154-544: ZA : Section 21 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
308-476: A bat SARS-like coronavirus and a pangolin coronavirus through cross-species transmission. The earliest available SARS-CoV-2 viral genomes were collected from patients in December 2019, and Chinese researchers compared these early genomes with bat and pangolin coronavirus strains to estimate the ancestral human coronavirus type; the identified ancestral genome type was labeled "S", and its dominant derived type
462-558: A phase 1 trial of an saRNA COVID-19 vaccine, used as a booster vaccine . The vaccine is designed to target both the spike protein of the SARS‑CoV‑2 virus, and viral proteins that may be less prone to genetic variation, to provide greater protection against SARS‑CoV‑2 variants. saRNA vaccines must use uridine, which is required for reproduction to occur. Variant of concern Variants of severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) are viruses that, while similar to
616-414: 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
770-764: A variant of interest ( VOI ), or in some countries a variant under investigation ( VUI ). During or after fuller assessment as a variant of concern the variant is typically assigned to a lineage in the Pango nomenclature system and to clades in the Nextstrain and GISAID systems. Historically, the WHO regularly listed updates on variants of concern (VOC), which are variants with an increased rate of transmission, virulence, or resistance against mitigations, like vaccines. The variant submissions from member states are then submitted to GISAID , followed by field investigations of
924-436: A $ 25 million grant to Moderna. The first human clinical trials using an mRNA vaccine against an infectious agent ( rabies ) began in 2013. Over the next few years, clinical trials of mRNA vaccines for a number of other viruses were started. mRNA vaccines for human use were studied for infectious agents such as influenza , Zika virus , cytomegalovirus , and Chikungunya virus . The COVID-19 pandemic , and sequencing of
1078-481: A 95% confidence or credibility level, unless otherwise stated. Currently, all estimates are approximations due to the limited availability of data for studies. For Alpha, Beta, Gamma and Delta, there is no change in test accuracy , and neutralising antibody activity is retained by some monoclonal antibodies. PCR tests continue to detect the Omicron variant. The WHO defines a previously circulating variant as
1232-479: A clinical trial conducted in more than 2,200 children aged 5–11 has generated a "robust" response and is safe. 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
1386-595: A critical aspect of in vivo delivery. One study showed, in comparing different routes, that lymph node injection leads to the largest T-cell response. Naked mRNA injection means that the delivery of the vaccine is only done in a buffer solution . This mode of mRNA uptake has been known since the 1990s. The first worldwide clinical studies used intradermal injections of naked mRNA for vaccination. A variety of methods have been used to deliver naked mRNA, such as subcutaneous, intravenous, and intratumoral injections. Although naked mRNA delivery causes an immune response,
1540-585: 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." In June 2021,
1694-401: 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, MRNA vaccine An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen -encoding mRNA into cells , which use
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#17327722109891848-552: A few nucleotides. Some of the potential consequences of emerging variants are the following: Variants that appear to meet one or more of these criteria may be labelled "variants under investigation" or "variants of interest" pending verification and validation of these properties. The primary characteristic of a variant of interest is that it shows evidence that demonstrates it is the cause of an increased proportion of cases or unique outbreak clusters; however, it must also have limited prevalence or expansion at national levels, or
2002-478: A foundation for similar research into using lipids to deliver mRNA. However, new lipids had to be invented to encapsulate mRNA strands, which are much longer than siRNA strands. Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid's outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted
2156-406: A more standardized fashion (with fewer error rates in production), which can improve responsiveness to serious outbreaks. The Pfizer–BioNTech vaccine originally required 110 days to mass-produce (before Pfizer began to optimize the manufacturing process to only 60 days), which was substantially faster than traditional flu and polio vaccines. Within that larger timeframe, the actual production time
2310-538: A mutual electrostatic repulsion . Additionally, mRNA is easily degraded by RNAases in skin and blood. Various methods have been developed to overcome these delivery hurdles. The method of vaccine delivery can be broadly classified by whether mRNA transfer into cells occurs within ( in vivo ) or outside ( ex vivo ) the organism. Dendritic cells display antigens on their surfaces , leading to interactions with T cells to initiate an immune response. Dendritic cells can be collected from patients and programmed with
2464-659: 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
2618-400: A range of diseases in model animals such as mice , chicken and primates . mRNA vaccines offer specific advantages over traditional vaccines . Because mRNA vaccines are not constructed from an active pathogen (or even an inactivated pathogen), they are non-infectious. In contrast, traditional vaccines require the production of pathogens, which, if done at high volumes, could increase
2772-539: A recombinant antigen-encoding viral vector (harmless carrier virus with an antigen transgene ) into the body. These antigens and viruses are prepared and grown outside the body. In contrast, mRNA vaccines introduce a short-lived synthetically created fragment of the RNA sequence of a virus into the individual being vaccinated. These mRNA fragments are taken up by dendritic cells through phagocytosis . The dendritic cells use their internal machinery ( ribosomes ) to read
2926-632: 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
