The Food and Drug Administration’s (FDA) vaccine advisory committee has approved the use of the COVID-19 vaccine developed by Pfizer Inc. (NYC) and BioNTech (Mainz, DEU) in the United States for those ages 16 years and older. In a Dec. 10, 2020, vote, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) approved the broader population group, while acknowledging the first doses will go to healthcare workers, including those in long-term care, and long-term care residents.

Those priority groups were designated by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP). (See related story, “Healthcare Workers Cleared for COVID-19 Shots, Long-Term Care Residents Raise Safety Concerns.”) ACIP was expected to sign off on the action, and vaccine distribution and immunizations in the first groups were to follow in rapid fashion.

There was a matter of contention among FDA advisors about including those 16 and 17 years of age, with some citing insufficient data but others urging the committee to go forward and approve the resolutions as written. The resolution that passed to grant the vaccine an Emergency Use Authorization (EUA) was written as a question: “Based on the totality of scientific evidence available, do the benefits of the Pfizer BioNTech vaccine outweigh its risk for use for individuals 16 years of age and older?”

Paul Offit, MD, a pediatrician and VRBPAC member, said at the meeting, “I support this statement as written. It’s never a question of when you know everything it’s a question of when you know enough. The fact of the matter is that 16- and 17-year-olds can get this infection. We have had children in our hospital who have had cardiac anomalies at 16 and 17 years old. We have such a [vaccine] benefit and all we have on the other side is a theoretical risk.”

The resolution question was approved in the affirmative by the FDA committee, with 17 “yes” votes, four “no” votes, and one abstention. The record number of daily COVID-19 deaths in the United States and the high efficacy of the vaccine were common threads throughout the discussions.

“A Phase III randomized and placebo-controlled trial using BNT162b2 in approximately 44,000 participants is currently ongoing to evaluate the vaccine’s safety and efficacy,” Pfizer said in documents submitted to the FDA. “Vaccine efficacy for the primary endpoint against confirmed COVID-19 occurring at least seven days after the second dose was 95.0% with eight COVID-19 cases in the vaccine group compared to 162 COVID-19 cases in the placebo group.”

Safety, Adverse Events

The frequency of serious adverse events was low (< 0.5%), without meaningful imbalances between study arms, Pfizer stated. There was a slight numerical imbalance of adverse events potentially representing allergic reactions, with more participants reporting hypersensitivity-related adverse events in the vaccine group (137 [0.63%]) compared with the placebo group (111 [0.51%]), Pfizer reported.

“Among non-serious unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the vaccine group compared with no cases in the placebo group, though the four cases in the vaccine group do not represent a frequency above that expected in the general population,” the company reported. Some of the palsy cases resolved naturally, but this condition will be tracked by the FDA.

Safety data presented to the FDA included approximately 38,000 participants 16 years of age randomized 1:1 to vaccine or placebo, with a median of two months of follow-up after the second dose. The findings suggest a favorable safety profile, with no specific safety concerns identified that would preclude issuance of an EUA. Participants enrolled through Nov. 14, 2020, brought the number of participants to 43,252, which was consistent with the safety profile, the company said.

“The most common solicited adverse reactions were injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), [and] fever (14.2%); severe adverse reactions occurred in 0.0% to 4.6% of participants, were more frequent after dose 2 than after dose 1, and were generally less frequent in participants  55 years of age ( 2.8%) as compared to younger participants ( 4.6%),” Pfizer reported.

There are unknown risks and safety issues that may not come to light until a larger number of people are vaccinated. “There are currently insufficient data to make conclusions about the safety of the vaccine in subpopulations, such as children less than 16 years of age, pregnant and lactating individuals, and immunocompromised individuals,” Pfizer reported.

Serious side effects to vaccines almost invariably occur within six weeks of getting a dose, although long-term effects cannot be ruled out, Offit said in comments before the meeting.

“Usually, if you have a serious side effect, you will find it out very quickly,” Offit said. “Now, that said, 20,000 people isn’t 20 million people and you are only going to find out a rare, serious event post-approval. That has always been true. But the good news is there are systems in place, like the vaccine safety [active systems] and the Vaccine Adverse Event Reporting System to pick that up.”

