The first COVID-19 vaccine to go into any American arms outside of a trial is Pfizer’s mRNA vaccine, which was designed and developed by the German biotech company BioNTech. Here, we give a rundown of basic facts about the vaccine and an overview of how it works.
Vaccine name: BNT162b2
Design type: mRNA
Dose number: 2, 21 days apart
Efficacy: 95% efficacy in preventing symptomatic COVID-19 in adults without prior evidence of infection a week or more after receipt of the second dose.
Safety: No serious safety concerns reported other than some rare allergic reactions. The shots routinely elicit a fairly strong temporary reaction in many people that can include injection site pain, fatigue, headache and chills.
Expected dose availability: Worldwide, up to 50 million doses, or enough for approximately 25 million people, by the end of 2020, with up to 1.3 billion doses expected in 2021.
Operation Warp Speed involvement: No support for the trials or research and development, but the U.S. government inked a $1.95 billion deal in July as part of OWS to buy 100 million doses. In December and February the U.S. announced agreements to purchase another 100 million doses each, for a total of 300 million doses to be delivered by the end of July 2021.
Storage considerations: Ultracold freezer temperatures of -80ºC to -60ºC (-112ºF to -76ºF) for long-term storage, with up to two weeks at standard freezer temperatures; after thawing, vaccine vials can be stored at refrigerator temperatures for up to five days.
The Pfizer/BioNTech vaccine is the first COVID-19 vaccine authorized for use in the U.S. The companies released promising interim results from a phase 3 trial on Nov. 9, and on Nov. 18 announced a final efficacy of 95% in preventing disease among adults without prior evidence of a SARS-CoV-2 infection.
Two days later, the company submitted its application to the FDA to receive an emergency use authorization, or EUA, for its vaccine in people 16 years of age and older. The FDA conducted a thorough review — including an analysis of the raw data — of the vaccine’s safety and efficacy, and issued an EUA on Dec. 11.
A day prior to the FDA’s authorization, an outside panel of experts advising the agency also backed the vaccine in a 17 to 4 vote, with one abstention, that based on the evidence available, “the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older.”
What is in the vaccine and how does it work?
As with most other COVID-19 vaccine designs, the Pfizer/BioNTech mRNA vaccine works by triggering an immune response against the spike protein of the SARS-CoV-2 virus, which sits on the surface of the virus and is what the virus uses to enter cells.
The vaccine is made of modified messenger RNA, or mRNA, wrapped in a special blend of fatty molecules known as lipid nanoparticles. The mRNA provides instructions for cells to make their own spike proteins, prompting the body to generate protective antibodies and activate T cells. The lipids help deliver the RNA into cells and prevent it from being degraded too quickly.
As the Centers for Disease Control and Prevention has explained, there is no way to catch COVID-19 from this type of vaccine because the vaccine is not made of a virus. And because the mRNA from the vaccine doesn’t enter the nucleus — the part of the cell that houses DNA — it “does not affect or interact with a person’s DNA,” contrary to some online rumors.
How was the vaccine developed?
Early phase clinical trials showed that two leading mRNA designs triggered neutralizing antibody responses that were better than those from people recovering from natural COVID-19 infection, with no serious adverse events.
But one candidate — BNT162b2, which prompts cells to make a full-length spike protein — did so with fewer side effects than the other. Based on the trial results and preclinical tests, the companies decided to move forward to a combined phase 2/3 randomized controlled trial testing two 30 microgram doses of BNT162b2 on volunteers.
The phase 2/3 trial began in late July, ultimately enrolling around 44,000 people in the U.S., Argentina, Brazil, Germany, South Africa and Turkey. Enrollment was expanded past the 30,000 initial target in September to include people infected with HIV, hepatitis B and hepatitis C, and to add teens as young as 16 years old. In October, the age requirement was lowered to 12 years old. Because of the limited data available on this population, however, Pfizer did not ask to include the 12- to 15-year-old age group in its EUA request.
How effective is the vaccine?
Pfizer announced in a Nov. 18 press release that its vaccine was 95% effective in preventing COVID-19 disease in adults without prior evidence of infection, as measured seven or more days after the second dose. The company reported similar efficacy rates across a variety of demographics, including racial and ethnic minorities and older adults.
The trial only looked at whether the vaccine prevented symptomatic disease, not whether the vaccine prevented people from becoming infected or whether the vaccine kept people from transmitting the virus. Additional data from the ongoing trial and other studies may help to answer these questions, as well as how long a vaccinated person is protected, which is unknown. The CDC has said that “a growing body of evidence” suggests those who are fully vaccinated are “potentially less likely to transmit SARS-CoV-2 to others.”
Data summarized by the FDA ahead of the advisory committee’s Dec. 10 meeting additionally suggested that disease protection may occur after a single dose, with an estimated efficacy of 82%. But because the trial did not test a single shot, the agency could not reach a conclusion about how well a single dose actually works.
A 95% efficacy does not mean that 95% of people will be protected by the vaccine. Instead, the math is a bit more complicated — and is a relative risk reduction calculation based on 162 cases of COVID-19 occurring in the placebo group and eight in the vaccine group.