3080-560: 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
3234-458: A variant that "has demonstrated to no longer pose a major added risk to global public health compared to other circulating SARS-CoV-2 variants", but should still be monitored. On 15 March 2023, the WHO released an update on the tracking system of VOCs, announcing that only VOCs will be assigned Greek letters. The variants listed below had previously been designated as variants of concern, but were displaced by other variants. As of May 2022 ,
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#17327722109893388-572: 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
3542-618: Is translated in the cytosol , so there is no need for the RNA to enter the cell nucleus , and the risk of being integrated into the host genome is averted. Modified nucleosides (for example, pseudouridines , 2'-O-methylated nucleosides) can be incorporated to mRNA to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity. The open reading frame (ORF) and untranslated regions (UTR) of mRNA can be optimized for different purposes (a process called sequence engineering of mRNA), for example through enriching
3696-515: Is a common last name . In the event that the WHO uses the entirety of the Greek alphabet, the agency considered naming future variants after constellations . While there are many thousands of variants of SARS-CoV-2, subtypes of the virus can be put into larger groupings such as lineages or clades . Three main, generally used nomenclatures have been proposed: Each national public health institute may also institute its own nomenclature system for
3850-559: Is a descendant of B.1.1.28, the name B.1.1.28.1 is not permitted and thus the resultant name is P.1), and has 17 unique amino acid changes, 10 of which in its spike protein, including the three concerning mutations: N501Y , E484K and K417T. The N501Y and E484K mutations favour the formation of a stable RBD-hACE2 complex, thus, enhancing the binding affinity of RBD to hACE2. However, the K417T mutation disfavours complex formation between RBD and hACE2, which has been demonstrated to reduce
4004-457: Is also developing a mRNA cancer vaccine against melanoma mRNA-4157/V940 . The goal of a vaccine is to stimulate the adaptive immune system to create antibodies that precisely target that particular pathogen . The markers on the pathogen that the antibodies target are called antigens . Traditional vaccines stimulate an antibody response by injecting either antigens , an attenuated (weakened) virus, an inactivated (dead) virus, or
4158-565: Is also known as 20I (V1), 20I/501Y.V1 (formerly 20B/501Y.V1), or 501Y.V1. From October to December 2020, its prevalence doubled every 6.5 days, the presumed generational interval. It is correlated with a significant increase in the rate of COVID-19 infection in United Kingdom , associated partly with the N501Y mutation. There was some evidence that this variant had 40–80% increased transmissibility (with most estimates lying around
4312-569: 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
4466-642: Is currently not known when the index case or "patient zero" occurred, the choice of reference sequence for a given study is relatively arbitrary, with different notable research studies' choices varying as follows: The variant first sampled and identified in Wuhan, China is considered by researchers to differ from the progenitor genome by three mutations. Subsequently, many distinct lineages of SARS-CoV-2 have evolved. The following table presents information and relative risk level for currently and formerly circulating variants of concern (VOC). The intervals assume
4620-480: Is more frequently resulting in serious illness in those cases. The South African health department also indicated that the variant may be driving the second wave of the COVID-19 epidemic in the country due to the variant spreading at a more rapid pace than other earlier variants of the virus. Scientists noted that the variant contains several mutations that allow it to attach more easily to human cells because of
4774-628: Is of the same lineage in the Pango nomenclature system, but has an additional E484K mutation. As of 17 March 2021, there were 39 confirmed cases of VOC -21FEB-02 in the UK. On 4 March 2021, scientists reported B.1.1.7 with E484K mutations in the state of Oregon . In 13 test samples analysed, one had this combination, which appeared to have arisen spontaneously and locally, rather than being imported. Other names for this variant include B.1.1.7+E484K and B.1.1.7 Lineage with S:E484K. On 18 December 2020,
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4928-551: Is only about 22 days: two weeks for molecular cloning of DNA plasmids and purification of DNA, four days for DNA-to-RNA transcription and purification of mRNA, and four days to encapsulate mRNA in lipid nanoparticles followed by fill and finish . The majority of the days needed for each production run are allocated to rigorous quality control at each stage. In addition to sharing the advantages of theoretical DNA vaccines over established traditional vaccines , mRNA vaccines also have additional advantages over DNA vaccines. The mRNA
5082-667: 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
5236-916: Is similar to that of conventional, non-RNA vaccines. However, those susceptible to an autoimmune response may have an adverse reaction to mRNA vaccines. The mRNA strands in the vaccine may elicit an unintended immune reaction – this entails the body believing itself to be sick , and the person feeling as if they are as a result. To minimize this, mRNA sequences in mRNA vaccines are designed to mimic those produced by host cells. Strong but transient reactogenic effects were reported in trials of novel COVID-19 mRNA vaccines; most people will not experience severe side effects which include fever and fatigue. Severe side effects are defined as those that prevent daily activity. The COVID-19 mRNA vaccines from Moderna and Pfizer–BioNTech have efficacy rates of 90 to 95 percent. Prior mRNA, drug trials on pathogens other than COVID-19 were not effective and had to be abandoned in
5390-671: 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
