Tracking the FDA advisory panel meeting on Covid-19 booster shots

Do most Americans already need Covid-19 booster shots, or at least will they soon? Those questions have been hotly debated in the public square over the past few weeks. But today, they’ll be debated in a formal setting where the discussion may affect whether the Biden administration carries through on an announced plan to offer adults booster jabs several months after they received their second shot of vaccine.

The debate will play out among members of the Food and Drug Administration’s vaccine expert panel, the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, which is meeting to review an application from Pfizer and BioNTech for a third dose of their messenger RNA vaccine, to be given six months after the second dose. While today’s discussion relates specifically to the Pfizer vaccine, it has implications for the future of boosters in general in this country.

In regulatory terms, the administration put the cart well out in front of the horse when it declared in August that a national campaign to administer third shots would begin the week of Sept. 20 — that’s next week — before the FDA had approved the Pfizer application and before the other two manufacturers supplying the United States had applied for the right to market a booster.

Now the horse is scrambling to assume its rightful position, beginning with VRBPAC. Next week, the Centers for Disease Control and Prevention’s equivalent panel, the Advisory Committee on Immunization Practices, is scheduled to meet for a day and a half to explore the issue. Since ACIP advises the CDC on whether it should recommend use of vaccines the FDA has approved, one might conclude that the planning scenario is premised on the FDA approving the Pfizer application sometime between the end of today’s meeting and the start of the ACIP meeting next Wednesday.

If it doesn’t, it will put the regulatory and public health agencies at odds with the administration and place acting FDA Commissioner Janet Woodcock and CDC Director Rochelle Walensky in highly awkward positions. They publicly signed off on the administration’s booster shot plan in August.

Different people see different things in the data that have been amassed so far on the efficacy of the mRNA vaccines — the Pfizer shot and the one made by Moderna, which has also applied for a booster license.

There is no argument that the remarkably strong protection against all infections that these vaccines exhibited in their Phase 3 trials has waned. Some people who are fully vaccinated are contracting Covid. But the vast majority of them have only mild or moderate symptoms. It’s still overwhelmingly true that the people who are being hospitalized or dying from Covid are people who are unvaccinated.

Many experts — including two FDA high-ranking officials who will be involved in today’s meeting — argue it’s not yet time to boost in this country. And the World Health Organization has been highly critical of the idea of boosting in affluent countries while most people in developing countries haven’t yet received a dose of vaccine.

Today’s proceedings — which can be viewed online here — are going to be really interesting. We’ll be live-blogging the hearing, which is scheduled to run from 8:30 a.m. to 4:45 p.m. EDT. The back-and-forth among the 19 panelists and data wranglers — the Pfizer representatives and the FDA staff — begins at 1:40 p.m. If there are going to be fireworks, they may start then.

Updates and analysis will be posted below in reverse chronological order.

— Helen Branswell

So what happens now?
5:30 p.m.: Today’s FDA panel was full of tension and drama, as the panelists rejected the broad FDA approval requested by Pfizer and instead, after a real-time deliberation with FDA representatives, voted unanimously that the FDA should recommend a booster shot for people over 65, for people with conditions that put them at high risk of complications from Covid-19, and for people whose jobs put them at high risk for complications from SARS-CoV-2.

So what now? Here are a few issues to watch in the weeks ahead:

