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Pfizer–BioNTech COVID-19 vaccine

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Pfizer–BioNTech COVID-19 vaccine
INN: tozinameran
Covid19 vaccine biontech pfizer 3.jpg
A vial of the Pfizer–BioNTech COVID‑19 vaccine for the U.S. market
Vaccine description
TargetSARS-CoV-2
Vaccine typemRNA
Clinical data
PronunciationTozinameran: /ˌtzɪˈnæmərən/ TOH-zih-NAM-ər-ən
Trade namesComirnaty[1][2]
Other namesBNT162b2, COVID-19 mRNA vaccine (nucleoside-modified)
AHFS/Drugs.comMultum Consumer Information
MedlinePlusa621003
License data
Pregnancy
category
Routes of
administration
Intramuscular
ATC code
Legal status
Legal status

ZA: Section 21 [28][29]

Full list of Pfizer-BioNTech vaccine authorizations
Identifiers
CAS Number
PubChem SID
DrugBank
UNII
KEGG

The Pfizer–BioNTech COVID-19 vaccine (INN: tozinameran), sold under the brand name Comirnaty,[2][22] is an mRNA-based COVID-19 vaccine developed by the German biotechnology company BioNTech. For its development, BioNTech collaborated with American company Pfizer to carry out clinical trials, logistics, and manufacturing.[30][31] It is authorized for use in people aged five years and older in some jurisdictions,[32] twelve years and older in some jurisdictions, and for people sixteen years and older in other jurisdictions,[2][33][20][34][35] to provide protection against COVID-19, caused by infection with the SARS-CoV-2 virus.[2][20] The vaccine is given by intramuscular injection. It is composed of nucleoside-modified mRNA (modRNA) encoding a mutated form of the full-length spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles.[36] Initial advice indicated that vaccination required two doses given 21 days apart,[24][37][38][39] but the interval was later extended to up to 42 days in the US,[24][40] and up to four months in Canada.[41][42]

Clinical trials began in April 2020;[37] by November 2020, the vaccine entered Phase III clinical trials, with over 40,000 people participating.[43] An 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.[39][44] Most side effects are mild to moderate in severity and are gone within a few days.[2][45] The most common include mild to moderate pain at the injection site, fatigue, and headaches.[46][47] Reports of serious side effects, such as allergic reactions, are very rare[a] and no long-term complications have been reported.[2][49]

The vaccine is the first COVID‑19 vaccine to be authorized by a stringent regulatory authority for emergency use[50][51] and the first cleared for regular use.[27] In December 2020, the United Kingdom was the first country to authorize its use on an emergency basis.[49] It is authorized for use at some level in the majority of countries.[52][53][54][55] On 23 August 2021, the Pfizer–BioNTech vaccine became the first COVID-19 vaccine to be approved in the United States by the Food and Drug Administration (FDA) for those aged sixteen years and older.[19][22][56]

As of September 2021, more than 1.5 billion COVID-19 vaccine doses have been shipped by the company worldwide.[57] As of 30 March 2021, Pfizer and BioNTech aimed to manufacture about 2.5 billion doses in 2021.[58][59] Distribution and storage is a logistical challenge because the vaccine needs to be stored at extremely low temperatures.[60]

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.[1][2][20][26] The vaccine is used to reduce morbidity and mortality from COVID-19.[24]

The vaccine is supplied in a multidose vial as "a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection".[20][26][61] It must be thawed to room temperature and diluted with normal saline before administration.[26][61]

The initial course consists of two doses.[24][26] 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.[62] 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.[62]

A third, fourth, or fifth dose can be added in some countries.[63][64][65][66][67]

Effectiveness

A test-negative[note 1] 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.[68] 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.[69]

On 27 August, the U.S. Centers for Disease Control and Prevention (CDC) published a study reporting that the effectiveness against infection decreased from 91% (8196%) to 66% (2684%) 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.[70]

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.[71] Effectiveness is generally expected to slowly decrease over time.[72]

Initial effectiveness by variant
Doses Severity of illness Delta Alpha Gamma Beta Omicron Others circulating previously[A]
1 Asymptomatic 30% (1741%)[74] 38% (2945%)[74] Not reported 17% (1023%)[75] Not reported 60% (5366%)
Symptomatic 33% (1547%)[74] 27% (1339%)[74] 43% (2259%)[76] Not reported 66% (5773%)
Hospitalization 94% (4699%)[B] 83% (6293%)[B] 56% (−9 to 82%)[76] 0% (019%)[75] Not reported 78% (6191%)
2 Asymptomatic 79% (7582%)[74] 92% (9093%)[74] Not reported 75% (7179%)[75] Not reported 92% (8895%)
Symptomatic 83% (7887%)[74] 92% (8894%)[74] 88% (6196%)[76] 88% (6696%)[C] 94% (8798%)
Hospitalization 96% (8699%)[B] 95% (7899%)[B] 100%[D][76] 100% (74100%)[75] 70% (6276%)[80] 87% (55100%)
3[E] Symptomatic 96% (8999%)[F] Not reported Not reported Not reported 76% (5686%)[G] Not reported
  1. ^ Surveillance study from 20 December 2020 to 1 February 2021 in Israel.[73] During this period, according to Nextstrain, the dominant variant in Israel was lineage B.1.1.50 and the Alpha variant was becoming dominant.
  2. ^ a b c d Preliminary data of effectiveness against hospitalization referenced by Public Health England.[77][78]
  3. ^ Effectiveness drops to 49% (2465%) in weeks 10–14 after the second dose and then stabilizes at 34%–37% thereafter.[79]
  4. ^ A confidence interval was not provided, so it is not possible to know the accuracy of this measurement.
  5. ^ Booster dose.
  6. ^ Efficacy data from a study with more than 10,000 participants.[81]
  7. ^ Effectiveness drops to about 45% 10 weeks after the booster dose.[82][79]