5544-538: The 501.V2 variant , also known as 501.V2, 20H (V2), 20H/501Y.V2 (formerly 20C/501Y.V2), 501Y.V2, VOC-20DEC-02 (formerly VOC -202012/02), or lineage B.1.351, was first detected in South Africa and reported by the country's health department . It has been labelled as Beta variant by WHO. Researchers and officials reported that the prevalence of the variant was higher among young people with no underlying health conditions, and by comparison with other variants it
5698-861: The FDA gave emergency use authorization for the Pfizer–BioNTech COVID-19 vaccine and a week later similar approval for the Moderna COVID-19 vaccine . Other mRNA vaccines continue to be developed, since the approval of the first mRNA vaccines. Moderna announced the development of mRNA vaccines for 15 diseases: Chikungunya virus , COVID-19, Crimean-Congo haemorrhagic fever , Dengue , Ebola virus disease , HIV , Malaria , Marburg virus disease , Lassa fever , Middle East respiratory syndrome coronavirus (MERS-CoV) , Nipah and henipaviral diseases, Rift Valley fever , Severe fever with Thrombocytopenia syndrome , Tuberculosis and Zika . Moderna
5852-503: 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
6006-572: The Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19. The first successful transfection of designed mRNA packaged within a liposomal nanoparticle into a cell was published in 1989. "Naked" (or unprotected) lab-made mRNA
6160-772: 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
6314-669: The Oxford–AstraZeneca vaccine is effective against the Gamma variant, although the exact level of efficacy has not yet been released. Preliminary data from a study conducted by Instituto Butantan suggest that CoronaVac is effective against the Gamma variant as well, and as of July 2021 has yet to be expanded to obtain definitive data. On 16 March 2022, the WHO has de-escalated the Gamma variant and its subvariants to "previously circulating variants of concern". The Delta variant, also known as B.1.617.2, G/452R.V3, 21A or 21A/S:478K,
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6468-600: 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,
6622-852: The University of Cambridge said in a BBC interview that lineage B.1.525 appeared to have "significant mutations" already seen in some of the other newer variants, which means their likely effect is to some extent more predictable. On 18 February 2021, the Department of Health of the Philippines confirmed the detection of two mutations of COVID-19 in Central Visayas after samples from patients were sent to undergo genome sequencing. The mutations were later named as E484K and N501Y, which were detected in 37 out of 50 samples, with both mutations co-occurrent in 29 out of these. On 13 March,
6776-453: The biotechnology research program ADEPT to develop emerging technologies for the US military . The agency recognized the potential of nucleic acid technology for defense against pandemics and began to invest in the field. DARPA grants were seen as a vote of confidence that in turn encouraged other government agencies and private investors to invest in mRNA technology. DARPA awarded at the time
6930-414: The guanine-cytosine content or choosing specific UTRs known to increase translation. An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed. Because mRNA is fragile, some vaccines must be kept at very low temperatures to avoid degrading and thus giving little effective immunity to
7084-453: The modified nucleoside technique reduced inflammation but hasn't eliminated it completely", and that "this may also explain the intense reactions such as aches and fevers reported in some recipients of the mRNA SARS-CoV-2 vaccines". These reactions though severe were transient and another view is that they were believed to be a reaction to the lipid drug delivery molecules. There is misinformation implying that mRNA vaccines could alter DNA in
7238-582: 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,
7392-406: 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. 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
7546-594: The Delta variant occurred among the fully vaccinated. In June 2021, reports began to appear of a variant of Delta with the K417N mutation. The mutation, also present in the Beta and Gamma variants, raised concerns about the possibility of reduced effectiveness of vaccines and antibody treatments and increased risk of reinfection. The variant, called "Delta with K417N" by Public Health England, includes two clades corresponding to
7700-712: The Department of Health confirmed the mutations constitutes a variant which was designated as lineage P.3. On the same day, it also confirmed the first COVID-19 case caused by the Gamma variant in the country. The Philippines had 98 cases of the Theta variant on 13 March. On 12 March it was announced that Theta had also been detected in Japan. On 17 March, the United Kingdom confirmed its first two cases, where PHE termed it VUI-21MAR-02. On 30 April 2021, Malaysia detected 8 cases of
7854-543: 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
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#17327722109898008-576: The Epsilon variant accounted for 36 per cent of samples collected at Cedars-Sinai Medical Center, and by January 2021, the Epsilon variant accounted for 50 per cent of samples. In a joint press release by University of California, San Francisco , California Department of Public Health , and Santa Clara County Public Health Department , the variant was also detected in multiple counties in Northern California. From November to December 2020,
8162-475: The FDA approved the use of lipid nanoparticles as a drug delivery system was in 2018, when the agency approved the first siRNA drug, Onpattro . Encapsulating the mRNA molecule in lipid nanoparticles was a critical breakthrough for producing viable mRNA vaccines, solving a number of key technical barriers in delivering the mRNA molecule into the host cell. Research into using lipids to deliver siRNA to cells became
8316-670: The L452R (previously also detected in other unrelated lineages) was of particular concern. From 17 March to 29 June 2021, the CDC listed B.1.429 and the related B.1.427 as "variants of concern". As of July 2021, Epsilon is no longer considered a variant of interest by the WHO, as it was overtaken by Alpha. From September 2020 to January 2021, it was 19% to 24% more transmissible than earlier variants in California. Neutralisation against it by antibodies from natural infections and vaccinations