• The ball now gets passed to ACIP. That’s the Advisory Committee on Immunization Practices, a separate committee that advises the Centers for Disease Control & Prevention, which is meeting next week. That committee, the FDA’s Peter Marks said, will likely “fine tune” the recommendations made today.
• What about people who received other shots? This vote only covers people who initially received the Pfizer vaccine. What about those who received the vaccines from Johnson & Johnson or Moderna? Those decisions still lie ahead.
• Will there be a political impact on the Biden administration? The White House got out ahead of the FDA and CDC by outlining a booster plan this summer. Now regulators are approving something much more limited. It’s not clear how that will play politically. As Jesse Goodman, a former FDA official, put it: “The process could have been handled better.”
• For companies, a tough day. Shares of Pfizer fell 1.3%, and partner BioNTech’s stock dipped 3.6%. Shares of Moderna dropped 2.4%. For Pfizer, today’s performance at the FDA panel was less than perfect. The company was cut off during its presentation for going long, and missed a chance to talk to the panelists about the concerns that mattered to them. But given the nature of those concerns, the quality of the company’s presentation may not have mattered.
• Who was the phantom vote? As we close out this blog, everyone in biotech will be gossiping about one thing: when the panel voted against the broad indication, an extra person who was a speaker, not a panelist, voted yes. Who were they? Was it an innocent mistake, or an attempt to influence the vote?

Thanks for tuning into this live blog. We’ll be back the next time there is a big FDA decision.

— Matthew Herper

Voting Question 2:

4:23 p.m.: Here is the rephrased question from the FDA: 

Based on the totality of scientific evidence available, including the safety and effectivenes data from clinical trial C4591001, do the known and potential benefits outweigh the known and potential risks of a Pfizer-BioNTech Covid-19 vaccine booster dose administered at least 6 months after the completion of the primary series for use in:

• individuals 65 years of age and older and
• individuals at high risk of severe covid-19

Vote: 18 Yes 0 No  0 Abstain

This will now apply to an emergency use authorization, not an approval.

— Matthew Herper

A rapidly evolving situation
4:05 p.m.: It became abundantly clear, during the discussion ahead of the voting question, that the panel was not going to vote to approve booster shots for a broad population. They were worried about the safety of the vaccine in younger people, and many said that the situation in Israel did not map to the one in the U.S. Eric Rubin, the Harvard professor and New England Journal of Medicine editor, commented that because of low vaccination rates, the benefit of boosters in controlling the pandemic might be limited.

So Peter Marks, the FDA official, and Arnold Monto, the panel’s chair, hatched a new plan. The panel would vote on the original question — the resounding 16-2 no vote — and then, after the vote, the panel made suggestions on a new question.

It’s clear they think a booster may be appropriate for older people — likely those over 60 or 65. They also wanted to make it available to those who are at higher risk from Covid, such as health care workers, people or are obese, and those who have diabetes. The FDA took took a 10 minute break to write a new question.

— Matthew Herper

Voting Question 1

3:30 p.m.: The committee voted on this question, with the intent to make revisions to the question if it did not pass so it is not the final word.

The question:

Do the safety and effectiveness data from clinical trial C4591001 support approval of a COMIRNATY booster dose administered at least 6 months after completion of the primary series for use in individuals 16 years of age and older?

The vote: 2 Yes 16 No 0 Abstain

Now the panel will discuss changes that could lead to a booster clearance for some groups.

— Matthew Herper

More from Marks
3 p.m. Before charging the committee to vote, the FDA’s Peter Marks issued what sounded like a plea not to dismiss data from Israel out of hand.

Marks thanked the committee members — and the outgoing FDA officials, Marion Gruber and Phil Krause. But he also emphasized that the decision on boosters should include “complex data that is evolving before our eyes.”

Again he emphasized that it is important to have a spirited discussion.

“It’s no secret here that there is still debate over the need for an additional Covid-19 vaccine at this phase of the pandemic,” Marks said. “But the emerging evidence such as that from our Israeli colleagues is very helpful. We also know that breakthrough infections, including some that are severe, are occurring in the United States.”

Then Marks reminded the panel that many vaccines require another dose months after the original course in order to induce long-term immunity. And he said that vaccines are not tasked only with preventing severe disease or hospitalization.

“The vaccines for other diseases noted here that are given to adults are not only indicated for the prevention of severe disease or hospitalization,” Marks said. “Realizing the benefits of reducing disease occurrence or transmission, these other vaccines are indicated for various severities of disease prevention and the intended population.”

