On the heels of a day-long meeting held Thursday, an FDA advisory panel has set the stage for the anticipated emergency use authorization (EUA) for Pfizer and BioNTech’s messenger RNA (mRNA)-based COVID-19 vaccine candidate.  The EUA for BNT162b2 could be grated as early as today.

FDA Commissioner Stephen M. Hahn, MD, and Peter Marks M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research, said in a media release today that the FDA “will rapidly work toward finalization and issuance of an emergency use authorization.” That approval will come within days, Alex Azar II, M.D., Secretary of Health and Human Services, said this morning on ABC’s “Good Morning America” adding: “We could see people getting vaccinated Monday, Tuesday of next week.”

The EUA will make BNT162 the first COVID-19 vaccine candidate to gain an FDA authorization, indicated for the prevention of COVID-19 in individuals 16 years of age and older. A second leading vaccine candidate up for EUA consideration by the advisory panel next week—Moderna’s mRNA-1273.

The FDA usually follows the recommendations of advisory committees like the one that considered BNT162b2 in a widely-anticipated day-long virtual meeting.

By a 17-4 vote with one abstention, the FDA’s Vaccine and Related Biologic Products Advisory Committee (VRBPAC) agreed that based on the totality of scientific evidence available, the benefits of BNT162b2 outweighed its risks for use in individuals 16 years of age and older.

“We are pleased with the committee’s strong majority vote, and if the FDA issues an authorization, stand at the ready to bring this vaccine to people in the United States in an effort to help combat this devastating pandemic,” Pfizer chairman and CEO Albert Bourla, DVM, PhD, said in a statement.

Added Ugur Sahin, CEO and co-founder of BioNTech: “I would like to thank the FDA’s advisory committee for recognizing the critical role that our vaccine may play in helping to address this ongoing pandemic. Today’s positive discussion and vote reinforces the potential of our COVID-19 vaccine candidate in helping to protect people against this deadly and devastating disease.”

Adverse reactions

During a discussion period before the vote, committee members discussed the handful of adverse reactions to the vaccine in the U.K., whose drug and vaccine regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA), disclosed two reports of anaphylaxis and one of a possible allergic reaction since the start of patient dosing on Tuesday. “Any person with a history of anaphylaxis to a vaccine, medicine, or food should not receive the Pfizer BioNTech vaccine,” MHRA chief executive June Raine stated.

Among FDA advisory committee members who voted yes was Paul A. Offit, M.D., director of the Vaccine Education Center and an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia. Offit earlier noted the reports of allergic patients in the U.K., and expressed concerns that Americans with severe allergies would shy away from taking BNT162b2 absent additional study by the companies about the vaccine’s effects in such people: “This issue is not going to die until we have better data.”

Responding to Offit, Marion Gruber, Ph.D., director of the FDA’s Office of Vaccines Research and Review, noted that the agency had included a warning for people with a history of allergy to any component of BNT162b2 in the vaccine’s prescribing information.

Offit spoke during a period before the vote focused on two discussion questions:

• Whether to adopt Pfizer’s plan to continue blinded, placebo-controlled follow-up in ongoing trials should BNT162b2 be made available through an EUA.
• How to further evaluate vaccine safety and effectiveness in populations who receive the Pfizer-BioNTech vaccine under an EUA.

Panel members also discussed whether patients randomized to placebo should be allowed to receive the Pfizer/BioNTech vaccine, as well as whether additional study was needed of the vaccine’s effects in pregnant and breastfeeding women.

“Though FDA and the VRBPAC chairman did not open up the discussion for members to explain the rationale behind their vote, from the previous discussion we believe the largest driver of the “no” and “abstain” votes was the inclusion of 16-17 year olds in the approval statement,” Geoffrey C. Porges, MBBS, Director of Therapeutics Research and a senior research analyst at SVB Leerink, wrote Thursday in a research note.

Fifth in the world

The FDA will be the fifth global regulatory agency to approve BNT162b2. Pfizer and BioNTech received temporary authorization November 30 from the U.K.’s MHRA for emergency use of BNT162b2—giving the companies their first authorization for a vaccine designed to protect against the virus. The first two patients were dosed on Tuesday: 90-year-old Margaret Keenan and an 81-year-old named William Shakespeare.

Bahrain followed with its own emergency approval on December 4. On Wednesday, Health Canada granted full approval to BNT162b2, with the first doses set to reach Canadian patients next week. The following day Saudi Arabia’s Food and Drug Authority approved registration of the vaccine, with the agency promising to ensure quality by analyzing samples from each incoming shipment before use in patients, according to the country’s official Saudi Press Agency.

The U.K.’s distinction as being first in the West to approve a COVID-19 vaccine—Russia approved Sputnik V back in August—rankled President Donald Trump enough for his chief of staff Mark Meadows to summon FDA Commissioner Stephen Hahn, MD, to the White House last week.

The meeting took place just under three weeks from November 20, the day Pfizer and BioNTech applied for the EUA. The EUA was supported in part with final efficacy data they announced earlier this week showing BNT162b2 to be 95% effective in their nearly 44,000-patient Phase III trial (NCT04368728) of the vaccine in participants without prior SARS-CoV-2 infection.