8470-510: 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
8624-463: The Pango lineages AY.1 and AY.2. It has been nicknamed "Delta plus" from "Delta plus K417N". The name of the mutation, K417N, refers to an exchange whereby lysine (K) is replaced by asparagine (N) at position 417. On 22 June, India's Ministry of Health and Family Welfare declared the "Delta plus" variant of COVID-19 a variant of concern, after 22 cases of the variant were reported in India. After
8778-528: 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
8932-625: 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
9086-405: The RNA in the cell nucleus. A retrovirus has mechanisms to be imported into the nucleus, but other mRNA (such as the vaccine) lack these mechanisms. Once inside the nucleus, creation of DNA from RNA cannot occur without a reverse transcriptase and appropriate primers , which both accompany a retrovirus, but which would not be present for other exogenous mRNA (such as a vaccine) even if it could enter
9240-407: The RNA strands and help their absorption into the cells. Reactogenicity , the tendency of a vaccine to produce adverse reactions, is similar to that of conventional non-RNA vaccines. People susceptible to an autoimmune response may have an adverse reaction to messenger RNA vaccines. The advantages of mRNA vaccines over traditional vaccines are ease of design, speed and lower cost of production,
9394-502: The S2 domain of the spike protein). As of 5 March 2021, it had been detected in 23 countries. It has also been reported in Mayotte , the overseas department/region of France. The first cases were detected in December 2020 in the UK and Nigeria, and as of 15 February 2021, it had occurred in the highest frequency among samples in the latter country. As of 24 February 56 cases were found in
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#17327722109899548-559: The Theta variant in Sarawak. As of July 2021, Theta is no longer considered a variant of interest by the WHO. The proportion of USA cases represented by the Iota variant had declined sharply by the end of July 2021 as the Delta variant became dominant. The variants listed below were once listed under variants under monitoring, but were reclassified due to either no longer circulating at
9702-573: The UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first medicines regulator to approve an mRNA vaccine, authorizing the Pfizer–BioNTech vaccine for widespread use. On 11 December, the US Food and Drug Administration (FDA) issued an emergency use authorization for the Pfizer–BioNTech vaccine and a week later similarly authorized the Moderna vaccine. In 2023
9856-432: The UK. Denmark, which sequences all its COVID-19 cases, found 113 cases of this variant from 14 January to 21 February 2021, of which seven were directly related to foreign travel to Nigeria. As of July 2021, UK experts are studying it to ascertain how much of a risk it could be. It is currently regarded as a "variant under investigation", but pending further study, it may become a " variant of concern ". Ravi Gupta , from
10010-539: 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
10164-551: 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. The BioNTech technology for
10318-441: The WHO did so on 7 June 2022. As of 15 March 2023 , The WHO defines a VOI as a variant "with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, virulence, antibody evasion, susceptibility to therapeutics and detectability" and that is circulating more than other variants in over one WHO region to such an extent that a global public health risk can be suggested. Furthermore,
10472-514: The WHO lists the following under "previously circulating variants of concern": First detected in October 2020 during the COVID-19 pandemic in the United Kingdom from a sample taken the previous month in Kent, lineage B.1.1.7, labelled Alpha variant by the WHO, was previously known as the first Variant Under Investigation in December 2020 (VUI – 202012/01) and later notated as VOC-202012/01. It
10626-560: The actual impact on the course of the disease is uncertain. A pre-print study by the Oswaldo Cruz Foundation published in early April found that the real-world performance of people with the initial dose of the Sinovac 's Coronavac Vaccine had approximately 50% efficacy rate. They expected the efficacy to be higher after the 2nd dose. As of July 2021, the study is ongoing. Preliminary data from two studies indicate that
10780-474: The announcement, leading virologists said there was insufficient data to support labelling the variant as a distinct variant of concern, pointing to the small number of patients studied. In the UK in July 2021, AY.4.2 was identified. Alongside those previously mentioned it also gained the nickname 'Delta Plus', on the strength of its extra mutations, Y145H and A222V. These are not unique to it, but distinguish it from
10934-446: The antigen to T cells and B cells . This triggers the production of antibodies specifically targeted to the antigen, ultimately resulting in immunity . The central component of a mRNA vaccine is its mRNA construct. The in vitro transcribed mRNA is generated from an engineered plasmid DNA, which has an RNA polymerase promoter and sequence which corresponds to the mRNA construct. By combining T7 phage RNA polymerase and
11088-501: The antigen of interest. The total amount of mRNA available to the cell is equal to the amount delivered by the vaccine. Dosage strength is limited by the amount of mRNA that can be delivered by the vaccine. Non-amplifying vaccines replace uridine with N1-Methylpseudouridine in an attempt to reduce toxicity. Self-amplifying mRNA (saRNA) vaccines replicate their mRNA after transfection. Self-amplifying mRNA has two open reading frames . The first frame, like conventional mRNA, codes for
11242-433: The antigen of interest. The second frame codes for an RNA-dependent RNA polymerase (and its helper proteins) which replicates the mRNA construct in the cell. This allows smaller vaccine doses. The mechanisms and consequently the evaluation of self-amplifying mRNA may be different, as self-amplifying mRNA is a much bigger molecule. SaRNA vaccines being researched include a malaria vaccine . Gritstone bio started in 2021
