the problem that the model is intended to solve.
The process of simplification typically reduces an ecosystem to a small number of state variables and mathematical functions that describe the nature of the relationships between them. The number of ecosystem components that are incorporated into the model is limited by aggregating similar processes and entities into functional groups that are treated as a unit.
After establishing the components to be modeled and the relationships between them, another important factor in ecosystem model structure is the representation of space used. Historically, models have often ignored the confounding issue of space. However, for many ecological problems spatial dynamics are an important part of the problem, with different spatial environments leading to very different outcomes. Spatially explicit models (also called "spatially distributed" or "landscape" models) attempt to incorporate a heterogeneous spatial environment into the model. A spatial model is one that has one or more state variables that are a function of space, or can be related to other spatial variables.
== Validation ==
After construction, models are validated to ensure that the results are acceptably accurate or realistic. One method is to test the model with multiple sets of data that are independent of the actual system being studied. This is important since certain inputs can cause a faulty model to output correct results. Another method of validation is to compare the model's output with data collected from field observations. Researchers frequently specify beforehand how much of a disparity they are willing to accept between parameters output by a model and those computed from field data.
== Examples ==
=== The Lotka–Volterra equations ===
One of the earliest, and most well-known, ecological models is the predator-prey model of Alfred J. Lotka (1925) and Vito Volterra (1926). This model takes the form of a pair of ordinary differential equations, one representing a prey species, the other its predator.
d
X
d
t
=
α
.
X
−
β
.
X
.
Y
{\displaystyle {\frac {dX}{dt}}=\alpha .X-\beta .X.Y}
d
Y
d
t
=
γ
.
β
.
X
.
Y
−
δ
.
Y
{\displaystyle {\frac {dY}{dt}}=\gamma .\beta .X.Y-\delta .Y}
where,
Volterra originally devised the model to explain fluctuations in fish and shark populations observed in the Adriatic Sea after the First World War (when fishing was curtailed). However, the equations have subsequently been applied more generally. Although simple, they illustrate some of the salient features of ecological models: modelled biological populations experience growth, interact with other populations (as either predators, prey or competitors) and suffer mortality.
A credible, simple alternative to the Lotka-Volterra predator-prey model and its common prey dependent generalizations is the ratio dependent or Arditi-Ginzburg model. The two are the extremes of the spectrum of predator interference models. According to the authors of the alternative view, the data show that true interactions in nature are so far from the Lotka-Volterra extreme on the interference spectrum that the model can simply be discounted as wrong. They are much closer to the ratio dependent extreme, so if a simple model is needed one can use the Arditi-Ginzburg model as the first approximation.
=== Others ===
The theoretical ecologist Robert Ulanowicz has used information theory tools to describe the structure of ecosystems, emphasizing mutual information (correlations) in studied systems. Drawing on this methodology and prior observations of complex ecosystems, Ulanowicz depicts approaches to determining the stress levels on ecosystems and predicting system reactions to defined types of alteration in their settings (such as increased or reduced energy flow, and eutrophication.
Conway's Game of Life and its variations model ecosystems where proximity of the members of a population are factors in population growth.
== See also ==
== References ==
== Further reading ==
Khan, M. F.; Preetha, P.; Sharma, A. P. (2015). "Modelling the food web for assessment of the impact of stock supplementation in a reservoir ecosystem in India". Fisheries Management and Ecology. 22 (5): 359–370. Bibcode:2015FisME..22..359K. doi:10.1111/fme.12134.
Panikkar, Preetha; Khan, M. Feroz; Desai, V. R.; Shrivastava, N. P.; Sharma, A. P. (2014). "Characterizing trophic interactions of a catfish dominated tropical reservoir ecosystem to assess the effects of management practices". Environmental Biology of Fishes. 98: 237–247. doi:10.1007/s10641-014-0255-6. S2CID 16992082.
Panikkar, Preetha; Khan, M. Feroz (2008). "Comparative mass-balanced trophic models to assess the impact of environmental management measures in a tropical reservoir ecosystem". Ecological Modelling. 212 (3–4): 280–291. Bibcode:2008EcMod.212..280P. doi:10.1016/j.ecolmodel.2007.10.029.
Feroz Khan, M.; Panikkar, Preetha (2009). "Assessment of impacts of invasive fishes on the food web structure and ecosystem properties of a tropical reservoir in India". Ecological Modelling. 220 (18): 2281–2290. Bibcode:2009EcMod.220.2281F. doi:10.1016/j.ecolmodel.2009.05.020.
== External links ==
Ecological modelling resources (ecobas.org)
Exposure Assessment Models United States Environmental Protection Agency
Ecotoxicology & Models (ecotoxmodels.org) | Wikipedia/Ecological_model |
In immunology, antiserum is a blood serum containing antibodies (either monoclonal or polyclonal) that is used to spread passive immunity to many diseases via blood donation (plasmapheresis). For example, convalescent serum, or passive antibody transfusion from a previous human survivor, was the only known effective treatment for Ebola infection with a high success rate of 7 out of 8 patients surviving.
Antisera are widely used in diagnostic virology laboratories. The most common use of antiserum in humans is as antitoxin or antivenom to treat envenomation.
Serum therapy, also known as serotherapy, describes the treatment of infectious diseases using the serum of animals that have been immunized against the specific organism or components of that organism that is causing the infection.
== History ==
In 1890, Emil von Behring and Kitasato Shibasaburō published their first paper on serum therapy.
Behring pioneered the technique, using guinea pigs to produce serum. Based on his observation that people who survived infection with the diphtheria bacterium never became infected again, he discovered that the body continually produces an antitoxin, which prevents survivors of infections from being infected again with the same organism.
It was necessary for Behring to immunize larger animals in order to produce enough serum to protect humans, because the amount of antiserum produced by guinea pigs was too little to be practical. Horses proved to be the best serum producer, as the serum of other large animals was not concentrated enough, and it was believed that horses did not carry any diseases that could be transferred to humans.
Due to World War I, a large number of horses were needed for military purposes. It was difficult for Behring to find enough German horses for his serum facility. He chose to obtain horses from Eastern European countries, mostly Hungary and Poland. Because of Behring's limited financial resources, most of the horses he selected were intended for slaughter; however, the usefulness of the animal to others had no influence on the production of serum. Serum horses were calm, well-mannered, and in good health. Age, breed, height, and color were irrelevant.
Horses were transported from Poland or Hungary to the Behring facilities in Marburg, in the West-Central part of Germany. Most of the horses were transported by rail and treated like any other freight load. During the interminable border crossing, horses were left at the mercy of the weather. Once the horses arrived in Marburg, they had 3 to 4 weeks to recover in a quarantine facility, where their data was recorded. They had to be in perfect medical condition for the immunization, and the quarantine facility ensured that they were free of microbes which could infect the other horses. In the Behring facilities, the horses were viewed as life savers; therefore, they were well treated. A few of the individual horses used for serum production were named, and celebrated for their service to medicine, both human and non-human.
At the end of the 19th century, every second child in Germany was infected with diphtheria, the most frequent cause of death in children up to 15 years of age. In 1891, Behring saved the life of a young girl with diphtheria by injecting antiserum for the first time in history. Serum horses proved to be saviors of diphtheria-infected people. Subsequently, proactive protective vaccination against diphtheria and other microbial diseases were developed, including treatments for tetanus, rabies, and snake venom.
In 1901, Behring won the first Nobel Prize in Medicine for his work in studying diphtheria.
Serum therapy became increasingly prevalent for infectious diseases, and was even used to treat patients during the influenza pandemic in 1918. The use of serum therapy was then quickly expanded to also treat diseases such as polio, measles, pneumococcus, Haemophilus influenza B, and meningococcus.
In the 1920s, Michael Heidelberger and Oswald Avery proved that antibodies were proteins that targeted the capsule of the virus or bacteria. The discovery of antibiotics in the 1940s diminished interest in treating bacterial infections with antiserum, but its use for viral infections continued with the development of ethanol fractionation of blood plasma (which allowed for purified antibodies), discovered by Edwin Cohn. Antisera were developed to prevent and/or treat diphtheria, tetanus, Hepatitis B, rabies, varicella zoster virus, cytomegalovirus, and botulinum. However, these treatments were not widely used.
In 1984, Milstein and Köhler won a Nobel Prize for their paper which described their method for making murine monoclonal antibodies by immortalizing B cells as hybridomas. Another breakthrough occurred in 2003. A new technology allowed for heavy and light chain immunoglobulin genes to be amplified from human B cells and cloned into expression vectors. In 2008, this method was refined with a greater ability to sort cells and clone, which led to the discovery of more human monoclonal antibodies.
In 1996, the United States Food and Drug Administration (FDA) approved the use of RSV-IGIV (Respigam), a polyclonal antibody drug to inhibit respiratory syncytial virus (RSV) for high-risk newborns. This was considered a breakthrough, as the clinical trial reduced infant hospitalizations by 41% and length of hospital stays by 53%. After 2 years, the product demand began to exceed the supply of plasma and Synagis, the first humanized monoclonal antibody, was approved in its place. Monoclonal antibodies became advantageous due to their decreased variability in quality, a decreased risk of bloodborne diseases, and increased potency. This enabled a large expansion of the uses of antiserum and opened the door for the treatment of autoimmune diseases.
The past 30 years have seen the transformation of how chronic and autoimmune diseases (e.g., cancer, ulcerative colitis) are treated, with 30 drugs of monoclonal antibodies, 28 for chronic conditions, being approved. Monoclonal antibodies are currently being researched to treat viral diseases without vaccines, such as HIV, SARS, and MERS.
== Modern use ==
Monoclonal antibodies are used to treat both acute and chronic conditions. Acute conditions may include, but are not limited to Ebola virus, envenomation (e.g., snake bites), and anthrax infection. Chronic conditions may include, but are not limited to rheumatoid arthritis, ulcerative colitis, and lupus.
There are four main types of monoclonal antibodies: murine, chimeric, humanized, and human.
Murine monoclonal antibodies are identified with the suffix "-omab". They originate from murine animals and can trigger allergic reactions in humans. An example is blinatumomab, which is used to treat acute lymphoblastic leukemia.
Chimeric monoclonal antibodies are identified with the suffix "-ximab". They originate partially from a murine animal and partially from a human. An example is infliximab, which is used to treat Crohn disease.
Humanized monoclonal antibodies are identified with the suffix "-zumab". They mostly originate from a human but differ in the component that attaches to its target. An example is crizanlizumab, which treats sickle cell disease.
Human monoclonal antibodies are identified with the suffix "-umab". They originate from a human. An example is ustekinumab, which treats psoriasis.
During the early stages of the COVID-19 pandemic, reliable treatment options had not yet been found or approved. Consequently, convalescent blood plasma was considered as a possibility and is used as a treatment option at least for severe cases. In May 2021, India was one of the first major countries to remove plasma from its national COVID-19 guidelines. This was after public criticism of the plasma's lack of effectiveness, criticism of health systems, and opinions from leading Indian scientists including Shahid Jameel, Soumyadeep Bhaumik, Gagandeep Kang, Soumitra Pathare, and others. The World Health Organization (WHO) recommended against use of plasma in COVID-19 in December 2021.
Monoclonal antibodies (casirivimab/imdevimab) were developed for the treatment of COVID-19.
On June 7, 2021, the FDA approved aducanumab, the first anti-Alzheimer's drug to be introduced into markets almost 20 years after the approval of memantine in 2003.
== How it works ==
Antibodies in the antiserum bind to the infectious agent or specifically, the antigen. The immune system then recognizes infectious agents or pathogens bound to antibodies and triggers a more robust immune response. The use of antiserum is particularly effective against pathogens which are capable of evading the unstimulated immune system but are not robust enough to evade the stimulated immune system. The existence of antibodies to the pathogen depends the on an initial survivor whose immune system, by chance, discovered a counter-agent to the pathogen or a host species which carries the pathogen but does not experience its effects. Further stocks of antiserum can then be produced from the initial survivor or from a donor organism (human or animal) that is inoculated with the pathogen and cured by some stock of pre-existing antiserum. Diluted snake venom is often used as an antiserum to give passive immunity to the snake venom itself.
Horses that were infected by a pathogen were vaccinated thrice in increasing dosage amounts. The time between each vaccination varied from each horse and its health condition. Normally, the horses needed a few weeks to produce the serum in the blood after the last vaccination. Even though they tried to observe the immune system of the horses during this immunization with painstaking care, most of the horses experienced appetite loss, fever, and, in worse cases, shock and dyspnea.
The highest immunization risk for horses was the production of antiserum for snake venom. The horse was immunized with all types of snake venom at the same time because it was not always possible to know by which snake species a person had been bitten. Therefore, the antiserum had to immunize the horse against the venom of every snake species.
In order to find when most antitoxins are produced in the blood cells, frequent blood samples were taken from the horses. At the point when the highest amount of antibodies were produced, 5 liters of blood, a 10th of the blood volume of a horse, were taken through a cannula. The blood was collected in a glass cylinder and brought to the laboratory in the Behring facilities. Above the rouleaux formation which contained the red blood cells, the serum was visible. The color of the serum varied from milky to brown. Concentration and sterility of the serum were checked carefully, and the serum was filtered many times. Protein content was decreased in order to use the serum for humans.
After the blood sampling, the horses could rest for 3 to 4 weeks and received extra food to recover from the blood loss. During this period of time, the horses were especially weak and prone to disease and infection.
Within a few years, with experience and observation of the horses, a rouleaux formation of the blood sample was placed back into the animal's body. This procedure is called plasmapheresis.
== References ==
== External links ==
Antisera at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Serotherapy |
COVI-VAC (codenamed CDX-005) is a COVID-19 vaccine developed by Codagenix, Inc. In December 2020, COVI-VAC started a Phase I clinical trial, involving 48 participants. The trial was scheduled to complete in June 2021, with results to be reported by May 2022. On September 29, 2021, Codagenix presented positive phase 1 data for COVI-VAC at IDWEEK2021. Data indicates that COVI-VAC is well tolerated, with no significant adverse events reported and that administration of the intranasal vaccine was immunogenic and capable of blocking nasal replication of the virus with minimal viral shedding, recorded at levels lower than those likely to result in subsequent transmission of COVID-19. Furthermore, COVI-VAC was shown to stimulate both serum and mucosal antibody immune responses.
== Medical uses ==
The vaccine is administered intranasally and requires a single dose.
== Pharmacology ==
COVI-VAC is a live attenuated vaccine.
== Clinical trials ==
=== Phase I ===
In December 2020, Codagenix started a Phase I trial in the United Kingdom.
In September 2021, Codagenix reported that the trial had shown COVI-VAC to be safe and immunogenic.
== References ==
== Further reading ==
Codagenix, Inc (26 July 2021). "First-in-human, Randomised, Double-blind, Placebo-controlled, Dose-escalation Study in Healthy Young Adults Evaluating the Safety and Immunogenicity of COVI-VAC, a Live Attenuated Vaccine Candidate for Prevention of COVID-19". | Wikipedia/COVI-VAC_(U.S._COVID-19_vaccine) |
The treatment and management of COVID-19 combines both supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support as needed, and a growing list of approved medications. Highly effective vaccines have reduced mortality related to SARS-CoV-2; for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important. Some people may experience persistent symptoms or disability after recovery from the infection, known as long COVID, but there is still limited information on the best management and rehabilitation for this condition.
Most cases of COVID-19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing. Good personal hygiene and a healthy diet are also recommended. As of April 2020 the U.S. Centers for Disease Control and Prevention (CDC) recommended that those who suspect they are carrying the virus isolate themselves at home and wear a face mask. As of November 2020 use of the glucocorticoid dexamethasone had been strongly recommended in those severe cases treated in hospital with low oxygen levels, to reduce the risk of death. Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing. Extracorporeal membrane oxygenation (ECMO) has been used to address respiratory failure, but its benefits are still under consideration. Some of the cases of severe disease course are caused by systemic hyper-inflammation, the so-called cytokine storm.
Although several medications have been approved in different countries as of April 2022, not all countries have these medications. Patients with mild to moderate symptoms who are in the risk groups can take nirmatrelvir/ritonavir (marketed as Paxlovid) or remdesivir, either of which reduces the risk of serious illness or hospitalization. In the US, the Biden Administration COVID-19 action plan includes the Test to Treat initiative, where people can go to a pharmacy, take a COVID test, and immediately receive free Paxlovid if they test positive.
Several experimental treatments are being actively studied in clinical trials. These include the antivirals molnupiravir (developed by Merck), and nirmatrelvir/ritonavir (developed by Pfizer). Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful, like fluvoxamine, a cheap and widely available antidepressant; As of December 2020, there was not enough high-quality evidence to recommend so-called early treatment. In December 2020, two monoclonal antibody-based therapies were available in the United States, for early use in cases thought to be at high risk of progression to severe disease. The antiviral remdesivir has been available in the U.S., Canada, Australia, and several other countries, with varying restrictions; it is not recommended for people needing mechanical ventilation and has been discouraged altogether by the World Health Organization (WHO), due to limited evidence of its efficacy. In November 2021, the UK approved the use of molnupiravir as a COVID treatment for vulnerable patients recently diagnosed with the disease.
The WHO, the Chinese National Health Commission, the UK National Institute for Health and Care Excellence, and the United States' National Institutes of Health, among other bodies and agencies worldwide, have all published recommendations and guidelines for taking care of people with COVID-19. As of 2020 Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.
== General support ==
Taking over-the-counter drugs such as paracetamol or ibuprofen, drinking fluids, taking honey to ease a cough, and resting may help alleviate symptoms.
== Medications ==
In the early months of the pandemic, many ICU doctors faced with the virus ventured to prescribe conjectured treatments because of the unprecedented circumstances. The standard of care for most intractable illnesses is that, as it develops over years, doctors build a body of research that tests various theories, compares and contrasts dosages, and measures one drug's power against another.
Antiviral development for SARS-CoV-2 has been disappointing. In January 2020, research into potential treatments started, and several antiviral drugs were in clinical trials.
In February 2020 with 'no known effective' treatments, the WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments. Antiviral medications were tried in people with severe disease.
As of March 2020 several medications were already approved for other uses or were already in advanced testing.
As of April 2020 trials were investigating whether existing medications could be used effectively against the body's immune reaction to SARS-CoV-2 infection. As of May 2020 several antiviral drugs were under investigation for COVID-19, though none had been shown to be clearly effective on mortality in published randomized controlled trials.
As of February 2021, in the European Union, the use of dexamethasone and remdesivir were authorized. Corticosteroids like dexamethasone have shown clinical benefit in treating COVID-19.
As of February 2021, the monoclonal antibody therapies bamlanivimab/etesevimab and casirivimab/imdevimab were found to reduce the number of hospitalizations, emergency room visits, and deaths. and both combination drugs received emergency use authorization by the US Food and Drug Administration (FDA).
As of February 2021 there were Emergency Use Authorizations for baricitinib, bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab.
As of July 2021, outpatient drugs budesonide and tocilizumab showed promising results in some patients but remained under investigation.
As of July 2021, a large number of drugs had been considered for treating COVID-19 patients.
As of November 2022, there was moderate-certainty evidence suggesting that dexamethasone, and systemic corticosteroids in general, probably cause a slight reduction in all-cause mortality (up to 30 days) in hospitalized patients with COVID‐19, the evidence was very uncertain at 120 days.
In March 2022, the BBC wrote, "There are now many drugs that target the virus or our body in different ways: anti-inflammatory drugs that stop our immune system overreacting with deadly consequences, anti-viral drugs that make it harder for the coronavirus to replicate inside the body and antibody therapies that mimic our own immune system to attack the virus"
The WHO recommendations on which medications should or should not be used to treat Covid-19 are continuously updated. As of July 2022, WHO strongly recommended for non-severe cases nirmatrelvir and ritonavir, and recommended conditionally Molnupiravir, Sotrovimab and Remdesivir. For severe cases WHO strongly recommended corticosteroids, IL-6 receptor blockers or Baricitinib and conditionally recommended casirivimab and imdevimab.
For patients in a life-threatening stage of the illness and in the presence of poor prognostic predictors, early antiviral treatment is essential.
Antiviral Treatments
Antiviral agents play a critical role in reducing disease severity and hospitalization rates. Remdesivir, an FDA-approved RNA polymerase inhibitor, has demonstrated efficacy in shortening recovery time in hospitalized patients with moderate to severe COVID-19. Additionally, newer oral antivirals like nirmatrelvir-ritonavir (Paxlovid) are widely used in high-risk outpatient populations to prevent progression to severe disease.
Immunomodulatory Therapies
Dysregulated immune responses contribute significantly to severe COVID-19 cases. Dexamethasone, a corticosteroid, has been shown to reduce mortality in critically ill patients requiring oxygen or ventilation. Janus kinase (JAK) inhibitors like baricitinib are also used to mitigate inflammation and improve patient outcomes.
Supportive Care
Supportive treatments remain vital, including oxygen therapy, anticoagulation for thrombotic complications, and prone positioning to improve respiratory function. Mechanical ventilation is reserved for patients with severe respiratory failure.
Ongoing research continues to refine these approaches, ensuring optimal patient outcomes in the evolving landscape of COVID-19
=== Ineffective ===
As of 2020, several treatments had been investigated and found to be ineffective or unsafe, and are thus were not recommended for use; these include baloxavir marboxil, lopinavir/ritonavir, ruxolitinib, chloroquine, hydroxychloroquine, interferon β-1a, and colchicine. As of 2021, favipiravir and nafamostat had shown mixed results but were still in clinical trials in some countries.
During the early part of 2020 convalescent plasma, plasma from persons who recovered from SARS-CoV-2 infection, was frequently used with anecdotal successes in reports and small case series. Subsequent trials found no consistent evidence of benefit. Conflicting outcomes from trials can be understood by noting that they transfused insufficient therapeutic doses of CCP.
As of February 2021, in the United States, only remdesivir had FDA approval for certain COVID-19 patients, and while early research had suggested a benefit in preventing death and shortening illness duration, this was not borne out by subsequent trials.
On 16 April 2021, the FDA revoked the emergency use authorization (EUA) for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID-19 in adults and certain pediatric patients.
As of July 2022, WHO strongly recommended against treating non-severe cases with convalescent plasma, hydroxychloroquine, lopinavir-ritonavir or colchicine and recommended conditionally against corticosteroids or ivermectin or fluvoxamine or nirmatrelvir and ritonavir
WHO also strongly recommended against treating severe cases with hydroxychloroquine or lopinavir-ritonavir or Baricitinib and conditionally recommended against ruxolitinib or tofacitinib, ivermectin or convalescent plasma.
As of September 2022, oral treatment of outpatients with metformin, ivermectin, and fluvoxamine were found to be ineffective in a large randomized, controlled trial.
=== Adjuvant anticoagulation ===
In general there is no good evidence that anticoagulants have any benefit in the treatment of COVID-19, other than poor quality evidence suggesting a possible effect on all-cause mortality.
== Respiratory support ==
People seriously ill with COVID-19 may require respiratory support. Depending on the severity, oxygen therapy, mechanical ventilation, and intravenous fluids may be required.
=== Mechanical ventilation ===
Most cases of COVID-19 are not severe enough to require mechanical ventilation or alternatives, but a percentage of cases are. Some of the people acutely ill with COVID-19 experience deterioration of their lungs and acute respiratory distress syndrome (ARDS) and/or respiratory failure. Due to the high risk of death, urgent respiratory support including mechanical ventilation is often required in these people. Mechanical ventilation becomes more complex as ARDS develops in COVID-19 and oxygenation becomes increasingly difficult.
People who undergo mechanical ventilation are at risk of ventilator-associated lung injury or of worsening an existing lung injury, this damage is called ventilatory-induced lung injury (VILI). The mechanism of this injury is thought to be due to trauma to the lungs caused by aerated regions of the lungs being over swollen (overdistension of the aerated alveoli) and atelectrauma (force on the alveolar that could lead to lung collapse).
Ventilators capable of pressure control modes and optimal PEEP are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax. An approach to enable the person to breath spontaneously while being mechanically ventilated by adjusting the level of sedation and the respirator settings has been suggested, with the goal of reducing atrophy of the diaphragm. There is no clear evidence to suggest that enabling spontaneous breathing early while being mechanically ventilated is either beneficial or detrimental for the person's recovery.
Other approaches to mechanical ventilation including avoiding intubation using a high flow nasal cannula or bi-level positive airway pressure are under investigation; their effectiveness compared to intubation is not clear. Some doctors prefer staying with invasive mechanical ventilation when available because this technique limits the spread of aerosol particles compared to a high flow nasal cannula.
The administration of inhaled nitric oxide to people being ventilated is not recommended, and evidence around this practice is weak.
=== Extracorporeal membrane oxygenation ===
Extracorporeal membrane oxygenation (ECMO) is an artificial lung technology that has been used since the 1980s to treat respiratory failure and acute respiratory distress syndrome when conventional mechanical ventilation fails. In this complex procedure, blood is removed from the body via large cannulae, moved through a membrane oxygenator that performs the lung functions of oxygen delivery and carbon dioxide removal, and then returned to the body. The Extracorporeal Life Support Organization (ELSO) maintains a registry of outcomes for this technology, and as of September 2020 it has been used in less than 120,000 patients over 435 ECMO centers worldwide with 40% mortality for adult respiratory patients.
Initial use of ECMO in COVID-19 patients from China early in the pandemic suggested poor outcomes, with less than 90% mortality. In March 2020, the ELSO registry began collecting data on the worldwide use of ECMO for patients with COVID-19 and reporting this data on the ELSO website in real time. In September 2020, the outcomes of 1,035 COVID-19 patients supported with ECMO from 213 experienced centers in 36 different countries were published in The Lancet, and demonstrated 38% mortality, which is similar to many other respiratory diseases treated with ECMO. The mortality is also similar to the 35% mortality seen in the EOLIA trial, the largest randomized controlled trial for ECMO in ARDS. This registry based, multi-center, multi-country data provide provisional support for the use of ECMO for COVID-19 associated acute hypoxemic respiratory failure. Given that this is a complex technology that can be resource intense, guidelines exist for the use of ECMO during the COVID-19 pandemic.
== Psychological support ==
Individuals may experience distress from quarantine, travel restrictions, side effects of treatment, or fear of the infection itself. To address these concerns, the National Health Commission of China published a national guideline for psychological crisis intervention on 27 January 2020.
According to the Inter-Agency Standing Committee (IASC) Guidelines on Mental Health and Psychosocial Support, the pandemic produced long-term consequences. Deterioration of social networks and economies, survivor stigma, anger and aggression, and mistrust of official information are long-term consequences.
In April 2020 The Lancet published a 14-page call for action focusing on the UK and stated conditions were such that a range of mental health issues was likely to become more common. BBC quoted Rory O'Connor in saying, "Increased social isolation, loneliness, health anxiety, stress, and an economic downturn are a perfect storm to harm people's mental health and wellbeing."
== Special populations ==
=== Concurrent treatment of other conditions ===
Early in the pandemic, theoretical concerns were raised about ACE inhibitors and angiotensin receptor blockers. Research in March 2020 found no evidence to justify stopping these medications in people who take them for conditions such as high blood pressure. One study from April 2020 found that people with COVID-19 and hypertension had lower all-cause mortality when on these medications. Similar concerns were raised about non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen; these were likewise not borne out, and NSAIDs may both be used to relieve symptoms of COVID-19 and continue to be used by people who take them for other conditions.
People who use topical or systemic corticosteroids for respiratory conditions such as asthma or chronic obstructive pulmonary disease should continue taking them as prescribed even if they contract COVID-19.
The principal for obstetric management of COVID-19 include rapid detection, isolation, and testing, profound preventive measures, regular monitoring of fetus as well as of uterine contractions, peculiar case-to-case delivery planning based on severity of symptoms, and appropriate post-natal measures for preventing infection.
=== Patients with simultaneous Influenza infection ===
Patients with simultaneous SARS CoV2 and Influenza infection are more than twice as likely to die and more than four times as likely to need ventilation as patients with only COVID. It is recommended that patients admitted to hospital with COVID should be routinely tested to see if they also have Influenza. The public are advised to get vaccinated against both Influenza and COVID.
== Epidemiology ==
Severe cases are most common in older adults (those older than 60 years, and especially those older than 80 years). Many developed countries do not have enough hospital beds per capita, which limits a health system's capacity to handle a sudden spike in the number of COVID-19 cases severe enough to require hospitalisation. This limited capacity is a significant driver behind calls to flatten the curve. One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died. In China, approximately 30% of people in hospital with COVID-19 are eventually admitted to ICU.
== References ==
== External links ==
=== Treatment guidelines ===
"JHMI Clinical Recommendations for Available Pharmacologic Therapies for COVID-19" (PDF). Johns Hopkins Medicine.
"Bouncing Back From COVID-19: Your Guide to Restoring Movement" (PDF). Johns Hopkins Medicine. Archived from the original (PDF) on 15 February 2021. Retrieved 5 December 2020.
"Guidelines on the Treatment and Management of Patients with COVID-19". Infectious Diseases Society of America (IDSA).
"Coronavirus Disease 2019 (COVID-19) Treatment Guidelines". National Institutes of Health.
World Health Organization. Corticosteroids for COVID-19: living guidance, 2 September 2020 (Report). hdl:10665/334125. WHO/2019-nCoV/Corticosteroids/2020.1.
World Health Organization (2022). Therapeutics and COVID-19: living guideline (Report). World Health Organization (WHO). WHO-2019-nCoV-therapeutics-2022.1. | Wikipedia/Treatment_and_management_of_COVID-19 |
The AbC-19 rapid antibody test is an immunological test for COVID-19 exposure developed by the UK Rapid Test Consortium and manufactured by Abingdon Health. It uses a lateral flow test to determine whether a person has IgG antibodies to the SARS-CoV-2 virus that causes COVID-19. The test uses a single drop of blood obtained from a finger prick and yields results in 20 minutes. The sensitivity of this test is 98.03% while the specificity is 99.56%. This test is paired with an easy-to-use mobile app which allows a trained professional to generate an antibody test certificate for storing on a person's smartphone.
== See also ==
COVID-19 rapid antigen test
== References ==
== External links ==
Official website Archived 9 June 2022 at the Wayback Machine
AbC 19 Rapid Test Instructions | Wikipedia/AbC-19_rapid_antibody_test |
COVID-19 Response Acceleration Task Force (Indonesian: Gugus Tugas Percepatan Penanganan COVID-19) was a task force that coordinated and oversaw the Indonesian government's efforts to accelerate the mitigation of the COVID-19 pandemic. It was established on 13 March 2020, coordinated by the Indonesian National Board for Disaster Management and involving the Ministry of Health, Indonesian National Police, and Indonesian Armed Forces. The task force executive board was led by Indonesian National Board for Disaster Management head Doni Monardo, with Coordinating Minister for Human Development and Cultural Affairs Muhadjir Effendy as the head of the advisory board.
The task force was dissolved on 20 July 2020 according to Perpres Nomor 82 Tahun 2020 (Presidential Regulation No. 82 of 2020). Its duties were moved to the COVID-19 handling task unit in the National COVID-19 Handling and Economic Recovery Committee.
== Background ==
A man from the Netherlands may have been the first confirmed coronavirus patient in Indonesia when he fell ill there in January. He was treated in three hospitals while he was ill in East Java in January 2020. Indonesia banned all flights from and to mainland China starting on 5 February. The government also stopped giving free visas and visas on arrival for Chinese nationals. Those who lived or had stayed in mainland China in the previous 14 days were barred from entering or transiting through Indonesia. Indonesians were discouraged from travelling to China.
The Ministry of Health ordered the installation of thermal scanners for at least 135 airport gates and port docks, and announced that provisioning over 100 hospitals with isolation rooms (to WHO-recommended standards) would begin. On 2 March 2020, President Joko Widodo confirmed the first two cases of COVID-19 in the country in a televised statement. According to the Minister of Health Terawan Agus Putranto, the patients contracted the virus from an infected Japanese person in Depok who later tested positive in Malaysia. Both Indonesian patients were subsequently hospitalized at Sulianti Saroso Infection Center Hospital, North Jakarta. Starting on 4 March, Jakarta MRT also began scanning the temperature of passengers entering the stations and denying access to those with symptoms of high fever.
Starting on 8 March, travel restrictions expanded to include Daejeon and Gyeongsangbuk-do in South Korea, Lombardy, Veneto and Emilia-Romagna regions of Italy, and Tehran and Qom in Iran. Visitors with travel history within those countries but outside of the aforementioned regions had to provide a valid health certificate during check-in for all transportation into Indonesia. Despite the restriction on travellers from South Korea, Indonesia still allowed flights from South Korea.
The first confirmed death from coronavirus in the country occurred on 11 March 2020. However, a Telkom employee who had died on 3 March tested positive for COVID-19 on 14 March; he had infected his wife and child.
On 13 March, the government designated 132 treatment facilities across Indonesia.
== Members ==
=== Executive board ===
=== Advisory board ===
== References ==
== External links ==
Official website | Wikipedia/COVID-19_Response_Acceleration_Task_Force |
Broad-spectrum antivirals (BSAs) are a class of molecules or compounds, which inhibit the infection of multiple viruses from the same (intra-family BSAs) or different (inter-family BSAs) virus families. BSAs could be divided into experimental and investigational agents, and approved drugs. BSAs work by inhibiting viral proteins (such as polymerases and proteases) or by targeting host cell factors and processes exploited by different viruses during infection. As of 2021, there are 150 known BSAs in varying stages of development, effective against 78 human viruses. BSAs are potential candidates for treatment of emerging and re-emerging viruses, such as ebola, marburg, and SARS-CoV-2. Many BSAs show antiviral activity against other viruses than originally investigated (such as remdesivir and interferon alfa). Efforts in drug repurposing for SARS-CoV-2 is currently underway. A database of BSAs and viruses they inhibit could be found here (https://drugvirus.info/).
== See also ==
Broad-spectrum antibiotic
Broad-spectrum therapeutic
== References == | Wikipedia/Broad-spectrum_antiviral_drug |
A booster dose is an extra administration of a vaccine after an earlier (primer) dose. After initial immunization, a booster provides a re-exposure to the immunizing antigen. It is intended to increase immunity against that antigen back to protective levels after memory against that antigen has declined through time. For example, tetanus shot boosters are often recommended every 10 years, by which point memory cells specific against tetanus lose their function or undergo apoptosis.
The need for a booster dose following a primary vaccination is evaluated in several ways. One way is to measure the level of antibodies specific against a disease a few years after the primary dose is given. Anamnestic response, the rapid production of antibodies after a stimulus of an antigen, is a typical way to measure the need for a booster dose of a certain vaccine. If the anamnestic response is high after receiving a primary vaccine many years ago, there is most likely little to no need for a booster dose. People can also measure the active B and T cell activity against that antigen after a certain amount of time that the primary vaccine was administered or determine the prevalence of the disease in vaccinated populations.
If a patient receives a booster dose but already has a high level of antibody, then a reaction called an Arthus reaction could develop, a localized form of Type III hypersensitivity induced by high levels of IgG antibodies causing inflammation. The inflammation is often self-resolved over the course of a few days but could be avoided altogether by increasing the length of time between the primary vaccine and the booster dose.
It is not yet fully clear why some vaccines such as hepatitis A and B are effective for life, and some such as tetanus need boosters. The prevailing theory is that if the immune system responds to a primary vaccine rapidly, the body does not have time to sufficiently develop immunological memory against the disease, and memory cells will not persist in high numbers for the lifetime of the human. After a primary response of the immune system against a vaccination, memory T helper cells and B cells persist at a fairly constant level in germinal centers, undergoing cell division at a slow to nonexistent rate. While these cells are long-lived, they do not typically undergo mitosis, and eventually, the rate of loss of these cells will be greater than the rate of gain. In these cases, a booster dose is required to "boost" the memory B and T cell count back up again.
== Polio booster doses ==
In the case of the polio vaccine, the memory B and T cells produced in response to the vaccine persist only six months after consumption of the oral polio vaccine (OPV). Booster doses of the OPV were found ineffective, as they, too, resulted in decreased immune response every six months after consumption. However, when the inactive polio vaccine (IPV) was used as a booster dose, it was found to increase the test subjects' antibody count by 39–75%. Often in developing countries, OPV is used over IPV, because IPV is expensive and hard to transport. Also, IPVs in tropical countries are hard to store due to the climate. However, in places where polio is still present, following up an OPV primary dose with an IPV booster may help eradicate the disease.
In the United States, only the IPV is used. In rare cases (about 1 in 2.7 million), the OPV has reverted to a strengthened form of the illness, and caused paralysis in the recipients of the vaccine. For this reason, the US only administers IPV, which is given in four increments (3 within their first year and a half after birth, then one booster dose between the ages 4–6).
== Hepatitis B booster doses ==
The need for a booster dose for hepatitis B has long been debated. Studies in the early 2000s that measured memory cell count of vaccinated individuals showed that fully vaccinated adults (those that received all three rounds of vaccination at the suggested time sequence during infancy) do not require a booster dose later in life. Both the United States Centers for Disease Control (CDC) and the Canadian National Advisory Committee on Immunization (NACI) supported these recommendations by publicly advising against the need for a hepatitis B booster dose. However, immuno-repressed individuals are advised to seek further screening to evaluate their immune response to hepatitis B, and potentially receive a booster dose if their B and T cell count against hepatitis B decrease below a certain level.
== Tetanus booster dose ==
The tetanus disease requires a booster dose every 10 years, or in some circumstances immediately following infection of tetanus. Td is the name of the booster for adults, and differs from the primary dose in that it does not include immunization against pertussis (whooping cough). While the US recommends a booster for tetanus every 10 years, other countries, such as the UK, suggest just two booster shots within the first 20 years of life, but no booster after a third decade. Neonatal tetanus is a concern during pregnancy for some women, and mothers are recommended a booster against tetanus during their pregnancy in order to protect their child against the disease.
== Whooping cough booster dose ==
Whooping cough, also called pertussis, is a contagious disease that affects the respiratory tract. The infection is caused by a bacterium that sticks to the cilia of the upper respiratory tract and can be very contagious. Pertussis can be especially dangerous for babies, whose immune systems are not yet fully developed, and can develop into pneumonia or result in the baby having trouble breathing. DTaP is the primary vaccine given against pertussis, and children typically receive five doses before the age of seven. Tdap is the booster for pertussis, and is advised in the US to be administered every ten years, and during every pregnancy for mothers. Tdap can also be used as a booster against tetanus.
Upon its invention in the 1950s, the pertussis vaccine was whole-cell (contained the entire inactivated bacterium), and could cause fever and local reactions in people who received the vaccine. In the 1990s, people in the US started using acellular vaccines (contained small portions of the bacterium), that had lower side effects but were also less effective at triggering an immunological memory response, due to the antigen presented to the immune system being less complete. This less effective, but safer vaccine, led to the development of the booster Tdap.
== COVID-19 booster dose ==
As of September 2021, protection against severe disease remained high at 6 months after vaccination despite lower efficacy in protection from COVID-19 infection. An international panel of scientists affiliated with the FDA, WHO, and several universities and healthcare institutions, concluded that there was insufficient data to determine the long-term protective benefits of a booster dose (only short-term protective effects were observed), and recommended instead that existing vaccine stock would save most lives if made available to people who had not received any vaccine.
Israel first rolled out booster doses of the Pfizer–BioNTech COVID-19 vaccine for at-risk populations in July 2021. In August this was expanded for the rest of the Israeli population. Effectiveness against severe disease in Israel was lower among people vaccinated either in January or April than in those vaccinated in February or March. During the first 3 weeks of August 2021, just after booster doses were approved and began to be deployed widely, a short-term protective effect of a third dose (relative to two doses) was suggested.
In the United States, the CDC rolled out booster shots to immunocompromised individuals during the summer of 2021 and originally planned to allow adults to receive a third dose of the COVID-19 vaccine starting in September 2021, with individuals becoming eligible starting 8 months after their second dose (for those who received a two-dose vaccine). After further data about long-term vaccine efficacy and the delta variant came to light, the CDC ultimately made recipients eligible for boosters 6 months after the second shot, in late October. Subsequently, vaccinations in the country surged.
In September 2021, the UK's Joint Committee on Vaccination and Immunisation recommended a booster shot for the over-50s and at-risk groups, preferably the Pfizer–BioNTech vaccine, meaning about 30 million adults should receive a third dose. The UK's booster rollout was extended to over-40s in November 2021.
Russia's Sputnik V COVID-19 vaccine, using similar technology to AstraZeneca's COVID-19 vaccine, in November 2021 introduced a COVID-19 booster called Sputnik Light, which according to a study by the Gamaleya Research Institute of Epidemiology and Microbiology has an effectiveness of 70% against the delta variant. It can be combined with all other vaccines and may be more effective with mRNA vaccines than mRNA boosters.
Booster shots can also be used after infections. In this regard, the UK's National Health Service recommends people to wait 28 days after testing positive for COVID-19 before getting their booster shots. Evidence shows that getting a vaccine after recovery from a COVID-19 infection provides added protection to the immune system.
== References == | Wikipedia/Booster_vaccine |
Vabiotech COVID-19 vaccine is a COVID-19 vaccine candidate developed by the Vaccine and Biological Production Company No. 1 (Vabiotech) in Vietnam.
== Clinical trials ==
=== Preclinical ===
In May 2020, Vietnam declared that their COVID-19 vaccine was developed after scientists successfully generated the novel coronavirus antigen in the lab. The vaccine has been developed by collaborating scientists at VABIOTECH in Hanoi and the Bristol University, it will be tested further in animals and evaluated for safety and effectiveness before a manufacturing process is embarked on. According to the National Institute of Hygiene and Epidemiology, it will take at least 12–18 months to develop vaccine that can work safely on human. During the testing phase, researchers experimented by injecting the mice in many ways and administering multiple antigen doses, with some mice injected with one or two doses of 3-10 micrograms each. After 10 days, 50 mice were in good health and being closely monitored for immune responses. After gaining positive results with immune response and antibody production, the trial vaccine would be developed into a complete and stable version qualified to be used on humans. The research team would also develop commercial production procedures for mass-production, including up to tens of millions of units.
In October 2020, the vaccine has been tested on 12 rhesus macaques (Macaca mulatta) in an island off the northern Quang Ninh province. The macaques are aged 3–5, weighing more than three kilograms each, and not infected with contagious diseases like tuberculosis or the HIV virus. Before being injected with the vaccine, they had their body temperatures, blood and swab samples taken and were kept separately in cages. They will be tested in two periods. In each period, they will be divided into two groups, with one being vaccinated and the other not. After that, they will be monitored daily on separate islands, before their blood samples are taken for further analysis. The testing will follow a similar model that maybe later performed on humans. The animals will be injected two shots of the vaccine, 18 to 21 days apart. A month after the second shot, researchers will assess the monkeys' immune response to see the difference between the injected group and the non-injected group. The result of these trials will be presented before the health ministry's ethical board within the following four months if experiments show the vaccine does produce effective immunogenicity and provide effective protection against COVID-19. It will be a foundation for the next stage for testing the vaccine on humans.
== References == | Wikipedia/Vabiotech_COVID-19_vaccine |
Minhai COVID-19 vaccine (Chinese: 康泰民海新冠疫苗), trademarked as KCONVAC (Chinese: 可维克; pinyin: Kěwéikè), is a COVID-19 vaccine developed by Shenzhen Kangtai Biological Products Co. Ltd and its subsidiary, Beijing Minhai Biotechnology Co., Ltd.
== Clinical trials ==
In October 2020, KCONVAC started phase I clinical trials with 180 participants in China. Later, KCONVAC started phase II trials with 1,000 participants in China.
In May 2021, KCONVAC started phase III trials for global trials with 28,000 participants.
=== Children and adolescents trials ===
In August 2021, KCONVAC started phase I trials with 84 participants in China.
In September, KCONVAC started phase II trials with 480 participants in China.
== Authorizations ==
On 14 May 2021, the vaccine became the fourth inactivated Chinese Vaccine to be authorised for emergency use.
== References == | Wikipedia/Minhai_COVID-19_vaccine |
Noora (Persian: نورا) is a COVID-19 vaccine candidate developed by Baqiyatallah University of Medical Sciences in collaboration with Plasma Darman Sarv Sepid Co. (lit. White Cypress Plasma Treatment) in Iran. Introduced in June 2021, it was announced as having "successfully passed the first phase of its clinical trial" two months later.
The clinical trial reported in the Journal of Medical Virology met a critical scrutiny in May 2023, after which the journal declared it as an invalid study and retracted it in March 2024. Independent research in 2024 indicated that the vaccine is very weak (poor immunogenicity and neutralization efficacy) unlikely useful for the later variants of SARS-CoV-2.
== History ==
Noora vaccine was developed by an Iranian team led by Jafar Salimian and Jafar Amani at the Baqiyatallah University of Medical Sciences in Tehran, which is supported by the Islamic Revolutionary Guard Corps. Its design and preparation started in the early 2020 and completed in June 2021. The vaccine with its Phase I clinical trial was officially launched on 27 June 2021. IRGC Commander-in-Chief Major General Hossein Salami and Health Minister Saeed Namaki officiated the unveiling, and Hossein Samadinia, head of the Baqiyatallah Hospital, received the first dose at the inaugural. Phase I clinical trial involved 70 volunteers and was completed in August 2021.
In March 2022, Hassan Abolqasemi, chancellor of Baqiyatallah University of Medical Sciences, announced that the Phase III clinical trial was completed that involved 10,000 participants. Soon after which the Iranian Ministry of Health gave it a permit for emergency use, and became the sixth COVID-19 vaccine (after COVIran Barekat, Pasto Covac, Razi Cov Pars, SpikoGen, and FAKHRAVAC) produced in Iran. The vaccine preparation and preclinical tests in mice, rabbits, and monkeys were reported in the journal Molecular Immunology in September 2022.
The first clinical trial led by Salimian and Amani, and supervised by Hassan Abolghasemi and Gholamhossein Alishiri, was published in the Journal of Medical Virology 27 August 2022. The report claims that the vaccine is effective, safe and capable of providing immunity. The report concludes:The results of this Phase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 μg is an appropriate dose for injection in the next phases of the trial.
== Medical uses ==
Noora vaccine requires three doses given by intramuscular injection on days 0, 21 and 35. Phase I clinical trial was claimed to indicate successful immunity against SARS-CoV-2 Omicron variant.
== Pharmacology ==
Noora is a recombinant RBD protein subunit vaccine. It contains three truncated parts of SARS-CoV-2: spike protein, receptor-binding protein and nucleoprotein. The immune response is enhanced by the addition of alum as an adjuvant.
== Manufacturing ==
By early 2022, 3 million doses were produced monthly. As of March 2022, 5 millions doses were produced.
== Clinical trials ==
== Controversy ==
In May 2023, Donald Forthal, chief of infectious diseases at the University of California, Irvine, wrote a commentary on the Phase I clinical trial paper in the Journal of Medical Virology, severely criticising the validity of the study. Forthal pointed out several data inconsistency, misrepresentation, vague experimental methods and conflict of interest that would have used to reject the paper in the first place. He made a concern that "a manuscript containing so many serious flaws would have been accepted for publication following peer review, and given these issues, a retraction may be in order". As the criticism was posted on PubPeer, other scientists also raised other concerns in the study. Australian epidemiologist Gideon Meyerowitz-Katz stated that the report had several other "impossible" and "contradictory" results.