As University of Florida biostatistician Natalie Dean explained in a Twitter thread, a 95% efficacy roughly means a vaccinated person has a 95% reduced risk of becoming sick, compared with a similar person who wasn’t immunized.
Dean also noted that it’s important to differentiate between efficacy, which is the metric used in a clinical trial, and real-world performance as measured in observational studies, which is called effectiveness. It’s possible that outside of the idealized conditions of a randomized controlled trial, the vaccine won’t perform quite as well, although 95% efficacy is still very good.
A study by the Centers for Disease Control and Prevention, published in late March 2021, found the Pfizer/BioNTech and Moderna vaccines were 90% effective in real-world conditions, two weeks after the second dose, and 80% effective two weeks after the first dose. The study monitored 3,950 health care personnel, first responders and other essential workers for 13 weeks.
In terms of the ability of the vaccine to reduce the risk of developing more serious COVID-19 illness, nine cases of severe COVID-19 occurred in the placebo group versus one in the vaccinated group in the clinical trial.
The FDA briefing document explained that the small number of severe COVID-19 cases “limits the overall conclusions that can be drawn; however, the case split does suggest protection from severe COVID-19 disease.”
How safe is the vaccine?
No serious safety concerns were reported in the trials. Anyone getting the vaccine, however, should be prepared for unpleasant side effects, including pain, redness and swelling at the site of injection, as well as fatigue, headache, chills and fever.
According to the data released ahead of the FDA advisory committee, these types of reactions were relatively common and tended to be more frequent and severe in younger people.
Underscoring the degree to which these should not be underestimated by the public, a nurse who participated in Pfizer’s trial and suspects she was in the vaccinated group shared in JAMA Internal Medicine that she had a high fever and felt quite ill for nearly two days after receiving her second shot.
As she noted, these effects were transient and “a normal sign of reactogenicity signaling an effective immune response” — in other words, the vaccine doing precisely what it should be doing. But it still caught her off guard because she wasn’t warned about it — and she counseled physicians and others to communicate that these responses are expected, so vaccine recipients are prepared.
Serious adverse events, which refer to potentially life-threatening or disabling events, occurred in fewer than 1% of participants, and at similar rates in those vaccinated and those not. The few instances the FDA considered possibly related to the vaccine in its briefing summary included one case of a shoulder injury and one instance of lymphadenopathy, or swelling of the lymph nodes, following vaccination (nonserious cases of lymphadenopathy affected 0.3% of those vaccinated, above the rate of the unvaccinated).
Among nonserious adverse events, the FDA noted that there were four cases of Bell’s palsy, a form of temporary facial paralysis, in the vaccine group, and none in the placebo group. This may not mean anything, as the frequency in the vaccine group was not higher than would be expected in the general population, but the agency plans to recommend monitoring for the condition as the vaccine is rolled out into a larger population.
A limited number of serious allergic reactions, including anaphylaxis, have been reported in the U.K. and U.S. since the Pfizer/BioNTech vaccine began to be administered. Anaphylaxis refers to a life-threatening reaction that usually occurs within seconds or minutes of exposure to an allergic substance. Many, but not all, of these people have a history of past severe allergic reactions.
At this time, the only people the FDA says should not receive the Pfizer/BioNTech vaccine are those who have had a serious allergic reaction to a previous dose of the vaccine or one of its ingredients. The CDC advises skipping the immunization if you have had an allergic reaction to polyethylene glycol, a form of which is in the vaccine, or polysorbate, which is similar to polyethylene glycol. The agency also recommends consulting with your physician if you have ever had an immediate allergic reaction to other vaccines or injectable therapies.
In a Dec. 12 press briefing, the FDA’s Center for Biologics Evaluation and Research Director Dr. Peter Marks said the agency would be monitoring the situation and noted that all vaccine administration sites would be equipped to deal with allergic reactions.
As of Jan. 18, there have been 4.7 cases of anaphylaxis per million doses of the Pfizer/BioNTech vaccine, according to the CDC. None of these cases has been fatal.
To find out what vaccine ingredient might be triggering these reactions, the NIH is gearing up to conduct a study in which people with a history of severe allergies receive the vaccine under close medical supervision.
Why does the vaccine need to be kept so cold?
The extreme cold is necessary to keep the highly sensitive lipid-encapsulated RNA molecules from degrading. Logistically, this cold chain requirement poses an extra hurdle in distributing the vaccine, since many potential vaccination sites lack the appropriate ultracold freezers and may not have a ready source of dry ice.
Pfizer has tried to mitigate some of these challenges by creating specialized “thermal shippers” for its vaccine that will maintain ultracold temperatures for up to 10 days if unopened and can store vials for as long as a month if refilled every five days with dry ice.
On Feb. 25, the FDA also began allowing the vaccines to be shipped or stored at regular freezer temperatures for up to two weeks, following data showing that the doses would remain stable under such conditions.
Rival company Moderna, which also used an mRNA design for its COVID-19 vaccine candidate, also requires freezing temperatures, but they are less severe, due to differences in the particular lipid nanoparticles used. The company announced in November that its vaccine should remain stable long-term at standard freezer temperatures and should last for 30 days in a refrigerator.
Editor’s note: This story will be updated as necessary.
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