11396-469: The binding affinity. The new variant was absent in samples collected from March to November 2020 in Manaus , Amazonas state, but it was detected for the same city in 42% of the samples from 15 to 23 December 2020, followed by 52.2% during 15–31 December and 85.4% during 1–9 January 2021. A study found that infections by Gamma can produce nearly ten times more viral load compared to persons infected by one of
11550-516: 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. The Pfizer–BioNTech COVID-19 vaccine
11704-461: 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
11858-444: The body's genomic DNA, located separately in the cell nucleus . Once the viral antigens are produced by the host cell, the normal adaptive immune system processes are followed. Antigens are broken down by proteasomes . Class I and class II MHC molecules then attach to the antigen and transport it to the cellular membrane, "activating" the dendritic cell. Once activated, dendritic cells migrate to lymph nodes , where they present
12012-402: The body, in vivo approaches have been investigated. They offer some advantages over ex vivo methods, particularly by avoiding the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection. Different routes of injection , such as into the skin , blood , or muscles , result in varying levels of mRNA uptake, making the choice of administration route
12166-571: The causative virus SARS-CoV-2 at the beginning of 2020, led to the rapid development of the first approved mRNA vaccines. BioNTech and Moderna in December of the same year obtained approval for their mRNA-based COVID-19 vaccines . On 2 December, seven days after its final eight-week trial, the UK Medicines and Healthcare products Regulatory Agency (MHRA) became the first global medicines regulator in history to approve an mRNA vaccine, granting emergency authorization for Pfizer–BioNTech's BNT162b2 COVID-19 vaccine for widespread use. On 11 December,
12320-403: 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. Based on the results of
12474-459: The classification would be elevated to a " variant of concern ". If there is clear evidence that the effectiveness of prevention or intervention measures for a particular variant is substantially reduced, that variant is termed a "variant of high consequence". SARS-CoV-2 variants are grouped according to their lineage and component mutations. Many organisations, including governments and news outlets, referred colloquially to concerning variants by
12628-414: The continuation of the COVID-19 pandemic . As of 24 September 2024 , the variants of interest as specified by the World Health Organization are BA.2.86 and JN.1, and the variants under monitoring are JN.1.7, KP.2, KP.3, KP.3.1.1, JN.1.18, LB.1, and XEC. The origin of SARS-CoV-2 has not been identified. However, the emergence of SARS-CoV-2 may have resulted from recombination events between
12782-405: The country in which they were first identified. After months of discussions, the World Health Organization announced Greek-letter names for important strains on 31 May 2021, so they could be easily referred to in a simple, easy to say, and non-stigmatising fashion. This decision may have partially been taken because of criticism from governments on using country names to refer to variants of
12936-461: The designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen (such as a virus ) or by a cancer cell . These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect
13090-568: 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
13244-427: The desired mRNA, then administered back into patients to create an immune response. The simplest way that ex vivo dendritic cells take up mRNA molecules is through endocytosis , a fairly inefficient pathway in the laboratory setting that can be significantly improved through electroporation . Since the discovery that the direct administration of in vitro transcribed mRNA leads to the expression of antigens in
13398-419: The difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system . One issue with lipid nanoparticles is that several of the breakthroughs leading to
13552-424: The early phases of trials. The reason for the efficacy of the new mRNA vaccines is not clear. Physician-scientist Margaret Liu stated that the efficacy of the new COVID-19 mRNA vaccines could be due to the "sheer volume of resources" that went into development, or that the vaccines might be "triggering a nonspecific inflammatory response to the mRNA that could be heightening its specific immune response, given that
13706-399: The effect is relatively weak, and after injection the mRNA is often rapidly degraded. Cationic polymers can be mixed with mRNA to generate protective coatings called polyplexes . These protect the recombinant mRNA from ribonucleases and assist its penetration in cells. Protamine is a natural cationic peptide and has been used to encapsulate mRNA for vaccination. The first time
13860-411: 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
14014-496: The evolution of SARS-CoV-2's genome (by means of random mutations) led to mutant specimens of the virus (i.e., genetic variants), observed to be more transmissible, to be naturally selected. Notably, both the Alpha and the Delta variants were observed to be more transmissible than previously identified viral strains. Some SARS-CoV-2 variants are considered to be of concern as they maintain (or even increase) their replication fitness in
14168-790: The face of rising population immunity, either by infection recovery or via vaccination. Some of the variants of concern show mutations in the RBD of the S-protein. The term variant of concern ( VOC ) for SARS-CoV-2 , which causes COVID-19 , is a category used for variants of the virus where mutations in their spike protein receptor binding domain (RBD) substantially increase binding affinity (e.g., N501Y) in RBD-hACE2 complex (genetic data), while also being linked to rapid spread in human populations (epidemiological data). Before being allocated to this category, an emerging variant may have been labeled
14322-524: The face. 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
14476-507: The few companies able to manufacture the requisite lipids were confronted with the challenge of scaling up production to respond to orders for several tons of lipids. In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses , lentiviruses , alphaviruses and rhabdoviruses , each of which can differ in structure and function. Clinical studies have utilized such viruses on