While the authors and the Baqiyatallah University remained silent, Journal of Medical Virology's editor-in-chief Shou-Jiang Gao invited justifications from the authors. The authors submitted the rebuttal, but after the third round of peer reviewing, they gave up on the final dateline of 23 November 2023 for revision. With no further response from the authors, the journal announced retraction of the paper on 2 March 2024, with a note:The retraction has been agreed due to concerns raised by third parties regarding issues with the data presented in the article. Several inconsistencies concerning the information provided about the analyzed subjects were additionally identified. Furthermore, the authors failed to disclose the presence of potential conflicts of interest that may have affected the interpretation of the results presented. Accordingly, the editors consider the conclusions of this manuscript to be invalid. The authors have been informed of the decision to retract but did not agree with it.One of the supervisors of the clinical trial, Abolghasemi claimed that the criticism and retraction were not of scientific causes but of prejudices, and his team was not given a chance for explanation. As he wrote to Retraction Watch: "Retraction of our article was a political decision not a scientific decision because there was a pressure on journal based on [apartheid] scientific issue. Our response to the comment never accepted by [PubPeer] and journal to be published."
An independent research team from Tehran University of Medical Sciences and Avicenna Research Institute experimentally analysed four COVID-19 vaccines developed in Iran. Their report in Iranian Journal of Immunology, published in March 2024, showed that Noora and SpikoGen do hot have the expected efficacy (as indicated by poor immunogenicity and neutralization efficacy). As the two vaccines do not provide protection from SARS-CoV-2 Delta variant, it is unlikely useful for the later variants of SARS-CoV-2.
== See also ==
Pharmaceuticals in Iran
COVID-19 pandemic in Iran
COVID-19 vaccine clinical research
== References == | Wikipedia/Noora_(vaccine) |
Kandakadu Treatment and Rehabilitation Centre previously known as the Kandakadu Drug Rehabilitation Centre is a rehabilitation center located in the Welikanda, Polonnaruwa District, North Central Province in Sri Lanka. It is currently operated by the Bureau of the Commissioner General of Rehabilitation under the Ministry of Justice. The rehabilitation centre is currently used to treat drug addicts and COVID-19 patients along with Senapura Rehabilitation Center. The centre was transformed into a Drug Rehabilitation Centre in 2014 to treat drug addicted persons by giving counselling, vocational education and training.
In March 2020, the rehabilitation centre was proposed by the Government of Sri Lanka as one of the major quarantine centres to conduct PCR tests for passengers and tourists from foreign countries during the COVID-19 pandemic. The Sri Lankan government made compulsory guidelines for passengers from foreign passengers to undergo a 14-day mandatory self quarantine at the centre. The Sri Lankan Army in collaboration with the Ministry of Health upgraded the facilities of the centre by setting up necessary medical tools, Wifi communication tools, thermometers, laundry and entertainment facilities for the patients.
In July 2020, the centre became a new epicentre of COVID-19 pandemic in Sri Lanka recording over 300 cases in the month of July. On 9 July 2020, Sri Lankan Army converted a quarantine centre into a COVID-19 hospital which is close to the Kandakadu Rehabilitation Centre.
== COVID-19 cluster ==
On 7 July, a new case was recorded from Welikada Prison, where an inmate had been transferred from the Treatment and Rehabilitation Centre in East Kandakadu for those addicted to drugs and controlled substances, to the prison on 27 June. On 9 July 2020, a record tally of 253 inmates at Kandakadu Treatment and Rehabilitation Centre were tested positive for COVID-19. On 10 July 2020, a total of 283 people from the Kandakadu Treatment and Rehabilitation Centre were tested positive for COVID-19. The centre emerged as a new COVID-19 cluster in the country.
== Frequent Clashes & Controversies ==
The military's key involvement at the center has often be a topic of controversy amongst human rights activists. Several clashes and inmate breakouts were reported in the recent past. Including the 2022 November clashes the December 2023 escape and the January 2024 clash and breakout.
== References == | Wikipedia/Kandakadu_Treatment_and_Rehabilitation_Centre |
V451 was a COVID-19 vaccine candidate developed by the University of Queensland and the Australian pharmaceutical company CSL Limited. The vaccine candidate used the University of Queensland's molecular clamp technology and the MF59 adjuvant.
== Description ==
V451 is a protein subunit vaccine. As part of the vaccine's design, researchers added "a fragment of one protein found on the HIV virus" as a "ground-breaking molecular clamp technology".
== Terminated trial ==
The development of the vaccine was cancelled on 11 December 2020 during its Phase I trial, after a number of trial participants were found to give false positive test results for HIV antibodies when they did not in fact have HIV. This was due to the HIV virus fragment used as a molecular clamp leading to "a partial antibody response" to HIV. This is an undesirable outcome as it will interfere with future HIV screening tests for affected participants.
Nine days prior to the termination, on 2 December, the first emergency use authorisation had been granted to a COVID-19 vaccine; the Pfizer–BioNTech COVID-19 vaccine in the United Kingdom. Following the termination of V451, vaccine production capacity by CSL Limited was diverted to the Oxford–AstraZeneca COVID-19 vaccine.
== References ==
== External links ==
Clinical trial number NCT04495933 for "A Study on the Safety, Tolerability and Immune Response of SARS-CoV-2 Sclamp (COVID-19) Vaccine in Healthy Adults" at ClinicalTrials.gov | Wikipedia/V451_vaccine |
Abdala, technical name CIGB-66, is a COVID-19 vaccine developed by the Center for Genetic Engineering and Biotechnology in Cuba. This candidate, named after a patriotic drama by Cuban independence hero José Martí, is a protein subunit vaccine containing COVID-derived proteins that trigger an immune response. The full results of the clinical trial have not yet been published. This candidate followed a previous one called CIGB-669 (MAMBISA).
The vaccine is one of two Cuba-developed COVID-19 vaccines which has passed Phase III trials, and has received emergency authorisation.
== Medical uses ==
The vaccine was administered in 3 doses spaced 2 weeks apart.
=== Efficacy ===
On 22 June 2021, official Cuban government sources reported that the results of an initial study by the Cuban Center for Genetic Engineering and Biotechnology involving 48,290 participants found a 92.28% efficacy rate at preventing symptomatic COVID-19. The report included a confidence interval of 85.74%–95.817% without a specified confidence level; analysis was based on 153 cases of symptomatic COVID, 142 of which were in the placebo group and 11 of which were in the approximately equal vaccinated group.
The measure of efficacy includes the initial strain of SARS-COV-2 as well as variants that were present in Cuba during the study, including Alpha, Beta, and Gamma strains. The Beta variant entered Cuba in January 2021 and became the predominant strain in Cuba, fuelling a rise in COVID cases.
As of 28 June 2021, Cuba has not yet released detailed information about the vaccine to the WHO or to the general public via a pre-print or a scientific article. It is planned to do so after the Cuba Health Agency (CECMED) authorises the vaccine for emergency use.
In September 2022, a study published in The Lancet Regional Health – Americas reported that the estimated vaccine effectiveness against severe illness was 93.3% in partially vaccinated individuals and 98.2% in those fully vaccinated; effectiveness against death was 94.1% and 98.7%, respectively. Effectiveness exceeded 92.0% across all age groups. The retrospective, real-world study was conducted during the Delta variant wave in Cuba, and the effectiveness against Omicron or subsequent variants remains unknown.
== Vaccine design ==
The vaccine was designed by researchers from the Center for Genetic Engineering and Biotechnology and has been described in a pre-print submission. The Abdala vaccine reportedly consists of a monomeric receptor binding domain subunit, residues 331-530 of the Spike protein of SARS-CoV-2 strain 156 Wuhan-Hu-1, expressed in the yeast Pichia pastoris at 30–40 mg/L fermentation yield. The vaccine antigen is polyhistidine-tagged to aid purification and is reportedly purified via immobilised metal affinity chromatography and subsequent hydrophobic interaction chromatography to >98% purity. For animal studies 50 μg of vaccine antigen per dose was adjuvanted with 0.3 mg aluminium hydroxide gel (Alhydrogel) and delivered in 500 μL phosphate buffer.
== Manufacturing ==
Venezuela claimed that it would manufacture the vaccine but, as of 2 May 2021, the claim had not yet materialised. State-owned EspromedBIO will manufacture the vaccine but some "arrangements" are needed to start production. In April, Nicolás Maduro said that a capacity of 2 million doses per month is hoped to be reached by August or September 2021. In June 2021, Vietnam's Ministry of Health announced that negotiations were ongoing between Cuba and Vietnam for Abdala vaccine production. The Institute of Vaccines and Medical Biologicals (IVAC) was named as the focal point for receiving technology transfer.
== History ==
=== Clinical trials ===
In July 2020, Abdala commenced phase I/II clinical trials.
The Phase III trial compares 3 doses of the vaccine administered at 0, 14 and 28 days against a placebo, with the primary outcome measuring the proportion of cases reported for each group 14 days after the third dose. The trial was registered on 18 March 2021. The first dose was administered on 22 March and by April 4, the 48,000 participants had received their first dose, and second doses started being administered from April 5. Third doses have started being administered on 19 April and on May 1, adherence to the three-dose protocol was over 97%.
In July 2021, Abdala started clinical trial phase I/II for children and adolescents aged 3-18.
==== Intervention study ====
124,000 people aged 19 to 80 received 3 doses of the vaccine as part of an intervention study, with the primary outcome measuring the proportion of cases and deaths for the vaccinated compared to the unvaccinated population.
A wider intervention study with the 1.7 million inhabitants of Havana is expected to start in May with the Abdala and Soberana 2 vaccine.
=== Authorizations ===
On 9 July 2021, Abdala was approved for emergency use in Cuba.
On 18 September 2021, Abdala was approved for emergency use in Vietnam.
On 16 December 2021, the Ministry of Health of Saint Vincent and the Grenadines announced that the Abdala vaccine was available at vaccination sites across the island. This announcement follows a donation of vaccines made by the Cuban government on 13 December 2021.
On 29 December 2021, Abdala was approved for emergency use in Mexico.
== Distribution ==
On 24 June 2021, Vice President of Venezuela Delcy Rodríguez announced that Venezuela had signed a contract for 12 million doses of the vaccine, and that these doses are to arrive in "the coming months". The first shipment of Abdala arrived in Venezuela the day following this announcement.
On 20 September, 2021, The Vietnamese Government has issued a resolution on purchase of 10 million doses of Abdala COVID-19 vaccine.
== References ==
== External links == | Wikipedia/Abdala_(vaccine) |
The MVC COVID-19 vaccine (Chinese: 高端新冠肺炎疫苗; pinyin: Gāoduān xīnguàn fèiyán yìmiáo; Wade–Giles: Kaotuan hsinkuan feiyen imiao), designated MVC-COV1901 and also known as the Medigen COVID-19 vaccine, is a protein subunit COVID-19 vaccine developed by Medigen Vaccine Biologics Corporation in Taiwan, American company Dynavax Technologies, and the U.S. National Institutes of Health.
== Technology ==
This vaccine is made by the recombinant S-2P spike protein. It is adjuvanted with CpG 1018 supplied by Dynavax, which was used in a previously FDA-approved adult hepatitis B vaccine.
== Clinical trials ==
On 16 February 2020, Medigen Vaccine Biologics Corporation (MVC) signed a collaboration agreement with US National Institutes of Health (NIH) for COVID-19 vaccine development. The partnership will allow MVC to obtain NIH's COVID-19 vaccine and related biological materials to conduct animal studies in Taiwan. On 23 July 2020, Medigen announced collaboration with Dynavax Technologies to develop COVID-19 vaccine.
On 13 October 2020, MVC received Taiwan's government subsidies for the initiation of Phase 1 Clinical Trial in Taiwan starting early October. The Phase 1 Clinical Trial was held at National Taiwan University Hospital with 45 participants ranging the age of 20–50.
On 25 January 2021, MVC initiated a Phase 2 Clinical Trial for its COVID-19 vaccine candidate MVC-COV1901 with the first participant being dosed. The multi-center, randomized, placebo-controlled trial included 3,844 participants aged 20 or older.
On 10 June 2021, MVC released its COVID-19 vaccine Phase 2 interim analysis results, and announced that it will request Emergency Use Authorization (EUA) with the concluding of the Phase 2 Clinical Trial.
Preliminary results from Phase I trials on 77 participants were published in June 2021, indicating what the authors described as "robust" immune system response elicited by the vaccine. The study assessed the humoral immune response by measuring quantities of binding IgG to S protein, and also the cellular immune response by measuring the quantities of IFN-γ and IL-4 secreting T cells.
On 20 July 2021, MVC filed a Phase 3 Clinical Trial IND application with Paraguay's regulatory authority, which was later approved. The Phase 3 Clinical Trial, however, was different from regular Phase 3 Clinical Trial, which uses immune-bridging trial to compare the performance of MVC COVID-19 vaccine with the Oxford-AstraZeneca COVID-19 vaccine. The decision was controversial as immuno-bridging trials were not as widely accepted as disease endpoint trials. However, many countries have already started the discussion of whether to accept immuno-bridging as the endpoint and later adopted. The trail was successfully completed and received EUA from Paraguay on February 14, 2022.
On 26 October 2021, the World Health Organization (WHO) selected Medigen vaccine as one of its Solidarity Trial Vaccines. The trial is designed to rapidly evaluate the efficacy and safety of promising new candidate vaccines selected by an independent vaccine prioritization advisory group.
=== Adolescents trial ===
In July 2021, Medigen commenced phase II trials for adolescents aged 12–18.
== Authorization ==
On 19 July 2021, MVC COVID-19 vaccine obtained Emergency Use Authorization (EUA) approval from the Taiwanese government after fulfilling EUA requirements set by Taiwanese authority. The EUA, however, was met with controversy due to the lack of efficacy data and Phase 3 Clinical Trial. The EUA was granted instead based on the immunobridging study in comparison with antibody found on people who received AstraZeneca vaccine. On August 23, 2021, President Tsai Ing-Wen was among the first Taiwanese to receive a dose of the vaccine.
== Controversies ==
In May 2021, when Taiwan experienced an outbreak of domestic cases, the government announced that the vaccine would be available in July despite the result of the phase 2 trial was yet to be announced. In June 2021, the vaccine had just completed the second phase clinical trial, but the vaccine was sent to Taiwan FDA for the application of EUA. Seroconversion rate was used as the surrogate endpoint, though there was lack of evidence at that time. Compared to EUA of vaccine issued in the US, both Moderna and BNT/Pfizer vaccine finished interim analysis from Phase 3 study, which Medigen vaccine skipped.
The controversy arose because immunobridging was not widely accepted as sufficient for EUA at the time. However, due to difficulty to conduct traditional, placebo-controlled efficacy trials in some countries, as few candidates are available or willing to participate, there were discussions to focus on immunobridging studies as an acceptable approach for authorizing COVID-19 vaccines by the International Coalition of Medicines Regulatory Authorities (ICMRA). As the result of the workshop convened in 24 June 2021, immunobridging has now been accepted by the UK, Australia, Canada, Singapore, and Switzerland among other countries. US FDA also authorized Pfizer-BioNTech vaccine for children 5 to 11 years old based on immunobridging alone.
== References ==
== External links == | Wikipedia/MVC_COVID-19_vaccine |
Vaccine diplomacy, a form of medical diplomacy, is the use of vaccines to improve a country's diplomatic relationship and influence of other countries. Meanwhile, vaccine diplomacy also "means a set of diplomatic measures taken to ensure access to the best practices in the development of potential vaccines, to enhance bilateral and/or multilateral cooperation between countries in conducting joint R&D, and, in the case of the announcement of production, to ensure the signing of a contract for the purchase of the vaccine at the shortest term." Although primary discussed in the context of the supply of COVID-19 vaccines, it also played a part in the distribution of the smallpox vaccine.
== Early history of vaccine diplomacy ==
Commentators have identified vaccine diplomacy occurring as far back as the first vaccine, Edward Jenner's smallpox vaccine. It has also been identified in Soviet involvement with the Albert Sabin polio vaccine. The UN has also brokered ceasefires in order to conduct vaccination campaigns such as with talibans in Afghanistan.
== During the COVID-19 pandemic ==
=== Australia ===
Australia promised to ensure early access to a vaccine "for countries in our Pacific family, as well as regional partners in Southeast Asia". to help them fight the COVID-19 pandemic.
=== China ===
China's infection rates and early success in handling the COVID-19 pandemic were sufficiently low that it could send vaccines abroad without domestic objections. By August 2021, China had donated 700 million vaccine does abroad, greater than the number from all other countries combined.: 199 As academic Suisheng Zhao writes, "Just by showing up and helping plug the colossal gaps in the global supply, China gained ground." Moreover, the Center for Strategic and International Studies found that its vaccine diplomatic activities earned China goodwill and influence in several middle-income countries, many of which are also notably involved in the Belt and Road Initiative, indicating that such diplomacy could have improved China's image and strengthened its relationships with countries that wished for, or already took part in, strong relationships with China. However, because most of Chinese distributed vaccines have gone to such middle-income countries, many of the poorest countries are left highly vulnerable, undercutting China's attempts to present itself as a benevolent giver of needed goods and undermining Xi's claim that a Chinese developed vaccine would be treated as a “global public good."
The Sinopharm BIBP vaccine is used for vaccinations by some countries in Asia, Africa, South America, and Europe. Sinopharm produced one billion doses of the BBIB vaccine in 2021, and supplied 200 million doses by May.
CoronaVac is used for vaccinations by some countries in Asia, South America, North America, and Europe. Sinovac had a production capacity of 2 billion doses a year and had delivered 600 million total doses.
Convidecia is used for vaccination by some countries in Asia, Europe, and Latin America. Production capacity for Ad5-NCov should reach 500 million doses in 2021.
China pledged US$2 billion to support efforts by WHO for programs against COVID-19, a US$1 billion loan to make its vaccine accessible for countries in Latin America and the Caribbean, and provide five Southeast Asian countries priority access to the vaccine. The Sinopharm BIBP vaccine and CoronaVac were approved by the WHO as part of COVAX. By July 2021, GAVI had signed advanced purchase agreements for 170 million doses of the Sinopharm BIBP vaccine, 350 million doses of CoronaVac, and 414 million doses of SCB-2019, another COVID-19 vaccine in Phase III trials.
All of these actions have been a component in enacting China's strategy of enacting mask diplomacy, where the state has distributed medical supplies, including COVID-19 vaccines, and financial support to other European countries, in an effort to restore China's historically maligned and recently ignominious image. While on the other hand, these actions have demonstrated that China is a pragmatic, self-driven problem solver, willing to establish alliances with other nations contrasting the United States' isolationist policies.
In addition, China is utilizing this opportunity to distance, and even shift the narrative regarding the start of COVID-19, as the virus was discovered in the nation. Although China gained some international sympathy, the country was also accosted by “accusations of fanning the pandemic by silencing early reports” and “dogged by international criticisms that trace the origins of the pandemic to a leak from a Wuhan lab.” A 2020 Pew Research poll further suggests a negative narrative surround China; upon polling citizens in 14 economically advanced nations, including East Asian neighbors Japan and South Korea, a median of 61% said China did "a bad job dealing with the [COVID-19] outbreak" and 78% said they had no confidence in President Xi. Such a poor global perception could suggest that China's distributed vaccines as a means of repairing or strengthening the country's international image. Providing vaccination doses allowed China to combat negative narratives about its early handling of the crisis and recast itself as a provider of needed goods, while cultivating goodwill and showcasing the nation’s technological strength. Through distributing their vaccines, China clearly took a stride to appear favorable in the eyes of the world, and perhaps reverse the criticism garnered at the early stages of the pandemic.
=== India ===
By late March 2021, India had produced 125 million doses of COVID-19 vaccines and had exported 55 million doses. 84 countries had received vaccines from India, either through COVAX, grants or regular purchases.
India sent millions of doses of COVID-19 vaccine to 95 countries including neighboring Bhutan, Afghanistan, Nepal, Bangladesh, Sri Lanka, Myanmar and the Maldives. India will also supply vaccines to Pakistan through COVAX initiative.
During the second wave of the COVID-19 pandemic in India, the Vaccine Maitri program was put on hold until July 2021 due to increased number of COVID cases in India. As of 29 May 2021, India had exported 66.4 million doses including 10.7 million vaccine provided as grant to more than 95 nations.
India's health ministry said the country will resume COVID-19 vaccine exports as a part of COVAX and Vaccine Maitri initiative, by October, promising supply development that comes ahead of high-level talks this week on solving vaccine inequity gaps, while World Health Organization chief Tedros Adhanom Ghebreyesus has hailed India's decision to resume COVID-19 vaccine exports as an "important development" in support of the goal to reach 40 per cent vaccination in all countries by end of the year.
=== Mexico ===
Secretary of Foreign Affairs of Mexico Marcelo Ebrard announced agreements with CanSino Biologics and Walvax to conduct clinical trials for vaccines from China, with the possibility of the manufacturing the vaccines in the country.
Marcelo Ebrard also announced agreements with Johnson & Johnson to trial its U.S. developed vaccine in Mexico.
=== Japan ===
In July 2020, Japan agreed to provide 11.6 billion yen (US$109 million) to five countries along the Mekong River: Cambodia, Laos, Myanmar, Thailand and Vietnam over concerns with China's influence on vaccine production and distribution in Asia.
=== Russia ===
Russia, the first country to claim a COVID-19 vaccine, Sputnik V, says twenty countries "including Brazil, Indonesia and the United Arab Emirates" have requested access.
=== Turkey ===
Turkey has sent or donated CoronaVac vaccines to Azerbaijan, Bosnia and Herzegovina, Northern Cyprus, and North Macedonia.
=== United States ===
During the Trump administration, Secretary of Health and Human Services Alex Azar said the United States will share a vaccine with other countries only after the United States' needs have been met. The United States has funded and placed multi-billion dollar orders purchasing hundreds of millions of vaccines from the United Kingdom's AstraZeneca and Germany's BioNTech SE in collaboration with American Pfizer. The United States offered vaccine development to Indonesia in an August 2020 phone call between Mike Pompeo and Retno Marsudi.
The Biden administration has promised to finance vaccine manufacturing in various nations with its announcement in the Quad Summit held in March 2021 that it will provide supply of up to one billion coronavirus vaccines across Asia by the end of 2022 along with India, Australia and Japan. The United States vaccine export policies have been criticised as "Vaccine Apartheid" by The Independent.
=== European Union ===
UK-based AstraZeneca was accused of prioritizing the UK market and when their EU vaccine production lagged behind the UK. Diplomatic protests from the Irish and UK sides resolved the matter and the threat was withdrawn. In March 2021, the EU planned to suspend vaccine exports once again in order to incentivize the UK to export its domestic vaccine production.
=== Vaccine nationalism ===
This led to fears about vaccine nationalism, where developed countries would benefit in producing home-grown vaccine and poorer countries would not get access to the vaccine as soon, ultimately prolonging the pandemic. A similar phenomenon was observed during the H1N1 Flu and Ebola crisis. During the pandemic situation, there is a "diplomatic race ... for potential vaccines."
Another concern has been that wealthier countries would gain prioritized access to vaccines based on their ability to pay. The COVAX program was established with the intention of counteracting this development. In 2021, an unequal distribution of vaccines based on the principle of vaccine nationalism was observed between high, middle, and low income countries. An August 2021 study concluded that this behavior has resulted in increased transmission of COVID-19, especially because it encourages the development of COVID-19 variants.
=== Possible collaboration among countries ===
In early August 2020, Malaysian Minister of Foreign Affairs Hishammuddin Hussein said on Twitter that he had spoken with both Chinese Foreign Minister Wang Yi and United States Secretary of State Mike Pompeo on methods to further collaboration on vaccines.
== See also ==
Aid
Soft power
Science diplomacy
Science diplomacy and pandemics
== Further reading ==
Hotez, Peter J. (2 March 2021). Preventing the Next Pandemic: Vaccine Diplomacy in a Time of Anti-science. JHU Press. ISBN 978-1-4214-4038-5.
== References == | Wikipedia/Vaccine_diplomacy |
The COVID-19 Immunity Task Force (CITF) is one of the Government of Canada's early efforts to track the 2020 coronavirus pandemic. An external, dedicated secretariat was established in order to maximize the efficiency of the CITF's work.
== Purpose ==
The CITF was to use a serology "to survey representative samples of the population for the presence of antibodies to the virus". Trudeau's press release on 23 April 2020, on the initiation of the CCITF listed several goals it would help to achieve notably that it would:
establish priorities and oversee the coordination of a series of country-wide blood test surveys that will tell us how widely the virus has spread in Canada and provide reliable estimates of potential immunity and vulnerabilities in Canadian populations.A Vaccine Surveillance Reference Group (VSRG) was also established within the CITF to monitor the safety and effectiveness of COVID-19 vaccines made available in Canada.
== Task Force membership ==
The CITF Board is composed of doctors, infectious disease experts, and policy makers.
=== Leadership Group ===
Executive Committee
David Naylor, Co-chair
Catherine Hankins, Co-chair
Timothy Evans, Executive Director
Heather Hannah
Mona Nemer
Howard Njoo
Gina Ogilvie
Jutta Preiksaitis
Gail Tomblin Murphy
Paul Van Caeseele
Government of Canada representatives
Theresa Tam, Chief Public Health Officer of Canada
Mona Nemer, Chief Science Advisor of Canada
Stephen Lucas, Deputy Minister of Health of Canada
Members
The CCITF leadership group expanded on 2 May 2020. Its additional members as of March 2022 are:
Provincial & Territorial representatives
Shelly Bolotin, Ontario
Marguerite Cameron, Prince Edward Island
Catherine Elliott, Yukon
Richard Garceau, New Brunswick
Heather Hannah, Northwest Territories
Mel Krajden, British Columbia
Christie Lutsiak, Alberta
Richard Massé, Quebec
Jessica Minion, Saskatchewan
Michael Patterson, Nunavut
Gail Tomblin Murphy, Nova Scotia
Paul Van Caeseele, Manitoba
== References ==
== External links ==
Covid-19 Test Kits | Wikipedia/COVID-19_Immunity_Task_Force |
The White House Coronavirus Task Force was the United States Department of State task force during the Trump administration. The goal of the Task Force was to coordinate and oversee the administration's efforts to monitor, prevent, contain, and mitigate the spread of coronavirus disease 2019 (COVID-19). Also referred to as the President's Coronavirus Task Force, it was established on January 29, 2020, with Secretary of Health and Human Services Alex Azar as chair. On February 26, 2020, U.S. vice president Mike Pence was named to chair the task force, and Deborah Birx was named the response coordinator.
The task force was succeeded by the White House COVID-19 Response Team under the Biden administration.
== Background ==
The first known case in the United States of COVID-19 was confirmed in the state of Washington on January 20, 2020, in a 35-year-old man who had returned from Wuhan, China on January 15. The White House Coronavirus Task Force was established on January 29, with Secretary of Health and Human Services Alex Azar as its chair. On January 30, the WHO declared a Public Health Emergency of International Concern and on January 31, the Trump administration declared a public health emergency, and placed travel restrictions on entry by non-citizens who had recently been in China. On February 26, U.S. vice president Mike Pence replaced Azar as chair.
== Members ==
== Actions ==
The task force reviewed all coronavirus-related actions by federal agencies, and overruled the Centers for Disease Control and Prevention (CDC) several times. The New York Times reported that the CDC's leadership has been criticized during the pandemic, for mismanaging the testing kit rollout and changing its guidance on transmission of the virus; the White House says it is following the science in overruling the CDC. In March 2020, the task force deployed a team to cope with test kit shortages across the country, overseen by Brett Giroir, recognizing that the shortages were a serious threat to the country.
Pete Gaynor, the administrator of the Federal Emergency Management Agency (FEMA) was involved and stated that the task force had directed FEMA to shift in March "from playing a supporting role in assisting the U.S Department of Health and Human Services, which was designated as the initial lead federal agency for the COVID-19 pandemic response, to coordinating the Whole-of Government response to the COVID-19 pandemic".
Peter Navarro was named in March the Defense Production Act policy coordinator for the federal government. The Defense Production Act gives the President broad powers to control manufacturing during emergencies. Navarro criticized the CDC for the testing problems, and has also criticized Fauci; critics like Chuck Schumer say Navarro is unqualified for the job.
Operation Warp Speed was initiated in early April to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics after a round-table meeting with Trump, Pence and industry executives at the White House on March 2.
On September 29, the task force overruled the CDC's recommendation regarding when passenger cruise ships should be allowed to resume sailing. The CDC wanted to extend the existing "no-sail" directive until February 2021, but the task force agreed with the cruise ship industry's recommendation that the prohibition end on October 31, 2020. Two unnamed federal health officials told The New York Times that on October 9 the task force rejected a proposed CDC order requiring passengers and employees to wear masks on all forms of public and commercial transportation in the United States, including airplanes, trains, buses, subways, and transit hubs. A federal mask mandate was supported by some airlines and the transportation worker unions; the task force said that such orders should be left up to states and local governments.
== Press briefings ==
On March 10, 2020, The Hill reported that U.S. Senate Republicans who had attended a briefing with President Donald Trump had encouraged him to hold more briefings and to make Anthony Fauci the "face of the federal government's response" because according to an unnamed senator, "he has credibility", he "speaks with authority" and he "has respect in the medical community". The role of Health and Human Services secretary Alex Azar was downsized, according to The Wall Street Journal, with Pence taking a larger role.
The Task Force livestreamed press briefings at whitehouse.gov to communicate updates, guidelines, and policy changes to the public during the COVID-19 pandemic in the United States. On March 16, the White House began holding the task force press briefings daily, often two hours long, but by late April the White House discussed reducing the frequency of these briefings. On April 25, there was no press briefing, and at that time no further press briefings had been scheduled. On May 5, Pence said that the administration was discussing "what the proper time is for the task force to complete its work"; the next day, Trump said that the task force would "continue on indefinitely" but would refocus on returning the nation to normal activity.
As the US entered a new phase of re-opening businesses and getting back to work, Pence named five new members to the task force on May 15, 2020. The task force gave a press briefing on May 15, and on May 22, Birx appeared with press secretary Kayleigh McEnany. For the rest of May and into June, the task force met once or twice weekly, behind closed doors, as the White House switched to an economic message. The task force gave another press briefing on July 8. Fauci said on July 10 that he had not given a briefing to Trump for two months, and had not seen him in person since June 2.
== See also ==
Scott Atlas, advisor to the task force
John Fleming, assistant to the President for Planning and Implementation, and liaison to White House Chief of Staff
Olivia Troye, former top aide to the White House Coronavirus Task Force
Great American Economic Revival Industry Groups
COVID-19 Advisory Board
White House COVID-19 Response Team
== References ==
== External links ==
"Coronavirus Disease 2019 (COVID-2019)". U.S. Department of State. | Wikipedia/White_House_Coronavirus_Task_Force |
ScienceUpFirst is a Canadian initiative launched to counter misinformation online, especially about COVID-19. Launched January 25, 2021, it brings together independent scientists, health care providers and science communicators.
== Goals and history ==
The initiative is the result of conversations between Senator Stan Kutcher and Timothy Caulfield, who were discussing ways to counter misinformation about COVID-19. In April 2021, the Government of Canada announced $2.25 million in funding for two new projects to increase uptake of COVID-19 vaccines, one of which was ScienceUpFirst. The initiative received $2,590,682 in new funding through the Canadian Association of Science Centres from the Public Health Agency of Canada's Immunization Partnership Fund.
The groups aims at disseminating information created by its members or selected from credible sources. Starting in March 2021, it also plans to track misinformation online and post science-based content to oppose it. In addition to recruiting athletes and celebrities, it's building a network of volunteers to increase the distribution of the selected information.
The initiative will be especially active against misinformation about COVID-19 vaccination, which threatens to have an impact on vaccination rates. Caulfield commented that the amount of disinformation circulating in the context of the COVID-19 pandemic is unlike anything experienced in decades. He hopes the campaign can get information to people looking online for reliable information.
The campaign is active on Twitter, Facebook, and Instagram. It tries to apply best practices in fighting misinformation that were identified by various studies on science communication and public opinion.
== Organization ==
ScienceUpFirst is organized around the Canadian Association of Sciences Centres, COVID-19 Resources Canada and the University of Alberta's Health Law Institute. Institutional partners of the initiative include the American Association for the Advancement of Science (AAAS), British Columbia Centre for Disease Control, the Canadian Institutes of Health Research, and the Royal Canadian Institute, along with a variety of community partners including 19 to Zero.
== References == | Wikipedia/ScienceUpFirst |
In connection with the COVID-19 pandemic, navies from several countries deployed hospital ships to combat the disease. Aside from providing health services, hospital ships would allow civilian hospitals to offload some of the patients, relieving the pressure on facilities ashore. However, this also means that each ship would battle the onboard outbreaks of their own
As the infections have slowed or fallen short of worst-case predictions, the hospital ships became unused or barely used.
== KRI dr. Soeharso ==
The Indonesian Navy KRI dr. Soeharso picked up 188 Indonesian crew of the cruise ship World Dream in the Durian Strait on 26 February 2020. The vessel took them to Sebaru Kecil Islet and placed under quarantine.
dr. Soeharso evacuated 89 crew of the cruise ship Diamond Princess from Indramayu thermal power plant port, after the crew got health certificate from Japan and flew to Kertajati International Airport. They then used buses to travel to port. The crew underwent a second round of test, of which one crew member had a positive result for COVID-19 and was hospitalized in Jakarta. 68 crew of Diamond Princess disembarked at Sebaru Kecil Islet. World Dream evacuees and Diamond Princess evacuees were housed at separated different blocks/buildings.
== KRI Semarang ==
The Indonesian Navy KRI Semarang transported 68 crews of the Diamond Princess who underwent observation for the coronavirus disease 2019 in Sebaru Kecil Islet to the Port of Tanjung Priok, North Jakarta, on 15 March 2020. She transported hand sanitizers from Singapore to Batam on 9 April 2020. On 18 May 2020, she was dispatched to carry COVID-19 testing kits and hand sanitizers from Yayasan Temasek Singapura, Singapore, to Indonesia.
== USNS Mercy ==
USNS Mercy was deployed to Los Angeles to provide hospital relief from the COVID-19 pandemic. The ship arrived and docked at the Port of Los Angeles cruise ship terminal on 27 March 2020. Her mission was to treat patients other than those with COVID-19, freeing up land-based hospitals to deal with the virus, similar to how USNS Comfort deployed in New York. As of 14 April, 2020, seven crew members have tested positive for the virus and been removed from the ship for quarantine, along with 100 other sailors who had contact with them. As of 15 April, Mercy had treated 48 patients, of whom 30 have been discharged. The ship departed Los Angeles on 15 May.
=== Related nearby train derailment ===
On 31 March, while the ship was docked, a Pacific Harbor Line freight train was derailed, with the wreckage coming to a stop just 230 m (250 yd) from the ship. In an apparent "bizarre attempt to expose a perceived conspiracy", the derailment was intentionally caused by the train engineer who told police that he was suspicious of the vessel and believed the ship was not "what they say it's for." No one was injured and the ship was not harmed; the engineer was charged with train wrecking.
== USNS Comfort ==
Comfort began deployment from Norfolk, Virginia, to New York Harbor on 28 March 2020 to help deal with the impact of the COVID-19 pandemic. Comfort arrived in New York on 30 March, and docked at Pier 90. Although the ship has 1,100 personnel and a capacity of 1,000 beds, as of 3 April it was treating only 22 patients; the low figure was attributable to "bureaucratic obstacles and military procedures."
The ship's stated mission was, originally, to treat patients who did not have COVID-19, freeing up land-based hospitals to focus on patients with the virus, and originally required a patient to test negative for the coronavirus before boarding, but on 3 April changed its process to no longer requires a negative test and to accept "asymptomatic, screened patients who will be isolated and tested immediately upon arrival." On 3 April, multiple patients with the virus spent the night aboard the ship after they were accidentally transferred to the ship from the Jacob K. Javits Center, where a field hospital was in operation; the patients were transferred back to the Javits Center after testing positive for the virus."
On 17 April it was announced that "the USNS COMFORT is prepared to admit patients within a one-hour traveling radius from the ship," and preparations were made to receive coronavirus patients from the Philadelphia area. The ship has removed half its 1000 beds so that it could isolate and treat coronavirus patients. On 21 April, Governor Cuomo told President Trump that the ship was no longer needed in New York. While docked in the city, it treated 179 patients.
== Splendid ==
Mediterranean Shipping Company's Grandi Navi Veloci converted one of their ferries, Splendid, into a hospital ship in order to treat coronavirus patients. The ship was delivered to Liguria, Italy, on 23 March 2020, and was made available for the symbolic cost of 1 EUR. With help from Registro Italiano Navale and a number of local and national companies, many of which donated their time, materials, and expertise, Splendid was converted into a hospital ship in roughly 10 days. Docked at Genoa's Ponte Colombo, the hospital ship is currently treating only coronavirus patients without serious pathologies, such as patients recovering after having been previously intubated.
== BRP Ang Pangulo ==
On 3 April 2020, President Rodrigo Duterte of the Philippines ordered the conversion of BRP Ang Pangulo of the Philippine Navy (PN) to accommodate COVID-19 patients. The presidential yacht was used as a 28-bed capacity isolation facility for military frontline workers during the COVID-19 pandemic.
On 30 April 2021, the PN has announced that the Ang Pangulo was prepared to admit coronavirus patients. The ship was docked at Pier 13, Manila South Harbor.
As of 22 January 2022, the PN announced that the ship was able to extend medical aid to a total of 2,450 patients in Siargao and the Dinagat Islands as part of its humanitarian missions in the area.
== References == | Wikipedia/Hospital_ships_designated_for_the_COVID-19_pandemic |
COVID-19 Contact-Confirming Application (COCOA) is a COVID-19 application for smartphones provided by the Ministry of Health, Labour and Welfare of Japan. The application uses Bluetooth to detect and record suspected close contacts between users. If the contact is diagnosed with COVID-19, the user will be notified. After receiving the notification, the user can consider self-isolation or go to a medical institution for treatment.
== Development ==
On May 20, 2020, Apple and Google began to provide the public health authorities of various countries with the new coronavirus infection notification (English: Exposure Notification). On May 26, 2020, the "New Coronavirus Infectious Disease Countermeasures Technical Team" released a specification that defines the contact confirmation application and related systems that use this API. After Persol Process & Technology received the project management and maintenance order with a price of 41.04 million yen, it subcontracted it to two companies, including Microsoft Japan and Fixer. The application itself is developed by the open source community "COVID-19 Radar Japan" composed of private IT technicians. The members include Japanese Microsoft employees, and Persol Process & Technology is responsible for maintenance and adjustments. On June 15, the Nikkei reported that the application was developed by Microsoft in the United States, and Microsoft in Japan later denied the content of the report.
At 15:00 on June 19, 2020, Google Play and App Store began to provide the 1.0.0 (initial trial version) version of the application. This version does not link to the information control and management support system (HER-SYS) of people infected with the new coronavirus, and there are many problems. Version 1.1.1 (trial version) fixes the problems of the previous version, and after accessing the above system, it will be published to the App Store on June 30, 2020, and to Google Play on July 1, 2020. The Ministry of Health, Labour and Welfare stated that it will maintain the trial version for about one month after its release (June 19, 2020), revising the design and functions.
On September 13, 2022, Digital Minister Taro Kono said that COCOA will be discontinued as Tokyo continues to simply details on COVID-19 patients' names and other details.
=== COVID-19 Radar Japan ===
The initiator Hirose told Diamond Online that the plan was promoted by himself and 5 other core members, including Hirose, 4 core members agreed to open the name for an interview.
Hirose Kazukai (the initiator of COVID-19 Radar Japan)
Yasuda Kristina (External External person in charge)
Noriko Matsumoto (designer in charge)
Tetsuhiko Kodama (designer in charge)
== Function ==
=== Record contact information ===
As long as the smart phones of both parties are installed with COCOA and Bluetooths are turned on, the devices will record each other's data (identification code) and store it as "contact information". The contact information is an encrypted record, and personal identity cannot be identified. After 14 days of storage, the recorded information will be automatically delete. For privacy reasons, the application does not use personally identifiable information such as phone numbers and location information (GPS).
=== Notify when contact with confirmed cases ===
A confirmed case of COVID-19 confirmed by PCR testing will receive a "processing number" issued by the health center after the diagnosis is confirmed. After entering COCOA, people who have been in contact with the confirmed case will be notified. The Japanese government stated that the processing number of a confirmed case will only be sent to the confirmed case itself by mail, etc., to prevent abusers from falsely reporting the diagnosis.
== Issues ==
=== Can't find application issue ===
When it was released on June 19, 2020, the Ministry of Health, Labour and Welfare urged users to search for "contact confirmation app" (contact confirmation app) in the App Store and other places, and install it (download) for free. After the release, many people reported that they "cannot download" or "cannot search". The Ministry of Health, Labour and Welfare finally published the application link on its official website, and clicked it to go directly to the installation interface.
=== Confirmed information registration problem ===
In version 1.0.0 of the app, when registering confirmed information, even if the input processing number is not issued by the "New Coronavirus Infected Persons and Other Information Grasp and Management Support System", it will display "completed". After receiving the report, the Ministry of Health, Labour and Welfare stated that it is temporarily suspending the issuance of the processing number. Since the system will check the processing number, if the entered processing number has not been issued, it will not be registered as a confirmed case, and other users will not receive contact notifications. This problem has been fixed in version 1.1.1 of the application.
=== Starting day display problem ===
In version 1.0.0 of the application, the start date will be displayed as today's date. The 1.1.1 version of the application has fixed this problem.
=== Confirmed cases cannot be registered in the app issue ===
The Ministry of Health, Labour and Welfare stated that it will stop issuing the processing number required for registration information since July 11 due to "the discovery of a confirmed case of new coronavirus infection that could not be registered in the app". The revised version (1.1.2) will be released on iOS on July 13 and Android on July 14 to fix this problem.
=== Problem reporting method ===
The Tuberculosis and Infectious Diseases Division of the Ministry of Health, Labour and Welfare stated that if problems are found, they can report through the consultation email address listed in the app and Q&A, or go to the issue report discussion area (Issues) in the GitHub project.
== See also ==
Protect each other
Health Code
== References ==
Government contact confirmation app, supplier is Persol. Japan Economic News. 2020-06-17 [2020-06-19]. (Archived from the original on 2020-06-19).
Notification of close contact with corona-infected persons Started using the app "COCOA". NHK News. 2020-06-19 [2020-06-19].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application. www.mhlw.go.jp. [2020-07-15].
New Coronavirus Contact Confirmation App. App Store. [2020-06-20].
Contact Confirmation Application Terms of Service. www.mhlw.go.jp. [2020-06-20].
Covid-19Radar / Covid19Radar, Project Covid19Radar, 2020-06-20 [2020-06-20]
Japan's new corona contact confirmation app, Android version also released Following iOS version. ITmedia NEWS. 2020-06-19 [2020-06-20].
Japanese contact confirmation app "COCOA" released today at 3:00 pm. ITmedia NEWS. 2020-06-19 [2020-06-19].
"Contact confirmation" application distribution start with infected people Information to short-distance user smartphones. Mainichi Shimbun. 2020-06-19 [2020-06-19].
"Contact confirmation" application distribution start with infected people Information to short-distance users' smartphones. Mainichi Shimbun. [2020-06-20].
Apple and Google release API of new corona "exposure notification" 22 countries including Japan have accessed. ITmediaNEWS. 2020-05-21 [2020-06-20].
The government's "contact confirmation app" specifications have been released. Available on iOS and Android in mid-June. Impress Watch. 2020-05-26 [2020-06-19].
The specifications of the new Corona contact confirmation app have been released-to an app that does not identify individuals using Bluetooth. 2020-05-28 [2020-06-20].
Development cost 41 million yen Will the "Corona Contact App" spread to 60% of the population? Smart FLASH [Kobunsha Shukanshi]. 2020-06-19 [2020-06-21].
Outline of Minister Kato's press conference (Friday, June 19, 2nd year of Reiwa 11: 13-11: 44). Www.mhlw.go.jp. [2020-06-24].
Directly hit the developer of Corona "contact confirmation app"! How is personal information handled? Is it effective? --Diamond Online
Treasure money Kanae. Hit the developer of Corona "contact confirmation app" directly! How is personal information handled? Is it effective? Diamond Online. Diamond Inc. 2020-06-20 [2020-06-25].
Is the contact confirmation app made by US MS? Japan MS denies that it is "not a fact". ITmedia NEWS. [2020-07-04].
Why was the release of the contact confirmation app delayed? Directly hit Deputy Minister of Health, Labor and Welfare Hashimoto, who leads the IT measures of Corona. Nikkei XTECH. [2020-06-23].
Nikkei Cross Tech (xTECH). The Ministry of Health, Labor and Welfare released a contact confirmation app around 3:00 pm on the 19th, and the functions were gradually improved with the trial version. Nikkei Cross Tech (xTECH). [2020-07-03].
Directly hit the developer of Corona "contact confirmation app"! How is personal information handled? Is it effective? Diamond Online. [2020-06-21].
Population estimation (fixed value in December of the first year of Reiwa (2019), estimated value in May of the second year of Reiwa (2020)) (announced on May 20, 2020). stat.go.jp. [2020-06-22].
Impress Co., Ltd. Contact confirmation application "COCOA" of the Ministry of Health, Labor and Welfare, notifications from positive people can be received from July 3. Keitai Watch. 2020-07-02 [2020-07-03].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-03 [2020-07-08].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-06 [2020-07-07].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-07 [2020-07-07].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-08 [2020-07-08].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-09 [2020-07-09].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-10 [2020-07-10].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-13 [2020-07-13].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-14 [2020-07-14].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-15 [2020-07-15].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-16 [2020-07-16].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-17 [2020-07-17].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application ｜ Ministry of Health, Labor and Welfare. Web.archive.org. 2020-07-20 [2020-07-20].
"COCOA" of the dense contact notification cannot be downloaded. Voices one after another. NHK News. 2020-06-19 [2020-06-19].
The Ministry of Health, Labor and Welfare will guide you if there is a problem with the contact notification application "COCOA". Keitai Watch. 2020-06-19 [2020-06-21].
Multiple problems with "contact confirmation app COCOA". NTV NEWS24. 2020-06-22 [2020-06-23].
Ministry of Health, Labor and Welfare's contact confirmation app, positive report "processing number" issuance started DL 4.99 million. ITmedia NEWS. [2020-07-03].
New Coronavirus Contact Confirmation App (COCOA) COVID-19 Contact-Confirming Application. Www.mhlw.go.jp. [2020-06-24].
Q & A. [2020-06-23].
Problem Report Bulletin Board (Issues) in the GitHub project. [2020-06-23].
== External links ==
Google Play link
App Store link | Wikipedia/COVID-19_Contact-Confirming_Application |
The CureVac COVID-19 vaccine (abbreviated CVnCoV) was a COVID-19 vaccine candidate developed by CureVac N.V. and the Coalition for Epidemic Preparedness Innovations (CEPI). The vaccine showed inadequate results in its Phase III trials with only 47% efficacy. In October 2021 CureVac abandoned further development and production plans for CVnCoV and refocused efforts on a cooperation with GlaxoSmithKline.
== Efficacy ==
On 16 June 2021, CureVac said its vaccine showed 47% efficacy from its Phase IIb/III trial. Later, the final result data showed an efficacy of 48% against symptomatic disease in all age groups and, for people aged 18 to 60 years, an efficacy of 53% against symptomatic disease, 77% against moderate and severe disease and 100% against hospitalization and death, as no cases were detected in the study. This was based on interim analysis of 134 COVID cases in its Phase III study conducted in Europe and Latin America. The final analysis for the trials requires a minimum of 80 additional cases.
== Pharmacology ==
CVnCoV is an mRNA vaccine that encodes the full-length, pre-fusion stabilized coronavirus spike protein, and activates the immune system against it. CVnCoV technology does not interact with the human genome. CVnCoV uses unmodified RNA, unlike the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine, which both use nucleoside-modified RNA.