With more than a quarter of a million people dead of coronavirus in the United States in a pandemic that continues to surge, the risk of not getting vaccinated has accumulated considerable weight. The United Kingdom has already approved the Pfizer vaccine and there was some pressure on the United States to get a vaccine on the market.

“There is another side to this – the choice not to get a vaccine is not a risk-free choice,” Offit said in a live stream interview before the FDA meeting.1 “It is a choice to take a different risk. The term ‘safety’ in the medical world means that benefits outweigh theoretical risks. It does not mean absolute safety. We may find that it causes a serious adverse event post-approval. I hope not, but we have to be open-minded to the fact that that might happen.”

The question public health officials weighed then is, “Does the severity of the pandemic, its multiple societal repercussions, warrant a kind of leap of faith to vaccines?”

“I just think you have to be humble in all of this there are things that I’m sure we don’t know yet, so we have to be open to the fact that we don’t know everything,” Offit said. “But on its face we are dealing with a pandemic that has brought us to our knees. We have massive joblessness, homelessness, and food insecurity. If this vaccine in any way looks like the topline data looks, it’s a lifesaver.”

‘Unprecedented’

The FDA panel was slated to meet again on Dec. 17, 2020, to consider a similar vaccine by Moderna Inc. (Cambridge, MA), which also uses a “messenger RNA” platform and has 95% efficacy. Offit said the development of these vaccines in less than a year is unprecedented.

“If you said to a thousand scientists when a paper was published [early in 2020] that reported the SARS-CoV-2 genome ... that in 11 months you are going to have two clinical trials with a novel vaccine strategy that is going to be studied in 44,000 and 30,000, respectively, using two different constructs of messenger RNA that will induce protection at least soon after the second dose of 95% in protecting against disease — including severe disease, including people greater than 65 years of age — no one would have thought it was possible,” Offit said. “I certainly wouldn’t have thought it was possible.”

There is one caveat, however, as the incidence of disease in the placebo groups in the vaccine trials was unexpectedly low — in the 0.7% or 0.85% range, Offit said.

“You would expect something more like 3% to 3.5%,” he said. “When you see it low like that you worry that you are seeing something called ‘volunteer bias.’ Who volunteers for these trials? It may be people who are attentive to their health, physical distancing, mask wearing, and therefore may be exposed to a lesser inoculum of virus. People who are exposed to a lower inoculum of virus are therefore less likely to suffer a moderate to severe disease.”

In real world circumstances, that means the vaccine may not be quite as effective as the 95% levels that stunned the scientific community, he warned. Another factor common to all vaccines is that people may already be incubating illness unrelated to immunization, or they may suffer an unrelated medical emergency after taking the shots.

“What worries me about this is that the SARS-CoV-2 vaccines are only designed to prevent SARS-CoV-2 — not everything else that happens in life,” Offit said. “And that is definitely going to happen, especially with people who are older and have more febrile conditions. They are going to get a vaccine, and a few days later they are going to have a stroke or a heart attack. We are going to have to do … epidemiology studies quickly to reassure people that it is occurring at the same rate as background.”

That said, he played down the side effects after receiving the shot — particularly the second one, which can be followed by a day of relative misery.

“These messenger-RNA vaccines do induce an immune response,” Offit said. “And when your immune response is activated, you have certain symptoms, which can be low-grade fever, headache, muscle ache, and fatigue. Enough so that you could miss a day of work — that’s possible. But this is a natural consequence of having an activated immune system.”

It remains unknown how long immunity induced by COVID-19 vaccines will last, he said. “These kinds of viruses, which do not have long incubation periods, where viremia is not part of pathogenesis, as a general rule, they induce immunity that is short-lived and incomplete,” he said. “By short-lived I mean years, not decades. By incomplete I mean no sterilizing immunity — so protection against moderate or severe disease but not necessarily mild disease. That’s OK — all you want to do is keep people out of the hospital and the morgue. I think [the vaccine] can certainly do that, even if there is some fading of immunity at six months, one year, or a two-year period.”

REFERENCE

  1. JAMA Network. Coronavirus Vaccine Update with Paul Offit. Conversations with Dr. Bauchner. Dec. 2, 2020. https://www.youtube.com/watch?v=V4xClOYM3iE