14630-400: 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
14784-639: 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. 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,
14938-527: The following three mutations in the receptor-binding domain (RBD) in the spike glycoprotein of the virus: N501Y , K417N, and E484K . The N501Y mutation has also been detected in the United Kingdom. On 16 March 2022, the WHO has de-escalated the Beta variant and its subvariants to "previously circulating variants of concern". The Gamma variant or lineage P.1, termed Variant of Concern 21JAN-02 (formerly VOC-202101/02) by Public Health England, 20J (V3) or 20J/501Y.V3 by Nextstrain , or just 501Y.V3,
15092-434: The frequency of the variant in sequenced cases from Northern California rose from 3% to 25%. In a preprint, CAL.20C is described as belonging to clade 20C and contributing approximately 36% of samples, while an emerging variant from the 20G clade accounts for some 24% of the samples in a study focused on Southern California. Note, however, that in the US as a whole, the 20G clade predominates, as of January 2021. Following
15246-411: The host cell also enhances protein production. For a vaccine to be successful, sufficient mRNA must enter the host cell cytoplasm to stimulate production of the specific antigens. Entry of mRNA molecules, however, faces a number of difficulties. Not only are mRNA molecules too large to cross the cell membrane by simple diffusion , they are also negatively charged like the cell membrane, which causes
15400-600: The increasing numbers of Epsilon in California, the variant has been detected at varying frequencies in most US states. Small numbers have been detected in other countries in North America, and in Europe, Asia and Australia. After an initial increase, its frequency rapidly dropped from February 2021 as it was being outcompeted by the more transmissible Alpha . In April, Epsilon remained relatively frequent in parts of northern California, but it had virtually disappeared from
15554-654: The induction of both cellular and humoral immunity , and lack of interaction with the genomic DNA . While some messenger RNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine , have the disadvantage of requiring ultracold storage before distribution, other mRNA vaccines, such as the Moderna vaccine , do not have such requirements. In RNA therapeutics , messenger RNA vaccines have attracted considerable interest as COVID-19 vaccines . In December 2020, Pfizer–BioNTech and Moderna obtained authorization for their mRNA-based COVID-19 vaccines. On 2 December,
15708-447: 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
15862-448: The mRNA and increase protein production. The mRNA nucleotides can be modified to both decrease innate immune activation and increase the mRNA's half-life in the host cell. The nucleic acid sequence and codon usage impacts protein translation. Enriching the sequence with guanine-cytosine content improves mRNA stability and half-life and, in turn, protein production. Replacing rare codons with synonymous codons frequently used by
16016-400: The mRNA and produce the viral antigens that the mRNA encodes. The body degrades the mRNA fragments within a few days of introduction. Although non-immune cells can potentially also absorb vaccine mRNA, produce antigens, and display the antigens on their surfaces, dendritic cells absorb the mRNA globules much more readily. The mRNA fragments are translated in the cytoplasm and do not affect
16170-527: 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,
16324-510: The middle to higher end of this range), and early analyses suggested an increase in lethality, though later work found no evidence of increased virulence. As of May 2021, the Alpha variant had been detected in some 120 countries. On 16 March 2022, the WHO has de-escalated the Alpha variant and its subvariants to "previously circulating variants of concern". Variant of Concern 21FEB-02 (previously written as VOC -202102/02), described by Public Health England (PHE) as "B.1.1.7 with E484K"
16478-438: The mixers. Another issue, with the large-scale use of this delivery method, is the availability of the novel lipids used to create lipid nanoparticles, especially ionizable cationic lipids. Before 2020, such lipids were manufactured in small quantities measured in grams or kilograms, and they were used for medical research and a handful of drugs for rare conditions. As the safety and efficacy of mRNA vaccines became clear in 2020,
16632-513: The modRNA into the human cells, but also as adjuvants . ALC-0159 is a polyethylene glycol conjugate, i.e., a PEGylated lipid. 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
16786-408: The nucleus. mRNA vaccines use either non-amplifying (conventional) mRNA or self-amplifying mRNA. Pfizer–BioNTech and Moderna vaccines use non-amplifying mRNA. Both mRNA types continue to be investigated as vaccine methods against other potential pathogens and cancer. The initial mRNA vaccines use a non-amplifying mRNA construct. Non-amplifying mRNA has only one open reading frame that codes for
16940-418: The nucleus. mRNA in the cytosol is very rapidly degraded before it would have time to gain entry into the cell nucleus. In fact, mRNA vaccines must be stored at very low temperature and free from RNAses to prevent mRNA degradation. Retrovirus can be single-stranded RNA (just as many SARS-CoV-2 vaccines are single-stranded RNA) which enters the cell nucleus and uses reverse transcriptase to make DNA from
17094-461: The original Delta variant. On 7 June 2022, the WHO has de-escalated the Delta variant and its subvariants to "previously circulating variants of concern". The Epsilon variant or lineage B.1.429, also known as CAL.20C or CA VUI1, 21C or 20C/S:452R, is defined by five distinct mutations (I4205V and D1183Y in the ORF1ab gene, and S13I, W152C, L452R in the spike protein's S-gene), of which
17248-657: The original version of the virus and could spread quicker or as quickly as Alpha. It carries L452R and P681R mutations in Spike; unlike Kappa it carries T478K but not E484Q. On 3 June 2021, Public Health England reported that twelve of the 42 deaths from the Delta variant in England were among the fully vaccinated, and that it was spreading almost twice as fast as the Alpha variant. Also on 11 June, Foothills Medical Centre in Calgary, Canada reported that half of their 22 cases of