== Manufacturing ==
Manufacturing of mRNA vaccines can be performed rapidly in high volume, including use of portable, automated printers ("RNA microfactories") for which CureVac has a joint development partnership with Tesla.
mRNA vaccines require stringent cold chain refrigeration throughout manufacturing, distribution and storage. The CureVac technology for CVnCoV uses a non-modified, more natural mRNA less affected by hydrolysis, enabling storage at 5 °C (41 °F) and relatively simplified cold chain requirements that facilitate up to three months of storage and distribution to world regions that do not have specialized ultracold equipment.
CureVac had a European-based network to accelerate manufacturing of CVnCoV, if proven safe and effective, for production of up to 300 million doses in 2021 and 600 million doses in 2022. An estimated 405 million doses would have been provided to EU states.
== Clinical trials ==
In June 2020, CureVac was launched for phase I trial with 280 participants. In August, CureVac was launched for phase II trials with 674 participants. In November, CureVac reported results of a Phase I-II clinical trial that CVnCoV (active ingredient zorecimeran) was well-tolerated, safe, and produced a robust immune response.
In December 2020, CureVac began a Phase III clinical trial of CVnCoV with 36,500 participants. Bayer will provide clinical trial support and international logistics for the Phase III trial, and may be involved in eventual manufacturing should the vaccine prove to be safe and effective. In February 2021, the EU's CHMP started a rolling review of CVnCoV. In April 2021, the same procedure began in Switzerland.
In June 2021, CureVac announced that the vaccine's efficacy against symptomatic disease is 48%. The company said the high number of variants in circulation may explain the low efficacy, but some scientists attribute the result to insufficient immunogenicity due to the use of unmodified mRNA (the Pfizer–BioNTech and Moderna vaccines use uracil-modified mRNA) or the dose being too low (12 μg, compared to 30 μg for Pfizer–BioNTech and 100 μg for Moderna). Neutralizing antibody levels in CureVac recipients were about the same as those in convalescence, but much lower than those seen in recipients of Pfizer–BioNTech or Moderna. The modified mRNA induces potent antibodies and other protective immune responses and circumvents the body's inflammatory reactions. Unmodified mRNA inhibits immunogenicity by triggering the production of interferons that block the generation of T helper cells, which direct B cells to produce antibodies. CureVac attempted to evade immune detection by altering the RNA sequence in a way that does not affect the coded protein, but structural differences in the non-coding regions might have affected immunogenicity. Unmodified mRNA may have decreased tolerability, leading to the adoption of a lower dose, but studies of the Pfizer–BioNTech and Moderna vaccines found only modest gains at higher doses. A next-generation vaccine from CureVac in collaboration with GlaxoSmithKline, also using unmodified mRNA, is more stable inside cells and produces higher levels of neutralizing antibodies in animals.
== Brand names ==
The manufacturer currently markets the vaccine under the name CVnCoV. Zorecimeran is the proposed international nonproprietary name (pINN).
== References ==
== External links ==
"Zorecimeran". Drug Information Portal. U.S. National Library of Medicine. | Wikipedia/CureVac_COVID-19_vaccine |
The ImmunityBio COVID-19 vaccine, codenamed hAd5, is a non replicating viral vector COVID-19 vaccine developed by the United States-based pharmaceutical company ImmunityBio.
== Manufacturing ==
The BioVac Institute, a state-backed South African vaccine company, plans to use a deal it won to manufacture coronavirus vaccines. The contract with America-based ImmunityBio Inc is currently conducting phase 1 vaccine trials in South Africa
ImmunityBio and BioVac plan to distribute the vaccines throughout South Africa and Africa.
== History ==
In April 2020, a product developed by ImmunityBio was rumoured to be a potential SARS-CoV-2 coronavirus vaccine.
On 1 June 2020, the product was selected for inclusion on the Operation Warp Speed subsidy list, in order to fund monkey trials. The company "hope to receive approval from the Food and Drug Administration to begin an initial safety trial in humans in June 2020."
=== Clinical trials ===
ImmunityBio Inc is currently conducting phase 1 vaccine trials in The United States and South Africa.
== References ==
== External links == | Wikipedia/ImmunityBio_COVID-19_vaccine |
The COVID-19 lab leak theory, or lab leak hypothesis, is the idea that SARS-CoV-2, the virus that caused the COVID-19 pandemic, came from a laboratory. This claim is highly controversial; there is a scientific consensus that the virus is not the result of genetic engineering, and most scientists believe it spilled into human populations through natural zoonosis (transfer directly from an infected non-human animal), similar to the SARS-CoV-1 and MERS-CoV outbreaks, and consistent with other pandemics in human history. Available evidence suggests that the SARS-CoV-2 virus was originally harbored by bats, and spread to humans from infected wild animals, functioning as an intermediate host, at the Huanan Seafood Market in Wuhan, Hubei, China, in December 2019. Several candidate animal species have been identified as potential intermediate hosts. There is no evidence SARS-CoV-2 existed in any laboratory prior to the pandemic, or that any suspicious biosecurity incidents happened in any laboratory.
Many scenarios proposed for a lab leak are characteristic of conspiracy theories. Central to many is a misplaced suspicion based on the proximity of the outbreak to the Wuhan Institute of Virology (WIV), where coronaviruses are studied. Most large Chinese cities have laboratories that study coronaviruses, and virus outbreaks typically begin in rural areas, but are first noticed in large cities. If a coronavirus outbreak occurs in China, there is a high likelihood it will occur near a large city, and therefore near a laboratory studying coronaviruses. The idea of a leak at the WIV also gained support due to secrecy during the Chinese government's response. The lab leak theory and its weaponization by politicians have both leveraged and increased anti-Chinese sentiment. Scientists from WIV had previously collected virus samples from bats in the wild, and allegations that they also performed undisclosed work on such viruses are central to some versions of the idea. Some versions, particularly those alleging genome engineering, are based on misinformation or misrepresentations of scientific evidence.
The idea that the virus was released from a laboratory (accidentally or deliberately) appeared early in the pandemic. It gained popularity in the United States through promotion by conservative personalities in early 2020, fomenting tensions between the U.S. and China. Scientists and media outlets widely dismissed it as a conspiracy theory. The accidental leak idea had a resurgence in 2021. In March, the World Health Organization (WHO) published a report which deemed the possibility "extremely unlikely", though the WHO's director-general said the report's conclusions were not definitive. Subsequent plans for laboratory audits were rejected by China.
Most scientists are skeptical of the possibility of a laboratory origin, citing a lack of any supporting evidence for a lab leak and the abundant evidence supporting zoonosis. Though some scientists agree a lab leak should be examined as part of ongoing investigations, politicization remains a concern. In July 2022, two papers published in Science described novel epidemiological and genetic evidence that suggested the pandemic likely began at the Huanan Seafood Wholesale Market and did not come from a laboratory.
== Background ==
The principal hypothesis for the origin of COVID-19 is that it became infectious to humans through a natural spillover event (zoonosis). That it became infectious to humans through escape from a laboratory where it was being studied is a minority position. The available evidence supports zoonosis. Although the origin of SARS-CoV-2 is not definitively known, arguments used in support of a laboratory leak are characteristic of conspiratorial thinking.
=== Zoonosis ===
Most new infectious diseases begin with a spillover event from animals, and furthermore, they spill over spontaneously (either by contact with wildlife animals, which are the majority of cases, or with farmed animals). For example, the emergence of Nipah virus in Perak, Malaysia, and the 2002 outbreak of SARS-CoV-1 in Guangdong province, China, were natural zoonosis traced back to wildlife origin. COVID-19 is considered by scientists to be "of probable animal origin". It has been classified as a zoonotic disease (naturally transmissible from animals to humans). Some scientists dispute this classification, since a natural reservoir has not been confirmed. The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic (capable of causing disease) before or after a spillover event.
Bats, a large reservoir of betacoronaviruses, are considered the most likely natural reservoir of SARS‑CoV‑2. Differences between bat coronaviruses and SARS‑CoV‑2 suggest that humans may have been infected via an intermediate host. Research into the natural reservoir of the virus that caused the 2002 SARS outbreak has resulted in the discovery of many SARS-like coronaviruses circulating in bats, most found in horseshoe bats. Analysis indicates that a virus collected from Rhinolophus affinis in a cave near the town of Tongguan in Yunnan province, designated RaTG13, has a 96% resemblance to SARS‑CoV‑2. The RaTG13 virus genome was the closest known sequence to SARS-CoV-2 until the discovery of BANAL-52 in horseshoe bats in Laos, but it is not its direct ancestor. Other closely related sequences were also identified in samples from local bat populations in Yunnan province. One such virus, RpYN06, shares 97% identity with SARS-CoV-2 in one large part of its genome, but 94% identity overall. Such "chunks" of very highly identical nucleic acids are often implicated as evidence of a common ancestor.
An ancestor of SARS-CoV-2 likely acquired "generalist" binding to several different species through adaptive evolution in bats and an intermediate host species. Estimates based on genomic sequences and contact tracing have placed the origin point of SARS-CoV-2 in humans as between mid-October and mid-November 2019. Some scientists (such as Fauci above and CIRAD's Roger Frutos) have suggested slow, undetected circulation in a smaller number of humans before a threshold event (such as replication in a larger number of hosts in a larger city like Wuhan) could explain an undetected adaption period.
The first known human infections from SARS‑CoV‑2 were discovered in Wuhan, China, in December 2019. Because many of the early infectees were workers at the Huanan Seafood Market, it was originally suggested that the virus might have originated from wild animals sold in the market, including civet cats, raccoon dogs, bats, or pangolins. Subsequent environmental analyses demonstrated the presence of SARS-CoV-2 in the market, with highest prevalence in areas of the market where animals known to be susceptible to SARS-CoV-2 infection were held. Early human cases clustered around the market, and included infections from two separate SARS-CoV-2 lineages. These two lineages demonstrated that the virus was actively infecting a population of animals in the market, and that sustained contact between those animals and humans had allowed for multiple viral transmissions into humans. All early cases of COVID-19 were later shown to be localized to the market and its immediate vicinity.
While other wild animals susceptible to SARS-CoV-2 infection are known to have been sold at Huanan, no bats or pangolins were sold at the market.
=== Wuhan Institute of Virology ===
The Wuhan Institute of Virology and the Wuhan Center for Disease Control are located within miles of the original focal point of the pandemic, Wuhan's Huanan Seafood Wholesale Market, and this very closeness has made it easy for conspiracy theories to take root suggesting the laboratory must be the virus' origin. However virology labs are often built near potential outbreak areas. Proponents of the lab leak theory typically omit to mention that most large Chinese cities have coronavirus research laboratories. Virus outbreaks tend to begin in rural areas, but are first noticed in large cities. Stephan Lewandowsky and colleagues write that the location of the Institute near the outbreak site is "literally a coincidence" and using that coincidence as a priori evidence for a lab leak typifies a kind of conjunction fallacy. Furthermore, they observe that is ironic lab leak proponents are keen to argue for the significance of proximity of laboratories to the outbreak, while ignoring the proximity of wet markets, which have long-been identified as potential origins for viral spillover events.
The Wuhan Institute of Virology (WIV) had been conducting research on SARS-like bat coronaviruses since 2005, and was involved in 2015 experiments that some experts (such as Richard Ebright) have characterized as gain-of-function. Others (including Ralph Baric) have disputed the characterization, pointing out that the experiments in question (involving chimeric viruses) were not conducted at the WIV, but at UNC Chapel Hill, whose institutional biosafety committee assessed the experiments as not "gain-of-function". Baric did acknowledge the risks involved in such studies, writing, "Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue ... The potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens."
The fact that the lab is in Wuhan, the city where the pandemic's early outbreak took place, and the fact that the research at WIV was being conducted under the less stringent biosafety levels (BSL) 2 and 3, has led to speculation that SARS-CoV-2 could have escaped from the Wuhan lab. Richard Ebright said one reason that lower-containment BSL-2 laboratories are sometimes used is the cost and inconvenience of high-containment facilities. Australian virologist Danielle Anderson, who was the last foreign scientist to visit the WIV before the pandemic, said the lab "worked in the same way as any other high-containment lab". She also said it had "strict safety protocols". The Huanan Seafood Market may have only served as a jumping off point for a virus that was already circulating in Wuhan, facilitating rapid expansion of the outbreak.
=== Prior lab leak incidents and conspiracy theories ===
Laboratory leak incidents have occurred in the past. A Soviet research facility in 1979 leaked anthrax and at least 68 people died. The 2007 foot-and-mouth outbreak in the UK was caused by a leaky pipe at a high-security laboratory. The SARS virus escaped at least once, and probably twice, from a high-level biocontainment laboratory in China.
Benign exposures to pathogens (which do not result in an infection) are probably under-reported, given the negative consequences of such events on the reputation of a host institution and low risk for widespread epidemics. Epidemiologist Marc Lipsitch and bacteriologist Richard Ebright have said that the risk of laboratory-acquired infection (especially with modified pathogens) is greater than widely believed.
No epidemic has ever been caused by the leak of a novel virus. The only incident of a lab-acquired infection leading to an epidemic is the 1977 Russian flu which was probably caused by a leaked strain of H1N1 that had circulated naturally until the 1950s.
Previous novel disease outbreaks, such as AIDS, H1N1/09, SARS, and Ebola have been the subject of conspiracy theories and allegations that the causative agent was created in or escaped from a laboratory. Each of these is now understood to have a natural origin. Anti-biotechnology activists falsely claimed that a plant pathogen of olive trees was the result of scientists' work, despite evidence to the contrary that the pathogen was not a laboratory strain. Studies later showed the origin was long before the workshop that was the subject of the false claims, and a more typical route of introduction by an imported plant.
=== Psychological and social factors ===
Survey work on the public in the United States has found that identity politics and racial resentment are factors informing overconfident belief in the lab leak theory and COVID-19 misinformation in general. The researchers propose that this shows how such beliefs are resistant to refutation because they are not subject only to evidence, but to ingrained attitudes and notions of self.
On social media the idea that COVID was a Chinese biological weapon has become widespread, and accords with rhetoric about how a yellow peril threatens white people. Science historian Fred Cooper and colleagues write that in the United Kingdom, attitudes to the Chinese have long been tainted by xenophobic stereotypes. Cooper draws a parallel between the Wuhan lab leak narrative, and the machinations of fictional supervillain Fu Manchu, who is "expert in the deadly application of animal and biological agents" and who has been depicted on television shows as threatening the West with lethal diseases.
== Proposed scenarios ==
The lab leak theory is not a single discrete proposed scenario, but a collection of various proposed scenarios on a spectrum with, at one end, a careless accident from legitimate research; at the other, the engineering and release of a Chinese biological weapon. While the proposed scenarios are theoretically subject to evidence-based investigation, it is not clear that any can be sufficiently falsified to placate lab leak supporters, as they are based on pseudoscientific and conspiratorial thinking.
There is no evidence that any laboratory had samples of SARS-CoV-2, or a plausible ancestor virus, prior to the start of the COVID-19 pandemic.
Various sources have hypothesised that SARS-CoV-2 could have leaked from the Wuhan Institute of Virology or another laboratory in Wuhan, such as the Wuhan Center for Disease Control. The theories vary on whether this was an intentional act or an accident. Theories also vary on whether the virus was modified by human activity prior to being released. By January 2020 some lab leak proponents were promoting a narrative with conspiracist components; such narratives were often supported using "racist tropes that suggest that epidemiological, genetic, or other scientific data had been purposefully withheld or altered to obscure the origin of the virus". David Gorski refers to "the blatant anti-Chinese racism and xenophobia behind lab leak, whose proponents often ascribe a nefarious coverup to the Chinese government". Gorski later stated the lab leak hypothesis hasn't "stood up to scientific scrutiny". The use of xenophobic rhetoric also caused a rise in anti-Chinese sentiment.
=== Origins ===
In the early days of the COVID-19 pandemic, speculation about a laboratory leak was confined to conspiracy-minded portions of the internet, including 4Chan and Infowars, but the ideas began to get wider traction after accusations about a "Chinese bioweapon" were originally published by Great Game India and then republished by the Red State Watch and Zero Hedge web sites. From there, the idea gained media traction and was championed by American conservative political figures.
The idea split into variants, including one that proposed Asian people were immune to COVID, or that the Chinese had a secret vaccine standing by for use. Some proposed that the Chinese government and World Health Organization were operating together in a conspiracy. The American president of the time, Donald Trump, used anti-Chinese rhetoric (such as "Kung flu") to feed the idea, and said in an April 2020 news conference that he had documents supporting the idea that SARS-CoV-2 had come from the Wuhan Institute of Virology.
In reaction to this politicized environment, most mainstream science and media sources assumed that the lab leak idea was no more than racially-fuelled propaganda, and by the summer of 2020 the idea was largely dismissed, until the next American president, Joe Biden, ordered an investigation into COVID's origins in 2021.
=== Accidental release of a natural virus ===
Some have hypothesised the virus arose in humans from an accidental infection of laboratory workers by contact with a sample extracted from a wild animal or by direct contact with a captive animal or its respiratory droplets or feces.
Former CDC director Robert R. Redfield said in March 2021 that in his opinion the most likely cause of the virus was a laboratory escape, which "doesn't imply any intentionality", and that as a virologist, he did not believe it made "biological sense" for the virus to be so "efficient in human to human transmission" from the early outbreak. The fact that scientists have not been successful in finding an intermediate host that picked up the virus from bats and passed it to humans is seen by some as evidence that supports a lab leak, according to The Guardian.
University of Utah virologist Stephen Goldstein has criticized the scientific basis of Redfield's comments, saying that since SARS-CoV-2's spike protein is very effective at jumping between hosts, one shouldn't be surprised that it transmits efficiently among humans. Goldstein said "If a human virus [such as SARS-CoV2] can transmit among mink, there's no basis to assume a bat virus [also SARS-CoV2] can't transmit among humans. Us humans may think we're very special – but to a virus we are just another mammalian host."
In June 2024, Deborah Birx, Donald Trump's Coronavirus Response Coordinator, in response to CNN's Kassie Hunt asking if there were efforts to discredit the lab leak theory, said "I do think it happened. If you look at what people said about Bob Redfield and how they disparaged him as a scientist because he wanted to bring forward the lab leak potential." She added: "And I think the reason [Redfield] felt he needed to bring it forward to push, was to push against this, ‘it had to be this way.’ Because we didn't know, and we knew we would never know."
==== WHO assessment ====
The WHO-convened Global Study of Origins of SARS-CoV-2, written by a joint team of Chinese and international scientists and published in March 2021, assessed introduction through a laboratory incident to be "extremely unlikely" and not supported by any available evidence, although the report stated that this possibility could not be wholly ruled out without further evidence. The report stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered less likely.
A small group of researchers said that they would not trust the report's conclusions because it was overseen by the Chinese government, and some observers felt the WHO's statement was premature. Other scientists found the report convincing, and said there was no evidence of a laboratory origin for the virus.
WHO Director-General Tedros Adhanom stated that the team had experienced difficulty accessing raw data on early COVID-19 cases and that the least likely hypothesis, a lab leak, required additional investigation because "further data and studies will be needed to reach more robust conclusions". The leader of the WHO investigatory team, Peter Ben Embarek, said "An employee of the lab gets infected while working in a bat cave collecting samples. Such a scenario, while being a lab leak, would also fit our first hypothesis of direct transmission of the virus from bat to human."
The United States, European Union, and 13 other countries criticized the WHO-convened study, calling for transparency from the Chinese government and access to the raw data and original samples. Chinese officials described these criticisms as "an attempt to politicise the study". Scientists involved in the WHO report, including Liang Wannian, John Watson, and Peter Daszak, objected to the criticism, and said that the report was an example of the collaboration and dialogue required to successfully continue investigations into the matter.
On 15 July 2021, WHO Director-General Tedros Adhanom Ghebreyesus said that the COVID-19 lab leak theory had been prematurely discarded by the WHO, following his earlier statements that a potential leak requires "further investigation, potentially with additional missions involving specialist experts". He proposed a second phase of WHO investigation, which he said should take a closer look at the lab leak idea, and asked the Chinese government to be "transparent" and release relevant data. Later on 17 July, Tedros called for "audits of relevant laboratories and research institutions" in the area of the initial COVID-19 cases. China's government refused saying it showed "disrespect" and "arrogance towards science". The United States criticised China's position on the follow-up origin probe as "irresponsible" and "dangerous".
In June 2022, the WHO's Scientific Advisory Group for Origins of Novel Pathogens (SAGO) published a preliminary report urged a deeper investigation into the possibility of a laboratory leak. The SAGO chair said in a press conference that "the strongest evidence is still around a zoonotic transmission". The AP described the report as a "sharp reversal" of the WHO's previous assessment, and Science.org described reactions from academics as mixed.
In early 2023, the WHO abandoned its original investigation into the origin of SARS-CoV-2, delegating work to its standing committee, the Scientific Advisory Group for Origins of Novel Pathogens (SAGO). This work will attempt to establish a COVID-19 timeline, search for similar viruses, and conduct further laboratory studies on animals and human samples.
==== Mojiang copper mine ====
Members of DRASTIC, a collection of internet activists advocating for the lab leak theory, have raised concerns over a respiratory outbreak that happened in the spring of 2012 near an abandoned copper mine in China, which Shi Zhengli's group investigated. Shi's group collected a sample of viral RNA and named it RaBtCoV/4991. Later, Shi's group published a paper about a virus named RaTG13 in Nature in February 2020. Via sequence comparisons, it became clear that RaBtCoV/4991 and RaTG13 were likely the same virus. Shi has said that the renaming was done to reflect the origin location and year of the virus.
Some proponents, including Nicholas Wade and pseudonymous DRASTIC member "TheSeeker268", argued that the renaming was an attempt to obscure the origins of the virus and hide how it could be related to a laboratory origin of the related SARS-CoV-2 virus. Scientists have said that RaTG-13 is too distantly related to be connected to the pandemic's origins, and could not be altered in a laboratory to create SARS-CoV-2. Nature later published an addendum to the 2020 RaTG13 paper addressing any possible link to the mine, in which Shi says that the virus was collected there, but that it was very likely not the cause of the miners' illnesses. According to the addendum, laboratory tests conducted on the workers' serum were negative, and "no antibodies to a SARS-like coronavirus had been found."
=== Accidental release of a genetically modified virus ===
There is a scientific consensus that SARS-CoV-2 is not the result of genetic engineering. Nevertheless, one conspiracy theory spread in support a laboratory origin suggests SARS-CoV-2 was developed for gain-of-function research on coronaviruses. The exact meaning of "gain of function" is disputed among experts. According to emailed statements by Shi Zhengli, director of the Center for Emerging Infectious Diseases at the Wuhan Institute of Virology, her lab has not conducted any unpublished gain-of-function experiments on coronaviruses, and all WIV staff and students tested negative for the virus in the early days of the pandemic.
==== Furin cleavage site ====
One strand of argumentation in favor of a lab leak rests on the premise that there is something "unnatural" about the genetic makeup of the SARS-CoV-2 virus, showing it must have been created by genetic engineering. Some claims of bioengineering focus on the presence of two sequential cytosine-guanine-guanine (CGG) codons in the virus' RNA, more precisely in the crucial furin cleavage site. The CGG codon is one of several codons that translates into an arginine amino acid, and it is the least common arginine codon in human pathogenic betacoronaviruses. Partially, this lack of CGG codons in human pathogenic coronaviruses is due to natural selection; B-cells in the human body recognize areas on virus genomes where C and G are next to each other (so-called CpG islands). The CGG codon makes up 5% of the arginine codons in the SARS-CoV-1 genome, and it makes up 3% of the arginine codons in the SARS-CoV-2 genome.
Proponents of an engineered virus, including journalist Nicholas Wade, say that two such uncommon codons in a row are evidence for a laboratory experiment; because of the low chance of a CGG codon pair occurring in nature, and in contrast, the common usage of CGG codons for arginine in genetic engineering work. This has been debunked by scientists, who note that the CGG codon is also present (and even more frequent) in other coronaviruses, including MERS-CoV, and that a codon being rare does not mean it cannot be present naturally. If the CGG codon had been engineered into the virus, it should have mutated out of the virus as it circulated in humans in the wild over several years, but the opposite has occurred. In fact, the presence of the furin cleavage site, which is responsible for a significant increase in transmissibility, largely outweighs any disadvantageous immune responses from B-cells triggered by the genetic sequences which code for it.
Another source of speculation is the mere presence of the furin cleavage site. It is absent in the closest known relatives of SARS-CoV-2 (but present in other betacoronaviruses, e.g., BtHpCoV-ZJ13). This anomaly is most probably the result of recombination, and is further unsurprising since the genetic lineage of these viruses has not been adequately explored, sampled, or sequenced. A common occurrence among other coronaviruses (including MERS-CoV, HCoV-OC43, HCoV-HKU1, and appearing in near-identical fashion in HKU9-1), the site is preceded by short palindromic sequences suggestive of natural recombination caused by simple evolutionary mechanisms. Additionally, the suboptimal configuration and poor targeting of the cleavage site for humans or mice when compared with known examples (such as HCoV-OC43 or HCoV-HKU1), along with the complex and onerous molecular biology work this would have required, is inconsistent with what would be expected from an engineered virus.
Project DEFUSE was a rejected DARPA grant application, that proposed to sample bat coronaviruses from various locations in China. The rejected proposal document was posted online by DRASTIC in September 2021. Co-investigators on the rejected proposal included the EcoHealth Alliance's Peter Daszak, Ralph Baric from UNC, Linfa Wang from Duke–NUS Medical School in Singapore, and Shi Zhengli from the Wuhan Institute of Virology. The grantees proposed to evaluate the ability of bat viruses to infect human cells in the laboratory using chimeric coronaviruses which were mutated in different locations, and to create protein-based vaccines out of the spike (S) protein (not the whole virus) which would be distributed to bats in the wild to reduce the chances of future human outbreaks. One proposed alteration was to modify bat coronaviruses to insert a cleavage site for the Furin protease at the S1/S2 junction of the spike (S) viral protein. There is no evidence that any genetic manipulation or reverse genetics (a technique required to make chimeric viruses) of SARS-related bat coronaviruses was ever carried out at the WIV. All available evidence points to the SARS-CoV-2 furin cleavage site being the result of natural evolution.
==== Political and government opinion ====
The situation reignited a debate over gain-of-function research, although the intense political rhetoric surrounding the issue has threatened to sideline serious inquiry over policy in this domain. Researchers have said the politicization of the debate is making the process more difficult, and that words are often twisted to become "fodder for conspiracy theories". The idea of an experiment conducted in 2015 on SARS-like coronaviruses being the source of the pandemic was reported in British tabloids early in the pandemic. Virologist Angela Rasmussen writes that this is unlikely, due to the intense scrutiny and government oversight gain-of-function research is subject to, and that it is improbable that research on hard-to-obtain coronaviruses could occur under the radar.
Kentucky Senator Rand Paul alleged that the US National Institutes of Health (NIH) had been funding gain-of-function research in Wuhan, accusing researchers including epidemiologist Ralph Baric of creating "super-viruses". Both Fauci and NIH Director Francis Collins denied that the US government supported such research. Baric likewise rejected Paul's allegations, saying his lab's research into cross-species transmission of bat coronaviruses did not qualify as gain-of-function. While a 2017 study of chimeric bat coronaviruses at the WIV listed NIH as a sponsor, NIH funding was only related to sample collection. A Washington Post fact-checker commented that "EcoHealth funding was not related to the experiments, but the collection of samples", and that "statements about Baric's research appear overblown". In October 2021, a spokesman for the NIH acknowledged that the EcoHealth Alliance had provided new data demonstrating that in a mouse experiment, a coronavirus had caused more weight loss than expected. This was described as an unexpected consequence of the research, and not its intended outcome or a component of the original funding proposal. Importantly, the NIH spokesman said this finding was provided in a late progress report, and was not available before prior statements about experiments at the WIV.
An August 2021 interim report authored by the minority staff of the Republican members of the US House Foreign Affairs Committee said that a laboratory leak origin for SARS-CoV-2 was more likely than a natural one. The report alleged that SARS-CoV-2 emerged in humans as a result of gain-of-function research made on the RaTG13 virus, collected in a cave in Yunnan province in 2012, which was afterwards accidentally released some time before 12 September 2019, when the database of the Wuhan Institute of Virology went offline. The August 2021 report relies mostly on existing public evidence, combined with internal documents from the CCP from before and during the early days of the pandemic.
The interim report was published coinciding with a joint investigation from ProPublica and Vanity Fair. Immediately following its publication, the report was heavily criticized by experts in diplomacy and the Chinese language for mistranslations and misinterpretations of Chinese documents. Bacteriologist and lab leak theory proponent Richard Ebright criticized the report for packaging pre-existing and previously examined evidence as new information. Evolutionary biologist Michael Worobey commented that the document seemed to be either "a cynical effort to try to win Republican votes" in the November 2022 midterm elections, or "a bunch of staffers with no ability to understand the science who stumbled across a bunch of misinformation and disinformation-filled tweets." Virologist Angela Rasmussen described the report as "an embarrassingly bad use of taxpayer money and resources." The final version of the report was released on 18 April 2023. The final version reiterated the interim position that the pandemic began in a laboratory incident in the fall of 2019, based on what it called a "preponderance of circumstantial evidence".
=== Fringe views on genetic engineering ===
The earliest known recorded mention of any type of lab leak theory appeared in the form of a tweet published on 5 January 2020, from a Hong Kong user named @GarboHK, insinuating that the Chinese government had created a new virus and intentionally released it. Similar ideas were later formalized in a preprint posted on BioRxiv on 31 January 2020, by researchers at the Indian Institute of Technology, claiming to find similarities between the new coronavirus' genome and that of HIV. The paper was quickly retracted due to irregularities in the researchers' "technical approach and...interpretation of the results". This claim was promoted by Luc Montagnier, a controversial French virologist and Nobel laureate, who contended that SARS-CoV-2 might have been created during research on a HIV/AIDS vaccine. Bioinformatics analyses show that the common sequences are short, that their similarity is insufficient to support the hypothesis of common origin, and that the identified sequences were independent insertions which occurred at varied points during the evolution of coronaviruses.
Further claims were promulgated by several anti-vaccine activists, such as Judy Mikovits and James Lyons-Weiler, who claimed that SARS-CoV-2 was created in a laboratory, with Mikovits going further and stating that the virus was both deliberately engineered and deliberately released. Weiler's analysis, where he argued that a long sequence in the middle of the spike protein of the virus was not found in other coronaviruses and was evidence for laboratory recombination, was dismissed by scientists, who found that the sequence in question was also found in many other coronaviruses, suggesting that it was "widely spread" in nature.
Chinese researcher Li-Meng Yan was an early proponent of deliberate genetic engineering, releasing widely criticised preprint papers in favor of the lab leak theory in the spring of 2020. After she released her preprints, political operatives (including Steve Bannon and Guo Wengui) arranged for Yan to flee to the United States in the summer of 2020 to engage in a speaking tour on right-wing media outlets, as a method of distracting from the Trump administration's handling of the COVID-19 pandemic. According to scientific reviewers from the Johns Hopkins Center for Health Security, Yan's paper offered "contradictory and inaccurate information that does not support their argument," while reviewers from MIT Press's Rapid Reviews: COVID-19 criticised her preprints as not demonstrating "sufficient scientific evidence to support [their] claims."
In September 2022, a panel assembled by The Lancet published a wide-ranging report on the pandemic, including commentary on the virus origin overseen by the group's chairman Jeffrey Sachs. This suggested that the virus may have originated from an American laboratory, a notion long-promoted by Sachs, including on the podcast of conspiracy theorist Robert F. Kennedy Jr. Reacting to this, virologist Angela Rasmussen commented that this may have been "one of The Lancet's most shameful moments regarding its role as a steward and leader in communicating crucial findings about science and medicine". Virologist David Robertson said the suggestion of US laboratory involvement was "wild speculation" and that "it's really disappointing to see such a potentially influential report contributing to further misinformation on such an important topic".
=== Deliberate release ===
Historian of science Naomi Oreskes says that she does not know of any credible scientists who support the view that the virus was released deliberately, while the version proposing the virus may have escaped accidentally is more plausible.
In the United States, Senator Marsha Blackburn proposed a bill that would allow people to lodge lawsuits against China for use of a "biological weapon", stating that "China has a 5,000-year history of cheating and stealing. Some things will never change".
== Political, academic and media attention ==
=== Media reports ===
The first media reports suggesting a SARS-CoV-2 lab leak appeared in the Daily Mail and The Washington Times in late January 2020. In a 31 January 2020 interview with Science Magazine, Professor Richard Ebright said there was a possibility that SARS-CoV-2 entered humans through a laboratory accident in Wuhan, and that all data on the genome sequence and properties of the virus were "consistent with entry into the human population as either a natural accident or a laboratory accident". A 5 February 2021 report from Caixin described these reports as rumors originating from two sources: a preprint paper by an Indian scholar posted to bioRxiv that was later withdrawn, and a BBC China report. On 8 February 2023, the acting director of the US National Institutes of Health (NIH) testified before a Republican-led House committee that the viruses studied in the Wuhan lab "bear no relationship" to SARS-CoV-2 and that suggesting equivalency would be akin to "saying that a human is equivalent to a cow".
In early 2021, the hypothesis returned to popular debate due to renewed media discussion. The renewed interest was prompted by two events. First, an article published in May by The Wall Street Journal reported that lab workers at the Wuhan Institute of Virology fell ill with COVID-19-like symptoms in November 2019. The report was based on off-the-record briefings with intelligence officials. The cases would precede official reports from the Chinese government stating the first known cases were in December 2019, although unpublished government data suggested the earliest cases were detected in mid-November. The Guardian stated that the WSJ article did little to confirm, in terms of good, quality evidence, the possibility of a lab leak; a declassified report from the National Intelligence Council likewise said that the fact the researchers were hospitalized was unrelated to the origins of the outbreak. Second, it was shown that Peter Daszak, the key organiser of the February 2020 statement in The Lancet, did not disclose connections to the Wuhan Institute of Virology. An addendum was later published by The Lancet, in which Daszak listed his previous cooperation with Chinese researchers.
After the publication of the WHO-convened report, politicians, talk show hosts, journalists, and some scientists advanced claims that SARS-CoV-2 may have come from the WIV. DRASTIC also contributed to its promotion, particularly via Twitter. In July 2021, a Harvard–Politico survey indicated that 52 percent of Americans believed that COVID-19 originated from a lab leak, while 28 percent believed that COVID-19 originated from an infected animal in nature. By March 2023, the percentage of Americans believing in lab origin had doubled (from 30% to 60%) since 3 years earlier, and the percentage of Americans believing in natural origins had halved (from 40% to 20%).
Science educationalist Heslley Machado Silva describes the idea of a China-produced virus as part of "xenophobic social network crusade" akin to a far-fetched movie scenario, which has nevertheless garnered many millions of internet adherents. Silva raises a plea for the pandemic to be a time for humanity to become "better and not an opportunity to foment hatred".
After May 2021, some media organizations softened previous language that described the laboratory leak theory as "debunked" or a "conspiracy theory". However, the prevailing scientific view remained that while an accidental leak was possible, it was highly unlikely.
=== China–US relations ===
The origin of COVID-19 became a source of friction in China–United States relations. The lab leak theory was promulgated in early 2020 by United States politicians and media, particularly US president Donald Trump, other prominent Republicans, and conservative media (such as Fox News pundit Tucker Carlson, and former Breitbart News publisher and White House chief strategist Steve Bannon). Trump had also referred to the virus as "kung flu", and the administration also expressed the intention to sanction China. In April 2020, Trump claimed to have evidence for the lab leak theory, but refused to produce it when requested. At that time, the media did not distinguish between the accidental lab leak of a natural virus and bio-weapon origin conspiracy theories. In online discussions, various theories – including the lab leak theory – were combined to form larger, baseless conspiracy plots.
In May 2020, Fox News host Tucker Carlson accused Anthony Fauci of having "funded the creation of COVID" through gain-of-function research at the Wuhan Institute of Virology (WIV). Citing an essay by science writer Nicholas Wade, Carlson alleged that Fauci had directed research to make bat viruses more infectious to humans. Facebook enacted a policy to remove discussion of the lab leak theory as misinformation; it lifted the ban a year later, in May 2021.
A BBC China report stated that on 14 February, Chinese president Xi Jinping proposed for biosafety to be incorporated into law; the following day, new measures were introduced to "strengthen the management of laboratories", especially those working with viruses. In April 2020, The Guardian reported that China had taken steps to tightly regulate domestic research into the source of the outbreak in an attempt to control the narrative surrounding its origins and encourage speculation that the virus started outside the country. In May 2020, Chinese state media carried statements by scientists countering claims that the seafood market and Institute of Virology were possible origin sites, including comments by George Gao, director of the Chinese Center for Disease Control and Prevention.
In the United States, anti-China misinformation spread on social media, including baseless bio-weapon claims, fueled aggressive rhetoric towards people of Asian ancestry, and the bullying of scientists. Some scientists were worried their words would be misconstrued and used to support racist rhetoric. A letter published in Science by Jesse Bloom and others, outlined the uncertain origin of SARS-CoV-2 and proved an impetus for misinformation. The letter was criticized by virologists and public health experts, who said that a "hostile" and "divisive" focus on the WIV was unsupported by evidence, was impeding inquiries into legitimate concerns about China's pandemic response and transparency by combining them with speculative and meritless argument, and would cause Chinese scientists and authorities to share less rather than more data.
Some members of the Chinese government have promoted a counter-conspiracy theory claiming that SARS‑CoV‑2 originated in the U.S. military installation at Fort Detrick. This theory has little support. Chinese demands to investigate U.S. laboratories are thought to be a distracting technique to push focus away from Wuhan.
=== Attacks on scientists ===
A consistent feature of all varieties of the lab leak theory is that they direct blame at scientists. Scientists are accused of engineering the virus or negligently allowing it to escape their laboratories, and then conspiring to cover-up their misdeeds.
Two Rutgers University faculty members – Richard Ebright and Bryce Nickels – have been prominent social media posters advancing the lab leak position, and have continually attacked COVID-19 researchers, and compared them to Nazis and Pol Pot. In March 2024, twelve scientists made a formal complaint to Rutgers about Ebright and Nickels, saying they had posted messages to social media which risked their safety and which could be defamatory. Ebright reacted to the complaint saying it was "a crude effort to silence […] opponents" and Nickels said the complaint contained "deliberate lies".
=== Negative societal effects ===
According to Paul Thacker (writing for the British Medical Journal), some scientists and reporters said that "objective consideration of COVID-19's origins went awry early in the pandemic, as researchers who were funded to study viruses with pandemic potential launched a campaign labelling the lab leak hypothesis as a 'conspiracy theory.'" In February 2020, a letter was published in The Lancet authored by 27 scientists and spearheaded by Peter Daszak which described some alternate origin ideas as "conspiracy theories". Filippa Lentzos said some scientists "closed ranks" as a result, fearing for their careers and grants. The letter was criticized by Jamie Metzl for "scientific propaganda and thuggery", and by Katherine Eban as having had a "chilling effect" on scientific research and the scientific community by implying that scientists who "bring up the lab-leak theory ... are doing the work of conspiracy theorists".
Early in 2020, scientists including Jeremy Farrar, Kristian G. Andersen, and Robert F. Garry, among others, sent emails to Anthony Fauci with questions regarding what Andersen referred to as "crackpot conspiracy theories" about a lab leak, and whether evidence supported them. NIH director Francis Collins was concerned at the time that discussion of the possibility could damage "international harmony". After the discovery of similar viruses in nature, more research into the genome, and the availability of more genomic sequences from the early days of the pandemic, these scientists publicly stated they supported the zoonotic theory as the most likely explanation.
Some journalists and scientists said they dismissed or avoided discussing the lab leak theory during the first year of the pandemic as a result of perceived polarization resulting from Donald Trump's embrace of the lab leak theory. The chair of the Board of Governors of the American Academy of Microbiology, Arturo Casadevall, said that, he (like many others) previously underestimated the lab leak hypothesis "mainly because the emphasis then [early in the pandemic] was on the idea of a deliberately engineered virus". However, by May 2021 it was a "long-simmering concern" in scientific circles, and that he perceived "greater openness" to it.
By fall 2022, the scientific consensus was that the pandemic most likely began with a natural zoonosis. The most likely natural reservoir is believed to reside in bats, with a possible intermediate host (such as palm civets, minks, or pangolins), before spillover into humans. In March 2023, James Alwine and colleagues argued that continuing to frame the lab leak hypothesis as being as likely as natural spillover was responsible for a misdirection of scientific effort, which could compromise progress towards preparing for future pandemics.
In August 2024 the Lancet Microbe published an editorial saying it is "simply wrong" to assert that SARS-CoV-2 is of unnatural origin, and ascribed continued interest in the unnatural origin idea to irresponsible journalism and political motivation. The editorial expressed concern that the furore around the virus's origins had a "chilling effect" on legitimate virology research and could jeopardise mankind's safety from pathogens in the future.
=== US government and intelligence agencies ===
In the United States, several intelligence agencies have assessed the likelihood of a lab leak origin for SARS-CoV-2. Such assessments are not equivalent to scientific activity, but weigh the veracity of sources as the basis for making an intelligence report.
An August 2021 report made at the request of President Biden assessed that the Chinese government did not have foreknowledge of the COVID-19 outbreak. Overall, the report was not conclusive about the virus' origin. Of the eight assembled teams, four (and the National Intelligence Council) were inclined, with low confidence, to uphold a zoonotic origin, three were unable to reach a conclusion and one (the FBI) supported, with moderate confidence, a lab leak. British intelligence agencies believe it is "feasible" that the virus began with a leak from a Chinese laboratory.
In February 2023, The Wall Street Journal reported that the United States Department of Energy, based on new intelligence, had shifted its view from "undecided" to "low confidence" that the pandemic originated with a lab leak. In the intelligence community, "low confidence" means the information is sourced to low-quality or otherwise untrustworthy sources. In the wake of these reports, FBI Director Christopher Wray reiterated the bureau's assessment, saying that the Government of China was doing its best to thwart any investigation. White House National Security Advisor Jake Sullivan responded to the report saying "some elements of the intelligence community have reached conclusions on one side, some on the other. A number of them have said they just don't have enough information to be sure", and there was still "no definitive answer" to the pandemic origins' question. The reassessment renewed the political debate around the issue in the US.
In June 2023, the Office of the Director of National Intelligence declassified their report on the virus' origins, in compliance with an Act of Congress compelling it to do so. The report stated that while the lab leak theory could not be ruled out, the overall assessment of the National Intelligence Council and a majority of IC assets (with low confidence) was that the pandemic most likely began as a zoonotic event. No evidence was found that SARS-CoV-2 or a progenitor virus existed in a laboratory, and there was no evidence of any biosafety incident. Proponents of the lab leak hypothesis reacted by accusing the agencies of conspiring with the Chinese, or of being incompetent. Covering the story for the Sydney Morning Herald, its science reporter Liam Mannix wrote that the US report marked the end of the lab leak case, and that it had ended "not with a bang, but a whimper".
In 2025, a CIA spokesperson said it assessed that the coronavirus is "more likely" to have leaked from a Chinese lab than to have come from animals, although the agency has "low confidence" in the conclusion. On April 18, 2025, the second administration of Donald Trump removed the online hub for federal COVID-19 resources, including COVID.gov and COVIDtests.gov, and redirected the domains to a whitehouse.gov landing page entitled "Lab Leak: The True Origins of COVID-19" endorsing the theory. Virologist Angela Rasmussen called the White House's website "pure propaganda, intended to justify the systematic devastation of... programs devoted to public health and biomedical research," and she said every claim made by the Trump administration was false or misleading.
=== Developments since 2022 ===
In June 2022, the WHO released a report advocating for more investigation into the lab leak theory. In response, Chinese Foreign Ministry spokesperson Zhao Lijian called the lab leak theory "a lie concocted by anti-China forces for political purposes, which has nothing to do with science".
In July 2022, two articles appeared in the journal Science analyzing all available epidemiological and genetic evidence from the earliest known cases in Wuhan. Based on two different analyses, the authors of both papers concluded that the outbreak began at the Huanan Seafood Wholesale Market and was unconnected to any laboratory. A third manuscript (a pre-print) examined RNA samples taken directly from the market in the spring of 2020 and detected SARS-CoV-2 RNA in environmental samples collected from animal stalls and sewage wells at the market. The RNA detected was highly similar to viruses which infected early outbreak patients who became sick after being present at the market. No virus was detected in any samples taken directly from animals at the market. University of Sydney virologist and co-author of both publications Edward C. Holmes commented that "The siren has definitely sounded on the lab leak theory" and "There's no emails. There's no evidence in any of the science. There's absolutely nothing".
== References ==
== Further reading ==
Kim JH, Park J (2023). "Perceived China Threat, Conspiracy Belief, and Public Support for Restrictive Immigration Control During the COVID-19 Pandemic". Race and Justice. 13 (1): 130–152. doi:10.1177/21533687221125818. PMC 9561504.
Komesaroff PA, Dwyer DE (September 2023). "The Question of the Origins of COVID-19 and the Ends of Science". J Bioeth Inq. 20 (4): 575–583. doi:10.1007/s11673-023-10303-1. PMC 10942872. PMID 37697176.
Zhu AL, Chen R, Rizzolo J, Qian J (June 2023). "Perceptions of COVID-19 origins and China's wildlife policy reforms". Glob Ecol Conserv. 43: e02463. Bibcode:2023GEcoC..4302463Z. doi:10.1016/j.gecco.2023.e02463. PMC 10076075. PMID 37069900.
== External links ==
Declassified report from the National Intelligence Council (Executive summary)
The Origins of COVID-19: an investigation of the Wuhan Institute of Virology – report by US House Foreign Affairs Committee Minority Staff
World Health Organisation report on the origins of COVID-19
=== Articles ===
Holmes, Eddie. The COVID ‘lab leak theory’ is dead: Researchers have confirmed the virus came from a Wuhan wet market. 15 Aug 2022. Royal Australian College of General Practitioners website.
Moore, John. The coronavirus lab leak hypothesis is damaging science, Aug. 2, 2024, Statnews website.
Qiu, Jane. Meet the scientist at the center of the covid lab leak controversy, February 9, 2022, MIT Technology Review. 8 June 2021
Maxmen, Amy. The COVID lab-leak hypothesis: what scientists do and don’t know: Nature examines arguments that the coronavirus SARS-CoV-2 escaped from a lab in China, and the science behind them. By Amy Maxmen & Smriti Mallapaty. June 8, 2021, Nature Magazine. | Wikipedia/COVID-19_lab_leak_theory |
A global energy crisis began in the aftermath of the COVID-19 pandemic in 2021, with much of the globe facing shortages and increased prices in oil, gas and electricity markets. The crisis was caused by a variety of economic factors, including the rapid post-pandemic economic rebound that outpaced energy supply, and escalated into a widespread global energy crisis following the Russian invasion of Ukraine. The price of natural gas reached record highs, and as a result, so did electricity in some markets. Oil prices hit their highest level since 2008.
Higher energy prices pushed families into poverty, forced some factories to curtail output or even shut down, and slowed economic growth. It was estimated in 2022 that an additional 11 million Europeans could be driven to poverty due to energy inflation. Europe's gas supply is uniquely vulnerable because of its historic reliance on Russia, while many emerging economies have seen higher energy import bills and fuel shortages.
== Causes ==
=== Slow supply recovery after pandemic ===
In 2020 the COVID-19 pandemic caused a rapid drop in energy demand and a corresponding cut in oil production, and despite the 2020 Russia–Saudi Arabia oil price war, OPEC responded slowly to the demand recovery under new normal, causing a supply-demand imbalance. The 2021–2023 global supply chain crisis further stressed the delivery of extracted petroleum.