Preventing Covid, or long Covid, could be every bit as good a reason for a booster as preventing hospitalization, Marks argued.

—  Matthew Herper

A blast from the past

1:30 p.m.: The closing speaker in the hour-long public comment session was a name that might be familiar to some readers. Paul Alexander, a Trump administration official who tried to ride roughshod over the Centers for Disease Control and Prevention, had words for both the FDA and the CDC. He also came to the defense of rapper Nicki Minaj, echoing her question about whether Covid vaccines endanger male fertility.

“People want to make this a joke and parody it, etc., but this is a very, very, serious consideration,” Alexander said, alluding to scientific papers that purport to find a drop in fertility among the vaccinated. “We need this investigated,” he said.

There is no evidence that the vaccines affect fertility.

In general terms, it appeared that Alexander, who before being hired by the Trump administration was an unpaid lecturer at McMaster University in Hamilton, Ontario, Canada, doesn’t think the Covid vaccines have been adequately tested. And he doesn’t believe children need to be vaccinated against Covid-19.

Alexander described himself as a health research methodologist in evidence-based medicine; EBM, as it’s called, is the field he studied at McMaster, where he got his PhD. He suggested the vaccine safety monitoring systems in use to look for safety signals among people who had been vaccinated were inadequate — though it was not always clear what exact point he was trying to make, or who he was purporting to represent.

“We are calling for longer–term studies and larger sample size, but longer term. We need medium- and long-term studies to best assess the safety and efficacy. Particularly safety. Particularly when you’re talking about putting these vaccines in our children’s arms,” Alexander said.

He did not address the issue of booster shots, which is the topic of today’s meeting. The FDA is not yet evaluating whether to allow use of Covid vaccines in children under the age of 12.

Alexander was a highly controversial figure in the summer and autumn of 2020, as the Trump administration tried to play down the threat of the pandemic. He was a top deputy to Michael Caputo, a Trump loyalist installed as head of communications at the Department of Health and Human Services.

In comments to officials made in July 2020, Alexander argued that exposing Americans who were at lower risk of complications to the virus would be a way to induce herd immunity.“There is no other way, we need to establish herd [immunity], and it only comes about allowing the non-high risk groups to expose themselves to the virus. PERIOD,” Alexander wrote, according to Politico, which reported the remarks in December.

Caputo and Alexander were also said to have interfered with CDC reports about Covid-19. When Caputo left on medical leave after comments in which he accused government scientists of “sedition,” Alexander also left the agency.

— Helen Branswell and Matthew Herper

Summing up the morning
1:20 p.m.: The morning’s FDA presentations flooded the panel with a deluge of data, often without giving clear answers on the questions that are likely to be pivotal to the discussion of whether or not to approve booster shots.

Here, to be clear, are the questions that seem most important to the panel’s deliberations. Has the ability of vaccines to protect against hospitalization and death from Covid-19 waned enough that boosters are needed? And are there any safety issues that could change the risk-benefit equation on a third dose?

Both Pfizer and the FDA itself, analyzing Pfizer’s data, focused mainly on the issue of whether vaccine efficacy wanes against symptomatic disease and whether common side effects, like fever and aches and pains, occur more with a third dose. The data seem to show efficacy wanes and the side effects of dose three are similar to dose two. There is a risk of swelling of the lymph nodes, as seen with earlier doses.

But that doesn’t answer questions about whether a booster prevents hospitalization, or whether there is a risk, such as myocarditis, that could mean the risks outweigh the benefits for some people — in particular for younger men and teenage boys.

That leaves discussion around those big, important questions to data from big national systems.

Jonathan Sterne, from the University of Bristol, presented data from the U.K. experience. In a long series of slides, he argued again and again that confounders, such as when people of different ages and risk levels got the vaccine, can lead to the appearance that the vaccine efficacy is waning when it is not. The message, given so softly it could be missed as Stene showed slide after overcrowded slide, was that the vaccine efficacy may be holding up better than expected. 