17402-400: The original, have genetic changes that are of enough significance to lead virologists to label them separately. SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19). Some have been stated, to be of particular importance due to their potential for increased transmissibility, increased virulence, or reduced effectiveness of vaccines against them. These variants contribute to
17556-544: The other lineages identified in Brazil (B.1.1.28 or B.1.195). Gamma also showed 2.2 times higher transmissibility with the same ability to infect both adults and older persons, suggesting P.1 and P.1-like lineages are more successful at infecting younger humans irrespective of sex. A study of samples collected in Manaus between November 2020 and January 2021, indicated that the Gamma variant is 1.4–2.2 times more transmissible and
17710-439: The pandemic, the relatively low number of infections (compared with later stages of the pandemic) resulted in fewer opportunities for mutation of the viral genome and, therefore, fewer opportunities for the occurrence of differentiated variants. Since the occurrence of variants was rarer, the observation of S-protein mutations in the receptor-binding domain (RBD) region interacting with ACE2 was also not frequent. As time went on,
17864-456: The plasmid DNA, the mRNA can be transcribed in the lab. Efficacy of the vaccine is dependent on the stability and structure of the designed mRNA. The in vitro transcribed mRNA has the same structural components as natural mRNA in eukaryotic cells . It has a 5' cap , a 5'-untranslated region (UTR) and 3'-UTR , an open reading frame (ORF), which encodes the relevant antigen, and a 3'-poly(A) tail . By modifying these different components of
18018-414: The practical use of that technology involve the use of microfluidics . Microfluidic reaction chambers are difficult to scale up, since the entire point of microfluidics is to exploit the microscale behaviors of liquids. The only way around this obstacle is to run an extensive number of microfluidic reaction chambers in parallel, a novel task requiring custom-built equipment. For COVID-19 mRNA vaccines, this
18172-458: 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
18326-412: The purposes of tracking specific variants. For example, Public Health England designated each tracked variant by year, month and number in the format [YYYY] [MM]/[NN], prefixing 'VUI' or 'VOC' for a variant under investigation or a variant of concern respectively. This system has now been modified and now uses the format [YY] [MMM]-[NN], where the month is written out using a three-letter code. As it
18480-553: The recipient. Pfizer–BioNTech's BNT162b2 mRNA vaccine has to be kept between −80 and −60 °C (−112 and −76 °F). Moderna says their mRNA-1273 vaccine can be stored between −25 and −15 °C (−13 and 5 °F), which is comparable to a home freezer, and that it remains stable between 2 and 8 °C (36 and 46 °F) for up to 30 days. In November 2020, Nature reported, "While it's possible that differences in LNP formulations or mRNA secondary structures could account for
18634-454: The risks of localized outbreaks of the virus at the production facility. Another biological advantage of mRNA vaccines is that since the antigens are produced inside the cell, they stimulate cellular immunity , as well as humoral immunity . mRNA vaccines have the production advantage that they can be designed swiftly. Moderna designed their mRNA-1273 vaccine for COVID-19 in 2 days. They can also be manufactured faster, more cheaply, and in
18788-505: The same E484K-mutation as found in the Gamma, Zeta, and Beta variants, and also carries the same ΔH69/ΔV70 deletion (a deletion of the amino acids histidine and valine in positions 69 and 70) as found in Alpha, N439K variant (B.1.141 and B.1.258) and Y453F variant ( Cluster 5 ). Eta differs from all other variants by having both the E484K-mutation and a new F888L mutation (a substitution of phenylalanine (F) with leucine (L) in
18942-557: 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. A test-negative case-control study published in August 2021, found that two doses of
19096-502: 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
19250-410: 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
19404-405: 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
19558-418: 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
19712-499: The south of the state and had never been able to establish a foothold elsewhere; only 3.2% of all cases in the United States were Epsilon, whereas more than two-thirds were Alpha. The Eta variant or lineage B.1.525, also called VUI -21FEB-03 (previously VUI-202102/03) by Public Health England (PHE) and formerly known as UK1188, 21D or 20A/S:484K, does not carry the same N501Y mutation found in Alpha , Beta and Gamma , but carries
19866-636: 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 ). In addition to the mRNA molecule, the vaccine contains the following inactive ingredients ( excipients ): The first four of these are lipids . The lipids and modRNA together form nanoparticles that act not only as carriers to get
20020-434: The synthetic mRNA, the stability and translational ability of the mRNA can be enhanced, and in turn, the efficacy of the vaccine improved. The mRNA can be improved by using synthetic 5'-cap analogues which enhance the stability and increase protein translation. Similarly, regulatory elements in the 5'-untranslated region and the 3'-untranslated region can be altered, and the length of the poly(A) tail optimized, to stabilize
20174-414: 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." Several platforms are being studied that may allow storage at higher temperatures. Before 2020, no mRNA technology platform (drug or vaccine) had been authorized for use in humans, so there
20328-439: 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,
20482-403: The update stated that "VOIs will be referred to using established scientific nomenclature systems such as those used by Nextstrain and Pango". Viruses generally acquire mutations over time, giving rise to new variants. When a new variant appears to be growing in a population, it can be labelled as an "emerging variant". In the case of SARS-CoV-2, new lineages often differ from one another by just