Additionally, as Europe sought to replace Russian gas, it bid up prices of U.S., Australian, and Qatari ship-borne liquefied natural gas (LNG), diverting supply away from traditional LNG customers in Asia. Because gas frequently sets the price at which electricity is sold, power prices soared as well. Both LNG producers and importers rushed to build new infrastructure to increase LNG export/import capacity, but these costly projects take years to come online.
=== Coal trade dispute ===
In December 2020, after months of restrictions, China fully blocked coal imports from Australia, which was China's largest source of imported coal.
=== Climate abnormality impact on renewable energy ===
In 2021, Brazil's worst drought in almost a century threatened its electricity supply. Brazil relies on hydropower for two-thirds of its electricity.
Euractiv reported that European Commissioner for Climate Action Frans Timmermans told the European Parliament in Strasbourg that "about one fifth" of the energy price increase "can be attributed to rising CO2 pricing on the EU's carbon market".
In 2022, Europe's driest summer in 500 years had serious consequences for hydropower generation and power plant cooling systems. According to the New York Times, the drought "reduced hydropower in Norway, threatened nuclear reactors in France and crimped coal transport in Germany." Record droughts in China and California also threatened hydropower generation.
=== Russo-Ukrainian war ===
Russia is a leading producer and exporter of oil and gas. In 2020, it was the third largest oil producer in the world, behind the United States and Saudi Arabia, with 60% of its oil exports going to Europe. Russia is traditionally the world's second-largest producer of natural gas, behind the United States, and has the world's largest gas reserves and is the world's largest gas exporter. In 2021, the country produced 762 bcm of natural gas, and exported approximately 210 bcm via pipeline.
The Russian military buildup outside Ukraine and subsequent invasion threatened the energy supply from Russia to Europe. International sanctions were introduced after Russia's annexation of Crimea in 2014, and subsequently tightened after Russia invaded Ukraine in February 2022; the new Nord Stream 2 pipeline's certification was later suspended. Russia had already refused to increase exports to Europe before its invasion, and the state reacted to European sanctions by reducing gas deliveries to Germany through the Nord Stream 1 pipeline, which it fully halted in early September, although the pipelines continued to contain natural gas. Gas leaks in late September resulted in the pipes becoming inoperable. The United States, as former President Joe Biden had promised, with the help of Norway, set depth charges and ruptured three of the four Nord Stream pipelines on September 26, 2022, forcing much of Europe to pay three times the amount for American natural gas, but not able that winter to supply enough to heat all homes that needed it. [Source: Who Bombed the Nord Stream Pipeline?, Barry Barnett, Peace Press April-May 2023 @ pjcsoco.org-peacepress /> Other pipelines, such as the Druzhba pipeline, largely continued to operate.
=== OPEC supply restrictions ===
In October 2022, OPEC+ cut oil production by two million barrels per day. OPEC+ claimed it is trying to prevent price volatility, although some analysts believe the goal is to increase oil prices, which had decreased over the previous few months. Saudi Arabia's foreign ministry stated that the OPEC+ decision was "purely economic" and taken unanimously by all members of the conglomerate.
== Global effects ==
=== World food crises ===
Food prices increased steeply as Covid lockdowns were lifted and rose even higher following Russia's invasion of Ukraine, putting millions of people at risk. According to the World Food Programme, the number of people facing acute food insecurity more than tripled between 2017 and 2021, and could further increase by 17% to 323 million in 2022. The two countries together account for almost 30% of global wheat exports and play a key role in global fertiliser supply. Russia's blockade of Black Sea ports disrupted food and other commodity exports from Ukraine, while the broader military campaign put the 2022 harvest at risk.
Natural gas is a significant key component in producing fertilizers. The development of synthetic nitrogen fertilizer has significantly supported global population growth—it has been estimated that almost half of the world's population is currently fed as a result of synthetic nitrogen fertilizer use.
Rising energy prices are pushing agricultural costs higher, contributing to increasing food prices globally. The agriculture and food industries use energy for various purposes. Direct energy use includes electricity for automated water irrigation, fuel consumption for farm machinery and energy required at various stages of food processing, packaging, transportation and distribution. The use of pesticides and mineral fertilizers results in large quantities of indirect energy consumption, with these inputs being highly energy intensive to manufacture. While the share varies considerably between regions—depending on factors such as weather conditions and crop types—direct and non-direct energy costs can account for 40% to 50% of total variable costs of cropping in advanced economies such as the United States. Higher energy and fertiliser prices therefore inevitably translate into higher production costs, and ultimately into higher food prices.
In May 2022, Máximo Torero, chief economist at the U.N. Food and Agriculture Organization, warned European politicians that if they move away from natural gas production too soon, the price of fertilizers will rise and more people in the world will suffer from hunger.
In 2023, 64% of firms that took part in a survey on investment were concerned about energy prices, while 46% were concerned about regulatory frameworks and pricing instability. Businesses in Central, Southern and Eastern Europe reported a higher rate of energy consumption increases of 25% or more than the EU average (77% vs. 68%).
Energy savings and energy efficiency were most often mentioned as responses to the energy shock by businesses in Europe, but they were less likely to renegotiate their energy contracts. (62% vs. 67%).
=== Energy transition ===
Aside from inflationary pressures, this energy crisis has also increased the use of coal in energy production worldwide. Coal use in Europe increased by 14% in 2021, and was expected to rise another 7% in 2022. Soaring natural gas prices have made coal more competitive in many markets, and some nations have resorted to coal as a substitute for potential energy rationing in the 2022–2023 winter. With demand for coal increasing in Asia and elsewhere, global coal consumption rose by 1.2% in 2022 to more than 8 billion tonnes for the first time in history; coal-fired power plants have been reopened or had their decommissioning postponed, and coal-production caps have been removed. The high prices of fossil fuels due to the 2022 Russian invasion of Ukraine, however, have made renewable-energy sources more attractive, and a February 2023 analysis by The Economist found that the invasion had "fast-tracked the green transition by an astonishing five to ten years". In Europe and the US, the green transition is viewed as a danger by 41% of energy-intensive manufacturers, compared to 31% of enterprises in non-energy heavy industries.
In 2023, approximately 32% of EU enterprises have invested in new, climate friendly business sectors and technology, to stay up to date with the green transition. When compared to the United States, more European Union businesses invest in or implement renewable energy and sustainable transportation.
In 2023, 70% of EU enterprises expect energy prices to rise by more than a quarter, compared to only 30% of US firms. In the same year, results from a survey showed that 51% of EU enterprises polled invested in energy efficiency.
Energy prices continue to be a key issue for companies in the EU, with many citing it as a factor for potential investment cuts. With the increase in energy prices in the EU (as compared to 30% of US firms experiencing this), it would take over a decade for energy costs to stabilise at low levels. European enterprises will need to find strategies to cope.
== Responses ==
=== 2021 ===
Overall, the response to this rising crisis has been to return to coal and other polluting energy sources, subsidizing prices, easing gas taxes, or even lowering the price of carbon dioxide emissions. These short-term solutions lower electricity bills but go exactly in the opposite direction of what is needed to prevent the 1.5 degree increase in temperatures, increasing the likelihood of a climate apocalypse.
Europeans rushed to increase gas imports from producers such as Algeria, Norway and Azerbaijan. EU members also introduced gas storage obligations and agreed on voluntary targets to cut gas and electricity demand by 15% through efficiency measures, greater use of renewables, and support for efficiency improvements.
The UK government has turned to Qatar to seek a long-term gas deal to ensure a stable supply of liquefied natural gas (LNG) to the UK. Former Prime Minister Boris Johnson asked Sheikh Tamim bin Hamad Al Thani, the Emir of Qatar, for help during a meeting at the UN General Assembly in September 2021. EU suspended an antitrust investigation into QatarEnergy in February 2022.
In October 2021, U.S. producer Venture Global LNG signed three long-term supply deals with China's state-owned Sinopec to supply liquefied natural gas. China's imports of U.S. natural gas will more than double.
On 28 October 2021, natural gas prices in Europe dropped by at least 12% after Gazprom announced it would increase supplies to Europe after Russian domestic storage sites were filled on about 8 November. Norway had increased gas production and lower coal prices in China also helped lower natural gas prices.
Hungarian Prime Minister Viktor Orbán blamed a record-breaking surge in energy prices on the European Commission's Green Deal plans. Politico reported that "Despite the impact of high energy prices, [EU Commissioner for Energy] Kadri Simson insisted that there are no plans to backtrack on the bloc's Green Deal, which aims to make the EU climate neutral by 2050." Speaking at the COP26 climate summit in Glasgow, Czech Prime Minister Babiš denounced the European Green Deal, saying that the European Commission "continues to propose dangerous policies such as the ban on combustible engines in 2035, or carbon allowances for transport and individual housing. Due to improper legislature and speculation, the price of emission allowances has gone out of control, resulting in the surging costs of electricity."
U.S. President Joe Biden's national security adviser Jake Sullivan released a statement calling on OPEC+ to boost oil production to "offset previous production cuts that OPEC+ imposed during the pandemic until well into 2022." On 28 September 2021, Sullivan met in Saudi Arabia with Saudi Crown Prince Mohammed bin Salman to discuss the high oil prices. The price of oil was about US$80 by October 2021, the highest since 2014. The United States delivered 16 billion cubic meters of LNG to Europe in January 2022, and 6 billion in February.
Iranian oil minister Javad Owji said if U.S.-led sanctions on Iran's oil and gas industry are lifted, Iran will have every capability to tackle the global energy crisis. The Biden administration was pressed on potential oil deals with Saudi Arabia, Venezuela, and Iran that would have them increase their oil production.
Qatar's energy minister Saad Sherida al-Kaabi stated that there "is a huge demand from all our customers, and unfortunately we cannot cater for everybody. Unfortunately, in my view, this is due to the market not investing enough in the [gas] industry."
European Commission President Ursula von der Leyen said that "Europe today is too reliant on gas and too dependent on gas imports. The answer has to do with diversifying our suppliers ... and, crucially, with speeding up the transition to clean energy."
European Commissioner for Climate Action Frans Timmermans suggested: "the best answer to this problem today is to reduce our reliance on fossil fuels."
In late October 2021, Russian ambassador Andrei Kelin denied that Russia is withholding gas supplies for political reasons. According to the ambassador, delivery of natural gas through Ukraine has been increased by up to 15% for November 2021, but it was unclear whether this increase would have an immediate effect on the natural gas supply in Europe. Furthermore, such an increase in gas delivery was hindered by a lack of modernization of the Ukrainian gas pipelines, according to the source.
=== 2022 ===
In the first collective action following the invasion, agreed on 1 March 2022, IEA member countries committed to release 62.7 million barrels of emergency oil stocks. On 1 April, they agreed to make a further 120 million barrels available from emergency reserves, the largest stock release in the IEA's history, which coincided with the release of additional barrels from the U.S. Strategic Petroleum Reserve. The two coordinated drawdowns in 2022 are the fourth and fifth in the history of the IEA, which was created in 1974. Previous collective actions were taken in 1991, 2005 and 2011.
The IEA has also published action plans to cut oil use with immediate impact, as well as plans for how Europe can reduce its reliance on Russian gas and how common citizens can reduce their energy consumption. This includes a 10-point action plan to reduce the EU's reliance on Russian Natural Gas.
German chancellor Olaf Scholz announced plans to build two new LNG terminals. Economy Minister Robert Habeck said Germany reached a long-term energy partnership with Qatar, one of the world's largest exporters of liquefied natural gas. Habeck said Germany plans to end imports of Russian natural gas by mid-2024. In May 2022, the European Commission proposed and approved a partial ban on oil imports from Russia, part of the economic response to the Russian invasion of Ukraine. On 18 May 2022, the European Union published plans to end its reliance on Russian oil, natural gas and coal by 2027.
On 13 July 2022, the Kremlin expressed hope that a visit by President Biden to Saudi Arabia to boost OPEC oil production would not foster anti-Russian sentiments there. Russia is the largest oil and gas exporter after Saudi Arabia and enjoys a highly valued cooperation with the Arab country in the framework of the OPEC group. But at current levels, major Gulf producers have little to spare, and Russia blames international sanctions for higher energy prices around the world.
Since the June 2022 G7 meeting, plans had been circulating to cap the price of Russian energy commodities as initially suggested by U.S. Treasury Secretary Janet Yellen and E.U. Commission President Ursula von der Leyen, in order to lower price levels for Western nations and deprive Russia of its profits. After G7 finance ministers expressed their intention to implement a price cap, a Kremlin spokesman responded, "companies that impose a price cap will not be among the recipients of Russian oil." Energy analysts have also expressed skepticism that a price cap would be realistic because the coalition is "not broad enough"; OPEC+ called the plan "absurd". Likely the U.S. and the E.U. will attempt to follow through with the plan by limiting Russia's access to Western insurance services.
In June 2022, the United States government agreed to allow Italian company Eni and Spanish company Repsol to import oil from Venezuela to Europe to replace oil imports from Russia. French Finance Minister Bruno Le Maire said that France negotiated with the United Arab Emirates to replace some Russian oil imports.
Additionally, on 15 June 2022, Israel, Egypt and the European Union signed a trilateral agreement to increase natural-gas sales to European countries seeking alternative sources to lessen their dependence on Russian energy supplies. In July 2022, the European Commission signed an agreement with Azerbaijan to increase natural gas imports.
In August 2022, policy specialists at the International Monetary Fund recommended that governments institute windfall profits taxes targeted at economic rents in the energy sector, excluding renewable energy to prevent hindering its further development.
On 29 September 2022, Germany presented a €200 billion plan to support industry and households. German Economy Minister Robert Habeck complained that the United States and other "friendly" gas supplier nations were profiting from the Ukraine war with "astronomical prices". He called for more solidarity by the U.S. to assist energy-pressed allies in Europe. French President Emmanuel Macron criticized the United States, Norway and other "friendly" natural gas supplier states for the extremely high prices of their supplies, saying that Europeans are "paying four times more than the price you sell to your industry. That is not exactly the meaning of friendship." For most of the time over the past ten years, the German spot price for electricity has been below €40 per MWh. Spot prices have increased to over €200 on average in 2022.
Natural gas prices in Europe reached their highest point in September 2022 at a multiple of roughly 25 compared to two years prior. While gas prices are currently falling quickly on the spot market, the cost to distribute gas in the coming year will still be close to €150 per MWh, or a multiple of about seven.
According to the IEA, approximately 100 million people with access to clean cooking may switch back to unhealthy cooking, and 75 million people who had recently gained access to electricity may no longer be able to afford it.
In general, many residents can no longer pay their energy expenses. Governments throughout Europe have responded—according to Bruegel, €674 billion have been set aside, with €264 billion going to Germany alone, to protect businesses and consumers from rising energy costs.
The Wilhelmshaven LNG terminal—the first of several new German LNG terminals being opened with an abbreviated regulatory process following the Russian invasion of Ukraine—received its first load of LNG in mid-December to initiate the commissioning process of the new terminal. The shipment was of US natural gas that had been carried from the recently opened Venture Global LNG terminal in Louisiana.
== EU emergency intervention ==
Since the last months of 2021 and until now, Europe has experienced an unprecedented increase in gas and energy automation, especially after Russia invaded Ukraine, where Russia has reduced its gas production and exports to EU countries. Russia is considered the most important supplier of the European Union in terms of natural gas, oil, and coal. Still, relations between the European Union and Russia have experienced great tension after the position of the European Union and member states on the Russian invasion of Ukraine. According to the Council of the European Union, the EU decided to ban coal imports from Russia in August 2022 and has denied 90% of Russian oil imports since September 2022. The EU has focused 3.5% of its income to oil and gas productions in the beginning of the Ukraine war.
This contention between Russia and the European Union has led to an increase in the price of gas and electricity. European citizens pay this higher price to meet their daily needs, and the industrial and commercial enterprises that use energy to produce their products, which will lead to an increase in the rate of inflation in Europe, higher prices, a decline in the purchasing power of citizens, and hence the contraction of the European economy. High oil prices have driven a depreciation in the euro and imported inflation.
In this regard, the European Union is facing a great challenge and pressure from European consumers and small and medium-sized enterprises (SMEs) to find solutions to reduce the effects of this crisis. Therefore, the European Commission proposes measures and urgent actions to reduce the cost of bills and protect consumers and businesses. 82% of EU firms are worried about the energy crisis, with 60% of businesses seeing it as a major issue. According to a survey conducted in 2022, significant uncertainty also reduces investment in energy efficiency by 4 percentage points. This is magnified when climate investments are included.
An example of the sharp increase in energy and food prices since Russia's invasion of Ukraine is the proportion of energy-poor German households—those that spend more than 10% of their net income on energy bills—which has doubled since 2021 to 41%.
=== Decoupling of gas and electricity prices ===
The debate has intensified in Europe on mechanisms to reform the energy and electricity market in the face of this crisis. One proposed solution is separating gas prices from electricity prices. As European Commission President, Ursula von der Leyen stated in her 2022 State of the Union Address: “The current design of the electricity market no longer does justice to consumers. They should reap the benefits of low-cost renewable energy sources. Therefore, we need to separate the dominant influence of gas on the price of electricity. That is why we are undertaking a deep and comprehensive electricity market reform.”
Indeed, in April this year, Spain and Portugal obtained preliminary approval from the European Commission to set a maximum gas price of 50 euros/MWh for an entire year. This decision and violation of European market rules were justified because Spain and Portugal can get gas from North African pipelines and therefore do not depend primarily on Russian gas, which places them in a safe position. Portugal had 1–3% increase in electricity prices, limited partially due to high levels of domestic sources such as hydropower, solar and wind.
However, the European Commission has yet to decide on this issue, despite numerous suggestions from member states such as Greece.
European customers have proved that price signals can be useful by voluntarily reducing their gas consumption by 23% in August and 7% overall so far in 2022 compared to the average over the previous three years.
=== Electricity demand reduction ===
The European Commission and the EU member states work together and individually on possible ways to keep gas and energy available in the EU for the winter of 2022 and the future.
According to Marc-Antoine Eyl-Mazzega, the director of the energy and climate center at the French institute for international relations, Europe is no longer the continent of stability and peace it once was. It now has the highest energy cost prices compared to the rest of the world, and strategic competitors now have an advantage over European players.
In August 2022, a regulation has passed under which member states agreed to reduce their demand for gas by 15%. This could be implemented with measures suitable to them. Although the adoption of this regulation was voluntary, the European council can reduce the demand for gas mandatory when running on security supplies.
Cutting energy consumption is a crucial topic of discussion and debate in Europe. The European Parliament, alongside other key EU institutions, has pledged to reduce heating to conserve power. For example, offices of the European Commission have reduced their heating and humidification temperatures by 2 °C.
EU member states have adopted a regulation to fill gas storage and share them in a spirit of solidarity. Although the EU countries face this crisis together as a bloc, the stake is different for each country. Countries with a higher import and use of Russian gas will be affected significantly more than those with less import and dependency.
The European Commission proposed the REPowerEU plan to reduce the EU's dependency on Russian energy supplies by fast-forwarding the clean energy transition of the EU. The Commission outlined a concept that will contribute to the acceleration of the EU energy transition by scaling up the deployment of Hydrogen known as the Hydrogen accelerator concept. This plan aims to produce and import 10 million tons of renewable Hydrogen respectively in the EU by 2030 (REPowerEU).
In a note highlighting short-term actions that can relieve the energy situation, the president of the EU commission and its members conveyed mission areas in which member states should act. A regulation to fill gas storages, diversify the supply sources of energy and commit to reducing the demand for energy by 15 percent EU member states have adopted this winter. With this, the underground gas reserves of the EU are filled to 83 percent of their capacity.
=== Solidarity contribution ===
Power generation companies and companies operating in the fossil fuel sector have enjoyed windfall profits due to the current European market situation, which has led the European Commission to impose mandatory contributions on these companies as a temporary measure to limit the impact of the crisis.
The special temporary tax will be calculated on taxable profits during the year 2022 and at the rate of no less than 33% of excess profits in the oil, gas, coal, and refining sectors. These solidarity contributions will help alleviate the severity of the current crisis. These contributions will be redistributed to all European consumers, including low-income families in the Member States, SMEs, and energy-intensive companies.
== See also ==
Price controls
9-Euro-Ticket
1970s energy crisis
Economic impact of the COVID-19 pandemic
Energy crisis
Energy democracy
Energy subsidy
Energy transition
Fossil fuel phase-out
German economic crisis (2022–present)
2022–2023 global food crises
2021–2023 inflation surge
2021–2023 global supply chain crisis
International sanctions during the Russian invasion of Ukraine
2020s commodities boom
2022–2023 Russia–European Union gas dispute
2020–2022 world oil market chronology
Strategic natural gas reserve
Lukoil oil transit dispute
== References ==
== Sources ==
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from IEA Global Energy Crisis, International Energy Agency, International Energy Agency.
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from Russia's War on Ukraine, International Energy Agency. International Energy Agency.
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from How the energy crisis is exacerbating the food crisis, International Energy Agency.
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from A 10-point plan to reduce the European Union's reliance on Russian natural gas, International Energy Agency. | Wikipedia/2021–2023_global_energy_crisis |
The Daily Telegraph, known online and elsewhere as The Telegraph, is a British daily broadsheet conservative newspaper published in London by Telegraph Media Group and distributed in the United Kingdom and internationally. It was founded by Arthur B. Sleigh in 1855 as The Daily Telegraph and Courier. The Telegraph is considered a newspaper of record in the UK. The paper's motto, "Was, is, and will be", was included in its emblem which was used for over a century starting in 1858.
In 2013, The Daily Telegraph and The Sunday Telegraph, which started in 1961, were merged, although the latter retains its own editor. It is politically conservative and supports the Conservative Party. It was moderately liberal politically before the late 1870s.
The Telegraph has had a number of news scoops, including the outbreak of World War II by rookie reporter Clare Hollingworth, described as "the scoop of the century", the 2009 parliamentary expenses scandal – which led to a number of high-profile political resignations and for which it was named 2009 British Newspaper of the Year – its 2016 undercover investigation on the England football manager Sam Allardyce, and the Lockdown Files in 2023.
In May 2025, investment management firm RedBird Capital Partners announced plans to acquire the newspaper's publisher for £500 million (about $674 million).
== History ==
=== Founding and early history ===
The Daily Telegraph and Courier was founded by Colonel Arthur B. Sleigh in June 1855 to air a personal grievance against the future commander-in-chief of the British Army, Prince George, Duke of Cambridge. Joseph Moses Levy, the owner of The Sunday Times, agreed to print the newspaper, and the first edition was published on 29 June 1855. The paper cost 2d and was four pages long. Nevertheless, the first edition stressed the quality and independence of its articles and journalists: "We shall be guided by a high tone of independent action." As the paper was not a success, Sleigh was unable to pay Levy the printing bill.
Levy took over the newspaper, his aim being to produce a cheaper newspaper than his main competitors in London, the Daily News and The Morning Post, to expand the size of the overall market. Levy appointed his son, Edward Levy-Lawson, Lord Burnham, and Thornton Leigh Hunt to edit the newspaper. Lord Burnham relaunched the paper as The Daily Telegraph, with the slogan "the largest, best, and cheapest newspaper in the world". Hunt laid out the newspaper's principles in a memorandum sent to Levy: "We should report all striking events in science, so told that the intelligent public can understand what has happened and can see its bearing on our daily life and our future. The same principle should apply to all other events—to fashion, to new inventions, to new methods of conducting business".
In 1876, Jules Verne published his novel Michael Strogoff, whose plot takes place during a fictional uprising and war in Siberia. Verne included among the book's characters a war correspondent of The Daily Telegraph, named Harry Blount—who is depicted as an exceptionally dedicated, resourceful and brave journalist, taking great personal risks to follow closely the ongoing war and bring accurate news of it to The Telegraph's readership, ahead of competing papers.
=== 1901 to 1945 ===
In 1908, The Daily Telegraph printed an article in the form of an interview with Kaiser Wilhelm II of Germany that damaged Anglo-German relations and added to international tensions in the build-up to World War I. In 1928, the son of Baron Burnham, Harry Lawson Webster Levy-Lawson, 2nd Baron Burnham, sold the paper to William Berry, 1st Viscount Camrose, in partnership with his brother Gomer Berry, 1st Viscount Kemsley and Edward Iliffe, 1st Baron Iliffe.
In 1937, the newspaper absorbed The Morning Post, which traditionally espoused a conservative position and sold predominantly amongst the retired officer class. Originally William Ewart Berry, 1st Viscount Camrose, bought The Morning Post with the intention of publishing it alongside The Daily Telegraph, but poor sales of the former led him to merge the two. For some years, the paper was retitled The Daily Telegraph and Morning Post before it reverted to just The Daily Telegraph.
In the late 1930s, Victor Gordon Lennox, The Telegraph's diplomatic editor, published an anti-appeasement private newspaper The Whitehall Letter that received much of its information from leaks from Sir Robert Vansittart, the Permanent Under-Secretary of the Foreign Office, and Rex Leeper, the Foreign Office's Press Secretary. As a result, Gordon Lennox was monitored by MI5. In 1939, The Telegraph published Clare Hollingworth's scoop that Germany was to invade Poland.
In November 1940, Fleet Street, with its close proximity to the river and docklands, was subjected to almost daily bombing raids by the Luftwaffe and The Telegraph started printing in Manchester at Kemsley House (now The Printworks entertainment venue), which was run by Camrose's brother Kemsley. Manchester quite often printed the entire run of The Telegraph when its Fleet Street offices were under threat. The name Kemsley House was changed to Thomson House in 1959. In 1986, printing of Northern editions of the Daily and Sunday Telegraph moved to Trafford Park and in 2008 to Newsprinters at Knowsley, Liverpool.
During the Second World War, The Daily Telegraph covertly helped in the recruitment of code-breakers for Bletchley Park. The ability to solve The Telegraph's crossword in under 12 minutes was considered to be a recruitment test. The newspaper was asked to organise a crossword competition, after which each of the successful participants was contacted and asked if they would be prepared to undertake "a particular type of work as a contribution to the war effort". The competition itself was won by F. H. W. Hawes of Dagenham who finished the crossword in less than eight minutes.
=== 1946 to 1985 ===
Both the Camrose (Berry) and Burnham (Levy-Lawson) families remained involved in management until Conrad Black took control in 1986. On the death of his father in 1954, Seymour Berry, 2nd Viscount Camrose assumed the chairmanship of the Daily Telegraph with his brother Michael Berry, Baron Hartwell as his editor-in-chief. During this period, the company saw the launch of sister paper The Sunday Telegraph in 1960.
=== 1986 to 2004 ===
Canadian businessman Conrad Black, through companies controlled by him, bought the Telegraph Group in 1986. Black, through his holding company Ravelston Corporation, owned 78% of Hollinger Inc. which in turn owned 30% of Hollinger International. Hollinger International in turn owned the Telegraph Group and other publications such as the Chicago Sun-Times, the Jerusalem Post and The Spectator.
On 18 January 2004, Black was dismissed as chairman of the Hollinger International board over allegations of financial wrongdoing. Black was also sued by the company. Later that day, it was reported that the Barclay brothers had agreed to purchase Black's 78% interest in Hollinger Inc. for £245m, giving them a controlling interest in the company, and to buy out the minority shareholders later. However, a lawsuit was filed by the Hollinger International board to try to block Black from selling his shares in Hollinger Inc. until an investigation into his dealings was completed. Black filed a countersuit but, eventually, United States judge Leo Strine sided with the Hollinger International board and blocked Black from selling his Hollinger Inc. shares to the twins.
On 7 March 2004, the twins announced that they were launching another bid, this time just for The Daily Telegraph and its Sunday sister paper rather than all of Hollinger Inc. The then owner of the Daily Express, Richard Desmond, was also interested in purchasing the paper, selling his interest in several pornographic magazines to finance the initiative. Desmond withdrew in March 2004, when the price climbed above £600m, as did Daily Mail and General Trust plc a few months later on 17 June.
=== Since 2004 ===
In November 2004, The Telegraph celebrated the tenth anniversary of its website, Electronic Telegraph, now renamed www.telegraph.co.uk. The Electronic Telegraph launched in 1995 with The Daily Telegraph Guide to the Internet by writer Sue Schofield for an annual charge of £180.00. On 8 May 2006, the first stage of a major redesign of the website took place, with a wider page layout and greater prominence for audio, video and journalist blogs.
On 10 October 2005, The Daily Telegraph relaunched to incorporate a tabloid sports section and a new standalone business section. The Daily Mail's star columnist and political analyst Simon Heffer left that paper in October 2005 to rejoin The Daily Telegraph, where he has become associate editor. Heffer has written two columns a week for the paper since late October 2005 and is a regular contributor to the news podcast. In November 2005, the first regular podcast service by a newspaper in the UK was launched. Just before Christmas 2005, it was announced that The Telegraph titles would be moving from Canada Place in Canary Wharf, to new offices at Victoria Plaza at 111 Buckingham Palace Road near Victoria Station in central London. The new office features a "hub and spoke" layout for the newsroom to produce content for print and online editions.
In October 2006, with its relocation to Victoria, the company was renamed the Telegraph Media Group, repositioning itself as a multimedia company. On 2 September 2008, the Daily Telegraph was printed with colour on each page for the first time when it left Westferry for Newsprinters at Broxbourne, Hertfordshire, another arm of the Murdoch company. The paper is also printed in Liverpool and Glasgow by Newsprinters. In May 2009, the daily and Sunday editions published details of MPs' expenses. This led to a number of high-profile resignations from both the ruling Labour administration and the Conservative opposition.
In June 2014, The Telegraph was criticised by Private Eye for its policy of replacing experienced journalists and news managers with less-experienced staff and search engine optimisers.
On 26 October 2019, the Financial Times reported that the Barclay Brothers were about to put the Telegraph Media Group up for sale. The Financial Times also reported that the Daily Mail and General Trust (owner of the Daily Mail, The Mail on Sunday, Metro and Ireland on Sunday) would be interested in buying.
The Daily Telegraph supported Liz Truss in the July–September 2022 Conservative Party leadership election.
In July 2023, it was announced that Lloyds Banking Group had appointed Mike McTighe as chairman of Press Acquisitions Limited and May Corporation Limited in order to spearhead the sale of The Telegraph and The Spectator.
==== Accusation of news coverage influence by advertisers ====
In July 2014, the Daily Telegraph was criticised for carrying links on its website to pro-Kremlin articles supplied by a Russian state-funded publication that downplayed any Russian involvement in the downing of the passenger jet Malaysia Airlines Flight 17. These had featured on its website as part of a commercial deal, but were later removed.
As of 2014, the paper was paid £900,000 a year to include the supplement Russia Beyond the Headlines, a publication sponsored by the Rossiyskaya Gazeta, the Russian government's official newspaper.
In February 2015, the chief political commentator of the Daily Telegraph, Peter Oborne, resigned. Oborne accused the paper of a "form of fraud on its readers" for its coverage of the bank HSBC in relation to a Swiss tax-dodging scandal that was widely covered by other news media. He alleged that editorial decisions about news content had been heavily influenced by the advertising arm of the newspaper because of commercial interests. Jay Rosen at New York University stated that Oborne's resignation statement was "one of the most important things a journalist has written about journalism lately".
Oborne cited other instances of advertising strategy influencing the content of articles, linking the refusal to take an editorial stance on the repression of democratic demonstrations in Hong Kong to the Telegraph's support from China. Additionally, he said that favourable reviews of the Cunard cruise liner Queen Mary II appeared in the Telegraph, noting: "On 10 May last year The Telegraph ran a long feature on Cunard's Queen Mary II liner on the news review page. This episode looked to many like a plug for an advertiser on a page normally dedicated to serious news analysis. I again checked and certainly Telegraph competitors did not view Cunard's liner as a major news story. Cunard is an important Telegraph advertiser."
In response, the Telegraph called Oborne's statement an "astonishing and unfounded attack, full of inaccuracy and innuendo". Later that month, Telegraph editor Chris Evans invited journalists at the newspaper to contribute their thoughts on the issue. Press Gazette reported later in 2015 that Oborne had joined the Daily Mail tabloid newspaper and The Telegraph had "issued new guidelines over the way editorial and commercial staff work together".
In January 2017, the Telegraph Media Group had a higher number of upheld complaints than any other UK newspaper by its regulator IPSO. Most of these findings pertained to inaccuracy, as with other UK newspapers.
In October 2017, a number of major western news organisations whose coverage had irked Beijing were excluded from Xi Jinping's speech event launching a new politburo. However, the Daily Telegraph had been granted an invitation to the event.
In April 2019, Business Insider reported The Telegraph had partnered with Facebook to publish articles "downplaying 'technofears' and praising the company".
==== Premature obituaries ====
The paper published premature obituaries for Cockie Hoogterp, the second wife of Baron Blixen, Dave Swarbrick in 1999, and Dorothy Southworth Ritter, the widow of Tex Ritter and mother of John Ritter, in August 2001.
==== Accusation of antisemitism ====
Editors for both the Daily Telegraph and the Sunday Telegraph have been criticised by Guardian columnist Owen Jones for publishing and authoring articles which espouse Cultural Marxism, an antisemitic conspiracy theory. In 2018, Allister Heath, the editor of the Sunday Telegraph wrote that "Cultural Marxism is running rampant." Assistant comment editor of the Daily Telegraph Sherelle Jacobs also used the term in 2019. The Daily Telegraph also published an anonymous civil servant who stated: "There is a strong presence of Anglophobia, combined with cultural Marxism that runs through the civil service."
==== False allegations of Islamic extremism ====
In January 2019, the paper published an article written by Camilla Tominey titled "Police called in after Scout group run from mosque is linked to Islamic extremist and Holocaust denier" in which it was reported that the police were investigating Ahammed Hussain, the Leader of the Scout Group at the Lewisham Islamic Centre, because he had links to extremist Muslim groups that promoted terrorism and antisemitism.
In January 2020, the paper issued an official apology and accepted that the article contained many falsehoods, and that Hussain had never supported or promoted terrorism, or been antisemitic. The paper paid Hussain damages and costs. In a letter sent to Hussain's lawyers accompanying the text of their published apology, the newspaper's lawyers wrote: "The article was published by our client following receipt of information in good faith from the Scout Association and the Henry Jackson Society; nevertheless our client now accepts that the article (using that expression to refer to both print and online versions) is defamatory of your client and will apologise to him for publishing it."
==== China Watch ====
In 2016, the Hong Kong Free Press reported that The Daily Telegraph was receiving £750,000 annually to carry a supplement called 'China Watch' as part of a commercial deal with Chinese state-run newspaper China Daily. The Guardian reported in 2018 that the China Watch supplement was being carried by The Telegraph along with other newspapers of record such as The New York Times, The Wall Street Journal and Le Figaro. The Telegraph published the supplement once a month in print, and published it online at least until March 2020.
In April 2020, The Telegraph removed China Watch from its website, along with another advertisement feature section by Chinese state-run media outlet People's Daily Online. The paper had run many pieces critical of China since the start of the COVID-19 pandemic.
==== COVID-19 misinformation ====
In January 2021, the British press regulator, the Independent Press Standards Organisation, ordered The Daily Telegraph to publish a correction to two "significantly misleading" claims in a comment article published by Toby Young. The July 2020 article "When we have herd immunity Boris will face a reckoning on this pointless and damaging lockdown," which spread COVID-19 misinformation that the common cold provided "natural immunity" to COVID-19 and that London was "probably approaching herd immunity". The regulator said that a correction was appropriate rather than a more serious response due to the level of scientific uncertainty at the time the comment was published. At the time of the ruling, The Telegraph had removed the comment article but had not issued a correction.
==== Climate change ====
The Telegraph has published multiple columns and news articles which promote pseudoscientific views on climate change, and misleadingly cast the subject of climate change as a subject of active scientific debate when there is a scientific consensus on climate change. It has published columns about the "conspiracy behind the Anthropogenic Global Warming myth", described climate scientists as "white-coated prima donnas and narcissists," and claimed that "global warming causes about as much damage as benefits." In 2015, a Telegraph news article incorrectly claimed that scientists predicted a mini-ice age by 2030. Climate change denying journalist James Delingpole was first to use "Climategate" on his Telegraph blog for a manufactured controversy where emails were leaked from climate scientists ahead of the Copenhagen climate summit and misleadingly presented to give the appearance that the climate scientists were engaged in fraud.
In 2014, The Telegraph was one of several media titles to give evidence to the House of Commons Select Committee 'Communicating climate science'. The paper told MPs they believe climate change is happening and humans play a role in it. Editors told the committee, "we believe that the climate is changing, that the reason for that change includes human activity, but that human ingenuity and adaptability should not be ignored in favour of economically damaging prescriptions."
In November 2023, the journalist and climate activist group DeSmog published its judgments for coverage of environmental topics in 171 of The Telegraph's opinion pieces from April to October 2023. DeSmog stated that of these 171 pieces, 85 per cent were categorized as "anti-green", defined as "attacking climate policy, questioning climate science and ridiculing environmental groups."
==== Owen Paterson ====
The Daily Telegraph, in particular its columnist and former editor Charles Moore, were staunch supporters of Owen Paterson, a former MP and minister who resigned after it was found that he had breached advocacy rules to lobby ministers for fees. A plan to overhaul the Commons standard and spare Paterson from being suspended and a possible recall petition that follows was leaked to the newspaper and it was "approvingly" splashed across the paper's front page. Boris Johnson flew back from the COP 26 summit in Glasgow to attend a Telegraph journalists' reunion at the Garrick and left the club with Moore the same evening.
==== 2023–2024 takeover bid ====
In June 2023, The Guardian and other newspapers reported that, following a breakdown in discussions relating to a financial dispute, Lloyds Bank was planning to take control of the companies owning the Telegraph titles and the Spectator and sell them off. Representatives of the Barclay family have described the reports as "irresponsible". By 20 October, a sale of the publications had been initiated after bankers seized control. Lloyds appointed receivers and started shopping the brands to bidders.
By November, it was revealed that the bid had been agreed upon by RedBird IMI, a joint venture between RedBird Capital Partners and International Media Investments, a firm based in the United Arab Emirates and owned by Sheikh Mansour bin Zayed Al Nahyan. The bid would see the firm take over The Telegraph, while allowing the Barclay family to repay a debt of £1.2 billion to Lloyds Bank. Conservative MPs raised national security concerns, and pushed the government to investigate the bid, as the United Arab Emirates had a poor reputation for freedom of speech. Culture secretary Lucy Frazer issued a public interest intervention notice on 30 November, preventing the group from taking over without further scrutiny from the media regulator Ofcom over potential breaches of media standards. Conservative MPs also called on Deputy Prime Minister Oliver Dowden to use the National Security and Investment Act 2021 to investigate the Emirati-backed bid.
Chairman Andrew Neil threatened to quit if the sale was approved, saying: "You cannot have a major mainstream newspaper group owned by an undemocratic government or dictatorship where no one has a vote." Fraser Nelson, editor of The Spectator, which would be included in the sale, also opposed the move, saying, "the very reason why a foreign government would want to buy a sensitive asset is the very reason why a national government should be wary of selling them."
In March 2024, the Lords voted in a new law, under which restrictions were imposed on foreign governments regarding the ownership of British newspapers and magazines, including only being allowed up to a 0.1 per cent stake. In April 2024, the UK government effectively banned RedBird IMI from taking over The Telegraph and The Spectator by introducing new laws which prevented foreign governments from owning British newspapers. RedBird also confirmed it would withdraw its takeover plans, saying they were "no longer feasible".
In April 2024, RedBird IMI confirmed to put up The Telegraph for sale again and to begin open auction. However, the Abu Dhabi fund suggested that it seek to recoup the £600 million it spent acquiring the newspaper, or will otherwise retain some involvement. The Telegraph was left in limbo, as the staff remained blocked from taking strategic decisions. The owner of The New York Sun, Dovid Efune came up as a leading bidder, but struggled to take over the paper. The Columbia Journalism Review dubbed it as “the newspaper auction from hell”.
On 17 January 2025, David Castelblanco, a partner at the Abu Dhabi fund RedBird, urged The Telegraph to make significant job cuts, including over 100 non-editorial roles. He also advised the executives to halt planned editorial investments, which included expansions of the U.S. newsroom. The intervention was likely to raise concerns about foreign interference and fuels fears of foreign influence in the decision-making process of The Telegraph. On 19 January, Sir Iain Duncan Smith stated that the UAE shouldn’t be allowed to acquire the British newspaper. He also accused the UK government of “foot-dragging” the process due to fear of upsetting the Emirates, and asked for an explanation about the Digital Markets, Competition and Consumers Act 2024. Sir Ed Davey also called for the Cultural Secretary Lisa Nandy to set a deadline for The Telegraph’s sale, and urged the ministers to ensure that the Abu Dhabi fund is “not improperly meddling in the meantime”.
== Circulation ==
It had a circulation of 270,000 in 1856, and 240,000 in 1863. It had a circulation of 1,393,094 in 1968, and 1,358,875 in 1978. It had a circulation of 1,439,000 in 1980, and 1,235,000 in 1984. It had a circulation of 1,133,173 in 1988. The paper had a circulation of 363,183 in December 2018, not including bulk sales. It descended further until it withdrew from newspaper circulation audits in 2020. The bulk of its readership has moved online; the Telegraph Media Group reported a subscription number of 1,035,710 for December 2023, composed of 117,586 for its print edition, 688,012 for its digital version and 230,112 for other subscriptions.
== Political stance ==
The Daily Telegraph supported Whig, and moderate liberal ideas, before the late 1870s. The Daily Telegraph is politically conservative and has endorsed the Conservative Party at every UK general election since 1945. The personal links between the paper's editors and the leadership of the Conservative Party, along with the paper's generally right-wing stance and influence over Conservative activists, have led the paper commonly to be referred to, especially in Private Eye, as the Torygraph.
When the Barclay brothers purchased the Telegraph Group for around £665 million in late June 2004, Sir David Barclay suggested that The Daily Telegraph might no longer be the "house newspaper" of the Conservatives in the future. In an interview with The Guardian, he said: "Where the government are right we shall support them." The editorial board endorsed the Conservative Party in the 2005 general election. During the 2014 Scottish independence referendum, the paper supported the Better Together 'No' Campaign. Alex Salmond, the former leader of the SNP, called The Telegraph "extreme" on Question Time in September 2015. In the 2016 United Kingdom European Union membership referendum, it endorsed voting to leave the EU.
In December 2015, The Daily Telegraph was fined £30,000 for "sending an unsolicited email to hundreds of thousands of its subscribers, urging them to vote for the Conservatives." During the 2019 Conservative Party leadership election, The Daily Telegraph endorsed their former columnist Boris Johnson. In 2019, former columnist Graham Norton, who had left the paper in late 2018, said "about a year before I left, it took a turn" and criticised it for "toxic" political stances, namely for a piece defending US Supreme Court then-nominee Brett Kavanaugh and for being "a mouthpiece for Boris Johnson" whose columns were allegedly published with "no fact-checking at all".
=== LGBT+ rights ===
In 2012, prior to the legalisation of same-sex marriage in the United Kingdom, Telegraph View published an editorial stating that it was a "pointless distraction" as "many [gay couples] already avail themselves of the civil partnerships introduced by Labour". The Telegraph wrote in another editorial that same year that it feared that changing "the law on gay marriage risks inflaming anti-homosexual bigotry".
In 2015, the newspaper published an article by former editor Charles Moore claiming a "gay rights sharia" was dictating what the LGBT+ community should believe, following Dolce & Gabbana's openly gay founders criticising gay adoptions. Moore wrote: "If you are gay, Mr Strudwick seemed to assert, there are certain things you must believe. Nothing else is permitted under the gay rights sharia." Moore has previously expressed his views that civil partnerships achieved a "balance" for heterosexual and homosexual couples. In 2013, he wrote: "Respectable people are truly terrified of being thought anti-homosexual. In a way, they are right to be, because attacking people for their personal preferences can be a nasty thing."
Also in 2015, The Telegraph published its "Out at Work" list, naming "the top 50 list of LGBT executives". Since then, The Telegraph appeared to shift towards a more liberal attitude on LGBT+ issues, publishing articles that then-Prime Minister Theresa May needed to be "serious about LGBT equality" and that "bathroom bills" in Texas – which were criticised as being transphobic – were "a Kafkaesque state intrusion". The newspaper also featured an article written by Maria Munir about their experience coming out to President Barack Obama as non-binary. Stonewall CEO Ruth Hunt penned an article in The Telegraph after the Orlando nightclub shooting in June 2016 that the attack on a gay nightclub "grew out of everyday homophobia".
Also in 2016, Telegraph Executive Director Lord Black was awarded Peer of the Year at the 2016 PinkNews Awards for his campaigning on LGBT rights. The Telegraph has published articles which have been criticised by PinkNews as transphobic. In 2017, the newspaper published an article by Allison Pearson titled: "Will our spineless politicians' love affair with LGBT ever end?", arguing that NHS patients' being asked their sexual orientation was unnecessary and another in 2018 with the headline: "The tyranny of the transgender minority has got to be stopped."
== Sister publications ==
=== The Sunday Telegraph ===
The Daily Telegraph's sister Sunday paper was founded in 1961. The writer Sir Peregrine Worsthorne is probably the best known journalist associated with the title (1961–1997), eventually being editor for three years from 1986. In 1989, the Sunday title was briefly merged into a seven-day operation under Max Hastings's overall control. In 2005, the paper was revamped, with Stella being added to the more traditional television and radio section. It costs £2.20 and includes separate Money, Living, Sport and Business supplements.
Circulation of The Sunday Telegraph in July 2010 was 505,214 (ABC).
=== Young Telegraph ===
Young Telegraph was a weekly section of The Daily Telegraph published as a 14-page supplement in the weekend edition of the newspaper. Young Telegraph featured a mixture of news, features, cartoon strips and product reviews aimed at 8–12-year-olds. It was edited by Damien Kelleher (1993–1997) and Kitty Melrose (1997–1999). Launched in 1990, the award-winning supplement also ran original serialised stories featuring popular brands such as Young Indiana Jones and the British children's sitcom Maid Marian and Her Merry Men. It featured the cartoon "Mad Gadget" by Chris Winn, and a computer game Mad Gadget: Lost In Time (1993) and a book Mad Gadget: Gadget Mad (1995) were produced.
In 1995, an interactive spin-off called Electronic Young Telegraph (EYT) was launched on floppy disk. Described as an interactive computer magazine for children, Electronic Young Telegraph was edited by Adam Tanswell, who led the relaunch of the product on CD-Rom in 1998. Electronic Young Telegraph featured original content including interactive quizzes, informative features and computer games, as well as entertainment news and reviews. It was later re-branded as T:Drive in 1999.
=== Website ===
Telegraph.co.uk is the online version of the newspaper. It uses the banner title The Telegraph and includes articles from the print editions of The Daily Telegraph and The Sunday Telegraph, as well as web-only content such as breaking news, features, picture galleries and blogs. It was named UK Consumer Website of the Year in 2007 and Digital Publisher of the year in 2009 by the Association of Online Publishers. The site is overseen by Kate Day, digital director of Telegraph Media Group. Other staff include Shane Richmond, head of technology (editorial), and Ian Douglas, head of digital production. In November 2012, international customers accessing the Telegraph.co.uk site would have to sign up for a subscription package. Visitors had access to 20 free articles a month before having to subscribe for unlimited access. In March 2013, the pay meter system was also rolled out in the UK.