This was contrasted with the experience in Israel, which was one of the first countries to embark on a booster campaign. The Israeli researchers also presented a detailed scientific argument, but there was a simple, easy-to-grasp core: cases were skyrocketing, they instituted a booster campaign, and that slowed down the outbreak.

When asked why Israel did not just vaccinate older, at-risk people, Sharon Elroy-Preiss, director of public health services at Israel’s Ministry of Health, said that would have meant leaving the vast majority of age groups that were infected unvaccinated, and thereby not slowing the spread of SARS-CoV-2. She also said that relatively young people, those as young as 40, were becoming sick.

Essentially, the panel will have to weigh those two case studies. The FDA’s question does not give them an obvious opportunity to decide boosters should be approved for some people not others. But panelists have been known to make cases to the agency that are outside of what it asked.

One experienced FDA watcher does not think that the panel will vote to approve boosters today. Umer Raffat, an analyst at Evercore ISI, an investment bank, surveyed past comments by the panelists and found that many are starting off with a sentiment that it may not yet be time for a booster, based on their previous statements.

— Matthew Herper

The public takes the stage

12:50 p.m.: A full hour of today’s meeting has been set aside for public comment. That session is underway now.

People who want to address the committee apply to speak. If there are more interested speakers than the timeframe allows, names are drawn by a lottery. Each person gets three minutes to speak.

Today’s speakers so far are a mix of people questioning the safety of all Covid vaccines, people urging the FDA to approve boosters now, and people urging FDA not to approve boosters at this point. There’s no clear frontrunner position yet.

— Helen Branswell

Pfizer gets the hook

11:40 a.m.: VRBPAC acting chairman Arnold Monto is trying to keep this meeting to schedule. But Pfizer’s presentation went long.

Monto warned Bill Gruber, senior vice-president, to wrap up his presentation when Gruber’s presentation extended the 45 minutes the company had to present its case. Gruber started speaking faster, but continued to move through the remaining slides in his set.

When Gruber attempted to review data from Israel — data that had already been presented by Israeli Ministry of Health officials — Monto was having none of it, cutting the company off before it finished its presentation.

Now Joohee Lee from FDA is presenting the agency’s analysis of the data presented in support of the application for a booster shot.

— Helen Branswell

The elephant in the room

10:50 a.m.: One of the big questions looming over the debate about giving third shots of the mRNA vaccines relates to safety. Specifically: Will rates of myocarditis and pericarditis rise after a third dose?

These are potentially serious heart issues and have been seen among a small portion of mainly younger males who received mRNA vaccines — though most of the cases have been a milder form, and have resolved without issue.

Israel, which has been reporting waning of protection after two doses, began a campaign to administer third shots on July 30. Officials at the health ministry reported on their findings, noting that so far they have only seen one case of myocarditis out of 1.2 million people who have received the booster shot.

The acting chairman of VRBPAC, Arnold Monto, made an important observation, though, in the Q&A that followed their presentation. Israel is administering the booster doses in reverse order by age, in other words, with the oldest adults first. So they haven’t yet got data showing what happens when the age cohort that has had the highest rate of these events, males under 30, gets a third shot.

— Helen Branswell

Overture

9:20 a.m. The opening moments of FDA advisory committee meetings are usually not filled with drama. But today’s were soaked with it, as top officials addressed controversies that are likely to seep through the day’s discussion.

Peter Marks, who is in charge of the biologics center that decides on vaccine approvals, spoke first, in front of a painting of a polar bear drinking tea that has been his background throughout these virtual meetings. He thanked the panel for its role in public health during the pandemic.

“We know that there may be differing opinions to the interpretation of the data regarding the potential need for additional doses,” Marks said. “And we strongly encourage all the different viewpoints to be voiced and discussed regarding the data, which is complex and evolving.”

He told the panel that decisions about Covid vaccines require real-time analysis of data, and noted that 2,000 Americans are dying every day from the disease right now. Then he gave members a stern direction.