The companies also submitted safety data from a randomized subset of approximately 8,000 participants ≥18 years of age, with unsolicited safety data from approximately 38,000 trial participants who were followed for a median of two months following the second dose of the two-dose vaccine candidate—the time period for safety data specified in FDA EUA guidance for emergency use applications.

Earlier this week, FDA staff scientists reviewed the Phase III data, confirming in a Briefing Document for the advisory panel the efficacy of BNT162b2 to be 95.0%, with eight COVID-19 cases in the group of patients receiving the vaccine, compared to 162 COVID-19 cases in a group randomized to placebo.

95% efficacy, one severe case

Those results were confirmed as well in “Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine,” a study published Thursday in The New England Journal of Medicine by researchers from Pfizer, BioNTech, and their clinical partners. According to that study, the 95% credible interval for vaccine efficacy (VE) was 90.3% to 97.6%, indicating that the true VE was at least 90.3% with a 97.6% probability given the available data.

Among 10 cases of severe COVID-19 with onset after the first dose, nine occurred in placebo recipients and one in a BNT162b2 recipient. The one severe COVID-19 participant was thus classified after a drop in oxygen levels, William Gruber, Pfizer senior vice president for vaccine research, said at the hearing.

A total of 43,448 participants received injections, of which 21,720 received BNT162b2 and 21,728 placebo. As of the data cut-off date of October 9, a total of 37,706 participants had a median of at least two months of safety data available after the second dose—and thus were part of the study’s main safety population.

Within that main safety population, 42.3% had racially and ethnically diverse backgrounds—including 28% of participants who identified as Hispanic or Latinx; 9.3% as black or African-American; 4.3% as Asian; 0.5% as American Indian or Alaska Native; and 0.2% as Native Hawaiian or Other Pacific Islander. Another 2.3% identified as multiracial.

Geographically, 76.7% of participants were from the United States, 15.3% from Argentina, 6.1% from Brazil, and 2% from South Africa. Just under half were female (49.4%), while 42.2% were ages 55 and older. [According to the FDA Briefing Document, 21.4% of participants were >65 years of age].

“The data presented in this report have significance beyond the performance of this vaccine candidate,” the researchers concluded. “The results demonstrate that COVID-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources.”

Asymptomatic infection and adolescents

Among limitations cited by researchers:

• The study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably.
• The study did not address whether vaccination prevented asymptomatic infection. The investigators said they planned to report at a later time on a serologic endpoint (SARS-CoV-2 N-binding antibody) that can detect a history of infection regardless of whether symptoms were present. That report is expected early next year.
• The study did not explore the vaccine’s ability to prevent COVID-19 in younger adolescents, children, and pregnant women. The researchers said safety and immune response data from the trial following the immunization of adolescents 12–15 years of age will be reported later, with additional studies planned to assess BNT162b2 in pregnant women, children younger than 12 years, and those in special risk groups, such as immunocompromised persons.

In data submitted to the FDA, Pfizer and BioNTech disclosed only 103 patients in their trial were ages 16–17—of which 26 unsolicited adverse events were reported in the 53 who were randomized to the vaccine, compared with five in the 50 randomized to placebo. Some advisory panel members asserted that the FDA had too little data on which to evaluate the vaccine’s effect on patients ages 16–17.

Adolescents ages 12–17 will be the focus of a new clinical trial announced Thursday by Moderna. “Our goal is to generate data in the spring of 2021 that will support the use of mRNA-1273 in adolescents in advance of the 2021 school year,” CEO Stéphane Bancel said in a statement.

Moderna’s Phase II/III TeenCove trial (NCT04649151) will assess the safety, reactogenicity, and immunogenicity of two doses of mRNA-1273 given 28 days apart. Moderna aims to enroll 3,000 participants, randomizing them to the two 100 μg doses or placebo. Participants will be followed through 12 months after the second vaccination in the trial, which the company is conducting with the Biomedical Advanced Research and Development Authority (BARDA).

BARDA is among federal agencies that have awarded up to $2.48 billion to Moderna toward R&D (up to $955 million), manufacturing, and delivery of 100 million doses of mRNA-1273 (up to $1.525 billion). Washington also ordered an initial 100 million doses of BNT162 for $1.95 billion, with the option to purchase 500 million additional doses at an undisclosed price.

Pfizer and BioNTech have studied BNT162b2, BNT162b1, and two other constructs of BNT162: a uridine containing mRNA (uRNA) candidate; and a candidate using self-amplifying mRNA (saRNA).

Pfizer and BioNTech have said they will be able to manufacture through their combined facilities up to 50 million vaccine doses globally by the end of 2020—including the initial 6.4 million doses set to be shipped in the United States next week—and up to 1.3 billion doses by the end of 2021.

Nancy Messonnier, M.D., director of the National Center for Immunization and Respiratory Diseases within the Centers for Disease Control and Prevention (CDC), told the advisory panel that officials have developed systems that will monitor for vaccine safety starting on the first day U.S. patients receive BNT162b2.