The site, which has been the focus of the group's efforts to create an integrated news operation producing content for print and online from the same newsroom, completed a relaunch during 2008 involving the use of the Escenic content management system, popular among northern European and Scandinavian newspaper groups. Telegraph TV is a Video on Demand service run by The Daily Telegraph and the Sunday Telegraph. It is hosted on The Telegraph's website, telegraph.co.uk. Telegraph.co.uk became the most popular UK newspaper site in April 2008. It was overtaken by Guardian.co.uk in April 2009 and later by "Mail Online". In December 2010, "Telegraph.co.uk" was the third most visited British newspaper website with 1.7 million daily browsers compared to 2.3 million for "Guardian.co.uk" and nearly 3 million for "Mail Online". In October 2023, "Telegraph.co.uk" was the tenth most visited UK newspaper site, with 13.8 million monthly visits, compared to the most popular, the BBC, with 38.3 million.
==== History ====
The website was launched, under the name electronic telegraph at midday on 15 November 1994 at the headquarters of The Daily Telegraph at Canary Wharf in London Docklands with Ben Rooney as its first editor. It was Europe's first daily web-based newspaper. At this time, the modern internet was still in its infancy, with as few as 10,000 websites estimated to have existed at the time – compared to more than 100 billion by 2009. In 1994, only around 1% of the British population (some 600,000 people) had internet access at home, compared to more than 80% in 2009.
Initially, the site published only the top stories from the print edition of the newspaper but it gradually increased its coverage until virtually all of the newspaper was carried online and the website was also publishing original material. The website, hosted on a Sun Microsystems Sparc 20 server and connected via a 64 kbit/s leased line from Demon Internet, was edited by Ben Rooney.
An early coup for the site was the publication of articles by Ambrose Evans-Pritchard on Bill Clinton and the Whitewater controversy. The availability of the articles online brought a large American audience to the site. In 1997, the Clinton administration issued a 331-page report that accused Evans-Pritchard of peddling "right-wing inventions". Derek Bishton, who by then had succeeded Rooney as editor, later wrote: "In the days before ET it would have been highly unlikely that anyone in the US would have been aware of Evans-Pritchard's work – and certainly not to the extent that the White House would be forced to issue such a lengthy rebuttal." Bishton, who later became consulting editor for Telegraph Media Group, was followed as editor by Richard Burton, who was made redundant in August 2006. Edward Roussel replaced Burton.
==== My Telegraph ====
My Telegraph offers a platform for readers to have their own blog, save articles, and network with other readers. Launched in May 2007, My Telegraph won a Cross Media Award from international newspaper organisation IFRA in October 2007. One of the judges, Robert Cauthorn, described the project as "the best deployment of blogging yet seen in any newspaper anywhere in the world".
== Notable stories ==
In December 2010, Telegraph reporters posing as constituents secretly recorded Business Secretary Vince Cable. In an undisclosed part of the transcript given to the BBC's Robert Peston by a whistleblower unhappy that The Telegraph had not published Cable's comments in full, Cable stated in reference to Rupert Murdoch's News Corporation takeover bid for BSkyB, "I have declared war on Mr Murdoch and I think we are going to win." Following this revelation, Cable had his responsibility for media affairs – including ruling on Murdoch's takeover plans – withdrawn from his role as business secretary.
In May 2011, the Press Complaints Commission upheld a complaint regarding The Telegraph's use of subterfuge: "On this occasion, the commission was not convinced that the public interest was such as to justify proportionately this level of subterfuge." In July 2011, a firm of private investigators hired by The Telegraph to track the source of the leak concluded "strong suspicion" that two former Telegraph employees who had moved to News International, one of them Will Lewis, had gained access to the transcript and audio files and leaked them to Peston.
=== 2009 MP expenses scandal ===
In May 2009, The Daily Telegraph obtained a full copy of all the expenses claims of British Members of Parliament. The Telegraph began publishing, in instalments from 8 May 2009, certain MPs' expenses. The Telegraph justified the publication of the information because it contended that the official information due to be released would have omitted key information about redesignating of second-home nominations. This led to a number of high-profile resignations from both the ruling Labour administration and the Conservative opposition.
=== 2016 Sam Allardyce investigation ===
In September 2016, Telegraph reporters posing as businessmen filmed England manager Sam Allardyce offering to give advice on how to get around on FA rules on player third party ownership and negotiating a £400,000 deal. The investigation saw Allardyce leave his job by mutual consent on 27 September and making the statement "entrapment has won".
== Reception and historical value ==
Denise Bates included The Daily Telegraph in a list of national newspapers which, because of the quality of their reporting, or the extent of their audience, stand out and are likely to be used for historical research. The editors of Encyclopaedia Britannica said that The Daily Telegraph has consistently had a "high standard of reporting". The Daily Telegraph was renowned for its foreign correspondents. According to the DNCJ, during the nineteenth century, The Daily Telegraph had excellent coverage of the arts. In 1989, Nicholas and Erbach said that The Daily Telegraph is factually accurate, and that its reputation for being so extends outside the country.
=== Awards ===
The Daily Telegraph has been named the National Newspaper of the Year in 2009, 1996 and 1993, while The Sunday Telegraph won the same award in 1999. Its investigation on the 2009 expenses scandal was named the "Scoop of the Year" in 2009, with William Lewis winning "Journalist of the Year". The Telegraph won "Team of the Year" in 2004 for its coverage of the Iraq War. The paper also won "Columnist of the Year" three years' running from 2002 to 2004: Zoë Heller (2002), Robert Harris (2003) and Boris Johnson (2004).
== Charity and fundraising work ==
In 1979, following a letter in The Daily Telegraph and a Government report highlighting the shortfall in care available for premature babies, Bliss, the special care baby charity, was founded. In 2009, as part of the Bliss 30th birthday celebrations, the charity was chosen as one of four beneficiaries of the newspaper's Christmas Charity Appeal. In February 2010, a cheque was presented to Bliss for £120,000.
In 2014, The Telegraph designed a newspaper-themed Paddington Bear statue, one of fifty located around London prior to the release of the film Paddington, which was auctioned to raise funds for the National Society for the Prevention of Cruelty to Children (NSPCC).
== Notable people ==
=== Editors ===
=== Notable columnists and journalists ===
== See also ==
List of the oldest newspapers
History of journalism
Newspaper of record
== References ==
== Further reading ==
Burnham, E. F. L. (1955). Peterborough Court: the story of the Daily Telegraph. Cassell.
Hart-Davis, Duff (1991). The house the Berrys built: inside the Telegraph, 1928-1986. Sevenoaks: Coronet. ISBN 9780340553367.
Hastings, Max (October 2024). Editor. London: Pan Macmillan. ISBN 9781035057344. A memoir of Hastings' ten years as the paper's editor.
Merrill, John C. and Harold A. Fisher. The world's great dailies: profiles of fifty newspapers (1980) pp. 111–16.
William Camrose: Giant of Fleet Street by his son Lord Hartwell. Illustrated biography with black-and-white photographic plates and includes an index. Concerns his links with The Daily Telegraph.
== External links ==
Official website | Wikipedia/The_Daily_Telegraph |
Stemirna COVID-19 vaccine is a COVID-19 vaccine candidate developed by Stemirna Therapeutics. The Stemirna COVID-19 vaccine is labeled as a mRNA vaccine which means it causes the body to make a protein specific to the vaccine which triggers a immune response from the body. Stemirna first started the production of vaccines in result of the COVID-19 pandemic, therefore the first vaccine the began producing was a COVID-19 vaccine.
== Research ==
Testing on mice and other non human primates, the vaccine showed results that would lead the body to produce antibodies that would stop the spread and limit the coronavirus therefore the vaccine seemed very promising for human trials. Stemirna explains that the research in Nanotechnology has been a big help into researching and create possible vaccines for the COVID-19 virus.
== History ==
Stemirna Therapeutics raised a total of 1.2 Billion RMB (Renminbi) which translates to a little less than 200 million US Dollars for the start of their production and testing trials. Li Hangwen, a co-founder of the company, stated they were confident in the vaccine's efficacy and safety based on ongoing Phase 1 and Phase 2 trial data conducted in Laos. Stemirna Therapeutics first began their clinical trials in Brazil as part of its Phase 3 testing. Li Hangwen, who is the chief executive of the company said that they were going to be able to produce 400 million doses of the vaccine each year. The stemirna Vaccine uses nanotechnology which has helped to quickly create diagnostic tools, vaccines, and antiviral treatments for SARS-CoV-2.
== References == | Wikipedia/Stemirna_COVID-19_vaccine |
The Sinopharm WIBP COVID-19 vaccine, also known as WIBP-CorV, is one of two inactivated virus COVID-19 vaccines developed by Sinopharm. Peer-reviewed results show that the vaccine is 72.8% effective against symptomatic cases and 100% against severe cases (26 cases in vaccinated group vs. 95 cases in placebo group). The other inactivated virus COVID-19 vaccine developed by Sinopharm is the BIBP vaccine (BBIBP-CorV) which is comparably more successful. 1 billion doses are expected to be produced per year.
== Medical uses ==
The vaccine is given by intramuscular injection. The administered is 2 doses in 3 weeks.
=== Efficacy ===
In May 2021, peer-reviewed results published in JAMA of Phase III trials in United Arab Emirates and Bahrain showed that the vaccine is 72.8% effective against symptomatic cases and 100% against severe cases (26 cases in vaccinated group vs. 95 cases in placebo group). 12,743 people received the vaccine and 12,737 people received the placebo in these trials.
== Manufacturing ==
In June 2021, a new factory started production with the capacity to manufacture 1 billion doses annually.
== History ==
In April 2020, China approved clinical trials for a candidate COVID-19 vaccine developed by Sinopharm's Beijing Institute of Biological Products (BIBP) and the Wuhan Institute of Biological Products (WIBP). Both vaccines are chemically-inactivated whole virus vaccines for COVID-19.
On August 13, 2020, the Wuhan Institute of Biological Products published interim results of its Phase I (96 adults) and Phase II (224 adults) clinical studies. The report noted the vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy would require Phase III trials.
=== Clinical trials ===
In March 2021, Cayetano Heredia University running the BIBP and WIBP trials in Peru announced they were seeking to suspend and unblind participants in the WIBP trials for lower efficacy and offer the participants the BIBP vaccine instead, which was showing efficacy.
=== Authorizations ===
On February 25, 2021, China approved the vaccine for general use.
According to The New York Times, the vaccine is only approved for limited use in United Arab Emirates. On August 19, 2021, the Philippines approved the vaccine for emergency use authorization.
== References ==
== External links == | Wikipedia/Sinopharm_WIBP_COVID-19_vaccine |
Media coverage of the COVID-19 pandemic includes reporting on the deaths of anti-vaccine advocates from COVID-19 as a phenomenon occurring during the COVID-19 pandemic. The media also reported on various websites documenting such deaths, with some outlets questioning whether this practice was overly unsympathetic. Reports noted phenomena including "deathbed conversions", in which vaccine opponents reportedly changed their minds and began encouraging vaccination before dying, with these claims meeting continued skepticism by vaccination opponents; and on groups of deaths within specific demographics, such as anti-vaccine radio hosts.
== Reporting on the phenomenon ==
Many news reports in 2021 noted instances in which persons described as anti-vaccination activists—those who advocated against use of the COVID-19 vaccine—themselves died from COVID-19, with The Hill, for example, reporting on the death of Marcus Lamb, a 64-year-old American televangelist, by saying that "[a]nother leader in the conservative media space has died from COVID-19 and his death marks a growing trend of like-minded anti-vaccine advocates that have themselves succumbed to the virus". The Washington Post noted that "the Internet has been a graveyard of stories about unvaccinated deaths, which make up the majority of the pandemic's current victims". A number of websites or social media outlets list such deaths, including "[a] website called Sorry Antivaxxer, which catalogues the COVID-19 deaths of people who had publicly posted their rejection of the vaccine", as well as "the Twitter account Covidiot Deaths, [and] the Reddit forum called the Herman Cain Award". The Hill article on the death of the televangelist noted three other media figures who had died of the disease, describing them as "conservative media leaders who caught COVID-19 and eventually died from the virus after refusing to take a vaccine and flouted anti-vaccine rhetoric".
Some commentators have criticized the practice of reporting these deaths, describing them as celebrating the suffering of others. Maura Judiks, writing in The Washington Post, criticized such outlets for promoting a lack of empathy for the survivors. It was reported in The New York Times that the social media profiles of anti-vaccination activists made their families susceptible to trolling after their deaths, even where the surviving family members were not anti-vaccination, or even encouraged vaccination based on their personal loss. It further reported the opinion of a psychologist that, in the United States, "sentiments underpinning these websites are an outgrowth of the nation's extreme polarization", with those who perceive themselves to be politically aligned against vaccination opponents taking pleasure in the suffering of perceived enemies. The cataloging of such deaths has been described as "heartless and unrepentant schadenfreude", and has been argued to derive not only from political differences, but from frustrations felt by overwhelmed medical professionals and healthcare systems. A column in the Los Angeles Times, following reactions to the COVID-19 death of antivaccine Orange County Deputy District Attorney, countered that there "may be no other way to make sure that the lessons of these teachable moments are heard", an opinion which itself "came under fire" in social media responses.
== Reporting of deathbed conversions ==
A number of news outlets also reported on deathbed conversions of opponents of vaccination or their peers, with some of those dying using their final days and hours to urge their followers and loved ones to be vaccinated. For example, The Hill reported that when one of the anti-vaccine talk radio hosts became seriously ill with COVID-19, he texted a friend to urge her to get vaccinated, telling her, "I wish I had gotten it", while Slate similarly reported that another radio host, who earlier "had expressed skepticism of the COVID-19 vaccine" had "changed his mind and urged friends and family members to get vaccinated from his hospital bed". The New York Times reported on the father of one such victim becoming an ardent proponent of vaccination. This was also reported in The BMJ in October 2021, in a piece which said that "[a]mong the people admitted to hospital with severe respiratory failure from COVID-19 pneumonia who have subsequently died, some had previously held strong anti-vaccine beliefs. Once critically ill, some have changed their minds and shared their stories on social media as a warning".
The Washington Post noted that "[t]he narrative is even more potent when the victim expresses a dying wish for others to get vaccinated, and regrets their decision not to". Whether reporting of these deaths actually encourages opponents of vaccination to change their position is unclear, but it has been asserted that proponents of vaccination "have expressed thanks for providing a record of anti-vaccine deaths that have helped them convince skeptics to get the shots". Geriatrics and acute general medicine consultant David Oliver, writing for The BMJ, notes that some anti-vaccine activists have accused doctors of falsifying these asserted changes of heart on the part of their patients. He added that addressing misinformation can reinforce conspiracy theories as a side effect.
== Notable instances ==
In August 2021, a number of American conservative talk radio hosts who had discouraged COVID-19 vaccination, or expressed skepticism toward the COVID-19 vaccine, died from COVID-19 complications. These included 65-year-old Marc Bernier, self-nicknamed "Mr. Antivax", from Daytona, Florida; 65-year-old Dick Farrel, who referred to the pandemic as a "SCAM DEMIC"; Jimmy DeYoung Sr, an octogenarian Christian radio host who decried the vaccine as a form of government control; and 61-year-old Phil Valentine, who compared vaccination status badges worn by medical workers with the yellow badges which German Jews were ordered to wear by the Nazis. In September 2021, another anti-vaccine conservative radio host, 62-year-old Bob Enyart, who "vocally refused to get vaccinated and actively spread false claims about the COVID-19 virus", died of COVID-19, prompting a new round of reports discussing the phenomenon within that demographic. The phenomenon was repeated in November 2021, when Marcus Lamb, co-founder of the Daystar Television Network who promoted skepticism toward all vaccines, died of COVID-19.
Olavo de Carvalho, a Brazilian COVID-19 vaccine critic, journalist, and conspiracy theorist, was reported by his daughter to have died of COVID-19 after testing positive.
When Hai Shaulian, a prominent Israeli opponent of vaccination, died from COVID-19 in September 2021, his supporters "claimed that he was murdered by government authorities... so that he would not disclose the truth about what they claim is a fictitious pandemic and a dangerous vaccine", a response characterized by Israeli newspaper Haaretz as a cult-like refusal to acknowledge reality.
== References == | Wikipedia/Deaths_of_anti-vaccine_advocates_from_COVID-19 |
Inovio COVID-19 vaccine is a COVID-19 vaccine candidate developed by Inovio Pharmaceuticals.
== History ==
In February 2020 after receiving details of the genetic sequence of the coronavirus, Inovio announced that it had produced a preclinical DNA-based vaccine as a potential therapy for COVID-19. Inovio is in competition to develop a coronavirus vaccine with numerous other companies, which were conducting preclinical or early-stage human research on more than 170 vaccine candidates, as of late June. In April 2020, Inovio began a Phase I trial of the COVID-19 vaccine candidate, INO-4800.
=== Clinical trials ===
Inovio is collaborating with Beijing Advaccine Biotechnology Co., a Chinese biotech firm, in order to speed its acceptance by regulatory authorities in China, with plans to begin human clinical trials of a candidate vaccine in China during the first half of 2020. Inovio has partnerships with manufacturers to scale up production of a vaccine if preliminary efficacy trials are successful. In April 2020, the company began human Phase I safety studies of its lead vaccine (INO-4800) in the United States, and a Phase I-II trial in South Korea, to test for immunization against the COVID-19 virus.
In early June, Inovio partnered with the International Vaccine Institute and Seoul National University, South Korea, to advance human research on INO-4800 in a Phase I-II safety and efficacy trial to be conducted on 120 participants at Seoul National University Hospital beginning in June. The trial is funded by the Coalition for Epidemic Preparedness Innovations and supported by the Korea Centers for Disease Control and Prevention and the Korea National Institute of Health.
On 23 April 2021 Inovio said the U.S. Department of Defense discontinued funding for the phase III portion of an ongoing trial of its COVID-19 vaccine candidate, INO-4800, in light of the broad availability of other COVID-19 vaccines in the U.S. The news followed recent phase I data showing '4800 performed about in line with already available competitors against the existing SARS-CoV-2 variants. NOVIO's global Phase 3 efficacy trial receives authorization to proceed from Brazil; other countries to follow.
On 26 August 2021 Inovio's global Phase 3 efficacy trial receives authorization to proceed from Brazil.
On 26 October 2021 The World Health Organization launched a Global Covid-19 Trial termed as the Solidarity Trial Vaccines. Inovio INO-4800 was chosen as the first DNA Vaccine to be introduced in the largest vaccine trial in history. The Countries of Colombia, Mali and the Philippines announced participation with many other countries yet to be named. The WHO is directly financing this trial.
On 14 December 2021 Inovio released Clinical Data on Phase 1 and 2 trials held in the USA. The Data showed zero Level 3 Adverse Events. Conclusion INO-4800 appears safe and tolerable as a primary series and as a booster with the induction of both humoral and cellular immune responses. In addition to eliciting neutralizing antibodies, INO-4800 also induced T cell immune responses as demonstrated by IFNγ ELISpot. Finally, as a homologous booster, INO-4800, when administered 6-10.5 months following the primary series, resulted in an increased immune response without increase in reactogenicity.
== References ==
== External links == | Wikipedia/Inovio_COVID-19_vaccine |
The Community Activities Restrictions Enforcement or CARE (Indonesian: Pemberlakuan Pembatasan Kegiatan Masyarakat, commonly referred to as the PPKM) was a cordon sanitaire policy of the Indonesian government since early 2021 to deal with the COVID-19 pandemic. Prior to the implementation of CARE, the government had implemented large-scale social restrictions (LSSR) which took place in a number of regions in Indonesia.
On 30 December 2022, Joko Widodo announced that the CARE policy had ended for all regions in Indonesia.
== Background ==
The Indonesian government first implemented CARE from 11 to 25 January 2021. The two weeks implementation of CARE was carried out based on the Instruction of the Minister of Home Affairs (Mendagri) Number 1 of 2021 and was implemented in the island of Java and Bali. Previously, in 2020, a number of provinces had implemented large-scale social restrictions (LSSR) to prevent the spread of COVID-19. According to Airlangga Hartanto as Chair of the Committee on COVID-19 Handling and National Economic Recovery (KPC-PEN), the initial initiative to apply for LSSR was with the regional government, while CARE was with the central government. The Deputy Chairperson of KPC-PEN Luhut Panjaitan said that LSSR was carried out non-uniformly, while CARE could be applied uniformly.
=== CARE Levels ===
On 21 July 2021, Tito Karnavian as Minister of Home Affairs announced a new term regarding the CARE mechanism with a scale from the first to the fourth level. The government can determine that an area can apply CARE based on the rate of transmission and the number of active cases of COVID-19 in an area. All cases were counted per 100,000 population per week.
== Enforcement ==
=== Summary ===
The following table contains a summary of the implementation of CARE, micro-CARE and emergency CARE which consists of several stages.
=== First-stage CARE ===
The first stage of CARE will be implemented in seven provinces in Java and Bali, namely Jakarta Special Capital Region, West Java, Banten, Central Java, Special Region of Yogyakarta, East Java, and Bali, starting from 11 January to 25 January 2021. A number of districts/cities in each province are prioritized to implement PPKM. There are four elements used as parameters for provinces, districts, or cities in the implementation of CARE, namely having
a death rate above the national average death rate,
cure rate below the national average,
active case rate above the national average active case rate, and
hospital bed occupancy rate for intensive care unit (ICU) and isolation room above 70%.
Restrictions on community activities are regulated in the Instruction of the Minister of Home Affairs Number 1 of 2021, namely:
limiting the workplace/office by implementing remote work by 75% and working from office (WFO) by 25% by implementing stricter health protocols;
carry out online teaching and learning activities;
essential sectors related to the basic needs of the community can still operate 100% with more stringent regulation of operating hours, capacity, and implementation of health protocols;
make settings for the application of restrictions:
restaurant activities (eating/drinking on site by 25% and for food service via delivery or take-away are still permitted according to restaurant operating hours with stricter implementation of health protocols; and
restriction of operating hours for shopping centers/malls until 7:00 PM WIB (Indonesian Western Time);
allow construction activities to operate 100% with stricter implementation of health protocols;
allow places of worship to operate with a capacity limitation of 50% with the implementation of stricter health protocols;
=== Second-stage CARE ===
The government has extended the CARE through the Instruction of the Minister of Home Affairs Number 2 of 2021. The second-stage CARE will be held from 26 January to 8 February 2021. In this second stage, the operating hours of shopping centers/malls are changed to 8:00 PM WIB. Meanwhile, based on the results of monitoring of 73 regencies/cities that have implemented PPKM, as many as 29 regencies/cities are still in the high-risk zone, 41 regencies/cities are in the moderate risk zone, and the remaining 3 regencies/cities are in the low-risk zone.
=== Micro-based CARE ===
After being implemented for two stages in which the results were economically ineffective, CARE was changed to micro-based CARE from 9 to 22 February 2021. As before, micro PPKM was implemented in a number of areas in seven provinces. However, in contrast to PPKM, in micro PPKM there are arrangements regarding the establishment of COVID-19 handling posts at village and sub-district levels, the operating hours of shopping centers/malls are more loosely regulated, namely until 9:00 PM WIB (Indonesian Western Time), as well as looser office restrictions, namely 50% working from the office and 50% working from home.
In micro-CARE, restrictions are made at the level of the rukun tetangga (neighbourhood) and rukun warga (hamlet). Based on the Instruction of the Minister of Home Affairs Number 3 of 2021, there are four control zones for the spread of COVID-19 in each RT.
Green zone — there are no cases of COVID-19 transmission in one RT area. Control scenarios: active surveillance, testing of all suspects, and routine and periodic case monitoring.
Second zone — there are 1 to 5 houses confirmed positive in one RT during the last seven days. Control scenarios: finding suspects and tracing close contacts, as well as self-isolation for positive patients and close contacts under close supervision.
Orange zone — there are 6 to 10 houses with confirmed positive cases of COVID-19 in one RT during the last seven days. Control scenario:
finding superfluous cases and close contact tracing, as well as self-isolation in positive patients and close contacts under close supervision,
closure of houses of worship, children's playgrounds, and other public places, other than essential sectors that are still allowed to operate.
Red zone — there are more than ten houses that have confirmed positive cases of COVID-19 in one RT during the last seven days. Control scenario:
finding suspected cases and tracing close contacts,
self-isolate or centrally under strict supervision,
closing houses of worship, children's play areas, and other public places except for the essential sector,
prohibit crowds of more than three people,
limiting entry and exit from the RT area to a maximum of 8:00 PM WIB, and
eliminate community social activities in the RT environment that cause crowds and have the potential to cause transmission.
After being implemented for two weeks, the government extended the micro PPKM many times. On June 7, 2021, the Head of the COVID-19 Handling Task Force Ganip Warsito conducted an evaluation of the Micro PPKM, examining from the surge in COVID-19 cases in Kudus, Central Java to implement better monitoring and evaluating of the data.
=== Emergency CARE ===
Emergency CARE takes effect from 3 to 25 July 2021, which targets a decrease in the addition of daily confirmed cases to below 10 thousand cases per day. This program is implemented in 136 districts/cities throughout Indonesia by differentiating the level of treatment based on the assessment value by using an approach between the indicators of transmission rate and response capacity, including the level of availability of beds in hospitals.
The tightening of activities carried out includes:
100% remote work for non-essential sectors;
All teaching and learning activities are conducted online;
For essential sectors, 50% of the maximum working staff from the office (WFO) is applied with health protocols, and for critical sectors, 100% maximum WFO is allowed with health protocols. (The coverage of essential sectors is finance and banking, capital markets, payment systems, information and communication technology, non-quarantine handling hotels, and export-oriented industries; critical sector coverage is energy, health, security, logistics and transportation, food, beverage and supporting industries. , petrochemicals, cement, national vital objects, disaster management, national strategic projects, construction, basic utilities (electricity and water), as well as industries for meeting the basic needs of people's daily needs; for supermarkets, traditional markets, grocery stores, and supermarkets that sell daily needs are limited to operating hours until 8:00 PM local time with a visitor capacity of 50%;
Activities at shopping centers/malls/trade centers are closed;
Restaurants and restaurants do not accept dine-in;
The implementation of construction activities (construction sites and project sites) operates 100% by implementing stricter health protocols;
Places of worship (mosques, musallas, churches, temples, monasteries, and pagodas), as well as other public places that function as places of worship are not to offer congregational prayer; people are to conduct prayer individually at their homes
Public facilities (public areas, public parks, public tourist attractions and other public areas) are temporarily closed;
Art/cultural activities, sports, and social activities (locations of arts, culture, sports facilities, and social activities that can cause crowds and crowds) are temporarily closed;
Public transportation (public transportation, mass transportation, taxis (conventional and online) and rental vehicles) is enforced with a maximum capacity setting of 70% by implementing stricter health protocols;
Wedding receptions are prohibited;
Travelers using long-distance transportation modes (airplanes, buses, and trains) must show a vaccine card (minimum vaccine dose I) and H-2 PCR for planes and antigen (H-1) for other long-distance transportation modes;
Regional government by deploying the Satpol PP with coordination with the Indonesian National Police assisted by the TNI to implement strict supervision and law enforcement of this policy, especially of point 3;
3T strengthening (testing, tracing, treatment) needs to be continuously implemented. Testing needs to be increased to a minimum of 1 per 1000 population per week, and needs to be increased until the positivity rate is less than 5%, and needs to be increased for suspects, namely those with symptoms, and also in close contacts; tracing should be carried out until >15 close contacts per confirmed case and quarantine should be carried out on those identified as close contacts. Once identified, close contacts should be checked immediately, and quarantine should be carried out. If the test results are positive, then isolation is necessary. If the results of the examination are negative, quarantine should be continued. On the 5th day of quarantine, it is necessary to carry out an exit-test to see if the virus was detected after/during the incubation period. If negative, then the patient is considered to have completed quarantine. Treatment needs to be done comprehensively according to the severity of the symptoms. Only patients with moderate, severe, and critical symptoms need to be hospitalized. Isolation needs to be done strictly to prevent transmission.
Achievement of vaccination target of 70% of the total population in priority cities/districts until August 2021
=== CARE level 1-4 ===
CARE level 1-4 is determined based on an assessment of the level of the pandemic situation, which is an indicator for tightening and relaxing efforts to prevent and overcome the COVID-19 pandemic. It could be that one area one day was at level 3, but due to lack of compliance with health protocols, crowding at the community level and so on, the following week it could turn into level 4. This is the terms of explanation:
==== Level 1 (New Normal) ====
Reference indicators for the level of one weekly confirmed case of less than 40 per 100,000 population, weekly treatment of less than 5 per 100,000 population, and weekly BOR of less than 60%. For this level, the conditions are:
100% WFO nonessential sectors for those already vaccinated; essential 100% WFO with two work shifts and critical 100% WFO.
supermarket/grocery store/traditional market open 100%.
shopping center/mall open with 100% capacity.
restaurants/restaurants with a maximum capacity of 75%.
school 100% face to face with strict health protocols.
100% places of worship with strict procedures.
100% public facilities with strict procedures.
100% social/cultural/sports activities with strict health protocols.
75% wedding reception with strict health protocols.
Public transportation is a maximum of 100% capacity and for travelers, the requirements are a vaccine card and an antigen test.
==== Level 2 (Transition One) ====
The reference indicators for the level of two weekly confirmed cases are 40 - 64 per 100,000 population, weekly treatment 5 to 9 per 100,000 population, and weekly BOR of less than 60%.For this level, the conditions are:
nonessential sectors 50% WFO for those already vaccinated; essential 100% WFO with two work shifts and critical 100% WFO.
supermarket/grocery store/traditional market open 75%.
shopping center/mall open with 50% capacity.
restaurants/restaurants with a maximum capacity of 50%.
school 50% online and 50% face to face.
places of worship 50% with strict procedures.
50% public facilities with strict health protocols.
50% social/cultural/sports activities with strict health protocols.
50% wedding reception with strict health protocols.
Public transportation is a maximum of 100% capacity and for travelers the requirements are a vaccine card and an antigen test.
==== Level 3 (Transition Two) ====
The reference indicators for level three are weekly confirmed cases of 65-100 per 100,000 population, weekly treatment 10-30 per 100,000 population, and weekly BOR of 60%-80%.
Provisions for social and economic activities:
online teaching and learning activities.
office activities 25% WFO and 75% WFH.
essential sector activities can be 100% WFO with strict health protocols.
supermarket/grocery store/traditional market open 50% capacity until 22.00.
shopping centers/malls open until 17.00 with 25% capacity.
construction activities can be 100% capacity with strict health protocols.
restaurants/restaurants, both stand-alone and in shopping centers can serve dine-in until 17.00 with a capacity of 25%.
restaurants/restaurants can still serve take away until 20.00; and specifically those that only serve take away can operate until 24.00.
places of worship are prohibited for congregational activities.
public facilities closed.
social/cultural/sports activities are prohibited.
wedding receptions are prohibited.
Community celebration activities with a maximum of 25% and without eating on the spot.
Public transportation is a maximum of 70% capacity, and for travelers the requirements are vaccine cards, PCR for planes, and antigens for others.
==== Level 4 (Very High Incidence) ====
For level four which was previously called emergency CARE, the reference indicators are weekly confirmed cases of more than 100 per 100,000 population, weekly treatment of more than 30 per 100,000 population, and weekly BOR of more than 80%.
Provisions for social and economic activities:
online teaching and learning activities (online).
non-essential sectors 0% work from office (WFO); essential sector 25% to 50% WFO depending on the type of service; while the critical sector can be 100% WFO.
supermarkets/grocery shops/traditional markets open at 50% capacity until 20.00.
shopping centers/malls are closed.
construction activities are only for national strategic projects (PSN) and public infrastructure can be at 100% capacity.
restaurants/restaurants only serve take away.
places of worship are prohibited for congregational activities.
public facilities closed.
social/cultural/sports activities are prohibited.
wedding receptions are prohibited.
public transportation maximum 70% capacity.
For travelers, the requirements are for a vaccine card and a PCR test for airplane passengers, while for other transports, a vaccine card and an antigen test are required.
From 121 regencies/cities in Java and Bali that apply Emergency CARE, there are 45 regencies/cities with an assessment score of 4, and 76 districts/cities with an assessment score of 3. Meanwhile, since July 12, there have been an additional 15 regencies/cities outside Java-Bali that have also implemented Emergency CARE until the same time limit as it was implemented in Java-Bali.
== Responses ==
=== During the Enforcement ===
In February 2021, an epidemiologist from the University of Indonesia, Tri Yunis Miko Wahyono, assessed that the implementation of CARE was still ineffective. He was of the opinion that the effectiveness of CARE at that time was still less than 30 percent. This is the result of weak supervision and application of 3T (test, tracing, and treatment) in the orange and red zones. Yordan Khaedir, a lecturer at the Faculty of Medicine, University of Indonesia, in his writings in Media Indonesia suggested the application of COVID-19 tracking applications such as Google Data to monitor community mobilization in certain areas. This is considered as one way to increase the effectiveness of social restrictions.
Inconsistent government policies are also a problem in dealing with the pandemic. In the same article, Tri Yuni Miko Wahyono considers the change from Indonesia large-scale social restrictions, the new normal, to Community Activities Restrictions Enforcement is one sign of inconsistent policies implemented by the government. Trubus Rahardiansyah, a public policy observer, views the implementation of micro CARE as "confusing and counterproductive". He questioned the government's policy of re-imposing restrictions on the scale of rukun tetangga and rukun warga even though it has proven to be ineffective. Bambang Rukmino, a police observer from the Institute for Security and Strategic Studies (ISESS), advised the police to be fair and consistent in enforcing the rules. He also commented on how the CARE rules were enforced at a food stall in Kudus, Central Java.
Reporting from Katadata.co.id, Dicky Budiman, an epidemiologist from Griffith University, and Laura Navika Yamani, an epidemiologist from Airlangga University, appreciated the government's implementation of micro Community Activities Restrictions Enforcement. Both consider this restriction as one of the better efforts than no policy at all. However, both of them advised the government to increase surveillance and conduct isolation for COVID-19 cases.
In June 2021, Kurniasih Mufidayati, a member of the House of Representatives Commission IX of the PKS Faction, emphasized the government's obligations as stated in Law Number 6 of 2018 concerning Health Quarantine. In article 4 of the law, the government is responsible for protecting the public from "diseases and/or Public Health Risk Factors that have the potential to cause a Public Health Emergency through the implementation of Health Quarantine". Chairperson of the Indonesian Legal Aid Foundation, Asfinawati, assessed that the implementation of restrictions such as PSBB and CARE is one of the government's options to avoid the obligation to fulfill basic needs as stipulated in the Quarantine Law. On a different occasion, Agus Pambagio, a public policy observer, also questioned the names of CARE thickening and emergency CARE, even though the law calls it quarantine.
Some traders and entrepreneurs consider the emergency CARE which will be implemented starting 3 July 2021, to be quite burdensome for them. The general chairman of the Indonesian Employers' Association, Hariyadi Sukamdani, is concerned that the emergency CARE will disrupt the cash flows of several companies and potentially lead to bankruptcy. The Deputy Chairperson of Indonesian Hotel and Restaurant Entrepreneurs, Emil Arifin, revealed that the ban on eating in places caused the restaurant's operational costs to not be met. This is because take away services on average only contribute to 10 to 20 percent of revenue. Secretary General of the Indonesian Market Traders Association, Reynaldi Sarijowan, reported a decline in turnover of market traders by 55 to 60%. He also stated that the reduction in operating hours and closing of traditional markets led to an increase in several basic commodities.
=== Post-enforcement ===
After the CARE policy lifted, business and industry sectors appreciated the lift. Indonesian Chamber of Commerce and Industry supported the move, hoped the lift will boost the economy.
Ministry of Religious Affairs prepared restoration regulation to restore the condition of religious places and praying places which were affected during the CARE period.
Despite such easement, the Ministry of Health advised the population to maintain a healthy lifestyle like in the pandemic period, since the pandemic has not yet ended.
== References == | Wikipedia/Community_Activities_Restrictions_Enforcement |
The Vaccine Taskforce in the United Kingdom of Great Britain and Northern Ireland was set up in April 2020 by the Second Johnson ministry, in collaboration with Chief Scientific Advisor Patrick Vallance and Chief Medical Officer Professor Chris Whitty, in order to facilitate the path towards the introduction of a COVID-19 vaccine in the UK and its global distribution. The taskforce coordinated the research efforts of government with industry, academics and funding agencies in order to expedite vaccine development and deployment.
The minister responsible for the body was the Secretary of State for Health and Social Care, although the body was a joint unit of the Department of Health and Social Care and the Department for Business, Energy and Industrial Strategy. Oversight was by the Parliamentary Under-Secretary of State for COVID-19 Vaccine Deployment, and in November 2020 the first person to take this role was Nadhim Zahawi MP.
The Vaccine Taskforce closed in autumn 2022. Its role in vaccine supply was merged into the UK Health Security Agency, and its work in bringing vaccine manufacture in-country transferred to the Office for Life Sciences.
== History ==
The body was set up in April 2020 by the Government's Chief Scientific Advisor, Sir Patrick Vallance.
On 16 May 2020, venture capitalist Kate Bingham was named to chair the body. On 1 July, Bingham told the Science and Technology Select Committee that Sarah Gilbert and "Oxford University (are) leading the world in developing a vaccine against COVID-19 and offers the best chance of having something protective against the virus as we go into winter."
On 12 September, it came to light that Sir John Bell was a member of the body.
On 14 October, the chair managed public expectation by stating that a vaccine for COVID-19 was expected to be no more efficacious than the flu vaccine, which immunises against the influenza virus with around 50 per cent success. Bingham added: "We shouldn't assume it's going to be better than a flu vaccine, because that's an equivalent – it's a mutating … respiratory virus that gets in through the nose and eyes and respiratory tract".
Speaking to BBC Scotland's The Seven on 17 October, Bingham said that the government would have to arrive at an agreement with the Joint Committee on Vaccination and Immunisation (JCVI) as to how any COVID-19 vaccine should be distributed; the staff of care homes and the elderly are likely to be prioritised. She stated that initially there would be a limited supply any COVID-19 vaccine.
On 18 October 2020, SAGE committee member, Sir Jeremy Farrar, commented on Sophy Ridge On Sunday that the Vaccine Taskforce "has done an absolutely extraordinary job" and the country is in an "extraordinarily strong position" with regard to the line-up of possible vaccines.
A government press release of 20 October shed further light on the initial formation of the taskforce, stating that it was created under the auspices of the Department for Business, Energy and Industrial Strategy (BEIS) in May 2020. Nadhim Zahawi was appointed to the new role of Parliamentary Under-Secretary of State for COVID-19 Vaccine Deployment on 28 November 2020, with responsibility for the taskforce. On 1 March 2021, ministerial responsibility transferred from BEIS to the Secretary of State for Health and Social Care, and the taskforce became a joint unit of BEIS and the Department of Health and Social Care.
== Personnel ==
On 14 June 2021, the microbiologist Sir Richard Sykes was appointed chair of the Vaccine Taskforce.
As of June 2022, the director-general of the taskforce is Madelaine McTernan.
=== Steering group ===
In June 2021, the Department for Business, Energy and Industrial Strategy confirmed in response to a Freedom of Information Act request that the taskforce's formal steering group had been disbanded, with the taskforce now being managed by a senior leadership team of civil servants and experts, with Sir Richard Sykes as its external chair.
=== Former membership ===
Until November 2020, the membership of the taskforce was unknown. A Freedom of Information Act request to obtain the membership was responded to with three pages of redacted names. As of that month, the steering group was made up of:
Kate Bingham, chair
Clive Dix, deputy chair
Nick Elliott MBE, Director-General, Department for Business, Energy and Industrial Strategy (BEIS)
Ruth Todd, Director, BEIS
Madelaine McTernan, Director, UK Government Investments
Tim Colley, Director, BEIS
Dan Osgood, Director, BEIS
Divya Chadha Manek, National Institute for Health Research
Ian McCubbin, Manufacturing Advisor – former Senior Vice President for Global Manufacturing and Supply at GlaxoSmithKline
Steve Bates, Chief Executive Officer, BioIndustry Association
Professor Jonathan Van-Tam, Clinical and Public Health Adviser to the VTF, Deputy Chief Medical Officer, Department of Health and Social Care
Representatives of other government departments and public sector organisations attended VTF Steering Group meetings as required
== Developments ==
On 20 October 2020, the Financial Times reported that potential COVID-19 vaccines would be selected for testing by the taskforce towards the end of the first quarter of 2021, but this was dependent on the outcome of "characterisation studies". The article also mentioned funding of £33.6 million being provided by government to accelerate the development of new COVID-19 vaccines by exposing human trial participants to the coronavirus in controlled conditions around 30 days after having received a shortlisted vaccine. The work of the taskforce was bolstered by a further tranche of £19.7 million in funding for clinical trial-related blood testing facilities at Public Health England, specifically at PHE Porton Down.
On 22 October, Oxford Immunotec announced that the company had been chosen by the taskforce to be the unique supplier of T cell testing for SARS-Cov-2. The move was underscored with a £3 million investment, as the Business Secretary, Alok Sharma, emphasised the importance of T cell diagnostic capabilities in assessing the performance of candidate vaccines within COVID-19 vaccine trials.
On 27 October 2020, an article by Bingham was published in The Lancet. It highlighted the taskforce's overall strategy of a diverse portfolio of vaccines, with an emphasis on those thought capable of achieving an immune response in the over-65s. From an initial pool of 240 potential vaccines, the taskforce selected six candidates which employ four varied methods: adenoviral vectors, mRNA, adjuvanted proteins, and whole inactivated viral vaccines. The article also revealed that Clive Dix was the taskforce's deputy chair. It was reported the following day that Bingham had warned in the Lancet article that first-generation COVID-19 vaccines would probably not be perfect, and would only lessen symptoms rather than prevent infection and that they "might not work for everyone or for long".
== Related bodies ==
The Department of Health and Social Care set up an Antivirals Taskforce in April 2021, to identify and deploy post-infection antiviral medicines which could be taken by people at home. By September 2022, the name of the body had changed to the COVID-19 Antivirals and Therapeutics Taskforce.
== See also ==
Joint Committee on Vaccination and Immunisation
COVID-19 vaccination programme in the United Kingdom
== References == | Wikipedia/Vaccine_Taskforce |
COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research (506 total candidates in April 2021), with 419 potential COVID-19 drugs in clinical trials, as of April 2021.
As early as March 2020, the World Health Organization (WHO), European Medicines Agency (EMA), US Food and Drug Administration (FDA), and the Chinese government and drug manufacturers were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies. The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.
In March 2020, the WHO initiated the "SOLIDARITY Trial" in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.
Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing. By June 2021, dozens of potential post-infection therapies were in the final stage of human testing – Phase III–IV clinical trials.
== Background ==
Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery. It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug normally takes more than a decade.
The term "preclinical research" is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies, such as experiments to determine effective doses and toxicity in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans. To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 therapies, according to several reports in early 2020. Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating infectious diseases is only 19%.
Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on biomarkers), while closely evaluating possible adverse effects of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is randomized, placebo-controlled, blinded, and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects.
The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%. Depending on its duration (longer more expensive) – typically a period of several months to two years – an average-length Phase II trial costs US$57 million (2013 dollars, including preclinical and Phase I costs). Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research.
Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials.
== Candidates ==
According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included:
antibodies (81 candidates)
antivirals (31 candidates)
cell-based compounds (34 candidates)
RNA-based compounds (6 candidates)
scanning compounds to be repurposed (18 candidates)
various other therapy categories, such as anti-inflammatory, antimalarial, interferon, protein-based, antibiotics, and receptor-modulating compounds.
Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. For an already-approved drug (such as hydroxychloroquine for malaria), Phase III–IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection. As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development, with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020.
Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, are also excluded. Drug candidates in Phase I–II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval. Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection – infectious and respiratory diseases – have a success rate of about 72%.
== Repurposed drug candidates ==
Drug repositioning (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments. Several existing antiviral medications, previously developed or used as treatments for Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, are being researched as COVID-19 treatments, with some moving into clinical trials.
During the COVID-19 pandemic, drug repurposing is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. In the usual drug development process, confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19.
Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution. In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II–III trials on four promising treatment options – the SOLIDARITY trial – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020.
In March 2020, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia."
== Novel antibody drugs ==
=== Convalescent plasma ===
Passive immunization with convalescent plasma or hyperimmune serum has been proposed as a potential treatment for COVID-19. As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvements for people with moderate or severe disease and does not decrease the risk of dying. The potential for adverse effects associated with convalescent plasma treatment is unknown.
In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened. As of May 2021, at least 12 randomized controlled trials on the effectiveness of convalescent plasma treatment were published in peer-reviewed medical journals. In addition, as of May 2021, 100 additional trials were 'ongoing' and 33 studies were reported as 'competed' but not yet published.
Argentina, Brazil, Costa Rica, and Mexico have pursued development of antisera. Brazil began development of an equine hyperimmune serum, obtained by inoculating horses with recombinant SARS-CoV-2 spike protein, in mid-2020. A consortium of Instituto Vital Brazil, UFRJ, the Oswaldo Cruz Foundation and the D'Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020, while Instituto Butantan in São Paulo completed animal testing in September. In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum. This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any statistically significant differences between the serum and placebo groups.
=== Bamlanivimab/etesevimab ===
=== Bebtelovimab ===
=== Casirivimab/imdevimab ===
=== Pemivibart ===
=== Regdanvimab ===
=== Sotrovimab ===
=== Tixagevimab/cilgavimab ===
=== Vilobelimab ===
== Novel viral replication inhibitors ==
=== Molnupiravir ===
== Novel protease inhibitors ==
=== Ensitrelvir ===
=== Nirmatrelvir/ritonavir ===
== Other ==
=== Sabizabulin ===
== Planning and coordination ==
=== Early planning ===
Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European Innovative Medicines Initiative, the US Critical Path Initiative to enhance innovation of drug development, and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs. To accelerate refinement of diagnostics for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed.
According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II–IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019. Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate. Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April. Other potential therapeutic candidates under pivotal clinical trials concluding in March–April are vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2, among others.
The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication. A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April.
By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries, and issued an urgent call to raise and rapidly invest $2 billion for vaccine development. Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments. The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments. In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19.
During March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development, and committed to investments of US$100 million in vaccine development across several countries. The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, with plans to establish a "vaccine bank" of new vaccines for implementation if another COVID-19 outbreak occurs. The Bill & Melinda Gates Foundation invested US$150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics.
==== Computer-assisted research ====
In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery. The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. The Consortium used up 437 petaFLOPS of computing power by May 2020.
The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks.
In March 2020, the distributed computing project Folding@home launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously.
Distributed computing project Rosetta@home also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to "accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab."
In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19".
=== International Solidarity and Discovery Trials ===
In March, the World Health Organization (WHO) launched the coordinated "Solidarity Trial" in 10 countries on five continents to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness. By late April, hospitals in over 100 countries were involved in the trial.
The individual or combined drugs undergoing initial studied are 1) lopinavir–ritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally. Following a study published by The Lancet on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020, reinstated it after the research was retracted, then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit.
With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe. The Solidarity project is designed to give rapid insights to key clinical questions:
Do any of the drugs reduce mortality?
Do any of the drugs reduce the time a patient is hospitalized?
Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?
Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but the WHO needed speed with quality for the trial across many hospitals and countries. A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by INSERM (Paris, France).
The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to John-Arne Røttingen, chief executive of the Research Council of Norway and chairman of the Solidarity trial international steering committee, the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems."
During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management.
A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Adaptive COVID-19 Treatment Trial ===
The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that "there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s)."
=== Operation Warp Speed ===
=== RECOVERY Trial ===
A large-scale, randomized controlled trial named the RECOVERY Trial was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the University of Oxford and is testing five repurposed drugs and also convalescent plasma. The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020.