“As we proceed, I would ask that we do our best to focus our deliberations on the science related to the application under consideration today and not on operational issues related to a booster campaign or on issues related to global vaccine equity. If we stray into those latter topics, the chair and I will gently bring us back into the scope of this advisory committee meeting.”

That was a dramatic instruction, because two top FDA officials recently announced plans to resign and the decision is said to be linked to White House pressure on the boosters and other decisions. Both were co-signatories on a Lancet article that made the case that the U.S. should wait on boosters in part because of issues of vaccine equity. And one of those FDA officials, Marion Gruber, gave remarks directly following Marks.

Her voice marked with emotion, Gruber said that this would likely be her last advisory committee meeting as an FDA official and thanked this and past committees. She then walked the panel through safety and efficacy considerations around the booster shot decisions.

Two things stood out. Quoting from her slides: “Concerns have been raised that declining neutralizing antibody titers or reduced effectiveness against symptomatic disease may herald significant declines against severe disease.” This is the fundamental efficacy question for the boosters. If immunity is waning, is it causing cases of asymptomatic or mild illness, or does it also mean vaccinated people are getting really sick or are landing in the hospital?

Gruber also highlighted that the booster shot must be safe, meaning, she said, that its benefits outweigh its risks. The main issue regarding safety is the risk of myocarditis or pericarditis, two types of inflammation involving the heart, that are rare side effects of the vaccine that appear more common in young men.

— Matthew Herper

The question

8:45 a.m.: So the FDA has posted what it is calling Question 1. As there is only one question posted online at this time, that name begs the question: Does the FDA expect to need to ask additional questions?

It may well. Because Question 1 is: “Do the safety and effectiveness data from clinical trial C4591001 support approval of a COMIRNATY booster dose administered at least 6 months after completion of the primary series for use in individuals 16 years of age and older?”

The vote is a yes or no option.

If members of the committee object to giving boosters to 16- and 17-year-olds — given there are no data supporting the need or exploring the risks for this group at this point — they could vote this down, prompting the FDA to ask if the panel believes boosters are warranted for a narrower age group.

Pfizer and BioNTech applied for a booster authorization for people 16 and older.

— Helen Branswell

Reading some tea leaves

7 a.m.: Matt and I are not in the predictions business. But there are a few observations we thought we could make that might point to where this discussion may end up.

Matt: A lot of data that one would normally expect for an FDA advisory panel are not available. For one thing, the immunogenicity data being used to argue for booster shots are from a comparatively small study. There were no recipients under 18, even though Pfizer is requesting authorization for boosters for those 16 and up. Participants over 65 received the booster along with Pfizer’s pneumococcal vaccine, Prevnar. The FDA says such extrapolation is allowed as long as “no age group-specific safety or effectiveness considerations would preclude such extrapolation.” So that could be a point of debate.

Normally, the FDA relies on what’s called regulatory quality data that it has had the opportunity to comb through and re-analyze. But for many of the studies being analyzed, briefing documents say, “FDA has not independently reviewed or verified the underlying data or their conclusions.” Still, the data all point in a similar direction, to some waning of immunity.

There is also the worry of myocarditis and pericarditis, a side effect that is very rare and has appeared mostly in young men. The clinical trials are not big enough to give information about this risk, but it is exactly the kind of risk-benefit calculus that FDA panels normally perform.

It would be surprising if the panel doesn’t back boosters for anyone, but it seems very possible they will try to identify groups that should or should not get the booster shots. That’s a key point of discussion to watch for. But, then again, that decision isn’t entirely the FDA’s job: it’s supposed to decide if the product meets the bar for authorization, not how to roll out boosters.

Helen: Indeed, the hard job on the booster question doesn’t necessarily rest with VRBPAC. It probably falls to the ACIP. That’s the group that actually maps out how approved vaccines should be used. The final step in that process requires the CDC director to sign off on the ACIP’s recommendation, but that is generally a pro forma thing.