On 12 November, 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.[83]

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.[79][82] For other variants, the effectiveness of the initial doses starts to decline in about six months.[84] A case-control study in Qatar from 1 January to 5 September 2021 found that effectiveness against infection peaked at 78% (95% CI, 7679%) 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% (9398%) in the second month and remaining almost stable through the sixth month, declining thereafter.[85]

On 21 October, a phase 3 trial showed that a booster dose given approximately 11 months after the second dose restored the protective effect to the 96% (95% CI, 8999%) efficacy level against symptomatic disease from the Delta variant.[86][81]

On 8 December, 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.[87]

On 14 December, 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.[88]

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.[89][90]

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.[91][92]

On 19 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.[93]

A 2021 report by the New South Wales Government (NSW Health) in Australia found that the Pfizer-BioNTech vaccine is safe for those suffering from 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 suffering from cancer, inflammatory bowel disease and various liver diseases be prioritised in the vaccination schedules over other patients that do not suffer from said conditions.[94]

On 20 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.[95][96]

Adverse effects

In large phase 3 trials for the vaccine there were no reported serious safety findings, and it observed low incidence of serious adverse events.[39][44]

Most side effects of the Pfizer–BioNTech COVID‑19 vaccine are mild to moderate in severity and are gone within a few days.[45][2] They are similar to other adult vaccines and are normal signs that the body is building protection to the virus.[45] During clinical trials, the common side effects affecting more than 1 in 10 people are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, and fever.[97] Fever is more common after the second dose.[97]

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.[2] 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."[2] Rare side effects (that may affect up to 1 in 1,000 people) include temporary one sided facial drooping and allergic reactions such as hives or swelling of the face.[2]

Allergy

Documented hypersensitivity to polyethylene glycol (PEG) (a very rare allergy) is listed as a contraindication to the COVID-19 Pfizer vaccine.[98] Severe allergic reaction has been observed in approximately eleven cases per million doses of vaccine administered.[99][100] 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.[99] 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.[101][102][103] 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."[104]

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.[105] 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.[105] 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.[106][107] Most affected individuals recover quickly with adequate treatment and rest.[108]

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,[109] triggering an immune response against infection by the virus protein.[110]

Sequence

The modRNA sequence of the vaccine is 4,284 nucleotides long.[111] 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;[36][112] 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[113] and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284).[111] The sequence contains no uridine residues; they are replaced by 1-methyl-3'-pseudouridylyl.[111] 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).[112]

Chemistry

In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):[17][104][97]

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.[114] ALC-0159 is a polyethylene glycol conjugate, i.e., a PEGylated lipid.[115]

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.[31][116]

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,[117] at a small Pfizer pilot plant in Chesterfield, Missouri[118][119] (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.[120]

The second stage is being conducted at a Pfizer plant in Andover, Massachusetts,[121] in the United States, and at BioNTech's plants in Germany.[117] The DNA is used as a template to build the desired mRNA strands,[120] which takes about four days.[117] 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.[120]

External video
video icon Loading dock operations at Pfizer's Portage, Michigan facility, December 13, 2020, C-SPAN
video icon President Joe Biden and Michigan Gov. Gretchen Whitmer tour the Portage, Michigan Pfizer facility with Pfizer CEO Albert Bourla, February 19, 2021, C-SPAN

The third stage is being conducted at Pfizer plants in Portage, Michigan[122] (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.[120] Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids.[123] As of November 2020, the major bottleneck in the manufacturing process is combining mRNA with lipid nanoparticles.[120] 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.[117]

Before May 2021,[124] the Pfizer plant in Puurs was responsible for all vials for destinations outside the United States.[117] 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).[117]

In February 2021, BioNTech announced it would increase production by more than 50% to manufacture 2 billion doses in 2021,[125] raised again at the end of March to 2.5 billion doses in 2021.[59]

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.[126] More than half the days in the production process are dedicated to rigorous testing and quality assurance at each of the three stages.[126] Pfizer also revealed that the process requires 280 components and relies upon 25 suppliers located in 19 countries.[117]

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.

Syringes containing Pfizer COVID-19 vaccine doses

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.[127] 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.[127]

The Marburg facility had previously specialized in cancer immunotherapy for Novartis.[128] 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.[128] 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).[128]

On 23 April 2021, the EMA authorised 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.[129][130]

At the end of April 2021, it was reported that Pfizer had started to export vaccine doses to Mexico and Canada from the Kalamazoo plant, which is much closer geographically to both countries than the Puurs plant.[124]

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.

The Pfizer–BioNTech vaccine must be kept at extremely low temperatures to ensure effectiveness, roughly between −80 and −60 °C (−112 and −76 °F).

The vaccine can be stored at 2 to 8 °C (36 to 46 °F) for thirty days before use[139][140] and at 25 °C (77 °F)[17][20] or 30 °C (86 °F) [141][5] 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).[142]