During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK, expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April. The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose dexamethasone (an anti-inflammatory steroid), hydroxychloroquine, and azithromycin (a common antibiotic). In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit.
On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support. In a controlled trial around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5).
By the end of June 2020, the trial had published findings regarding hydroxychloroquine and dexamethasone. It had also announced results for lopinavir/ritonavir which were published in October 2020. The lopinavir-ritonavir and hydroxychloroquine arms were closed to new entrants after being shown to be ineffective. Dexamethasone was closed to new adult entries after positive results and by November 2020, was open to child entries.
=== PANORAMIC trial ===
Launched in December 2021, the PANORAMIC trial will test the effectiveness of molnupiravir and nirmatrelvir/ritonavir in preventing hospitalisation and helping faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. PANORAMIC is sponsored by the University of Oxford and funded by the National Institute for Health Research (NIHR). As of March 2022 has over 16,000 people enrolled as participants making it the largest study into COVID-19 antivirals.
== See also ==
Cost of drug development
COVID Moonshot
== References ==
== Further reading ==
Kaplon H, Reichert JM (2021). "Antibodies to watch in 2021". mAbs. 13 (1): 1860476. doi:10.1080/19420862.2020.1860476. PMC 7833761. PMID 33459118.
McCreary EK, Pogue JM (April 2020). "Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options". Open Forum Infectious Diseases. 7 (4): ofaa105. doi:10.1093/ofid/ofaa105. PMC 7144823. PMID 32284951.
Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, et al. (2020). "Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline". mAbs. 12 (1): 1854149. doi:10.1080/19420862.2020.1854149. PMC 7755170. PMID 33319649.
Yang L, Liu W, Yu X, Wu M, Reichert JM, Ho M (July 2020). "COVID-19 antibody therapeutics tracker: a global online database of antibody therapeutics for the prevention and treatment of COVID-19". Antib Ther. 3 (3): 205–12. doi:10.1093/abt/tbaa020. PMC 7454247. PMID 33215063.
== External links ==
R&D Blueprint and COVID-19, World Health Organization
Coronaviruses by US National Institute for Allergy and Infectious Diseases
COVID-19 therapeutics tracker Regulatory Affairs Professionals Society
"COVID-19 treatments: research and development". European Medicines Agency (EMA). 18 February 2021. Archived from the original on 23 October 2021. Retrieved 16 June 2021. | Wikipedia/COVID-19_drug_development |
AWcorna, originally termed ARCoV and also known as the Walvax COVID-19 vaccine, is an mRNA COVID-19 vaccine developed by Walvax Biotechnology, Suzhou Abogen Biosciences, and the PLA Academy of Military Science. In contrast to other mRNA COVID-19 vaccines, such as those by Pfizer-BioNTech and Moderna, this vaccine primarily targets the SARS-CoV-2 receptor-binding domain of the spike protein, rather than the entire spike protein. It is approved for Phase III trials in China, Mexico, Indonesia, and Nepal.
It was granted emergency use approval in Indonesia in September 2022.
== Manufacturing ==
ARCoV is an mRNA vaccine which consists of lipid nanoparticle–encapsulated mRNA encoding the receptor binding domain of SARS-CoV-2. It was the first mRNA vaccine to be approved for clinical trials in China. Manufactured as a liquid, ARCoV is thermostable at room temperature for at least 1 week. Reuters later reported that it can be stored at (2–8 °C) for six months.
Scrips noted that Abogen created its own solid lipid nanoparticle to deliver the vaccine.
In December, Walvax started constructing a facility to produce 120 million doses of the vaccine each year. If successful, production of ARCoV could start in early 3rd quarter 2021.
== Clinical trials ==
=== Phase I and II trials ===
Preclinical studies in mice and primates have shown ARCoV elicited a Th1-biased cellular response and robust antibodies against SARS-CoV-2.
In June 2020, Walvax began a Phase I trial to evaluate safety, tolerance, and preliminary immunogenicity with 168 participants aged 18–59 in Hangzhou divided into low-dose, medium-dose, and high-dose groups.
In January 2021, Walvax began a Phase II trial to evaluate immunogenicity and safety of different doses with 420 participants aged 18–59 in Yongfu and Xiangfen divided into low-dose, medium-dose, high-dose, and placebo groups.
In January 2022, the outcome of a Phase 1 study conducted in Shulan (Hangzhou, Zhejiang Province, China) was published in The Lancet. The vaccine doses trialed were 5, 10, 15, 20, 25 μg, and placebo. The trial measured anti-SARS-CoV-2 RBD IgG using a standardised ELISA, and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. IFN-γ and IL-2 production were also measured, so are side effects. It was determined that fever was the most common systemic adverse reaction, but most of the fever resolved within 2 days after vaccination. The 15 μg group induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. All doses were well tolerated. A surprising unsolicited adverse reaction was a low lymphocyte count in those receiving the vaccine. This occurred in the majority of vaccinated individuals regardless of the dose, whereas only 10% of the placebo group encountered such adverse reaction. The authors pointed out that the lymphocyte count recovered to normal after 4 days.
Low lymphocyte count could be a significant adverse event, especially for individuals who are unknowingly infected with SARS-CoV-2 at the time of vaccination. It is well known that a SARS-CoV-2 infection induces a decreased lymphocyte count, and those with a lower lymphocyte count following infection face a significantly worse prognostic. Considering that those infected by the SARS-CoV-2 are already under the strain of a low lymphocyte count, it will be imperative to ensure that those being vaccinated in the future are not infected by the virus at the time of vaccination.
=== Phase III trials ===
The Phase III trials would enroll an estimated 28,000 participants. Elderly people over 60 years old are planned to comprise 25% of trial participants and randomly assigned into the study group and control group at a ratio of 1:1.
In July 2021, Phase III trials started in Yunnan and Guangxi in China with 2,000 people. Those provinces had previously experienced occasional small outbreaks from imported cases.
In August 2021, Phase III trials were approved in Mexico with 6,000 people. Previously in 2020, Walvax had previously expressed an interest in making the vaccine in Mexico.
In August 2021, Phase III trials were approved in Indonesia.
In July 2021, Phase III trials were awaiting approval by Malaysia's National Pharmaceutical Regulatory Agency (NPRA).
In August 2021, Phase III trials were approved in Nepal with 3,000 people in Dharan.
Colombia, Pakistan, and Turkey are other countries being considered for further trials.
== References == | Wikipedia/Walvax_COVID-19_vaccine |
A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.
Some researchers claim that cancerous cells routinely arise and are destroyed by the immune system (immunosurveillance); and that tumors form when the immune system fails to destroy them.
Some types of cancer, such as cervical cancer and liver cancer, are caused by viruses (oncoviruses). Traditional vaccines against those viruses, such as the HPV vaccine and the hepatitis B vaccine, prevent those types of cancer. Other cancers are to some extent caused by bacterial infections (e.g. stomach cancer and Helicobacter pylori). Traditional vaccines against cancer-causing bacteria (oncobacteria) are not further discussed in this article.
== Method ==
One approach to cancer vaccination is to separate proteins from cancer cells and immunize patients against those proteins as antigens, in the hope of stimulating the immune system to kill the cancer cells. Research on cancer vaccines is underway for treatment of breast, lung, colon, skin, kidney, prostate and other cancers.
Another approach is to generate an immune response in situ in the patient using oncolytic viruses. This approach was used in the drug talimogene laherparepvec, a variant of herpes simplex virus engineered to selectively replicate in tumor tissue and to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigens released following viral lysis, creating a patient-specific vaccine.
== Mechanism of action ==
Tumor antigen vaccines work the same way that viral vaccines work, by training the immune system to attack cells that contain the antigens in the vaccine. The difference is that the antigens for viral vaccines are derived from viruses or cells infected with virus, while the antigens for tumor antigen vaccines are derived from cancer cells. Since tumor antigens are antigens found in cancer cells but not normal cells, vaccinations containing tumor antigens should train the immune system to target cancer cells not healthy cells. Cancer-specific tumor antigens include peptides from proteins that are not typically found in normal cells but are activated in cancer cells or peptides containing cancer-specific mutations. Antigen-presenting cells (APCs) such as dendritic cells take up antigens from the vaccine, process them into epitopes, and present the epitopes to T-cells via Major Histocompatibility Complex proteins. If T-cells recognize the epitope as foreign, the adaptive immune system is activated and target cells that express the antigens.
== Prevention vs. treatment ==
Viral vaccines typically work by preventing the spread of the virus. Similarly, cancer vaccines can be designed to target common antigens before cancer evolves if an individual has appropriate risk factors. Additional preventive applications include preventing the cancer from evolving further or undergoing metastasis and preventing relapse after remission. Therapeutic vaccines focus on killing existing tumors. While cancer vaccines have generally been demonstrated to be safe, their efficacy still needs improvement. One way to potentially improve vaccine therapy is by combining the vaccine with other types of immunotherapy aimed at stimulating the immune system. Since tumors often evolve mechanisms to suppress the immune system, immune checkpoint blockade has recently received a lot of attention as a potential treatment to be combined with vaccines. For therapeutic vaccines, combined therapies can be more aggressive, but greater care to ensure the safety of relatively healthy patients is needed for combinations involving preventive vaccines.
== Types ==
Cancer vaccines can be cell-based, protein- or peptide-based, gene-based (DNA/RNA). or live attenuated bacterial- or viral organisms.
Cell-based vaccines include tumor cells or tumor cell lysates. Tumor cells from the patient are predicted to contain the greatest spectrum of relevant antigens, but this approach is expensive and often requires too many tumor cells from the patient to be effective. Using a combination of established cancer cell lines that resemble the patient's tumor can overcome these barriers, but this approach has yet to be effective. Canvaxin, which incorporates three melanoma cell lines, failed phase III clinical trials. Another cell-based vaccine strategy involves autologous dendritic cells (dendritic cells derived from the patient) to which tumor antigens are added. In this strategy, the antigen-presenting dendritic cells directly stimulate T-cells rather than relying on processing of the antigens by native APCs after the vaccine is delivered. The best known dendritic cell vaccine is Sipuleucel-T (Provenge), which only improved survival by four months. The efficacy of dendritic cell vaccines may be limited due to difficulty in getting the cells to migrate to lymph nodes and interact with T-cells.
Peptide-based vaccines usually consist of cancer specific-epitopes and often require an adjuvant (for example, GM-CSF) to stimulate the immune system and enhance antigenicity. Examples of these epitopes include Her2 peptides, such as GP2 and NeuVax. However, this approach requires MHC profiling of the patient because of MHC restriction. The need for MHC profile selection can be overcome by using longer peptides ("synthetic long peptides") or purified protein, which are then processed into epitopes by APCs.
Gene-based vaccines are composed of the nucleic acid (DNA/RNA) encoding for the gene. The gene is then expressed in APCs and the resulting protein product is processed into epitopes. Delivery of the gene is particularly challenging for this type of vaccine. At least one drug candidate, mRNA-4157/V940, is investigating newly developed mRNA vaccines for use in this application.
Live attenuated, ampicillin-susceptible Listeria monocytogenes strains are part of CRS-207 vaccine.
== Clinical trials ==
The clinicaltrials.gov website lists over 1900 trials associated with the term "cancer vaccine". Of these, 186 are Phase 3 trials.
In a Phase III trial of follicular lymphoma (a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID (on average) prolonged remission by 44.2 months, versus 30.6 months for the control.
On April 14, 2009, Dendreon Corporation announced that their Phase III clinical trial of sipuleucel-T, a cancer vaccine designed to treat prostate cancer, had demonstrated an increase in survival. It received U.S. Food and Drug Administration (FDA) approval for use in the treatment of advanced prostate cancer patients on April 29, 2010.
Interim results from a phase III trial of talimogene laherparepvec in melanoma showed a significant tumour response compared to administration of GM-CSF alone.
A 2015 Trial Watch review of peptide-based vaccines summarized the results of more than 60 trials that were published in the 13 months preceding the article. These trials targeted hematological malignancies (cancers of the blood), melanoma (skin cancer), breast cancer, head and neck cancer, gastroesophageal cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and colorectal cancers. The antigens included peptides from HER2, telomerase (TERT), survivin (BIRC5), and Wilms' tumor 1 (WT1). Several trials also used "personalized" mixtures of 12-15 distinct peptides. That is, they contain a mixture of peptides from the patient's tumor that the patient exhibits an immune response against. The results of these studies indicate that these peptide vaccines have minimal side effects and suggest that they induce targeted immune responses in patients treated with the vaccines. The article also discusses 19 clinical trials that were initiated in the same time period. These trials are targeting solid tumors, glioma, glioblastoma, melanoma, and breast, cervical, ovarian, colorectal, and non-small lung cell cancers and include antigens from MUC1, IDO1 (Indoleamine 2,3-dioxygenase), CTAG1B, and two VEGF receptors, FLT1 and KDR. Notably, the IDO1 vaccine is being tested in patients with melanoma in combination with the immune checkpoint inhibitor ipilimumab and the BRAF (gene) inhibitor vemurafenib.
The following table, summarizing information from another recent review shows an example of the antigen used in the vaccine tested in Phase 1/2 clinical trials for each of 10 different cancers:
== Approved oncovaccines ==
Oncophage was approved in Russia in 2008 for kidney cancer. It is marketed by Antigenics Inc.
Sipuleucel-T, Provenge, was approved by the FDA in April 2010 for metastatic hormone-refractory prostate cancer. It is marketed by Dendreon Corp.
CimaVax-EGF was approved in Cuba in 2011. Similar to Oncophage, it is not yet approved for use in the United States, although it is already undergoing phase II trials to that end.
Bacillus Calmette-Guérin (BCG) was approved by the FDA in 1990 as a vaccine for early-stage bladder cancer. BCG can be administered intravesically (directly into the bladder) or as an adjuvant in other cancer vaccines.
== Abandoned research ==
CancerVax (Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and FavId FavId (Favrille Inc) are examples of cancer vaccine projects that have been terminated, due to poor phase III and IV results.
== Desirable characteristics ==
Cancer vaccines seek to target a tumor-specific antigen as distinct from self-proteins. Selection of the appropriate adjuvant to activate antigen-presenting cells to stimulate immune responses, is required. Bacillus Calmette-Guérin, an aluminum-based salt, and a squalene-oil-water emulsion are approved for clinical use. An effective vaccine should also stimulate long term immune memory to prevent tumor recurrence. Some scientists claim both the innate and adaptive immune systems must be activated to achieve total tumor elimination.
== Antigen candidates ==
Tumor antigens have been divided into two categories: shared tumor antigens; and unique tumor antigens. Shared antigens are expressed by many tumors. Unique tumor antigens result from mutations induced through physical or chemical carcinogens; they are therefore expressed only by individual tumors.
In one approach, vaccines contain whole tumor cells, though these vaccines have been less effective in eliciting immune responses in spontaneous cancer models. Defined tumor antigens decrease the risk of autoimmunity, but because the immune response is directed to a single epitope, tumors can evade destruction through antigen loss variance. A process called "epitope spreading" or "provoked immunity" may mitigate this weakness, as sometimes an immune response to a single antigen can lead to immunity against other antigens on the same tumor.
For example, since Hsp70 plays an important role in the presentation of antigens of destroyed cells including cancer cells, this protein may be used as an effective adjuvant in the development of antitumor vaccines.
== Hypothesized problems ==
A vaccine against a particular virus is relatively easy to create. The virus is foreign to the body, and therefore expresses antigens that the immune system can recognize. Furthermore, viruses usually only provide a few viable variants. By contrast, developing vaccines for viruses that mutate constantly such as influenza or HIV has been problematic. A tumor can have many cell types of cells, each with different cell-surface antigens. Those cells are derived from each patient and display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish cancer cells from normal cells. Some scientists believe that renal cancer and melanoma are the two cancers with most evidence of spontaneous and effective immune responses, possibly because they often display antigens that are evaluated as foreign. Many attempts at developing cancer vaccines are directed against these tumors. However, Provenge's success in prostate cancer, a disease that never spontaneously regresses, suggests that cancers other than melanoma and renal cancer may be equally amenable to immune attack.
However, most vaccine clinical trials have failed or had modest results according to the standard RECIST criteria. The precise reasons are unknown, but possible explanations include:
Disease stage too advanced: bulky tumor deposits actively suppress the immune system using mechanisms such as secretion of cytokines that inhibit immune activity. The most suitable stage for a cancer vaccine is likely to be early, when the tumor volume is low, which complicates the trial process, which take upwards of five years and require many patients to reach measurable end points. One alternative is to target patients with residual disease after surgery, radiotherapy or chemotherapy that does not harm the immune system.
Escape loss variants (that target a single tumor antigen) are likely to be less effective. Tumors are heterogeneous and antigen expression differs markedly between tumors (even in the same patient). The most effective vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor mutating and becoming resistant to the therapy.
Prior treatments may have modified tumors in ways that nullify the vaccine. (Numerous clinical trials treated patients following chemotherapy that may destroy the immune system. Patients who are immune suppressed are not good candidates for vaccines.)
Some tumors progress rapidly and/or unpredictably, and they can outpace the immune system. Developing a mature immune response to a vaccine may require months, but some cancers (e.g. advanced pancreatic) can kill patients in less time.
Many cancer vaccine clinical trials target patients' immune responses. Correlations typically show that the patients with the strongest immune responses lived the longest, offering evidence that the vaccine is working. An alternative explanation is that patients with the best immune responses were healthier patients with a better prognosis, and would have survived longest even without the vaccine.
== Recommendations ==
In January 2009, a review article made recommendations for successful oncovaccine development as follows:
Target settings with a low disease burden.
Conduct randomized Phase II trials so that the Phase III program is sufficiently powered.
Do not randomize antigen plus adjuvant versus adjuvant alone. The goal is to establish clinical benefit of the immunotherapy (i.e., adjuvanted vaccine) over the standard of care. The adjuvant may have a low-level clinical effect that skews the trial, increasing the chances of a false negative.
Base development decisions on clinical data rather than immune responses. Time-to-event end points are more valuable and clinically relevant.
Design regulatory into the program from inception; invest in manufacturing and product assays early.
== See also ==
Immunotherapy
Cancer immunotherapy
Coley's toxins
Chemoprophylaxis
HPV vaccines
Therapeutic vaccines
Cancer vaccine targeting CD4+ T cells
Personalized mRNA cancer vaccine therapy
Ludwig Institute for Cancer Research
Cancer Research Institute
== References ==
== External links ==
Cancer Immunotherapy Consortium (coordinated early-phase clinical trials of therapeutic cancer vaccines)
Society for Immunotherapy of Cancer
Association for the Immunotherapy of Cancer
Tumor antigen vaccine entry in the public domain NCI Dictionary of Cancer Terms
List of cancer vaccine clinical trials at clinicaltrials.gov.
[1] | Wikipedia/Tumor_antigen_vaccine |
The Inter-Agency Task Force for the Management of Emerging Infectious Diseases (IATF-EID) is an inactive task force organized by the executive of the government of the Philippines to respond to affairs concerning emerging infectious diseases in the country.
== History ==
The IATF-EID was created through Executive Order No. 168 issued by President Benigno Aquino III in 2014. It was organized as the government's instrument to assess, monitor, contain, control and prevent the spread of any potential epidemic in the Philippines.
== Mandate ==
An inter-sectoral collaboration to establish preparedness and ensure efficient government response to assess, monitor, contain, control, and prevent the spread of any potential epidemic in the Philippines.
=== COVID-19 pandemic ===
The IATF-EID convened in January 2020 to address the growing viral outbreak in Wuhan, China. They made a resolution to manage the spreading of the new virus, which was known at the time as 2019 novel coronavirus (2019-nCoV) and eventually renamed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. On March 9, 2020, President Duterte called the IATF-EID amidst the rising cases of COVID-19 in the Philippines, after declaring a state of public health emergency on the disease.
On March 25, 2020, the IATF-EID revealed a National Action Plan (NAP) to slow down the spread of COVID-19. The NAP was created to effectively and efficiently implement and decentralize the system of managing the COVID-19 pandemic. In addition, the IATF-EID created the National Task Force Against COVID-19 headed by Department of National Defense Secretary Delfin Lorenzana, which handles the operational command. At the same time, the IATF-EID became the "policy-making body of operations" while the National Incident Command administers the daily concerns and operations.
The Joint Task Force COVID-19 Shield (JTF-CV Shield) was a task force intended to enforce quarantine protocols in border checkpoints and streets, and maintain peace, order, and security throughout the country to help control the spread of COVID-19. The task force is composed of the Philippine National Police (PNP), the Armed Forces of the Philippines (AFP), the Philippine Coast Guard (PCG), the Bureau of Fire Protection (BFP), and Barangay tanods.
To be able to respond to more localized issues and concerns, Regional Inter-Agency Task Force in their respective regions were organized. Local Government Units (LGU’s) in the provinces, cities, municipalities, and barangays were Local Inter-Agency Task Forces chaired by the Local Chief Executives and Barangay Captains/Chairmen were organized.
Following the withdrawal of the State of Public Health Emergency on COVID-19 on July 22, 2023, the task force was deactivated.
== Composition ==
The IATF-EID is composed of the following executive departments and agencies:
Chair: Department of Health
Co-Chair:
Department of the Interior and Local Government
Members
Department of Agriculture
Department of Budget and Management
Department of Education
Department of Finance
Department of Foreign Affairs
Department of Information and Communications Technology
Department of Justice
Department of Labor and Employment
Department of Migrant Workers
Department of National Defense
Department of Public Works and Highways
Department of Science and Technology
Department of Social Welfare and Development
Department of Tourism
Department of Trade and Industry
Department of Transportation
Office of the Executive Secretary
Presidential Communications Office
Presidential Management Staff
Office of the Special Assistant to the President
Commission on Higher Education
Technical Education and Skills Development Authority
National Economic and Development Authority
Office of the Chief Presidential Legal Counsel
Civil Service Commission
National Security Council
National Disaster Risk Reduction and Management Council
The Joint Task Force COVID-19 Shield was composed of the following who ensured that IATF Guidelines/Protocols were strictly enforced.
Lead Agency: Philippine National Police
Members:
Armed Forces of the Philippines
Bureau of Fire Protection
Philippine Coast Guard
Office of Civil Defense
All local government units
== Legal actions ==
The resolutions issued by the IATF-EID in relation to the COVID-19 pandemic were the subject of petitions separately filed in 2022 by Jose Montemayor Jr., Nicanor Perlas III, and the Passengers and Riders Organization (Pasahero) Inc. The petitioners questioned the constitutionality of directives issued by the IATF-EID, as well as by government agencies and local government units, particularly Makati, arguing that these violated right to life and liberty without due process of law, hindered right to travel, and are discriminatory against the unvaccinated.
On July 11, 2023, the Supreme Court en banc unanimously dismissed these petitions which had been consolidated, thus upholding the constitutionality of the regulations.
== Notes ==
== References == | Wikipedia/Inter-Agency_Task_Force_for_the_Management_of_Emerging_Infectious_Diseases |
A vaccine passport or proof of vaccination is an immunity passport employed as a credential in countries and jurisdictions as part of efforts to control the COVID-19 pandemic via vaccination. A vaccine passport is typically issued by a government or health authority, and usually consists of a digital or printed record. Some credentials may include a scannable QR code, which can also be provisioned via mobile app. It may or may not use a COVID-19 vaccine card as a basis of authentication.
The use of vaccine passports is based on the general presumption that a vaccinated individual would be less likely to transmit SARS-CoV-2 to others, and less likely to experience a severe outcome (hospitalization or death) if they were to be infected, thus making it relatively safer for them to congregate. A vaccine passport is typically coordinated with policies enforced by individual businesses, or enforceable public health orders, that require patrons to present proof of vaccination for COVID-19 as a condition of entry or service.
Government-mandated use of vaccine passports typically applies to discretionary public spaces and events (such as indoor restaurants, bars, or large-scale in-person events, such as concerts and sports), and not essential businesses, such as retail stores or health care. In France, Italy, Ireland, and Canada, vaccine uptake increased after various levels of governments announced plans to introduce vaccine passports. An intention by some jurisdictions is to prevent future lockdowns and restrictions.
Vaccine passports are controversial and have raised scientific, ethical and legal concerns. Critics have also argued that vaccine passports violate civil liberties via coercion. In the United States, there is no vaccine passport at a federal level, and some US states have preemptively banned vaccine passports in certain public and private sector contexts, citing discrimination and privacy concerns. England initially decided against mandating vaccine passports due to worries that discrimination and economic harm would occur, but later joined the other nations of the United Kingdom in mandating vaccine passports due to the threat of the Omicron variant.
== History and background ==
Many governments, including Finland and Germany, expressed early interest in the concept. Vaccine passports were seen as a potential way to permit a faster economic recovery from large-scale lockdowns that apply to all residents (especially within the travel and tourism industries), improve the confidence of patrons concerned for their health and safety, and to incentivize vaccination in order for a population to potentially reach "herd immunity".
In May 2020, Chile started issuing "release certificates" to patients who had recovered from COVID-19, but "the documents will not yet certify immunity". Many governments including Finland, Germany, the United Kingdom, and the United States expressed interest in the concept.
The Royal Society published a report on 19 February 2021 where a lead author of the report, Professor Melinda Mills, Director of the Leverhulme Centre for Demographic Science at the University of Oxford said: “Understanding what a vaccine passport could be used for is a fundamental question – is it literally a passport to allow international travel or could it be used domestically to allow holders greater freedoms? The intended use will have significant implications across a wide range of legal and ethical issues that need to be fully explored and could inadvertently discriminate or exacerbate existing inequalities.” The report lists 12 essential criteria for an international standard.
On 12 March 2021, Ecma International announced its intention to create an international standard which prevents counterfeits and protects private data as much as possible in a "Call for Participation on Vaccine Passports International Standardization" that referenced the earlier report from the UK's Royal Society. In August 2021, Ecma International announced revisions to Ecma-417 (Architectures for distributed real-time access systems) relevant to standards for vaccine passports.
An early advocate of immunity passports during the COVID-19 pandemic was Sam Rainsy, the Cambodian opposition leader. In exile and under confinement in Paris, he proposed immunity passports as a way to help restart the economy in a series of articles which he began in March 2020 and published in The Geopolitics and The Brussels Times. The proposals were also published in French. The idea became increasingly relevant as evidence of lasting acquired immunity became clear.
Proponents of the idea such as Sam Rainsy, co-founder of the opposition Cambodia National Rescue Party (CNRP) have argued that immunity, whether acquired naturally or through vaccination, is a resource which needs to be used to limit the impact of the pandemic on the global economy. Many people in Cambodia depend entirely for their living on a tourism industry which has been wiped out. Poor countries can also benefit from recording immunological status as this will reduce wastage of scarce vaccines. The immunity passport proposed by Rainsy was effectively adopted in the EU under the name of "health pass".
As of 4 April 2021, it was not yet clear whether vaccinated people that remain asymptomatic are still contagious and are thus silent spreaders of the virus putting unvaccinated people at risk. "A lot of people are thinking that once they get vaccinated, they’re not going to have to wear masks anymore," said Michal Tal, an immunologist at Stanford University. "It’s really going to be critical for them to know if they have to keep wearing masks, because they could still be contagious."
In January 2021, Israel announced that Israelis who had received their second vaccination and those who had proof of recovery from infection would be eligible for a Green Pass, exempting them from isolation requirements and mandatory COVID-19 tests, including those on arrival from overseas. In February 2021, Israel became one of the first countries to implement a vaccine passport system, dubbed the Green Pass. They are required in order to access venues such as gyms, hotels, bars, and restaurants. In October 2021, Israel announced an update to its guidelines, requiring that the most recent vaccine dose (or proof of recovery) to have been during the past six months. This change made Israel the first country to make a booster shot a requirement for its vaccine passport system.
== By region ==
=== Africa ===
==== Morocco ====
In August 2021, Morocco established a nightly curfew between 23:00 and 04:30, exempting those fully vaccinated. The curfew was lifted in November 2021.
=== Asia ===
==== Azerbaijan ====
Beginning on 1 September 2021, Azerbaijan required proof of vaccination for people over 18 to enter virtually all public spaces, and a national mandate of 1 October required vaccination of all state-regulated workers.
==== China ====
In February 2020, China started to use digital "health codes", available on a variety of platforms including WeChat and Alipay with scannable QR barcodes displaying a "traffic light" system of colours to enter public transport, shops, restaurants and malls. It was used 40 billion times between February and March.
In March 2021, an "International Travel Health Certificate" was created. In March 2021, the government of China rolled out the world's first COVID-19 vaccine passport system through a partnership with Alipay and WeChat. The system provides a health certificate that includes an individual's vaccine status and the results of COVID-19 testing. Initially, the system would only indicate that an individual had been vaccinated if they received a Chinese-made coronavirus vaccine, leading to criticism, though by April 2021 the system began to accept records of receiving the Pfizer-BioNTech, Moderna, and Janssen vaccines. As of March 2021, the app was optional and its use was restricted to Chinese citizens. The digital health passport is intended to better facilitate travel. Privacy advocates and Chinese netizens have expressed concerns regarding the potential invasive data collection and the use of data for non-health monitoring purposes.
==== Iran ====
According to Minister of health and education requires passport number, Iranian national ID card code for issuing vaccine digital foreign travel card.
==== Israel ====
Israel was one of the first countries to issue what is known as a Green Pass in February 2021. The pass was discontinued on 1 June 2021, but following a surge of new infections, it was reinstated on 29 July 2021. In October 2021, all existing Green Passes were voided if the most recent shot was administered more than 6 months ago. A new pass would be issued upon proof of a third (booster) dose or a recovery within the past 6 months. A temporary Green Pass could also be obtained with a negative viral test, but must be paid for by the individual unless ineligible for vaccination. Starting 1 March 2022, most COVID-19 regulations were relaxed, and a Green Pass is now only required to enter old age homes.
==== Japan ====
On 19 July 2021, Japan began accepting applications for its COVID-19 vaccination passport program. When issued, the passports will be in paper form in both Japanese and English, showing the holder's date(s) of inoculation and the vaccine type, and are available free of charge. As of 20 December 2021, entry restrictions were relaxed for Japan vaccine passport holders in 76 countries.
==== Saudi Arabia ====
Residents attending restaurants, cafes and public spaces like malls, shopping centres and markets must be fully vaccinated. The country uses the Tawakkalna app which includes information for health appointments, vaccination status and alerts users to COVID-19 exposure for contact tracing purposes.
==== Singapore ====
Since 10 August 2021, all residents dining out must be fully vaccinated by showing proof of vaccination using the TraceTogether or HealthHub app, or use the TraceTogether token. Proof of vaccination has been progressively implemented in almost all public venues since 13 October 2021, starting with shopping malls, retail shops, entertainment venues except bars, nightclubs and karaoke parlours, attractions, cruises and eateries. It has since been expanded to include large events, public libraries, selected events at community buildings and will be expanded to tertiary institutions, places of lodging, small events and workplaces from January 2022.
==== South Korea ====
On 1 November 2021, a vaccine passport system went into effect in South Korea as part of a "living with COVID-19" strategy, requiring vaccination of all residents wishing to access high-risk areas such as bars, restaurants, gyms and saunas must be vaccinated.
==== Taiwan ====
On 25 October 2021, the Taiwanese government announced that the digital COVID certificate system in the country had been completed. In December 2021, the system was also recognised by the EU as an equivalent of the EU Digital Covid Certificate. On 20 January 2022, Taiwan officially released the certificate and implemented rules that it be required before entering bars or karaoke alike.
=== Europe ===
==== European Union ====
The European Union offers an EU Digital COVID Certificate (EUDCC), also known as the Green Pass, a digitally-signed proof of vaccination, proof of a recent recovery, or a recent negative test, for use when travelling within the Schengen area with fewer restrictions.
===== Bulgaria =====
On 19 October 2021, the caretaker Minister of Health of Bulgaria, Stoycho Katsarov, introduced the Green Certificate (Bulgarian: Зелен Сертификат). Since 21 October 2021, all visitors to cinemas, theaters, concerts, museums, galleries, supermarkets over 300 square meters, fitness centers, gyms, restaurants and entertainment centers in Bulgaria have to prove that they are vaccinated, have a valid negative test from last 72 hours or have been ill recently. The restrictions ended on 10 March 2022.
===== Denmark =====
Denmark introduced a Coronapas on 21 April 2021. Those unvaccinated with a recently negative test of 72 hours or previous infection of COVID-19 of up to 12 weeks prior were included in the pass system. Due to the high uptake of vaccines, Denmark retired their system on 10 September 2021.
===== France =====
France issued a Health Pass (or Pass Sanitaire in French) on 9 August 2021, for use in non-essential settings for those 18 and older. To obtain the pass people must be fully vaccinated or undertake a test within 72 hours of attending a non-essential space or have recovered recently from an infection of the virus. The initial announcement of the pass system is believed to have encouraged an additional one million people to sign up for vaccination the day following the announcement, and is credited to encouraging a further 3.7 million people to sign up for vaccination in the following week. Starting 1 October 2021, those age 12 and older will require a Pass Sanitaire to enter public sites like restaurants, cinemas, and sporting events.
===== Germany =====
In Germany, proof of COVID vaccinations or recent recovery, is typically entered in the International Certificate of Vaccination or Prophylaxis (German: Impfausweis), similar to how other vaccinations for other diseases are recorded. The entry in this booklet can be used to acquire an EU Digital COVID Certificate, in accordance with EU Directive 2021/953, effective 1 July 2021.
===== Hungary =====
Outside of the application of the EUDCC, Hungary recognises Kazakh and Indian vaccine passports.
===== Ireland =====
In July 2021, Ireland introduced a vaccine certificate program (EU Digital COVID Certificate) which allowed vaccinated individuals to attend cafes, bars and restaurants. Due to one of the highest uptakes of COVID-19 vaccines in the world, the Republic of Ireland (but not Northern Ireland) had plans to retire their vaccine passport program on 22 October 2021 however this was postponed due to increased COVID-19 cases and hospital numbers. On 22 January 2022, the Republic of Ireland's vaccine passport programme was retired, except for international travel.
===== Italy =====
In August 2021 the Italian government extended the requirement of the EU Digital COVID Certificate, also known as a Green Pass, to the participation in sports events and music festivals, but also to access to indoor places like bars, restaurants and gyms, as well as to long-distance public transportation. On 15 October 2021, Italy became the first country in the world to require its entire workforce, public and private, to have a government-issued health pass.
===== Sweden =====
On 1 December 2021 the Swedish government introduced vaccine passports for indoor events with more than 100 people. Indoor events with more than 100 participants who do not use vaccination certificates must follow specific guidelines to avoid spreading the disease.
===== Ukraine =====
In Ukraine, citizens with at least one dose of a vaccine are allowed to attend certain high-risk indoor settings which would normally be closed or heavily restricted in hot spots.
===== United Kingdom =====
Proof of vaccination programs exist in the Home Nations of the United Kingdom, with England and Wales referring to them as "NHS COVID Pass", Scotland as "NHS Scotland Covid Status", and Northern Ireland as "COVIDCert NI". By December 2021, all four nations had mandated proof of vaccination or a recent negative test in specific settings. The exact rules vary by nation, but they primarily applied to venues such as cinemas, nightclubs, and venues hosting large organized events (including but not limited to concerts and sporting events).
In September 2021, Secretary of Health Sajid Javid stated that England would not implement a mandate for proof of vaccination, following pushback from Conservative members of parliament and business leaders over potential discrimination and economic harm. Prime Minister Boris Johnson subsequently stated that England would focus on a strategy of contact tracing, rapid testing, and the rollout of vaccine boosters, and only included mandatory proof of vaccination in a package of "plan B" measures (including a reintroduction of mask mandates) in the event of another surge of COVID-19 cases. The spread of Omicron variant in England would lead to the implementation of "plan B", resulting in proof of vaccination for nightclubs and large events becoming mandatory beginning 15 December. These restrictions ended on 27 January 2022.
===== North Macedonia =====
Residents wishing to attend events, bars, restaurants, and other dining establishments must present proof of vaccination.
=== North America ===
==== Canada ====
The implementation of digital proof of vaccination in Canada has largely been conducted at the provincial and territorial level, with the federal government specifying the SMART Health Card document and QR code standard designed to be suitable for international travel.
As of November 2021, all ten provinces in Canada, and two of the three territories, had implemented or announced plans to implement a provincially-regulated vaccine passport.
==== Federal requirements and mandates ====
Beginning 30 October 2021 proof of vaccination became mandatory for all passengers aged 12 and older boarding domestic and/or international commercial airplanes departing from most Canada-based airports, and those riding on the cross-country Via Rail services.
Travellers by land (via the United States border) are required to be fully vaccinated to enter Canada and must provide a negative test 72-hours before land crossing. An exception was made for essential workers, until January 15, 2022 when essential workers (mainly truckers) were required to be fully vaccinated to re-enter the country. In late-January 2022, a convoy to and demonstration in the federal capital of Ottawa—supported primarily by far-right activists and groups—was held to protest this change.
===== Alberta =====
Alberta implemented the Restrictions Exemption Program (REP) from 20 September 2021 to 8 February 2022, after re-establishing a state of emergency on 15 September 2021. The government described the program as an opt-in system, allowing establishments to operate with fewer restrictions. Visitors at these establishments were required to present a proof of vaccination or a recent negative test. If a facility does not participate, or is prohibited from participating, it was required to comply with all public health orders, such as reduced capacity and/or being prohibited from offering indoor dining.
Due to Omicron variant, even establishments participating in REP became subject to restrictions in December 2021, including restrictions on the capacity of large venues (50%), and restaurants subject to limits on table sizes, a prohibition on entertainment, and operating hours.
The city of Calgary passed a municipal bylaw on 23 September 2021 to mandate participation in REP by all industries that are eligible to do so. The bylaw ceased on 9 February 2022 due to the lifting of the REP by the provincial government. The city considered reimplementing the mandate at the municipal level (as haveseveral U.S. cities) but such a proposal was rejected by the city council committee.
===== Manitoba =====
Manitoba was the first province to introduce a passport system in Canada on 17 July 2021. The passport requirement was removed for movie theatres, museums and galleries on 7 August 2021, only to be reinstated on 3 September 2021, upon Manitoba expanding its passport system. The province utilized physical Immunization Cards which faced supply shortages in production.
===== Quebec =====
Quebec was the second province to implement a vaccine passport system on 1 September 2021, using QR codes.
===== Northwest Territories =====
The Northwest Territories will implement an opt-in vaccine passport system on 22 October 2021 using original vaccination receipts.
===== Other provinces =====
British Columbia has created a Proof of vaccination system which utilises a QR code. The system initially relied on paper receipts of the BC vaccine receipt and gradually migrated to a digital system. The QR code can also be physically printed out.
New Brunswick requires a Proof of Vaccination system using original immunisation records.
Newfoundland and Labrador has plans to release a QR code based system for their vaccine passport.
Nova Scotia has a Proof of Full Vaccination Policy using original government issued proof of vaccination.
Ontario introduced a vaccine passport system on 22 September 2021. The system initially relied on original vaccine paper receipts, but gradually began switching over to verifiable QR codes along with the introduction of the "Verify Ontario" mobile app on 22 October 2021. As of 4 January 2022, only vaccine receipts with verifiable QR codes and the "Verify Ontario" mobile app will be accepted at venues where proof of vaccine is required.
Prince Edward Island uses the PEI Vax Pass Program using original government issued vaccination information.
Saskatchewan has a Proof of vaccination mandate, effective from 1 October 2021 to 13 February 2022.
Yukon territory will implement a passport system on 30 November 2021 to access non-essential indoor facilities.
==== United States ====
Although the Centers for Disease Control and Prevention (CDC) issues a COVID-19 vaccine card that may be accepted as proof of vaccination (but is vulnerable to forgery and counterfeiting, and thus not a verifiable proof of vaccination), the United States does not have a federal framework for a digital vaccine passport, and federal officials explicitly ruled out doing so, citing privacy and human rights concerns. This leaves their implementations up to individual states and territories.
Prior to the issue becoming politicised, public views on vaccine passports were evenly split and the divide crossed, rather than followed, political and ideological lines. Since then, criticism and conspiracy theories surrounding the vaccines in general, and in turn vaccine mandates, largely came from the political right; for example, U.S. representative for Georgia's 14th congressional district Marjorie Taylor Greene, a Republican, asserted that requesting the disclosure of one's vaccine status was a violation of data privacy rules for the health care industry, even though said rules only apply to entities such as health insurers.
The state governments of California, Hawaii, Louisiana, New York, North Carolina, Delaware, and Virginia have each rolled out mechanisms where residents can choose to receive proof of COVID-19 vaccination in the form of a scannable QR code by linking to records within each state's immunization registry. Illinois has a Vax Verify website, where residents can download proof of COVID-19 vaccination for businesses that require it. In New Jersey, residents can obtain a digital COVID-19 vaccination record through its mobile app Docket; Governor Phil Murphy specifically avoided using the term "vaccine passport" to describe the service.
Each state credential has varying degrees of interoperability with other state and foreign governments; some states have closed systems, with QR codes that are only usable within the issuing state, and others have broad interoperability, with New York offering both types of credentials for its residents. Arizona, Maryland, Mississippi, North Dakota, Washington, West Virginia, Puerto Rico, and the District of Columbia have contracted with the organization MyIR that interfaces with governmental vaccination records to produce a PDF proof of vaccination, but has also moved toward scannable QR codes. Health departments in Indiana, Colorado, and Georgia can provide proof of vaccination in PDF form but not via a QR code.
At least 20 states have prohibited public agencies from issuing or requiring a vaccine passport, while Alabama, Florida, Iowa, Montana, and Texas also made it illegal for any private entity to request proof of vaccination as a condition of service, under the assertion that they discriminate against those who have made a personal choice to not receive the vaccine.
===== Los Angeles County =====
Los Angeles County began a proof of vaccination system for indoor bars, restaurants, venues and nightclubs on 7 October 2021.
===== New York City =====
New York City began its Excelsior Pass or Key to NYC vaccine passport system for dining, fitness, events and indoor entertainment on 13 September 2021.
===== New Orleans =====
New Orleans began to require proof of vaccination or a negative test to enter indoor bars, restaurants, events, fitness, and sporting events on 16 August 2021.
=== South America ===
==== Brazil ====
In December 2020, the Brazilian Senate approved a document giving digital proof of all vaccinations – not just those in respect of COVID-19. However, the urgency for creating such a digital proof of vaccination came from the COVID-19 pandemic.
==== Chile ====
In May 2021, then Health Ministry Subsecretary, Paula Daza, mandated the "mobility pass" (pase de movilidad) in gyms, restaurants and swimming pools. This document was given to people with two doses of the COVID-19 vaccine, later it was upscaled to three doses and later on in the same year four doses were required, being one of the most drastic vaccines passports in the world. Chile is the only country in the world with entry procedures such as requiring homologation of vaccines to travel to.
=== Oceania ===
==== New Zealand ====
On 17 November 2021, the New Zealand Government launched a vaccine certificate called My Vaccine Pass for individuals who have been vaccinated against COVID-19. The vaccine pass is required to enter hospitality venues, community, sport and faith-based gatherings as defined by the COVID-19 Protection Framework.
They came into force on 29 November 2021. On 23 November, the New Zealand Government launched the NZ Pass Verifier to scan the passes.
On April 5, 2022, vaccine passes will no longer be required for most venues.
On June 1, 2022, all vaccine passes will become invalid, and will no longer be required for any venue.
== Arguments and controversy ==
As of September 2021, the World Health Organization (WHO) acknowledged that mandatory COVID-19 vaccine passports would be discriminatory against countries with little access to vaccinations, but could eventually be considered for international travel when vaccine access improves.
=== Effect on vaccine uptake ===
In some jurisdictions, vaccine uptake increased after various levels of governments announced plans to mandate their use.
=== Ethical and social issues ===
The ethical issues that arise in the acceptability of vaccine passports revolve around the policy objectives and the intended use. The public health restriction on implementing vaccine passports limits the freedom of an individual to perform social activities.
People who are privileged to receive the vaccination will have gained access to going back to normal life while low-income populations will remain disproportionately low on vaccinations which hinders their ability to participate in non-essential activities.
Due to the imbalance in the distribution of vaccines in the developing world, there are concerns about the inequity of vaccine passports for travellers. On 15 April 2021, the World Health Organization's emergency committee opposed vaccination passports, saying, "States parties are strongly encouraged to acknowledge the potential for requirements of proof of vaccination to deepen inequities and promote differential freedom of movement".
However, many countries may increasingly consider the vaccination status of travellers when deciding to allow them entry or whether to require them to quarantine. "Some sort of vaccine certificate will be important" to reboot travel and tourism, according to Dr. David Nabarro, special envoy on COVID-19 for the WHO, in February 2021.
In March 2021, Bernardo Mariano, the WHO's Director of Digital Health and Innovation, said that "We don't approve the fact that a vaccination passport should be a condition for travel." Lawmakers in several US states are also considering legislation to prohibit COVID-19 vaccination passports.
Ethical concerns about vaccine passports have been raised by Human Rights Watch (HRW). According to HRW, requiring vaccine passports for work or travel could force people into taking tests or risk losing their jobs, create a perverse incentive for people to intentionally infect themselves to acquire immunity certificates, and risk creating a black market of forged or otherwise falsified vaccine cards.
By restricting social, civic, and economic activities, vaccine passports may "compound existing gender, race, ethnicity, and nationality inequities." Immunity certificates also face privacy and human rights concerns.
=== Digital privacy ===
A security vulnerability in the app used by New Jersey and Utah briefly made it possible to request the QR codes of other users, containing encoded name, date of birth, and vaccination history information. On 24 September 2021, Saskatchewan Health Authority stated that digital vaccine records obtained in the province between 19 and 24 September may have accidentally contained the wrong QR code for the specific user.
=== Vaccination certificates ===
=== Natural immunity ===
People may acquire a degree of natural immunity from SARS-CoV-2 when they are exposed to the live virus, and develop a primary immune response which produces antibodies that can recognize specific variants. As of May 2021, the WHO reported that more than 90% of individuals established recognizable antibodies within four weeks after an infection. For most people, these detectable antibodies roughly stay for at least 6–8 months. However, antibodies may not guarantee immunity from novel variants and mutations of SARS-CoV-2. The uncertainty of the science behind immunity to SARS-CoV-2 has raised issues over their applicability within passport frameworks.
It has been argued that the primary difference is that vaccination certificates such as the Carte Jaune incentivize individuals to obtain vaccination against a disease, while immunity passports incentivize individuals to get infected with and recover from a disease.
== See also ==
COVID-19 vaccine card
COVID-19 vaccine
Deployment of COVID-19 vaccines
Electronic health record
Living with COVID-19
Patient record access
Vaccination requirements for international travel
== References == | Wikipedia/Vaccine_passports_during_the_COVID-19_pandemic |
The PANORAMIC trial (short for Platform Adaptive Trial of Novel Antivirals for Early Treatment of COVID-19 in the Community) is a clinical trial in the United Kingdom testing the effectiveness of new antiviral drugs at the early stages of COVID-19 infections. The study aims to find out if antivirals can prevent death and hospitalisation and help faster recovery for people aged over 50 and those at higher risk due to underlying health conditions. The trial was launched in December 2021, and had nearly 30,000 people enrolled as participants.
== Overview ==
PANORAMIC is a platform trial that compares groups who are having symptoms of COVID: one receives standard care (same as best care in the NHS) and others receive standard care plus antiviral treatment. Participants take part from home online or via phone and the antivirals are delivered to them.
=== Participants ===
People could enroll in the study if they had symptoms of COVID (confirmed by a test) less than 5 days prior to enrolling. They had to be either aged 50 or over, or have a preexisting health condition.