Should VRBPAC recommend that the FDA approve the Pfizer booster, they could do so with the knowledge that that doesn’t commit the country to offering everyone who got the Pfizer vaccine a third dose. ACIP will decide whether everyone needs to be boosted, or whether the program should start in a more targeted fashion, with elderly Americans — especially those living in nursing homes — and front-line health care workers. Those two groups were the first vaccinated and are also the people at highest risk, either because they are frequently exposed to SARS-CoV-2 (health workers) or because their aging immune systems don’t generate robust responses to vaccines (the elderly).

A special ACIP meeting for next Wednesday and Thursday was announced this week. Someone must have thought they’d have something to discuss.

ACIP has already met twice to discuss boosters in general terms. The committee hasn’t exactly sounded bullish on the need for them, and there have certainly been rumblings about members of the committee feeling that the White House got over its skis by announcing the booster program before boosters had been green lit by the FDA and CDC.

But there’s been a fair amount of turnover on ACIP over the past couple of months. The committee has a new chair and two new members, with a third in the wings, awaiting final approval of his or her appointment. (There are typically 15 members, including the chair.) It’s harder right now to predict how ACIP will come down on the issue because those new members don’t have a voting track record.

— Helen Branswell and Matthew Herper

Some booster background

7 a.m.: Good morning.

In order to understand today’s discussions, a bit of a vaccinology primer might be helpful.

Vaccines teach the immune system to recognize disease threats. They do so in a variety of ways, for example by injecting into our systems killed viruses or genetic coding that will prompt our cells to pump out versions of a protein found on the surface of a virus, triggering production of immune weapons that specifically target that particular threat.

Most vaccines are given in a series of two, three, or more shots. The first primes the immune system to recognize a threat; the subsequent shot or shots boost that initial response to generate (hopefully) long-lasting protection.

It’s not uncommon to space the first and the last shots in a series over several months. But both Pfizer and Moderna spaced their jabs out over a tight interval — three and four weeks, respectively — to try to vaccinate people quickly in the face of the pandemic threat.

Evidence from the United Kingdom, which used longer intervals between shots, suggests that a vaccinology truism — a longer interval is a more effective interval — probably is true here as well.

Experts argue about whether a booster is needed now. But most believe one may eventually be needed. And most acknowledge that people who get a third shot of the mRNA vaccines will have better, more long-lasting protection.

“I think having a late boost is going to make this a much better vaccine,” Barney Graham, who designed the structure for the vaccines made by Moderna and a number of other producers while he was deputy director of the Vaccine Research Center at the National Institutes of Health, said in a recent interview.

“Giving a boost to people would make them more protected and would reduce transmission. Now the question, I guess, is do you need to boost and what incremental value is there in boosting? Or do we have enough memory and a rapid enough … response that we’d be protected relatively well? And honestly, as the viruses are evolving and making more rapid transit from the upper to lower airway, I’m not sure the memory we have is going to be sufficient.”

As the last part of Graham’s remark implies, much of the thinking about the need to boost is steeped in the disquiet generated by the Delta variant — a highly transmissible form of the virus that has swept the globe in recent months.

At 68, Graham said, “I don’t know how well I would do if I get exposed to the Delta virus.” He added: “What I know is that the boost would work. We know now in humans and animals that a boost really pushes the antibody levels even higher than they were after the second dose.”

As for the WHO’s argument that a third dose for Americans delays first doses in low-income countries, Graham proposed a different way of thinking about the issue. If these vaccines truly are three-dose shots — if the third dose is critical to getting lasting protection — the world needs to know that, he said.

But Paul Offit, director of the Children’s Hospital of Philadelphia’s Vaccine Education Center and co-inventor of the rotavirus vaccine, has publicly stated he thinks it’s premature to be giving all adults booster shots at this point.

Offit is on VRBPAC. He’s unlikely to bite his tongue here.

— Helen Branswell