20636-495: 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
20790-596: 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
20944-412: The vaccine had entered phase III clinical trials , 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
21098-400: The vaccine in the European Union. 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
21252-445: 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. Before COVID‑19 vaccines, creating a vaccine for an infectious disease from scratch had never before been produced in less than
21406-405: 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
21560-447: 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
21714-478: 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
21868-544: The variant. Updated definitions, published on the 4 October 2023, add variants of interest (VOI) and variants under monitoring (VUM) to the World Health Organization's working definitions for SARS-CoV-2 variants. Other organisations such as the CDC in the United States typically define their variants of concern slightly differently; for example, the CDC de-escalated the Delta variant on 14 April 2022, while
22022-486: The virus; the WHO mentioned the potential for mentioning country names to cause stigma. After using all the letters from Alpha to Mu (see below), in November 2021 the WHO skipped the next two letters of the Greek alphabet, Nu and Xi, and used Omicron, prompting speculation that Xi was skipped to avoid offending Chinese leader Xi Jinping . The WHO gave as the explanation that Nu is too easily confounded with "new" and Xi
22176-592: Was a globally dominant variant that spread to at least 185 countries. It was first discovered in India . Descendant of lineage B.1.617, which also includes the Kappa variant under investigation, it was first discovered in October 2020 and has since spread internationally. On 6 May 2021, British scientists declared B.1.617.2 (which notably lacks mutation at E484Q) as a "variant of concern", labelling it VOC-21APR-02, after they flagged evidence that it spreads more quickly than
22330-405: Was a risk of unknown effects. The 2020 COVID-19 pandemic required faster production capability of mRNA vaccines, made them attractive to national health organisations, and led to debate about the type of initial authorization mRNA vaccines should get (including emergency use authorization or expanded access authorization ) after the eight-week period of post-final human trials. Reactogenicity
22484-453: 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. 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
22638-798: Was detected in Tokyo on 6 January 2021 by the National Institute of Infectious Diseases (NIID). It has been labelled as Gamma variant by WHO. The new variant was first identified in four people who arrived in Tokyo having travelled from the Brazilian Amazonas state on 2 January 2021. On 12 January 2021, the Brazil-UK CADDE Centre confirmed 13 local cases of the new Gamma variant in the Amazon rainforest. This variant of SARS-CoV-2 has been named lineage P.1 (although it
22792-468: Was developed by including both a viral antigen and replicase encoding gene. The method was used in mice to elicit both a humoral and cellular immune response against a viral pathogen. The next year mRNA encoding a tumor antigen was shown to elicit a similar immune response against cancer cells in mice. The first human clinical trial using ex vivo dendritic cells transfected with mRNA encoding tumor antigens ( therapeutic cancer mRNA vaccine )
22946-454: Was injected a year later into the muscle of mice. These studies were the first evidence that in vitro transcribed mRNA with a chosen gene was able to deliver the genetic information to produce a desired protein within living cell tissue and led to the concept proposal of messenger RNA vaccines. Liposome-encapsulated mRNA encoding a viral antigen was shown in 1993 to stimulate T cells in mice. The following year self-amplifying mRNA
23100-400: Was labeled "L" to reflect the mutant amino acid changes. Independently, Western researchers carried out similar analyses but labeled the ancestral type "A" and the derived type "B". The B-type mutated into further types including B.1, which is the ancestor of the major global variants of concern, labeled in 2021 by the WHO as alpha , beta , gamma , delta and omicron variants. Early in
23254-610: Was moderately reduced, but it remained detectable in most diagnostic tests. Epsilon (CAL.20C) was first observed in July 2020 by researchers at the Cedars-Sinai Medical Center , California , in one of 1,230 virus samples collected in Los Angeles County since the start of the COVID-19 epidemic . It was not detected again until September when it reappeared among samples in California, but numbers remained very low until November. In November 2020,
23408-435: Was shown to be capable of evading 25–61% of inherited immunity from previous coronavirus diseases, leading to the possibility of reinfection after recovery from an earlier COVID-19 infection. As for the fatality ratio, infections by Gamma were also found to be 10–80% more lethal. A study found that people fully vaccinated with Pfizer or Moderna have significantly decreased neutralisation effect against Gamma, although
23562-458: Was started in 2001. Four years later, the successful use of modified nucleosides as a method to transport mRNA inside cells without setting off the body's defense system was reported. Clinical trial results of an mRNA vaccine directly injected into the body against cancer cells were reported in 2008. BioNTech in 2008, and Moderna in 2010, were founded to develop mRNA biotechnologies. The US research agency DARPA launched at this time
23716-419: Was the main manufacturing bottleneck. Pfizer used such a parallel approach to solve the scaling problem. After verifying that impingement jet mixers could not be directly scaled up, Pfizer made about 100 of the little mixers (each about the size of a U.S. half-dollar coin ), connected them together with pumps and filters with a "maze of piping," and set up a computer system to regulate flow and pressure through
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