=== Treatments ===
The antivirals tested in the study were molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid).
== Results ==
=== Molnupiravir ===
Results from the trial showed that for higher risk, vaccinated adults molnupiravir does not reduce the chances of hospitalisation and death. However molnupiravir was found to help people recover four days sooner and reduces the amount of virus in the body (viral load). Participants receiving molnupiravir reported feeling better in comparison to those who received usual care.
Even though molnupiravir reduced the amount of virus after a 5-day treatment, the virus was still present and infectious in some of the participants. Furthermore those taking the medicine had fewer antibodies compared to those who did not which is a potential issue for boosting immunity.
After a 6-month follow-up, the PANORAMIC study showed that people who took the antiviral molnupiravir felt better, had fewer and less severe COVID-19 symptoms, took less time off and needed healthcare services less compared to those who received standard care. However, differences between the two groups were small and were evident only if a large number of people received molnupiravir.
=== Nirmatrelvir/ritonavir ===
As of March 2025, the results of PANORAMIC regarding nirmatrelvir/ritonavir are still being analysed.
== Significance ==
According to a paper reviewing how the PANORAMIC trial was delivered, learnings from the trial could be useful in preparing for future pandemics and for health research in general. The main recommendation of the review was that research conducted in primary care settings (as opposed to hospitals) should play a central role in future pandemics to help prevent the worsening of symptoms and hospitalisation. Further recommendations included the use of the platform study format, focusing on recruiting participants in care homes, and working on ways to rapidly deliver medicine to participants. The review also stressed the importance of building trust with diverse communities so that participation and involvement in research can be inclusive.
== Leadership and funding ==
The trial is led by Chris Butler and Richard Hobbs (University of Oxford) and Paul Little (University of Southampton). PANORAMIC is sponsored by the University of Oxford and funded and delivered by the National Institute for Health and Care Research (NIHR).
== Awards ==
The PANORAMIC trial received the Prix Galien Best Public Sector Innovation Award in 2024.
== See also ==
COVID-19 drug repurposing research
COVID-19 drug development
AGILE trial
RECOVERY Trial
Solidarity trial
== References ==
== External links ==
Official website | Wikipedia/PANORAMIC_trial |
COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy, effectiveness, and safety. As of November 2022, 40 vaccines are authorized by at least one national regulatory authority for public use:
one DNA vaccine: ZyCoV-D
four RNA vaccines: Pfizer–BioNTech, Moderna, Walvax, and Gemcovac
twelve inactivated vaccines: Chinese Academy of Medical Sciences, CoronaVac, Covaxin, CoviVac, COVIran Barekat, FAKHRAVAC, Minhai-Kangtai, QazVac, Sinopharm BIBP, WIBP, Turkovac, and VLA2001.
six viral vector vaccines: Sputnik Light, Sputnik V, Oxford–AstraZeneca, Convidecia, Janssen, and iNCOVACC
sixteen subunit vaccines: Abdala, Corbevax, COVAX-19, EpiVacCorona, IndoVac, MVC-COV1901, Noora, Novavax, Razi Cov Pars, Sanofi–GSK, Sinopharm CNBG, Skycovione, Soberana 02, Soberana Plus, V-01, and ZF2001.
one virus-like particle vaccine: CoVLP
As of June 2022, 353 vaccine candidates are in various stages of development, with 135 in clinical research, including 38 in phase I trials, 32 in phase I–II trials, 39 in phase III trials, and 9 in phase IV development.
== Formulation ==
A wide variety of technologies are being used to formulate vaccines against COVID-19. The development and deployment of mRNA vaccines and viral vector vaccines has been outstandingly rapid and can be described as revolutionary. However, global vaccine equity against COVID-19 has not been achieved. Conventional vaccine manufacturing approaches using whole inactivated virus (WIV), protein-based subunit vaccines, and virus-like particles (VLPs) may offer advantages in the development of vaccines for use in low- and middle-income countries (LMICs) and in addressing vaccine access gaps.
Many vaccine candidates use adjuvants to enhance immunogenicity, as part of the delivery system or as an accompanying immune stimulant. Vaccine adjuvant formulations using aluminum salts or "alum" may be particularly effective for technologies using inactivated COVID-19 virus and for recombinant protein-based or vector-based vaccines.
== Status ==
=== Clinical trials ===
The clinical trial process typically consists of three phases, each following the success of the prior phase. Trials are doubly blind in that neither the researcher nor the subject know whether they receive the vaccine or a placebo. Each phase involves randomly-selected subjects who are randomly assigned to serve either as recipients are controls:
Phase I trials test primarily for safety and preliminary dosing in healthy subjects. Dozens of subjects.
Phase II trials evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects. Hundreds of subjects. Sometimes Phase I and II trials are combined.
Phase III trials typically involve more participants at multiple sites, include a control group, and test effectiveness of the vaccine to prevent the disease (an "interventional" or "pivotal" trial), while monitoring for adverse effects at the selected dose. Safety, efficacy, and clinical endpoints may vary, including the definition of side effects, infection or amount of transmission, and whether the vaccine prevents moderate or severe infection.
A clinical trial design in progress may adopt an "adaptive design". If accumulating data provide insights about the treatment, the endpoints or other aspects or the trial can be adjusted. Adaptive designs may shorten trial durations and use fewer subjects, possibly expediting decisions, avoiding duplication of research efforts, and enhancing coordination of design changes.
=== Vaccine candidates in human trials ===
The table below shows various vaccine candidates and the phases which they had completed per the references. Current phases are also shown along with other details.
==== Homologous prime-boost vaccination ====
In July 2021, the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) issued a joint statement reporting that a booster dose is not necessary for those who have been fully vaccinated.
In August 2021, the FDA and the CDC authorized the use of an additional mRNA vaccine dose for immunocompromised individuals. The authorization was extended to cover other specific groups in September 2021.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
==== Heterologous prime-boost vaccination ====
The World Health Organization (WHO) defines heterologous prime-boost immunization as the "administration of two different vectors or delivery systems expressing the same or overlapping antigenic inserts." A heterologous scheme can sometimes be more immunogenic than some homologous schemes.
In October 2021, the FDA and the CDC authorized the use of either homologous or heterologous vaccine booster doses.
Some experts believe that heterologous prime-boost vaccination courses can boost immunity, and several studies have begun to examine this effect. Despite the absence of clinical data on the efficacy and safety of such heterologous combinations, Canada and several European countries have recommended a heterologous second dose for people who have received the first dose of the Oxford–AstraZeneca vaccine.
In February 2021, the Oxford Vaccine Group launched the Com-COV vaccine trial to investigate heterologous prime-boost courses of different COVID-19 vaccines. As of June 2021, the group is conducting two phase II studies: Com-COV and Com-COV2.
In Com-COV, the two heterologous combinations of the Oxford–AstraZeneca and Pfizer–BioNTech vaccines were compared with the two homologous combinations of the same vaccines, with an interval of 28 or 84 days between doses.
In Com-COV2, the first dose is the Oxford–AstraZeneca vaccine or the Pfizer vaccine, and the second dose is the Moderna vaccine, the Novavax vaccine, or a homologous vaccine equal to the first dose, with an interval of 56 or 84 days between doses.
A study in the UK is evaluating annual heterologous boosters by randomly combining the following vaccines: Oxford–AstraZeneca, Pfizer–BioNTech, Moderna, Novavax, VLA2001, CureVac, and Janssen.
On 16 December, WHO recommendations on heterologous vaccinations suggested a general trend of increased immunogenicity when one of the doses is of an mRNA vaccine, particularly as the last dose. The immunogenicity of a homologous mRNA course is roughly equivalent to a heterologous scheme involving a vector vaccine and an mRNA vaccine. However, the WHO has emphasized the need to address many evidence gaps in heterologous regimens, including duration of protection, optimal interval between doses, influence of fractional dosing, effectiveness against variants and long-term safety.
== Efficacy ==
Vaccine efficacy is the reduction in risk of getting the disease by vaccinated participants in a controlled trial compared with the risk of getting the disease by unvaccinated participants. An efficacy of 0% means that the vaccine does not work (identical to placebo). An efficacy of 50% means that there are half as many cases of infection as in unvaccinated individuals.
COVID-19 vaccine efficacy may be adversely affected if the arm is held improperly or squeezed so the vaccine is injected subcutaneously instead of into the muscle. The CDC guidance is to not repeat doses that are administered subcutaneously.
It is not straightforward to compare the efficacies of the different vaccines because the trials were run with different populations, geographies, and variants of the virus. In the case of COVID-19 prior to the advent of the delta variant, it was thought that a vaccine efficacy of 67% may be enough to slow the pandemic, but the current vaccines do not confer sterilizing immunity, which is necessary to prevent transmission. Vaccine efficacy reflects disease prevention, a poor indicator of transmissibility of SARS‑CoV‑2 since asymptomatic people can be highly infectious. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) set a cutoff of 50% as the efficacy required to approve a COVID-19 vaccine, with the lower limit of the 95% confidence interval being greater than 30%. Aiming for a realistic population vaccination coverage rate of 75%, and depending on the actual basic reproduction number, the necessary effectiveness of a COVID-19 vaccine is expected to need to be at least 70% to prevent an epidemic and at least 80% to extinguish it without further measures, such as social distancing.
The observed substantial efficacy of certain mRNA vaccines even after partial (1-dose) immunization indicates a non-linear dose-efficacy relation already seen in the phase I-II study. It suggests that personalization of the vaccine dose (regular dose to the elderly, reduced dose to the healthy young, additional booster dose to the immunosuppressed) might allow accelerating vaccination campaigns in settings of limited supplies, thereby shortening the pandemic, as predicted by pandemic modeling.
Ranges below are 95% confidence intervals unless indicated otherwise, and all values are for all participants regardless of age, according to the references for each of the trials. By definition, the accuracy of the estimates without an associated confidence interval is unknown publicly. Efficacy against severe COVID-19 is the most important, since hospitalizations and deaths are a public health burden whose prevention is a priority. Authorized and approved vaccines have shown the following efficacies:
=== Effectiveness ===
Evidence from vaccine use during the pandemic shows vaccination can reduce infection and is most effective at preventing severe COVID-19 symptoms and death, but is less good at preventing mild COVID-19. Efficacy wanes over time but can be maintained with boosters. In 2021, the CDC reported that unvaccinated people were 10 times more likely to be hospitalized and 11 times more likely to die than fully vaccinated people.
The CDC reported that vaccine effectiveness fell from 91% against Alpha to 66% against Delta. One expert stated that "those who are infected following vaccination are still not getting sick and not dying like was happening before vaccination." By late August 2021, the Delta variant accounted for 99 percent of U.S. cases and was found to double the risk of severe illness and hospitalization for those not yet vaccinated.
In November 2021, a study by the ECDC estimated that 470,000 lives over the age of 60 had been saved since the start of the vaccination roll-out in the European region. According to a June 2022 study, COVID‑19 vaccines prevented an additional 14.4 to 19.8 million deaths in 185 countries and territories from 8 December 2020 to 8 December 2021.
On 10 December 2021, the UK Health Security Agency reported that early data indicated a 20- to 40-fold reduction in neutralizing activity for Omicron by sera from Pfizer 2-dose vaccinees relative to earlier strains. After a booster dose (usually with an mRNA vaccine), vaccine effectiveness against symptomatic disease was at 70%–75%, and the effectiveness against severe disease was expected to be higher.
According to early December 2021 CDC data, "unvaccinated adults were about 97 times more likely to die from COVID-19 than fully vaccinated people who had received boosters".
A meta-analysis looking into COVID-19 vaccine differences in immunosuppressed individuals found that people with a weakened immune system are less able to produce neutralizing antibodies. For example, organ transplant recipients need three vaccines to achieve seroconversion. A study on the serologic response to mRNA vaccines among patients with lymphoma, leukemia, and myeloma found that one-quarter of patients did not produce measurable antibodies, varying by cancer type.
In February 2023, a systematic review in The Lancet said that the protection afforded by infection was comparable to that from vaccination, albeit with an increased risk of severe illness and death from the disease of an initial infection.
A January 2024 study by the CDC found that staying up to date on the vaccines could reduce the risk of strokes, blood clots and heart attacks related to COVID-19 in people aged 65 years or older or with a condition that makes them more vulnerable to said conditions.
==== Studies ====
Real-world studies of vaccine effectiveness measure the extent to which a certain vaccine prevents infection, symptoms, hospitalization and death for the vaccinated individuals in a large population under routine conditions.
In Israel, among the 715,425 individuals vaccinated by the mRNA vaccines from 20 December 2020, to 28 January 2021, starting seven days after the second shot, only 317 people (0.04%) displayed mild/moderate COVID-19 symptoms and only 16 people (0.002%) were hospitalized.
CDC reported that under real-world conditions, mRNA vaccine effectiveness was 90% against infections regardless of symptom status; while effectiveness of partial immunization was 80%.
In the UK, 15,121 health care workers from 104 hospitals who had tested negative for antibodies prior to the study, were followed by RT-PCR tests twice a week from 7 December 2020 to 5 February 2021, a study compared the positive results for the 90.7% vaccinated share of their cohort with the 9.3% unvaccinated share, and found that the Pfizer-BioNTech vaccine reduced all infections (including asymptomatic), by 72% (58–86%) three weeks after the first dose and 86% (76–97%) one week after the second dose, while Alpha was dominant.
In Israel a study conducted from 17 January to 6 March 2021, found that Pfizer/BioNTech reduced asymptomatic Alpha infections by 94% and symptomatic COVID-19 infections by 97%.
A study on the Queensland Population having only ever been exposed to the Omicron strain of COVID-19 found vaccine effectiveness against symptomatic hospitalizations to be 70% in the general population and similar for First Nations peoples.
A study among pre-surgical patients across the Mayo Clinic system in the United States, showed that mRNA vaccines were 80% protective against asymptomatic infections.
A UK study found that a single dose of the Oxford–AstraZeneca COVID-19 vaccine is about 73% (27–90%) effective in people aged 70 and older.
A study finds that nearly all teenagers admitted to intensive care units because of COVID-19 were unvaccinated.
==== Pregnancy and fertility ====
Studies have not observed a correlation between COVID vaccination and fertility.
A UK study found COVID vaccination is safe for pregnant women and is associated with a 15% decrease in the odds of stillbirth. Vaccination is recommended for pregnant women because pregnancy increases the risk of severe COVID. Researchers at St George's, University of London, and the Royal College of Obstetricians and Gynaecologists investigated 23 published studies and trials involving 117,552 vaccinated pregnant women. There was no increased risk of complications during pregnancy. Almost all pregnant women admitted to UK hospitals with COVID were unvaccinated.
A US study of 46,079 pregnancies concluded that COVID vaccination is safe and does not raise the risk of preterm birth or small size babies.
=== Variants ===
The interplay between the SARS-CoV-2 virus and its human hosts was initially natural but is now being altered by the prompt availability of vaccines. The potential emergence of a SARS-CoV-2 variant that is moderately or fully resistant to the antibody response elicited by the COVID-19 vaccines may necessitate modification of the vaccines. The emergence of vaccine-resistant variants is more likely in a highly vaccinated population with uncontrolled transmission. Trials indicate many vaccines developed for the initial strain have lower efficacy for some variants against symptomatic COVID-19. As of February 2021, the US Food and Drug Administration believed that all FDA authorized vaccines remained effective in protecting against circulating strains of SARS-CoV-2.
==== Alpha (lineage B.1.1.7) ====
Limited evidence from various preliminary studies reviewed by the WHO indicated retained efficacy/effectiveness against disease from Alpha with the Oxford–AstraZeneca vaccine, Pfizer–BioNTech and Novavax, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated retained antibody neutralization against Alpha with most of the widely distributed vaccines (Sputnik V, Pfizer–BioNTech, Moderna, CoronaVac, Sinopharm BIBP, Covaxin), minimal to moderate reduction with the Oxford–AstraZeneca and no data for other vaccines yet.
In December 2020, a new SARS‑CoV‑2 variant, the Alpha variant or lineage B.1.1.7, was identified in the UK.
Early results suggest protection to the variant from the Pfizer-BioNTech and Moderna vaccines.
One study indicated that the Oxford–AstraZeneca COVID-19 vaccine had an efficacy of 42–89% against Alpha, versus 71–91% against other variants.
Preliminary data from a clinical trial indicates that the Novavax vaccine is ~96% effective for symptoms against the original variant and ~86% against Alpha.
==== Beta (lineage B.1.351) ====
Limited evidence from various preliminary studies reviewed by the WHO have indicated reduced efficacy/effectiveness against disease from Beta with the Oxford–AstraZeneca vaccine (possibly substantial), Novavax (moderate), Pfizer–BioNTech and Janssen (minimal), with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated possibly reduced antibody neutralization against Beta with most of the widely distributed vaccines (Oxford–AstraZeneca, Sputnik V, Janssen, Pfizer–BioNTech, Moderna, Novavax; minimal to substantial reduction) except CoronaVac and Sinopharm BIBP (minimal to modest reduction), with no data for other vaccines yet.
Moderna has launched a trial of a vaccine to tackle the Beta variant or lineage B.1.351. On 17 February 2021, Pfizer announced neutralization activity was reduced by two-thirds for this variant, while stating that no claims about the efficacy of the vaccine in preventing illness for this variant could yet be made. Decreased neutralizing activity of sera from patients vaccinated with the Moderna and Pfizer-BioNTech vaccines against Beta was later confirmed by several studies. On 1 April 2021, an update on a Pfizer/BioNTech South African vaccine trial stated that the vaccine was 100% effective so far (i.e., vaccinated participants saw no cases), with six of nine infections in the placebo control group being the Beta variant.
In January 2021, Johnson & Johnson, which held trials for its Janssen vaccine in South Africa, reported the level of protection against moderate to severe COVID-19 infection was 72% in the United States and 57% in South Africa.
On 6 February 2021, the Financial Times reported that provisional trial data from a study undertaken by South Africa's University of the Witwatersrand in conjunction with Oxford University demonstrated reduced efficacy of the Oxford–AstraZeneca COVID-19 vaccine against the variant. The study found that in a sample size of 2,000 the AZD1222 vaccine afforded only "minimal protection" in all but the most severe cases of COVID-19. On 7 February 2021, the Minister for Health for South Africa suspended the planned deployment of about a million doses of the vaccine whilst they examine the data and await advice on how to proceed.
In a study reported in March and May 2021, the efficacy of the Novavax vaccine (NVX-CoV2373) was tested in a preliminary randomized, placebo-controlled study involving 2684 participants who were negative for COVID at baseline testing. Beta was the predominant variant to occur, with post-hoc analysis indicating a vaccine efficacy of Novavax against Beta of 51.0% for HIV-negative participants.
==== Gamma (lineage P.1) ====
Limited evidence from various preliminary studies published in 2021 reviewed by the WHO have indicated likely retained efficacy/effectiveness against disease from Gamma with CoronaVac and Sinopharm BIBP, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated retained antibody neutralization against Gamma with Oxford–AstraZeneca and CoronaVac (no to minimal reduction) and slightly reduced neutralization with Pfizer–BioNTech and Moderna (minimal to moderate reduction), with no data for other vaccines yet.
The Gamma variant or lineage P.1 variant (also known as 20J/501Y.V3), initially identified in Brazil, seems to partially escape vaccination with the Pfizer-BioNTech vaccine.
==== Delta (lineage B.1.617.2) ====
Limited evidence from various preliminary studies published in 2021 reviewed by the WHO have indicated likely retained efficacy/effectiveness against disease from Delta with the Oxford–AstraZeneca vaccine and Pfizer–BioNTech, with no data for other vaccines yet. Relevant to how vaccines can end the pandemic by preventing asymptomatic infection, they have also indicated reduced antibody neutralization against Delta with single-dose Oxford–AstraZeneca (substantial reduction), Pfizer–BioNTech and Covaxin (modest to moderate reduction), with no data for other vaccines yet.
In October 2020, a new variant was discovered in India, which was named lineage B.1.617. There were very few detections until January 2021, but by April it had spread to at least 20 countries in all continents except Antarctica and South America. Mutations present in the spike protein in the B.1.617 lineage are associated with reduced antibody neutralization in laboratory experiments. The variant has frequently been referred to as a 'Double mutant', even though in this respect it is not unusual. the latter two of which may cause it to easily avoid antibodies. In an update on 15 April 2021, PHE designated lineage B.1.617 as a 'Variant under investigation', VUI-21APR-01. On 6 May 2021, Public Health England escalated lineage B.1.617.2 from a Variant Under Investigation to a Variant of Concern based on an assessment of transmissibility being at least equivalent to the Alpha variant.
==== Omicron (lineage BA.2 and BA.2.12.2) ====
COVID-19 vaccine effectiveness was studied in adults without immunocompromising conditions in 10 US states between 18 December 2021 – 10 June 2022, when Omicron was prevalent. 3 doses of mRNA COVID-19 vaccines was 69% against COVID-19–associated hospitalization 7–119 days after the third vaccine dose and 52% against COVID-19–associated hospitalization more than 4 months after the 3rd dose. Among adults aged ≥50 years, COVID-19 vaccine effectiveness against COVID-19–associated hospitalization ≥120 days after receipt of dose 3 was only 32%, increasing to 66% ≥7 days after the fourth dose.
=== Effect of neutralizing antibodies ===
One study found that the in vitro concentration (titer) of neutralizing antibodies elicited by a COVID-19 vaccine is a strong correlate of immune protection. The relationship between protection and neutralizing activity is nonlinear. A neutralization as low as 3% (95% CI, 1–13%) of the level of convalescence results in 50% efficacy against severe disease, with 20% (14–28%) resulting in 50% efficacy against detectable infection. Protection against infection quickly decays, leaving individuals susceptible to mild infections, while protection against severe disease is largely retained and much more durable. The observed half-life of neutralizing titers was 65 days for mRNA vaccines (Pfizer–BioNTech, Moderna) during the first 4 months, increasing to 108 days over 8 months. Greater initial efficacy against infection likely results in a higher level of protection against serious disease in the long term (beyond 10 years, as seen in other vaccines such as smallpox, measles, mumps, and rubella), although the authors acknowledge that their simulations consider only protection from neutralizing antibodies and ignore other immune protection mechanisms, such as cell-mediated immunity, which may be more durable. This observation also applies to efficacy against variants and is particularly significant for vaccines with a lower initial efficacy; for example, a 5-fold reduction in neutralization would indicate a reduction in initial efficacy from 95% to 77% against a specific variant, and from a lower efficacy of 70% to 32% against that variant. For the Oxford–AstraZeneca vaccine, the observed efficacy is below the predicted 95% confidence interval. It is higher for Sputnik V and the convalescent response, and is within the predicted interval for the other vaccines evaluated (Pfizer–BioNTech, Moderna, Janssen, CoronaVac, Covaxin, Novavax).
=== Drug interactions ===
Methotrexate reduces the immune response to COVID-19 vaccines, making them less effective. Pausing methotrexate for two weeks following COVID-19 vaccination may result in improved immunity. Not taking the medicine for two weeks might result in a minor increase of inflammatory disease flares in some people.
== Side effects ==
All vaccines, including COVID-19 ones, can have minor side effects related to the mild trauma associated with the introduction of a foreign substance into the body. These include soreness, redness, rash, and inflammation at the injection site. Other common side effects include fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain) which generally resolve within a few days.
Serious adverse events that follow the administration of vaccines are of high interest to the public. It is important to recognize that the occurrence of an adverse event following vaccination does not necessarily mean that the vaccine caused the adverse event; the health problem may have been unrelated. Reporting of all adverse events, careful followup and statistical analysis of occurrences are required to determine whether or not a specific health problem is more likely to occur after a vaccine is administered.
More serious side effects are very rare. Before COVID-19 vaccines such as Moderna and Pfizer/BioNTech were authorized for use in the general population, they had to pass phase III studies involving tens of thousands of people. Any serious side effects that did not appear during that testing are likely to occur less often than ~1 in 10,000 cases. It is important that Phase III trials be diverse, to ensure that safety results apply broadly. It is possible that side effects may affect a population that was not adequately represented during the initial testing. Pregnant women, immunocompromised people, and children are usually excluded from initial studies because they may be at higher risk. Further studies may be done to ensure their safety before vaccines are authorized for use in such populations. Subsequent examinations of the use of COVID vaccines in pregnant people and in children have shown similar outcomes to the general population and do not suggest greater risk for these groups.
== References == | Wikipedia/COVID-19_vaccine_clinical_research |
The Sanofi–Translate Bio COVID-19 vaccine, also known as MRT5500 or VAW00001, was a COVID-19 vaccine candidate developed by Sanofi Pasteur and Translate Bio. The development was stopped in September 2021.
== History ==
In June 2020, Sanofi, after lagging behind its competitors, "accelerated" the development of the vaccine via the smaller biotech firm Translate Bio, with a US$425 million partnership.
Development of the vaccine halted in September 2021, with Sanofi citing the difficulty of running placebo-controlled studies with other mRNA vaccines (such as Pfizer's and Moderna's) already on the market. Despite this, the company reported "promising results" in its initial trials.Sanofi has continued testing its recombinant protein vaccine, developed collaboratively with GlaxoSmithKline, to serve as a booster dose for other COVID-19 vaccines.
== References ==
== External links == | Wikipedia/Sanofi–Translate_Bio_COVID-19_vaccine |
The Moderna COVID‑19 vaccine, sold under the brand name Spikevax, is a COVID-19 vaccine developed by the American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA). Depending on the jurisdiction, it is authorized for use in humans aged six months, twelve years, or eighteen years and older. It provides protection against COVID-19, which is caused by infection by the SARS-CoV-2 virus.
It is designed to be administered in two or three 0.5-mL doses given by intramuscular injection, primarily into the deltoid muscle, at an interval of at least 28 days apart. The World Health Organization advises an eight-week interval between doses to optimize efficacy. Additional booster doses are approved in some regions to maintain immunity. Clinical trials and real-world data have demonstrated the vaccine's high efficacy, with significant effectiveness observed two weeks post-administration of the second dose, offering 94% protection against Covid and robust defense against severe cases. The vaccine's efficacy spans various demographics, including age, sex, and those with high-risk medical conditions.
It is an mRNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. In August and September 2022, bivalent versions of the vaccine (Moderna COVID-19 Vaccine, Bivalent) containing elasomeran/elasomeran 0-omicron (Spikevax Bivalent Zero/Omicron) were authorized for use as booster doses in individuals aged 18 or older in the United Kingdom, Switzerland, Australia, Canada, the European Union, and the United States. The second component of the version of the bivalent vaccine used in the United States is based on the Omicron BA.4/BA.5 variant, while the second component of the bivalent vaccine version used in other countries is based on the Omicron BA.1 variant. The vaccine's effectiveness against variants has been extensively studied, indicating varying degrees of protection. For instance, during the prevalence of the Delta variant, effectiveness against infection slightly decreased over time. The vaccine's longevity and continuous protection are under study, with ongoing research focusing on its duration of effectiveness, which remains partially undetermined as of the latest updates.
The safety profile of the vaccine is favorable, with common side effects including injection site pain, fatigue, and headaches. Severe reactions like anaphylaxis are exceedingly rare. Concerns regarding myocarditis, have been identified but are typically mild and manageable. The vaccine's formulation utilizes mRNA technology, encapsulated within lipid nanoparticles to ensure cellular uptake and immune system response.
== Medical uses ==
The Moderna COVID‑19 vaccine is used to provide protection against infection by the SARS‑CoV‑2 virus in order to prevent COVID‑19.
The vaccine is given by intramuscular injection into the deltoid muscle of the arm. The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of eight weeks between doses.
A third, fourth, or fifth dose can be added in some countries.
=== Efficacy ===
Evidence of vaccine efficacy starts about two weeks after the first dose. High efficacy is achieved with full immunization, two weeks after the second dose, and was evaluated at 94.1%: at the end of the vaccine study that led to emergency authorization in the US, there were eleven cases of COVID‑19 in the vaccine group (out of 15,181 people) versus 185 cases in the placebo group (15,170 people). Moreover, there were zero cases of severe COVID‑19 in the vaccine group, versus eleven in the placebo group. This efficacy has been described as "astonishing" and "borderline historic" for a respiratory virus vaccine, and it is similar to the efficacy of the Pfizer–BioNTech COVID-19 vaccine.
Efficacy estimates were similar across age groups, sexes, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID‑19. Only individuals aged 18 or older were studied. Studies are underway to gauge efficacy and safety in children aged 0–11 (KidCOVE) and 12–17 (TeenCOVE).
A further study conducted by the US Centers for Disease Control and Prevention (CDC) between December 2020, and March 2021, on nearly 4 thousand health care personnel, first responders, and other essential and frontline workers concluded that under real-world conditions, mRNA vaccine effectiveness of full immunization (14 days or more after second dose) was 90% against SARS-CoV-2 infections, regardless of symptoms, and vaccine effectiveness of partial immunization (14 days or more after first dose but before second dose) was 80%.
The duration of protection provided by the vaccine is unknown as of April 2021, and a two-year followup study is underway to determine the duration.
Preliminary results from a phase III trial indicate that vaccine efficacy is durable, remaining at 93% six months after the second dose.
=== Effectiveness ===
A vaccine is generally considered effective if the estimate is ≥50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.
In August 2021, results from a study suggested that the effectiveness against infection decreased from 91% (81–96%) to 66% (26–84%) when the Delta variant became predominant in the US, which may be due to unmeasured and residual confounding related to a decline in vaccine effectiveness over time.
=== Specific populations ===
Limited data are available on the safety of the Moderna COVID‑19 vaccine during pregnancy. The initial study excluded pregnant women or discontinued them from vaccination upon a positive pregnancy test. Studies in animals found no safety concerns and clinical trials are underway to evaluate the safety and efficacy of COVID‑19 vaccines in pregnant women. Real-world observations through the CDC v-safe tracking program have not uncovered unusual numbers of adverse events or outcomes of interest. Based on the results of a preliminary study, the US CDC recommends that pregnant women get vaccinated with the COVID‑19 vaccine.
== Adverse effects ==
The World Health Organization (WHO) stated that "the safety data supported a favorable safety profile" and that the vaccine's AE (adverse event) profile "did not suggest any specific safety concerns". The most common adverse events were pain at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain).
The US Centers for Disease Control and Prevention (CDC) has reported anaphylaxis (a severe allergic reaction) in 2.5 cases per million doses administered and has recommended a 15-minute observation period after injection. Delayed cutaneous reactions at injection sites resulting in rash-like erythemas have also been observed in rare cases but are not considered serious or contraindications to subsequent vaccination. The incidence rate for local adverse erythema is about 10.8%. In 1.9% of cases, redness may extend to a size of 100 mm or greater.
In June 2021, the US CDC confirmed that myocarditis or pericarditis occurs in about 13 of every 1 million young people, mostly male and over the age of 16, who received the Moderna or the Pfizer–BioNTech vaccine. Most affected individuals recover quickly with adequate treatment and rest.
Additional side effects include extensive swelling of the vaccinated limb.
== Pharmacology ==
Moderna's technology uses a nucleoside-modified messenger RNA (modRNA) compound codenamed mRNA-1273. The mRNA-1273 drug delivery system uses a PEGylated lipid nanoparticle drug delivery (LNP) system. Once the compound is inside a human cell, the mRNA links up with the cell's endoplasmic reticulum. The mRNA-1273 is encoded to trigger the cell into making a specific protein using the cell's normal manufacturing process. The vaccine encodes a version of the spike protein with a modification called 2P, in which the protein includes two stabilizing mutations in which the original amino acids are replaced with prolines, developed by researchers at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. Once the protein is expelled from the cell, it is eventually detected by the immune system, which begins generating efficacious antibodies.
== Chemistry ==
The vaccine contains the following ingredients:
The active ingredient is an mRNA sequence containing a total of 4101 nucleotides that encodes the full-length SARS-CoV-2 spike (S) glycoprotein, with two mutations (K986P and V987P) designed to stabilize the pre-fusion conformation. The sequence is further optimized by:
all uridines (U) substituted with N1-methylpseudouridine (U → m1Ψ),
flanked by an artificial 5' untranslated region (UTR) and a 3' UTR derived from the human alpha globin gene (HBA1),
introduction of two additional stop codons,
terminated by a 3' poly(A) tail.
A putative sequence of the vaccine has been published on a forum for professional virologists, obtained by direct sequencing of residual vaccine material in used vials.
The vaccine mRNA is dissolved in an aqueous buffer containing tromethamine, tromethamine hydrochloride, sodium acetate, and sucrose. The mRNA is encapsulated in lipid nanoparticles that stabilize the mRNA and facilitate its entry into cells. The nanoparticles are manufactured from the following lipids:
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),
cholesterol,
PEG2000-DMG (polyethylene glycol (PEG) 2000-dimyristoyl glycerol (DMG)), and
SM-102
== Manufacturing ==
Moderna is relying extensively on contract manufacturing organizations to scale up its vaccine manufacturing process. The first step of the process—synthesis of DNA plasmids (to be used as a template for synthesis of mRNA)—has been handled by a contractor called Aldevron based in Fargo, North Dakota. For the remainder of the process, Moderna contracted with Lonza Group to manufacture the vaccine at facilities in Portsmouth, New Hampshire in the United States, and in Visp in Switzerland, and purchased the necessary lipid excipients from CordenPharma. Besides CMOs, Moderna also manufactures the vaccine at its own production facility in Norwood, Massachusetts. Another manufacturing site for the vaccines for the market outside the U.S. (since the end of 2021) is in Geleen in the Netherlands, produced by its manufacturing partner Lonza. Earlier, Lonza did produce the vaccine for the EU, U.K. and Canada at its site in Switzerland only, but had to cut projected deliveries to the U.K. and Canada earlier in 2021 due to production issues.
For the tasks of filling and packaging vials (fill and finish), Moderna entered into contracts with Catalent in the United States and Laboratorios Farmacéuticos Rovi in Spain. In April 2021, Moderna expanded its agreement with Catalent to increase manufacturing output at the latter's plant in Bloomington, Indiana. The expansion will allow Catalent to manufacture up to 400 vials per minute and fill an additional 80 million vials per year. Later that month, Moderna announced its plans to spend billions of dollars to boost production of its vaccines, potentially tripling the output in 2022, claiming as well that it would make no less than 800 million doses in 2021. The increase in production is in part attributed to improvements made by the company in manufacturing methods.
The Moderna news followed preliminary results from the Pfizer-BioNTech vaccine candidate, BNT162b2, with Moderna demonstrating similar efficacy, but requiring storage at the temperature of a standard medical refrigerator of 2–8 °C (36–46 °F) for up to thirty days or −20 °C (−4 °F) for up to four months, whereas the Pfizer-BioNTech candidate requires ultracold freezer storage between −80 and −60 °C (−112 and −76 °F). Low-income countries usually have cold chain capacity for only standard refrigerator storage, not ultracold freezer storage. In February 2021, the restrictions on the Pfizer vaccine were relaxed when the US Food and Drug Administration (FDA) updated the emergency use authorization (EUA) to permit undiluted frozen vials of the vaccine to be transported and stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use. The Moderna vaccine should not be stored at a temperature below −50 °C (−58 °F).
In November 2020, Nature reported that "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions."
== History ==
=== Original version ===
In January 2020, Moderna announced development of an RNA vaccine, codenamed mRNA-1273, to induce immunity to SARS-CoV-2.
Moderna received US$955 million from the Biomedical Advanced Research and Development Authority (BARDA), an office of the US Department of Health and Human Services. BARDA funded 100% of the cost of bringing the vaccine to FDA licensure.
The United States government provided $2.5 billion in total funding for the Moderna COVID‑19 vaccine (mRNA-1273). Private donors also made contributions to the vaccine's development. The Dolly Parton COVID-19 Research Fund contributed $1 million.
==== Phase I–II clinical trials ====
In March 2020, the phase I human trial of mRNA-1273 began in partnership with the US National Institute of Allergy and Infectious Diseases. In April, the US Biomedical Advanced Research and Development Authority (BARDA) allocated up to $483 million for Moderna's vaccine development. Plans for a phase II dosing and efficacy trial to begin in May were approved by the US Food and Drug Administration (FDA). Moderna signed a partnership with Swiss vaccine manufacturer Lonza Group, to supply 300 million doses per annum.
In May 2020, Moderna began a phase IIa clinical trial recruiting six hundred adult participants to assess safety and differences in antibody response to two doses of its candidate vaccine, mRNA-1273, a study expected to complete in 2021.
In July 2020, Moderna scientists published preliminary results of the phase I dose escalation clinical trial of mRNA-1273, showing dose-dependent induction of neutralizing antibodies against S1/S2 as early as 15 days post-injection. Mild to moderate adverse reactions, such as fever, fatigue, headache, muscle ache, and pain at the injection site were observed in all dose groups, but were common with increased dosage. The vaccine in low doses was deemed safe and effective in order to advance a phase III clinical trial using two 100-μg doses administered 29 days apart.
In July 2020, Moderna announced in a preliminary report that its Operation Warp Speed candidate had led to production of neutralizing antibodies in healthy adults in phase I clinical testing. "At the 100-microgram dose, the one Moderna is advancing into larger trials, all 15 patients experienced side effects, including fatigue, chills, headache, muscle pain, and pain at the site of injection." The troublesome higher doses were discarded in July from future studies.
In September 2021, a study funded by the National Institute of Allergy and Infectious Diseases reported a strong immune response after six months, even at low doses, suggesting that more doses could be deployed from a limited vaccine supply. Six months after low-dose vaccination, 67% of participants still had memory cytotoxic T cells, suggesting that immune memory is stable. The study also found that cross-reactive T cells acquired during infection with other coronaviruses that cause the common cold increased the response to the vaccine.
==== Phase III clinical trials ====
Moderna and the National Institute of Allergy and Infectious Diseases began a phase III trial in the US in July 2020, with a plan to enroll and assign thirty-thousand volunteers to two groups – one group receiving two 100-μg doses of mRNA-1273 vaccine and the other receiving a placebo of 0.9% sodium chloride. As of 7 August, more than 4,500 volunteers had enrolled.
In September 2020, Moderna published the detailed study plan for the clinical trial. In September 2020, CEO Stéphane Bancel said that, if the trial is successful, the vaccine might be available to the public as early as late March or early April 2021. As of October 2020, Moderna had completed the enrollment of 30,000 participants needed for its phase III trial. The US National Institutes of Health announced in November 2020, that overall trial results were positive.
Since September 2020, Moderna has used Roche Diagnostics' Elecsys Anti-SARS-CoV-2 S test, authorized by the US Food and Drug Administration (FDA) under an emergency use authorization (EUA) in November 2020. According to an independent supplier of clinical assays in microbiology, "this will facilitate the quantitative measurement of SARS-CoV-2 antibodies and help to establish a correlation between vaccine-induced protection and levels of anti-receptor binding domain (RBD) antibodies." The partnership was announced by Roche on 9 December 2020.
A review by the FDA in December 2020, of interim results of the phase III clinical trial on mRNA-1273 showed it to be safe and effective against COVID‑19 infection resulting in the issuance of an EUA by the FDA.
In February 2021, results from phase III clinical trial were published in the New England Journal of Medicine, indicating 94% efficacy in preventing COVID‑19 infection. Side effects included flu-like symptoms, such as pain at the injection site, fatigue, muscle pain, and headache. The clinical trial is ongoing and is set to conclude in late 2022.
Pregnant and breastfeeding women were also excluded from the initial trials used to obtain the emergency use authorization, though trials in those populations were expected to be performed in 2021.
In March 2021, in order to increase the span of vaccination beyond adults, Moderna started the clinical trials of vaccines on children age 6-months to 11-years-old in the US and in Canada (KidCove),
in addition to the existing and fully-enrolled study on 12-17 year-olds (TeenCOVE).
==== Authorizations ====
===== Expedited =====
As of December 2020, the Moderna COVID‑19 vaccine was under evaluation for emergency authorization or approval by multiple countries which would enable rapid rollout of the vaccine in the United Kingdom, the European Union (EU), Canada, and the United States.
In December 2020, the Moderna COVID‑19 vaccine was authorized by the US Food and Drug Administration (FDA) under an emergency use authorization (EUA) for people aged 18 years of age and older. This is the first product from Moderna that has been authorized by the FDA. In June 2022, the EUA was expanded to include people aged six months through sixteen years of age. In April 2023, the authorization for the original, monovalent, version of the vaccine in the US was withdrawn. As of April 2023, only the bivalent (Original and Omicron BA.4/BA.5) version of the vaccine is authorized in the US.
In December 2020, the Moderna COVID‑19 vaccine was authorized by Health Canada.
In January 2021, the Moderna COVID‑19 vaccine was authorized for use in Israel by its Ministry of Health.
In February 2021, the Moderna COVID‑19 vaccine was authorized for use in Singapore by its Health Sciences Authority.
In April 2021, the World Health Organization (WHO) granted emergency use listing.
In May 2021, the Moderna COVID‑19 vaccine was authorized for emergency use in the Philippines by the Philippines Food and Drug Administration.
In 2020, Moderna partnered with Takeda Pharmaceutical Company, and the Japan Ministry of Health, Labour and Welfare (MHLW). The vaccine is known as "COVID-19 Vaccine Moderna Intramuscular Injection". In May 2021, COVID‑19 Vaccine Moderna Intramuscular Injection (formerly TAK-919) was authorized for emergency use in Japan.
In June 2021, the Moderna COVID‑19 vaccine was authorized for use in India by the Drugs Controller General of India. The same day, the vaccine was also approved by the Ministry of Health of Vietnam for emergency use in the country.
In August 2021, Malaysia's National Pharmaceutical Regulatory Agency (NPRA) gave conditional registration for emergency use of the Moderna COVID‑19 vaccine.
===== Standard =====
In January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization and the recommendation was accepted by the European Commission the same day. In July 2021, the EMA extended the use of the COVID‑19 Vaccine Moderna to include people aged 12 to 17.
In January 2021, Swissmedic granted temporary authorization for the Moderna COVID-19 mRNA Vaccine in Switzerland.
In March 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization in the United Kingdom.
In August 2021, Spikevax was granted provisional approval in Australia. The approval was updated in September 2021, to include people aged twelve and older.
The Moderna Spikevax COVID-19 vaccine was authorized in Canada in September 2021, for people aged 12 and older.
The Moderna Spikevax COVID-19 vaccine was authorized in the US in January 2022, for people aged 18 and older.
The Moderna Spikevax Bivalent Zero/Omicron vaccine was approved for medical use in the United Kingdom in August 2022.
In September 2022, the CHMP of the EMA recommended converting the conditional marketing authorizations of the vaccine into standard marketing authorizations. The recommendation covers all existing and upcoming adapted Spikevax vaccines, including the recently approved adapted Spikevax bivalent Original/Omicron BA.1.
==== Boosters ====
In January 2021, Moderna announced that it would offer a third dose of its vaccine to people who were vaccinated twice in its phase I trial. The booster would be made available to participants six to twelve months after they got their second dose. The company said it may also study a third shot in participants from its phase III trial, if antibody persistence data warranted it. It also started testing to see if a third shot of the existing vaccine could be used to fend off the virus variants.
In August 2021, the US Food and Drug Administration (FDA) and the US Centers for Disease Control and Prevention (CDC) authorized the use of an additional mRNA vaccine dose for immunocompromised individuals.
In September 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started evaluating the use of a booster dose of the Moderna COVID-19 vaccine to be given at least six months after the second dose in people aged twelve years and older.
In October 2021, the European Medicines Agency (EMA) stated that people with "severely weakened" immune systems can receive an extra dose of either the Pfizer–BioNTech COVID-19 vaccine or the Moderna COVID-19 vaccine starting at least 28 days after their second dose.
In October 2021, the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) authorized the use of either homologous or heterologous vaccine booster doses. The authorization was expanded to include all adults in November 2021.
=== Variants ===
In January 2021, Moderna started development of a new form of its vaccine, called mRNA-1273.351, that could be used as a booster shot against the Beta variant (lineage B.1.351). In February 2021, Moderna announced that it had manufactured and shipped sufficient amounts of mRNA-1273.351 to the National Institutes of Health to run phase I clinical trials. Moderna also investigated a multivalent booster, mRNA-1273.211, which combines a 50-50 mix of mRNA-1273 and mRNA-1273.351.
A bivalent version of the vaccine containing elasomeran/imelasomeran (Spikevax bivalent Original/Omicron) was approved for use in the United Kingdom and in Australia in August 2022. It was approved for use in Canada in September 2022.
In October 2022, the FDA amended the authorization for the bivalent booster to cover people aged six years of age and older. In December 2022, the FDA amended the authorization for the bivalent booster to cover people aged six months and older.
==== XBB.1.5 monovalent vaccine ====
In September 2023, the FDA approved an updated a monovalent (single) component Omicron variant XBB.1.5 version of the vaccine (Spikevax 2023-2024 formula) as a single dose for individuals aged twelve years of age and older; and authorized the Moderna COVID-19 Vaccine 2023-2024 formula under emergency use for individuals aged 6 months through 11 years of age. The updated version was tested in a small human trial of 101 participants; 50 received the monovalent XBB.1.5 version, compared to 51 who received a version containing XBB.1.5, BA.4 and BA.5. All participants had previously received four doses of older formulations of the Moderna COVID-19 vaccine. The safety profile of the authorized XBB.1.5 was found to be "consistent with previously authorized vaccines." The approvals and emergency authorizations for the bivalent version of the vaccine were revoked. Health Canada authorized the Moderna Spikevax COVID-19 vaccine (Omicron XBB.1.5 subvariant) (andusomeran) in September 2023. The MHRA approved the use of the Moderna (Spikevax) XBB.1.5 vaccine in September 2023.
==== JN.1 monovalent vaccine ====
In September 2024, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) approved Moderna's JN.1-adapted COVID-19 vaccine for use in adults and children aged six months and older.
In September 2024, the European Union authorized the Spikevax JN.1 vaccine.
In September 2024, Swissmedic authorized the Spikevax JN.1 vaccine.
In September 2024, the Taiwan Food & Drug Administration authorized the Spikevax JN.1 vaccine.
==== KP.2 monovalent vaccine ====
In August 2024, the FDA approved and granted emergency authorization for a monovalent Omicron KP.2 version of the Moderna COVID-19 vaccine. The approval of Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to ModernaTX Inc. and the EUA amendment for the Moderna COVID-19 Vaccine (2024-2025 Formula) was issued to ModernaTX Inc.
== Society and culture ==
About 155 million doses of the Moderna COVID-19 vaccine, including about 3.1 million doses in children and adolescents (below 18 years of age) were administered in the EU/EEA from authorization to 26 June 2022.
=== Brand names ===
mRNA-1273 was the code name during development and testing, elasomeran is the international nonproprietary name (INN), and Spikevax is the brand name.
Davesomeran is the INN for the BA.5 variant in the bivalent version of the vaccine. Andusomeran is the INN for the XBB 1.5 variant version of the vaccine.
=== Economics ===
In June 2020, Singapore signed a pre-purchase agreement for Moderna, reportedly paying a price premium in order to secure early stock of vaccines, although the government declined to provide the actual price and quantity, citing commercial sensitivities and confidentiality clauses.
In August 2020, the US government signed an agreement to buy 100 million doses of Moderna's anticipated vaccine, which the Financial Times said Moderna planned to price at US$50–60 per course. In November 2020, Moderna said it will charge governments who purchase its vaccine between US$25 and US$37 per dose while the EU is seeking a price of under US$25 per dose for the 160 million doses it plans to purchase from Moderna.
In 2020, Moderna obtained purchase agreements for mRNA-1273 with the European Union for 160 million doses and with Canada for up to 56 million doses. In December 2020, a tweet by the Belgium Budget State Secretary revealed the E.U. would pay US$18 per dose, while The New York Times reported that the US would pay US$15 per dose.
Moderna reported revenue of US$200 million from its COVID‑19 vaccine in 2020, and $17.7 billion in 2021.
=== Paused vaccinations ===
Out of concern that the vaccine may increase the risk of myocarditis in young people under age 30, Finland, Sweden, Germany, and France recommended Moderna vaccinations not be used for this age group in October/November 2021.
=== Controversies ===
In May 2020, after releasing partial and non-peer-reviewed results for only eight of 45 candidates in a preliminary pre-phase I stage human trial directly to financial markets, the CEO announced on CNBC an immediate $1.25 billion rights issue to raise funds for the company, at a $30 billion valuation, while Stat said, "Vaccine experts say Moderna didn't produce data critical to assessing COVID‑19 vaccine."
In July 2020, disputes between Moderna and government scientists over the company's unwillingness to share data from the clinical trials were revealed.
Moderna also faced criticism for failing to recruit people of color in clinical trials.
In August 2021, the US Department of Health and Human Services announced a plan to offer a booster dose eight months after the second dose, citing evidence of reduced protection against mild and moderate disease and the possibility of reduced protection against severe disease, hospitalization, and death. Scientists and the WHO reaffirmed the lack of evidence on the need for a booster dose for healthy people and that the vaccine remains effective against severe disease months after administration. In a statement, the WHO and SAGE said that, while protection against infection may be diminished, protection against severe disease will likely be retained due to cell-mediated immunity. Research into optimal timing for boosters is still ongoing, and a booster too early may lead to less robust protection.
==== Misinformation ====
Videos on video-sharing platforms circulated around May 2021 showing people having magnets stick to their arms after receiving the vaccine, purportedly demonstrating the conspiracy theory that vaccines contain microchips, but these videos have been debunked.
In November 2021, a White House correspondent for the conservative outlet Newsmax falsely tweeted that the Moderna vaccine contained luciferase "so that you can be tracked."
=== Patent litigation ===
The PEGylated lipid nanoparticle (LNP) drug delivery system of mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology. On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.
== Explanatory notes ==
== References ==
== Further reading ==
Corum J, Zimmer C (7 May 2021). "How Moderna's Vaccine Works". The New York Times.
Moderna (17 December 2020). "VRBPAC mRNA-1273 Sponsor Briefing Document". US Food and Drug Administration. Archived from the original (PDF) on 15 December 2020.
Committee for Medicinal Products for Human Use (CHMP) (11 March 2021). "Assessment report: COVID-19 Vaccine Moderna" (PDF). European Medicines Agency. Archived (PDF) from the original on 20 January 2021.
"Clinical Study Protocol mRNA-1273-P301" (PDF). Moderna. 20 August 2020. Archived from the original (PDF) on 17 September 2020.
Dickerman BA, Gerlovin H, Madenci AL, Kurgansky KE, Ferolito BR, Figueroa Muñiz MJ, et al. (January 2022). "Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans". The New England Journal of Medicine. 386 (2): 105–115. doi:10.1056/nejmoa2115463. PMC 8693691. PMID 34942066.
World Health Organization (2021). Background document on the mRNA-1273 vaccine (Moderna) against COVID-19: background document to the WHO Interim recommendations for use of the mRNA-1273 vaccine (Moderna), 3 February 2021 (Report). World Health Organization (WHO). hdl:10665/339218. WHO/2019-nCoV/vaccines/SAGE_recommendation/mRNA-1273/background/2021.1.
== External links ==
Product information from the US Centers for Disease Control and Prevention
Spikevax Safety Updates from the European Medicines Agency | Wikipedia/Moderna_vaccine |
Vaccine Maitri ("Vaccine Friendship") is a humanitarian initiative undertaken by the Indian government to provide COVID-19 vaccines to countries around the world. The government started providing vaccines from 20 January 2021. As of 21 February 2022, India had delivered around 16.29 crore (162.9 million) doses of vaccines to 96 countries. Of these, 1.43 crore (14.3 million) doses were gifted to 98 countries by the Government of India. The remaining 10.71 crore were supplied by the vaccine producers under its commercial and 4.15 crore were supplied by COVAX obligations. In late March 2021, the Government of India temporarily froze exports of the Covishield, citing India's own COVID crisis and the domestic need for these vaccines.
The Health Minister of India, Mansukh Mandaviya announced in September that India will resume the export of vaccines from October to the rest of the world.
200,000 doses of COVID-19 vaccines were gifted by India to the UN peacekeepers on 27 March to be distributed to all peacekeeping missions.
== Vaccines ==
India has two approved COVID-19 vaccines: Covishield and Covaxin. Both of them were exported and used in foreign grants by the Government of India.
=== Covishield ===
On 1 January 2021, the Drug Controller General of India, approved the emergency or conditional use of Covishield. Covishield is developed by the University of Oxford and its spin-out company, Vaccitech.
=== Covaxin ===
On 2 January 2021, Covaxin India's first COVID-19 vaccine, developed by Bharat Biotech in association with the Indian Council of Medical Research and National Institute of Virology received approval from the Drug Controller General of India for its emergency or conditional usage.
== Vaccine supply ==
India kicked off international shipment of the vaccines on 20 January 2021, only four days after starting its own vaccination program. Bhutan and Maldives were the first countries to receive vaccines as a grant by India. This was quickly followed by shipments to Nepal, Bangladesh, Myanmar and Seychelles. By mid-March 2021, India was also supplying vaccines on a commercial basis to countries including Canada, the UK, and Saudi Arabia.
The Serum Institute of India was selected as a key supplier of cost-effective COVID-19 vaccines to the COVAX initiative, 19.8 million doses of Covishield vaccines were supplied by India to various countries through the initiative.
In May, when COVAX was already short 140 million doses, the Serum Institute announced that it expected to maintain its suspension of vaccine deliveries to COVAX through the end of 2021 due to the second wave of COVID-19 in India and the US ban on export of key raw materials.
As of 21 February 2022, India had exported total 16,29,63,500 doses including 1,42,67,000 vaccine provided as grant, 10,71,48,000 as commercial, and 4,15,48,500 through COVAX to 96 nations.
== International reaction ==
=== International organizations ===
IMF: IMF chief economist Gita Gopinath lauded India for playing a key role during the crisis by dispatching vaccines to many countries. She said "I also want to mention that India really stands out in terms of its vaccine policy. If you look at where exactly is one manufacturing hub for vaccines in the world – that will be India."
=== Countries ===
Jamaica of the OACPS has thanked Indian efforts in delivering vaccines to developing and least developed countries.
Nepal Prime minister Khadga Prasad Oli thanked India stating; “We got an early chance to administer the Covid-19 vaccine. For this, I thank our neighbouring nation India, its government, the people, and especially Prime Minister Narendra Modi. They sent 10 lakh doses of vaccines to us as a grant within a week of the roll-out in India.”
St. Lucia on behalf of CARICOM thanked India for providing vaccine supplies to them.
Barbados Prime Minister Mia Amor Mottley thanked Prime Minister Narendra Modi for the supply of "Made in India" COVID-19 vaccines. She tweeted, "PM Modi made it possible for more than 40,000 persons in Barbados and tens of thousands elsewhere, to receive their 1st dose of COVISHIELD via Vaccine Maitri before receiving his. A genuine demonstration of generosity. Thank you and we wish you continued good health."
Antigua and Barbuda Prime Minister Gaston Browne had thanked Prime Minister of India Narendra Modi "for demonstrating an act of benevolence, kindness and empathy", for sending vaccines to Caribbean countries.
Afghanistan Afghanistan's ambassador to India Farid Mamundzay said "Thank you, India for providing Afghan people lifesaving gift on the first day of 2022!"
=== Leaders who received vaccines provided by India ===
Cambodia – Heng Samrin, Say Chhum
Nepal – KP Sharma Oli
== Gallery ==
== See also ==
Vaccine diplomacy
COVID-19 vaccination in India
== References == | Wikipedia/Vaccine_Maitri |
As of 12 August 2024, 13.53 billion COVID-19 vaccine doses have been administered worldwide, with 70.6 percent of the global population having received at least one dose. While 4.19 million vaccines were then being administered daily, only 22.3 percent of people in low-income countries had received at least a first vaccine by September 2022, according to official reports from national health agencies, which are collated by Our World in Data.
During a pandemic on the rapid timeline and scale of COVID-19 cases in 2020, international organizations like the World Health Organization (WHO) and Coalition for Epidemic Preparedness Innovations (CEPI), vaccine developers, governments, and industry evaluated the distribution of the eventual vaccine(s). Individual countries producing a vaccine may be persuaded to favor the highest bidder for manufacturing or provide first-class service to their own country. Experts emphasize that licensed vaccines should be available and affordable for people at the frontlines of healthcare and in most need.
In April 2020, it was reported that the UK agreed to work with 20 other countries and global organizations, including France, Germany, and Italy, to find a vaccine and share the results, and that UK citizens would not get preferential access to any new COVID‑19 vaccines developed by taxpayer-funded UK universities. Several companies planned to initially manufacture a vaccine at artificially low prices, then increase prices for profitability later if annual vaccinations are needed and as countries build stock for future needs.
The WHO had set out the target to vaccinate 40% of the population of all countries by the end of 2021 and 70% by mid-2022, but many countries missed the 40% target at the end of 2021.
== Distribution ==
Note about table in this section: Number and percentage of people who have received at least one dose of a COVID-19 vaccine (unless noted otherwise). May include vaccination of non-citizens, which can push totals beyond 100% of the local population. Table is updated daily by a bot.
=== Phased distribution ===
Many countries have implemented phased distribution plans that prioritize those at highest risk of complications such as the elderly and those at high risk of exposure and transmission such as healthcare workers.
In the United States, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) voted in December 2020, that the first doses of the vaccine should be prioritized for healthcare workers and residents and staff of nursing homes. ACIP recommended that the second phase of distribution (Phase 1b) include persons aged ≥75 years and non-healthcare frontline essential workers such as those employed in grocery stores, restaurants, military, law enforcement, fire departments, retail, sanitation, schools, public transportation, self-storage, hotels, warehousing, and news media. However, states control the final plans for prioritization, distribution, and logistics of vaccinating everyone as supply becomes available.
The European Union began phased vaccine rollout on 27 December 2020. Each member state is managing distribution with a common focus on prioritizing healthcare workers, people at high risk of exposure, the elderly, and those with serious health conditions.
The COVID‑19 vaccination programme in the United Kingdom prioritized elder care facility residents and carers, followed by healthcare workers and those over 80 years of age. Subsequent phases are based largely on age, declining from 75 years in 5-year increments.
Some countries used accelerated dose 1 plans with extended dose 2 intervals after the first dose in order to extend vaccination to as many people as possible until vaccine availability improved. Data suggests that people who have recovered from COVID-19 may only require a single dose of an mRNA vaccine to reach full two dose immunity.
=== Mixed series ===
The use of the different vaccines in a two-shot regimen is not widespread; there is no data on the efficacy of mixed series for COVID-19 vaccines but such series are not expected to be unsafe or ineffective. The US Centers for Disease Control and Prevention (CDC) recommends the use of a mixed series only in exceptional circumstances, such as where a second dose of the same vaccine cannot be delivered in a reasonable timeframe. In Canada, authorities were investigating the effectiveness of a mixed series and ultimately recommended the use of a first shot consisting of the Oxford-AstraZeneca COVID-19 vaccine, followed by one of the mRNA vaccines. In June 2021, German authorities recommended using mRNA vaccines as a second shot after an AstraZeneca shot in younger people as a precaution to avoid a rare blood clotting side effect associated with the AstraZeneca vaccine. Thailand began mixing-and-matching doses of the AstraZeneca and Sinovac vaccines in July 2021 amid concerns about the Sinovac vaccine's long-term protection.
=== Equitable access ===
During 2020, as the COVID‑19 pandemic escalated globally and vaccine development intensified, the World Health Organization (WHO) COVAX facility adopted the motto "No one is safe unless everyone is safe" to emphasize the need for equitable vaccination. The facility set a goal of supplying COVID‑19 vaccines to nearly 100 low-to-middle income countries that could not afford them. COVAX sought to fundraise US$6.8 billion to purchase and deliver vaccines to participating countries in proportion to their populations. On 18 December 2020, the facility announced agreements with vaccine manufacturers to supply 1.3 billion doses for 92 low-middle income countries in the first half of 2021.
Yet, by mid-December, some 16 countries representing only 14% of the world's population had preordered more than 10 billion vaccine doses or about 51% of the available world supply. Specifically, Canada, Australia, and Japan – having only 1% of the world's COVID‑19 cases – had collectively reserved some 1 billion vaccine doses, while the COVAX facility had reserved only a few hundred million doses. At the Group of Seven summit in June 2021, the United States promised to distribute 500 million vaccine doses internationally; this distribution began on 17 August.
Preorders from rich countries were made during 2020 with 13 different vaccine manufacturers, whereas those for low-to-middle income countries were made primarily for the Oxford–AstraZeneca COVID-19 vaccine, which is lowest in cost and has no special refrigeration needs.
The CEPI, the WHO, and charitable vaccine organizations, such as the Gates Foundation and GAVI, raised over US$20 billion during the first half of 2020, to fund vaccine development and preparedness for vaccinations, particularly for children in under-developed countries. CEPI, which was created to monitor fair distribution of infectious disease vaccines to low- and middle-income countries, has recommended considering manufacturing capacity, financing and purchasing, and releasing vaccine developers from liability. Despite opposition from some vaccine manufacturers, CEPI revised its February 2020 equitable access policy to apply specifically to its COVID‑19 vaccine funding:
"prices for vaccines will be set as low as possible for territories that are or may be affected by an outbreak of a disease for which CEPI funding was used to develop a vaccine;
"information, know-how and materials related to vaccine development must be shared with (or transferred to) CEPI" so that it can assume responsibility for vaccine development if a company discontinues expenditures for a promising vaccine candidate;
CEPI would have access to, and possible management of, intellectual property rights (i.e., patents) for promising vaccines;
"CEPI would receive a share of financial benefits that might accrue from CEPI-sponsored vaccine development, to re-invest in support of its mission to provide global public health benefit"; and
data transparency among development partners should maintain the WHO Statement on Public Disclosure of Clinical Trial Results, and require results to be published in open-access publications.
International groups, such as the Centre for Artistic Activism and Universities Allied for Essential Medicines, advocate for equitable access. Scientists have encouraged collaboration between the WHO, CEPI, corporations, and governments to ensure that vaccines are distributed in an evidence-based manner based on infection risk and to prioritize healthcare workers, vulnerable populations, and children.
By mid-March 2021, 67 countries, mostly in Africa and the Middle East, had not yet reported any vaccinations. Countries that had begun vaccinations were generally prioritizing populations such as health workers or the elderly. It has also been suggested that elective surgery recipients should be prioritized since a patient recovering from surgery would be more vulnerable than average. Some expressed concern over the short shelf-life of the Moderna and Pfizer-BioNTech vaccines, which expire within hours after being removed from the freezer; they argued that, once the vaccine is unfrozen, it is better to apply these doses to anyone who can be found rather than discard the doses.
As of March 2021, the United States had ordered twice the necessary doses to cover its own population, but it remained unclear when it might share surplus doses with other countries. In April 2021, Vanity Fair reported that it would be difficult to share surplus doses with other countries because the U.S. government had expressly agreed in its contracts with vaccine manufacturers to use doses only in the United States and its territories. The manufacturers requested this clause because most other countries do not have liability protections for vaccines as expansive as the Public Readiness and Emergency Preparedness Act.
In late November 2021 the World Health Organization published, "it is vitally important that inequities in access to COVID-19 vaccines are urgently addressed to ensure that vulnerable groups everywhere, including health workers and older persons, receive their first and second doses, alongside equitable access to treatment and diagnostics." Inequalities in vaccine distribution facilitate the emergence of new variants like SARS-CoV-2 Omicron variant.
==== Concerns ====
An analysis conducted in late 2020 of premarket vaccine purchase commitments indicated that wealthy countries may receive their vaccines in 2020–21 while developing countries may be excluded from vaccinations until 2023–24. Data from April 2021 comports with this expectation since 25% of the population in high income countries have been vaccinated compared to only 0.2% in low income countries.
The head of the World Health Organization said on 4 August 2021 that rich countries had administered about 100 doses per 100 people while poor countries had administered only about 1.5 doses for every 100 people, and therefore, in his estimation, it was important to prioritize vaccination in poor countries before offering booster vaccines in rich countries. The WHO Director General Tedros Adhanom Ghedreyesus raised concerns about rich countries hoarding vaccines at the expense of citizens in poorer nations who wait for vaccines to either become available or are donated. The WHO Regional Office of Africa highlighted vaccine discard in African countries, after Nigeria destroyed about 1 million donated doses of AstraZeneca vaccine after being donated with only a few weeks till expiration. Other countries such as Malawi, and South Sudan have either destroyed expired or close to expiring vaccines or paused donated shipments due to expiration concerns.
==== Discarding ====
It is estimated that least 215 million doses of COVID-19 vaccines purchased by EU countries have been discarded as per 2023, based on vaccine prices reported in the media.
=== Intellectual property ===
The first polio vaccine was never patented; some have argued that similar treatment of an effective COVID‑19 vaccine could enable fair distribution.
Initially, negotiations at the World Trade Organization (WTO) on the issue of waiving patent rights were blocked for months by resistance by the US, Switzerland, Norway, and the EU. Initially one observer considered the US position unlikely to change, but as of April 2021 the US administration was discussing the issue and then reversed course and announced its support for a patent waiver for COVID-19 vaccines on 5 May 2021. 400 non-profit organizations and 115 members of the European Commission have signed a letter urging the United States and Europe to side with the WTO members in the global south.
==== Debate ====
Some question if patent waiver proposals formulated for small molecule drugs can be applied to complex biologics like vaccines. One vaccine production expert argued that "there is an unrecognized gap in understanding ... nearly all of the people who are providing views on the value of removing patent protections have zero experience in vaccine development and manufacturing." Indeed, most of the advocacy in favor of patent waivers has come from the public health community (which has drawn inspiration from the history of raucous HIV/AIDS activism in the 1980s and 1990s), while most members of the vaccinology community (i.e., actual experts on development and production of vaccines) have effectively refused to lend their credibility to such proposals by either remaining silent or refusing to take any position.
Small molecule drugs are easy to copy and can be quickly brought to market by generic drug manufacturers who are not required to run their own full-scale clinical trials because they can piggyback on regulatory approvals obtained by original drug manufacturers. In contrast, "there is no such thing as generic vaccines". The manufacturer of each independently developed vaccine (including a purported copy of an existing vaccine) must run its own clinical trials to establish safety and efficacy. Independent copying of an existing first-generation vaccine is so hard that the resulting second-generation vaccine is often a significant improvement over the first-generation technology and is itself patentable.
Although Moderna has stated that it will not seek enforcement of its patents during the pandemic, a patent waiver (voluntary or involuntary) would not force a vaccine manufacturer to disclose the complete knowledge (i.e., know-how) for making a vaccine, which is not found in patents. The World Health Organization (WHO) has promoted the COVID-19 Technology Access Pool to facilitate disclosures, but participation is voluntary and none of the vaccine manufacturers have joined. Without access to the original vaccine manufacturer's know-how, reverse engineering the manufacturing process is difficult and expensive with no guarantee of success. Even if a third party succeeds, they must prove that fact to the satisfaction of regulatory authorities. For small molecule drugs, proving bioequivalence of a generic drug to the original drug costs only about US$1 to $2 million; but for biologics, proving biosimilarity of a third-party product to the original product requires clinical trials, with costs ranging from US$100 to $250 million. One financial analyst specializing in pharmaceuticals estimated that it would take a minimum of two years after patent waiver for the first independent reproductions of a COVID-19 vaccine to reach the market, which may be too long to have any net impact on global public health. While discussing the idea of "open source" COVID-19 vaccine manufacturing, Bill Gates said: "There's not a single additional vaccine that would have come out of that .... no free IP would have improved anything related to this pandemic." His foundation has instead helped other countries reach licensing deals as in the case of the Oxford/AstraZeneca vaccine being produced by India's Serum Institute. Another concern, raised by Pfizer CEO Albert Bourla, is that allowing unauthorized third-party vaccine production would severely disrupt vaccine developers' efforts to ramp up vaccine production when original developers and third-party producers all end up competing for the same scarce raw materials.
This is why some conclude that voluntary technology transfers are the superior option for producing more doses—since the transferor's active assistance can help the transferee bypass time-consuming clinical trials by taking advantage of existing approvals for the transferor's vaccine—and others describe patent waiver proposals as "more symbolic than practical". Derek Lowe has characterized the U.S. government's May 2021 announcement of support for patent waiver proposals as "almost as much of a PR move as anything else". By November 2021, the prospects for approval of such proposals (which by WTO tradition must be unanimous) looked increasingly remote; participants criticized the United States for not working to bridge the gap between supporters and opponents. Meanwhile, Tedros Adhanom Ghebreyesus has rejected the dichotomy between waiving patents and initiating technology transfers by including both measures as part of a list of four steps towards increasing vaccine production. He pointed out that the TRIPS agreement signed by all members of the WTO already allows for an emergency waiver of intellectual property rights in countries with free manufacturing capacities.
Several observers have noted that the vaccine patent waiver debate involves an issue expected to outlast the COVID-19 pandemic: who will control the broader technology of RNA therapeutics. Howard Dean has accused Narendra Modi of trying to gain access to such technology by promoting the "disingenuous" claim that patent waivers will accelerate vaccine production. Josh Rogin has pointed out that control of mRNA technology has "national security implications" for the United States, and that its development was initially funded by U.S. taxpayers through DARPA for that reason.
Central to the debate is whether profits from strong intellectual property rights are necessary to ensure that someone will conduct the applied research which turns promising laboratory experiments into marketable drugs and vaccines. Such research is dauntingly expensive (on average, $3 billion per successful drug) and nearly always fails (only 12 percent of drugs which enter clinical trials ultimately obtain FDA approval), and "governments have neither the money nor the risk tolerance to take over the role of businesses in developing pharmacy-ready medicines". Moderna co-founder Robert S. Langer has argued that early private investors deserve "a lot of credit" for its successful COVID-19 vaccine since they "put the money in way before" the U.S. federal government got involved, and thereby laid the foundation for the company's success many years later.
The risk of waiving patents for COVID-19 vaccines is that it sets a precedent which may discourage the private sector from future investments in vaccines and other lifesaving technologies, and in turn, future technologies not yet developed will never come to market when the public sector fails to pick up the slack. As one financial analyst explained: "It would be intensively counterproductive, in the extreme, because what it would say to the industry is: 'Don't work on anything that we really care about, because if you do, we're just going to take it away from you.'" The "most depressing" worst-case outcome is that pharmaceutical firms give up on saving lives and focus on inventing quality of life treatments which are more profitable and less likely to be expropriated; the most notorious examples of such treatments are Pfizer's Viagra and Allergan's Botox. The "threat of losing developers is real" in the vaccine sector, which had withered away to only a handful of companies by the turn of the 21st century and by 2021 had only recently begun to grow again. However, Peter Bach has argued that whether this risk might be worth it deserves to be frankly debated: "If this action allows for more access and more people to have their lives saved today in 2021 and the consequence is down the road we may not have some new gene therapy for 100 kids, then that's the trade-off worth discussing".
=== Sovereignty ===
Favored distribution of vaccines within one or a few select countries, called "vaccine sovereignty", is a criticism of some of the vaccine development partnerships, such as for the AstraZeneca-University of Oxford vaccine candidate, concerning whether there may be prioritized distribution first within the UK and to the "highest bidder" – the United States, which made an advance payment of US$1.2 billion to secure 300 million vaccine doses for Americans, even before the AstraZeneca-Oxford vaccine or a Sanofi vaccine was proved safe or effective. Concerns exist about whether some countries producing vaccines may impose protectionist controls by export restrictions that would stockpile a COVID‑19 vaccine for their own population.
The Chinese government pledged in May 2020, that a successful Chinese vaccine would become a "global, public good", implying enough doses would be manufactured for both national and global distribution. Unlike mRNA vaccines, which have to be stored at subzero temperatures, inactivated vaccines from Sinovac and Sinopharm require ordinary refrigeration and may have more appeal in developing countries. In November 2021, the Chinese government pledged to donate in 2022 a further 600 million vaccine doses to Africa, and supply another 400 million through other routes including production by Chinese companies in Africa.
In June 2020, the Serum Institute of India (SII) – a major manufacturer of global vaccines – reached a licensing agreement with AstraZeneca to make 1 billion doses of vaccine for low-and-middle income countries, of which half of the doses would go to India. Similar preferential homeland distribution may exist if a vaccine is manufactured in Australia.
=== Illegal distribution ===
In the United States, the vaccine distribution line, while varying by state, has placed healthcare workers and senior citizens high on the list for COVID-19 vaccination, while less essential workers are secondary recipients. Due to the long process of distribution, some individuals tried to secure a more favorable position on the vaccination list, such as by bribery or making donations to hospitals. In response, state governments imposed large fines and other penalties for violation of federal vaccine distribution guidelines. A COVID-19 vaccine black market enabled some individuals to buy illegal early access to a vaccine.
By mid-February 2021, China had arrested 80 people involved in vaccine contraband, and the Colombian government intercepted a freezer with 70 doses of a Chinese-manufactured vaccine that a traveler brought with her into the airport without any accompanying paperwork.
=== Vaccine tourism ===
In the later half of February 2021, it was reported that wealthy and influential people from Canada and European countries flew to the United Arab Emirates to secure early access to the vaccine. The UAE promoted Dubai as a vaccine holiday hub for the wealthy, who could pay a large sum of money to get inoculated before they became eligible for vaccination in their home countries. Some Canadians who maintained second homes in the United States were able to get vaccines earlier.
As restrictions on vaccine eligibility were lowered in the United States, wealthier individuals from other countries with slower vaccination rates were reportedly travelling to the United States to be vaccinated. The U.S. state of Alaska announced in April 2021 that it would intentionally offer free vaccinations to tourists at major Alaskan airports starting 1 June 2021. In an effort to guard against vaccine tourism, Greece restricted its eligibility to those with a social security number. However, this had the effect of excluding part of the elderly or immigrant population as well as some Greek citizens who worked abroad before the pandemic.
In the European Union, several travel agencies offered "vaccine vacations". The Maldives also offered vaccines as part of holiday travel packages.
== Cost ==
An effective vaccine for COVID‑19 could save trillions of dollars in global economic impact, according to economists Arnab Acharya and Sanjay Reddy who advocate suspending patent protections for vaccines temporarily and compensating the affected companies. Any price tag in the billions would therefore look small in comparison. In early stages of the pandemic, it was not known if it would be possible to create a safe, reliable and affordable vaccine for this virus, and it was not known exactly how much the vaccine development could cost. Even with several vaccines on the market, the antigenicity changes in new variants of the virus mean that the billions of dollars could still be invested without success.
Before an effective vaccine was developed, it was clear that billions of doses would need to be manufactured and distributed worldwide. In April 2020, the Gates Foundation estimated that manufacturing and distribution could cost as much as US$25 billion. Gates also admitted "Ideally, there would be global agreement about who should get the vaccine first, but given how many competing interests there are, this is unlikely to happen". From Phase I clinical trials, 84–90% of vaccine candidates fail to make it to final approval during development, and from Phase III, 25.7% fail – the investment by a manufacturer in a vaccine candidate may exceed US$1 billion and end with millions of useless doses given advanced manufacturing agreements. In the case of the Oxford-AstraZeneca COVID-19 vaccine, 97% of this came from taxpayer money.
As of November 2020, companies subsidized under the United States' Operation Warp Speed program have set initial pricing at US$19.50 to US$25 per dose, in line with the influenza vaccine. In December 2020, a Belgian politician briefly published the confidential prices agreed between vaccine producers and the EU:
== Supply chain ==
Deploying a COVID‑19 vaccine may require worldwide transport and tracking of 10–19 billion vial doses, an effort readily becoming the largest supply chain challenge in history. As of September 2020, supply chain and logistics experts expressed concern that international and national networks for distributing a licensed vaccine were not ready for the volume and urgency, due mainly to deterioration of resources during 2020 pandemic lockdowns and downsizing that degraded supply capabilities. Globally, supplies critical to vaccine research and development are increasingly scarce due to international competition or national sequestration.
Addressing the worldwide challenge faced by coordinating numerous organizations – the COVAX partnership, global pharmaceutical companies, contract vaccine manufacturers, inter- and intranational transport, vaccine storage facilities, and health organizations in individual countries – Seth Berkley, chief executive of GAVI, stated: "Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles all the way along the supply chain."
As an example highlighting the immensity of the challenge, the International Air Transport Association stated that 8,000 Boeing 747 cargo planes, equipped for precision vaccine cold storage, would be needed to transport one dose for the entire population in the more than 200 countries experiencing the COVID‑19 pandemic. GAVI states that "with a fast-moving pandemic, no one is safe, unless everyone is safe."
In contrast to the multibillion-dollar investment in vaccine technologies and early-stage clinical research, the post-licensing supply chain for a vaccine has not received the same planning, coordination, security or investment. A major concern is that resources for vaccine distribution in low- to middle-income countries, particularly for vaccinating children, are inadequate or non-existent, but could be improved with cost efficiencies if procurement and distribution were centralized regionally or nationally. In September, the COVAX partnership included 172 countries coordinating plans to optimize the supply chain for a COVID‑19 vaccine, and the United Nations Children's Fund joined with COVAX to prepare the financing and supply chain for vaccinations of children in 92 developing countries. As of 2023, more than 1.6 billion COVAX doses have been provided to poor nations, assisting in the vaccination of 52% of their population, compared to a global average of 64%.
=== Logistics ===
Logistics vaccination services assure necessary equipment, staff, and supply of licensed vaccines across international borders. Central logistics include vaccine handling and monitoring, cold chain management, and safety of distribution within the vaccination network. The purpose of the COVAX facility is to centralize and equitably administer logistics resources among participating countries, merging manufacturing, transport, and overall supply chain infrastructure. Included are logistics tools for vaccine forecasting and needs estimation, in-country vaccine management, potential for wastage, and stock management.
Other logistics factors conducted internationally during distribution of a COVID‑19 vaccine may include:
visibility and traceability by barcodes for each vaccine vial
sharing of supplier audits
sharing of chain of custody for a vaccine vial from manufacturer to the individual being vaccinated
use of vaccine temperature monitoring tools
temperature stability testing and assurance
new packaging and delivery technologies
stockpiling
coordination of supplies within each country (personal protective equipment, diluent, syringes, needles, rubber stoppers, refrigeration fuel or power sources, waste-handling, among others)
communications technology
environmental impacts in each country
A logistics shortage in any one step may derail the whole supply chain, according to one vaccine developer. If the vaccine supply chain fails, the economic and human costs of the pandemic may be extended for years.
=== Manufacturing capacity ===
By August 2020, when only a few vaccine candidates were in Phase III trials and were many months away from establishing safety and efficacy, numerous governments pre-ordered more than 2 billion doses at a cost of more than US$5 billion. Pre-orders from the British government for 2021 were for five vaccine doses per person, a number dispiriting to organizations like the WHO and GAVI which are promoting fair and equitable access worldwide, especially for developing countries. In September, CEPI was financially supporting basic and clinical research for nine vaccine candidates, with nine more in evaluation, under financing commitments to manufacture 2 billion doses of three licensed vaccines by the end of 2021. Before 2022, 7–10 billion COVID‑19 vaccine doses may be manufactured worldwide, but the sizable pre-orders by affluent countries – called "vaccine nationalism" – threaten vaccine availability for poorer nations.
The RNA vaccines from Moderna and Pfizer-BioNTech are unusually difficult to produce because they rely upon encapsulation of mRNA in lipid nanoparticles, a novel technology which has never been scaled up before for mass production. As of February 2021, this was thought to be the primary bottleneck in the manufacturing of such vaccines. In November 2021, Moderna CEO Stéphane Bancel claimed that the company had a backlog of tens of millions of doses of its vaccine destined for Africa because COVAX or individual governments could not take delivery. He cited delays with dose administration, a shortage of refrigerator space, and delays getting customs documents.
Vaccines must be handled and transported according to international regulations, be maintained at controlled temperatures that vary across vaccine technologies, and be used for immunization before deterioration in storage. The scale of the COVID‑19 vaccine supply chain is expected to be vast to ensure delivery worldwide to vulnerable populations. Priorities for preparing facilities for such distribution include temperature-controlled facilities and equipment, optimizing infrastructure, training immunization staff, and rigorous monitoring. RFID technologies are being implemented to track and authenticate a vaccine dose from the manufacturer along the entire supply chain to the vaccination.
In September 2020, Grand River Aseptic Manufacturing agreed with Johnson & Johnson to support the manufacture of its vaccine candidate, including technology transfer and fill and finish manufacturing. In October 2020, it was announced that the Moderna vaccine candidate will be manufactured in Visp, Switzerland by its partner Lonza Group, which plans to produce the first doses in December 2020. The newly built 2,000-square-metre facility will ramp up production to 300 million doses annually. The ingredient will be shipped frozen at −70 °C to Spain's Laboratorios Farmacéuticos Rovi SA for the final stage of manufacturing. Lonza's site in Portsmouth, New Hampshire, aimed to start making vaccine ingredients exclusively for the U.S. by November 2020. Compounding the concerns over massive pre-orders by wealthy countries, manufacturing capacity is also limited by the fact that most vaccines are patented by companies in those countries. India and South Africa proposed a waiver to the TRIPS Agreement which would remove exclusivity agreements as a barrier to setting up new facilities but the measure is being blocked by the G7.
=== Cold chain ===
Different vaccines have different shipping and handling requirements. For example, the Pfizer-BioNTech COVID‑19 vaccine must be shipped and stored between −80 and −60 °C (−112 and −76 °F), must be used within five days of thawing, and has a minimum order of 975 doses, making it unlikely to be rolled out in settings other than large, well-equipped hospitals. The Moderna vaccine vials require storage above −40 °C (−40 °F) and between −25 and −15 °C (−13 and 5 °F). Once refrigerated, the Moderna vaccine can be kept between 2 and 8 °C (36 and 46 °F) for up to 30 days.
Vaccines (and adjuvants) are inherently unstable during temperature changes, requiring cold chain management throughout the entire supply chain, typically at temperatures of 2–8 °C (36–46 °F). Because COVID‑19 vaccine technologies are varied among several novel technologies, there are new challenges for cold chain management, with some vaccines that are stable while frozen but liable to heat, while others should not be frozen at all, and some are stable across temperatures. Failure to maintain cold chain temperature stability results in damage that can reduce or even eliminate vaccine efficacy. Sinopharm and Sinovac's vaccines are examples of inactivated vaccines which can be transported using existing cold chain systems at 2–8 °C (36–46 °F).
modRNA vaccine technologies in development may be more difficult to manufacture at scale and control degradation, requiring ultracold storage and transport. As examples, Moderna's RNA vaccine candidate requires cold chain management just above freezing temperatures between 2 and 8 °C (36 and 46 °F) with limited storage duration (30 days), but the Pfizer-BioNTech RNA candidate requires storage between −80 and −60 °C (−112 and −76 °F), or colder throughout deployment until vaccination. In February 2021, Pfizer and BioNTech asked the U.S. Food and Drug Administration (FDA) to update the emergency use authorization (EUA) to permit the vaccine to be stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use. As of May 2021, Walvax is conducting Phase III trials for its mRNA vaccine which could be stored at room temperature for six months.
After a vaccine vial is punctured to administer a dose, it is viable for only six hours, then must be discarded, requiring attention to local management of cold storage and vaccination processes. Because the COVID‑19 vaccine will likely be in short supply for many locations during early deployment, vaccination staff will have to avoid spoilage and waste, which typically are as much as 30% of the supply. The cold chain is further challenged by the type of local transportation for the vaccines in rural communities, such as by motorcycle or delivery drone, need for booster doses, use of diluents, and access to vulnerable populations, such as healthcare staff, children and the elderly.
=== Air and land transport ===
Coordination of international air cargo is an essential component of time- and temperature-sensitive distribution of COVID‑19 vaccines, but, as of September 2020, the air freight network is not prepared for multinational deployment. "Safely delivering COVID‑19 vaccines will be the mission of the century for the global air cargo industry. But it won't happen without careful advance planning. And the time for that is now. We urge governments to take the lead in facilitating cooperation across the logistics chain so that the facilities, security arrangements and border processes are ready for the mammoth and complex task ahead," said IATA's Director General and CEO, Alexandre de Juniac, in September 2020.
For the severe reduction in passenger air traffic during 2020, airlines downsized personnel, trimmed destination networks, and put aircraft into long-term storage. As the lead agencies for procurement and supply of the COVID‑19 vaccine within the WHO COVAX facility, GAVI and UNICEF are preparing for the largest and fastest vaccine deployment ever, necessitating international air freight collaboration, customs and border control, and possibly as many as 8,000 cargo planes to deliver just one vaccine dose to multiple countries.
Two of the first approved vaccines, Pfizer and BioNTech's Pfizer-BioNTech COVID‑19 vaccine and Moderna's mRNA-1273, must be kept cold during transport. Keeping the temperatures sufficiently low is accomplished with specially-designed containers and dry ice, but dry ice is only allowed in limited quantities on airplanes as the gases released via sublimation may be toxic. In the United States, the Federal Aviation Administration (FAA) limits the amount of dry ice on a Boeing 777-224 to 3,000 lb (1,400 kg), but it temporarily allowed United Airlines to transport up to 15,000 lb (6,800 kg)—nearly 1 million doses—between Brussels and Chicago. The Centers for Disease Control and Prevention (CDC) tasked McKesson Corporation with vaccine distribution in the U.S.; the company handled all major vaccines except Pfizer's. American Airlines, Boeing, and Delta Air Lines are also working to increase dry ice transportation capacity, and American, Delta, and United each operate their own cold storage networks in the US. FedEx and UPS have installed ultra-cold freezers at air cargo hubs in Europe and North America, and UPS can manufacture 1,200 lb (540 kg) of dry ice per hour.
=== Security and corruption ===
Medicines are the world's largest fraud market, worth some $200 billion per year, making the widespread demand for a COVID‑19 vaccine vulnerable to counterfeit, theft, scams, and cyberattacks throughout the supply chain. The vaccine has been referred to as "the most valuable asset on earth"; Interpol called it "liquid gold" and warned of an "onslaught of all types of criminal activity". Anticorruption, transparency, and accountability safeguards are being established to reduce and eliminate corruption of COVID‑19 vaccine supplies. Absence of harmonized regulatory frameworks among countries, including low technical capacity, constrained access, and ineffective capability to identify and track genuine vs. counterfeit vaccines, may be life-threatening for vaccine recipients, and would potentially perpetuate the COVID‑19 pandemic. Tracking system technologies for packaging are being used by manufacturers to trace vaccine vials across the supply chain, and to use digital and biometric tools to assure security for vaccination teams. In December 2020, Interpol warned that organized crime could infiltrate the vaccine supply chain, steal product through physical means, and data theft, or even offer counterfeit vaccine kits. Further, vaccines which require constant freezing temperatures are also susceptible to sabotage.
GPS devices will be used in the United States to track the vaccines. In Colorado, the vaccine shipments will be escorted by Colorado State Patrol officers from Denver International Airport to the state's eight distribution points; the exact plans are confidential and law enforcement will "maintain a low-key profile".
Peripheral businesses may also be affected. An IBM security analyst told The New York Times that petrochemical companies are being targeted by hackers due to their central role in producing dry ice.
On 21 May 2020, the FDA made public the cease-and-desist notice it had sent to North Coast Biologics, a Seattle-based company that had been selling a purported "nCoV19 spike protein vaccine". On 21 January 2021, its founder, Johnny Stine, was arrested on a federal warrant charging him with introducing misbranded drugs into interstate commerce, a misdemeanor. Stine pleaded guilty in August 2021. On 8 March 2022, he was sentenced to five years' probation and ordered to pay $246,986 in restitution.
=== National infrastructure ===
The WHO has implemented an "Effective Vaccine Management" system, which includes constructing priorities to prepare national and subnational personnel and facilities for vaccine distribution, including:
Trained staff to handle time- and temperature-sensitive vaccines
Robust monitoring capabilities to ensure optimal vaccine storage and transport
Temperature-controlled facilities and equipment
Traceability
Security
Border processes for efficient handling and customs clearance within individual countries may include:
Facilitating flight and landing permits
Exempting flight crews from quarantine requirements
Facilitating flexible operations for efficient national deployment
Granting arrival priority to maintain vaccine temperature requirements
== Tailored vaccination strategies ==
During a pandemic wave, rapid vaccination of those driving virus dissemination (the socially active) and vaccination of those at highest risk (the elderly, often socially less active) are two desirable goals that are at odds in the setting of limited vaccine supply. However, the recent study (published in 2022) on the national COVID-19 vaccination schedules in 29 countries (EU, UK, and Israel) shows that all researched schedules prioritized criteria referring to higher risk (being over 65 years old and/or having coexisting health conditions) over the criteria referring to virus dissemination (occupation and/or housing conditions). Postponing a second vaccine dose (the first is more important for avoiding a severe disease course) to allow faster access to the first dose for more persons has been chosen as deployment strategies in some countries. Using a reduced mRNA vaccine dose in the younger, who have a lower disease risk, a stronger immune response to the vaccination but are key drivers of pandemic waves, may allow reaching more persons faster, with vaccination strategy models predicting a significant reduction of nation-wide case load and deaths. On the other side, protection of some groups, e.g. the elderly or the immunosuppressed may require additional booster doses. Concerns regarding the impact of vaccination in pregnancy, compounded through miss information disseminated through numerous sources including social media platforms, led to poor uptake in this group, despite evidence COVID-19 vaccination has no detrimental impact on live birth or miscarriage.
== Liability ==
On 4 February 2020, US Secretary of Health and Human Services Alex Azar published a notice of declaration under the Public Readiness and Emergency Preparedness Act for medical countermeasures against COVID‑19, covering "any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID‑19, or the transmission of SARS-CoV-2 or a virus mutating therefrom", and stating that the declaration precludes "liability claims alleging negligence by a manufacturer in creating a vaccine, or negligence by a health care provider in prescribing the wrong dose, absent willful misconduct". The declaration is effective in the United States through 1 October 2024.
In the European Union, the COVID‑19 vaccines are licensed under a Conditional Marketing Authorisation which does not exempt manufacturers from civil and administrative liability claims. While the purchasing contracts with vaccine manufacturers remain secret, the manufacturers remain liable even for side-effects not known at the time of licensure.
Pfizer has been criticised for demanding far-reaching liability waivers and other guarantees from countries such as Argentina and Brazil, which go beyond what was expected from other countries such as the US (above).
== See also ==
== Notes ==
== References == | Wikipedia/Deployment_of_COVID-19_vaccines |
The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients.
Dendritic cells (DCs) are antigen presenting cells for the induction of antigen specific T cell response. DC-based immunotherapy is safe and can promote antitumor immune responses and prolonged survival of cancer patients.
== Human DC subsets ==
=== Immature dendritic cells ===
Non-activated (immature) DCs are usually located in the peripheral non-lymphoid tissues and they can present self-antigens to T cells, that leads to immune tolerance either through T cell deletion or through the differentiation of regulatory T cells.
=== Mature dendritic cells ===
Mature DCs have ability to present antigens in the lymphoid tissues, and to prime, activate, and expand immune effector cells with unique functions and cytokine profiles.
=== Myeloid dendritic cells (cDCs) ===
Myeloid or conventional DCs (cDCs) are derived from myeloid progenitor cells in the bone marrow and are characterized by expression of CD11c. cDCs can be subdivided into 3 groups: monocyte-derived DCs, CD1a- interstitial DCs, and CD1a+ Langerhans cells.
=== Plasmacytoid dendritic cells (pDCs) ===
Plasmacytoid dendritic cells (pDCs) differentiate from lymphoid progenitor cells in the lymphoid tissues. They express CD123 and product high levels of type I interferon. pDCs also contribute to inflammatory responses in the steady state and in pathology. During inflammatory response, inflammatory DCs (iDCs) are generated from monocytes.
== Function of cancer therapeutic vaccines ==
The main goal of the therapeutic vaccines is to elicit cellular immunity. They should prime naïve T cell, and induce transition from chronically activated non-protective CD8+ T cells to healthy CD8+ T cells that can produce cytotoxic T lymphocytes (CTLs), which recognize and eliminate cancer cells by recognizing specific antigens. This process also creates long-lived memory CD8+ T cells that will act to prevent relapse. The most critical step in vaccination is the effective presentation of cancer antigens to T cells, and because of DCs are the most efficient antigen presenting cells, they are the promising option for improvement of therapeutic vaccines.
== Methods for exploiting dendritic cells in cancer therapeutic vaccines ==
DC-based immunotherapy approach can be employed in two ways:
=== Direct targeting/stimulating of the DCs in vivo to accentuate their anticancer phenotype ===
Many trials evaluating in vivo DC stimulation with synthetic peptides failed because of inability of effective stimulation of CD4+ cellular responses and stimulation of Th2 type cytokines. The solution showing clinical responses was pre-treatment with single-dose cyclophosphamide as well as vaccination with tumor associated antigens (TAAs) and granulocyte macrophage colony stimulating factor (GM-CSF).
=== Stimulation of the DCs ex vivo and infusing them back into the host for carrying out anticancer effector function ===
In this way, DCs’ precursors are isolated from the patient through leukapheresis and after maturation/stimulation of these precursors ex vivo, fully mature DCs are injected back into the patient. There are different ways applied to generate cancer cells-specific DCs. We can used specific TAAs, tumor lysates, created DC-cancer cell fusions, electroporation/transfection of DCs with total cancer cell-mRNA or tumor derived exosomes (TDEs) by the stimulation. There is also the possibility of additional co-stimulating with cytokine “cocktails” to assure strong maturation.
== Dendritic cell vaccine against brain tumor ==
The most well-known source of antigens used for vaccines in Glioblastoma (Aggressive type of brain tumor) investigations were whole tumor lysate, CMV antigen RNA and tumor associated peptides for instance EGFRvIII. The initial studies showed that patients developed immune responses as measured by Interferon-gamma expression in the peripheral blood, systemic cytokine responses, or CD8+ antigen specific T cell expansion. Clinical response rates were not as vigorous as the immune response rates. Overall survival (OS) and progression free survival (PFS) varied in different studies but were enhanced compared to historical controls.
== Dendritic cell vaccine against COVID-19 ==
Autologous dendritic cells previously loaded ex-vivo with SARS-CoV-2 spike protein. Subjects eligible for treatment will be those who at baseline, are not actively infected with SARS-CoV-2, have no evidence of prior infection with SARS-CoV-2 based on serologic testing, and give informed consent for a vaccination with AV-COVID-19. The patient population will include the elderly and others at higher risk for poor outcomes after COVID-19 infection. For this reason, individuals will not be excluded solely on the basis of age, body mass index, history of hypertension, diabetes, cancer, or autoimmune disease.
== Sipuleucel-T ==
Sipuleucel-T is the first DCs- based cancer vaccine for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC), approved by the US Food and Drug Administration (FDA) . It is an active cellular immunotherapy, which involves obtaining antigen-presenting autologous dendritic cells from the patient following a leukapheresis procedure. The cells are incubated ex vivo in the presence of a recombinant fusion protein PA2024 containing a prostate antigen, prostate acid phosphatase and GM-CSF, an immune-cell activator. The cells are then returned to the patient to generate an immune response.
== References == | Wikipedia/Dendritic_cell-based_cancer_vaccine |
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