Tracking the FDA advisory panel meeting on Moderna’s Covid vaccine booster

With people who received the Pfizer-BioNTech Covid-19 vaccine already in the process of getting booster shots, attention is shifting this week to what to do with people who received one of the two other vaccines in use in the U.S., the two-dose Moderna vaccine and the one-shot Johnson & Johnson product.

Members of the Food and Drug Administration’s vaccine expert panel, the Vaccines and Related Biological Products Advisory Committee (VRBPAC), are meeting today to discuss Moderna’s application for a booster shot for its product and again Friday to discuss the J&J application.

The Biden administration has made it clear that it wants to boost all Americans who have been vaccinated, suggesting they should receive an additional jab six months or later after the last dose in their original vaccine regimen. Though the World Health Organization has asked wealthy countries to hold off on using boosters to make more vaccine available to low-income countries, and some experts have argued most people don’t currently need boosters, the administration has been unswerving on this policy.

Moderna has applied for authorization for a booster for people 18 and older — the age range currently able to get the company’s mRNA vaccine. It is proposing to give less vaccine in its booster than it does in its regular jabs, 50 micrograms compared to 100 micrograms in the full dose. That difference may make Moderna boosters less reactogenic — less likely to trigger side effects — than the first two doses in its series.

Some studies have shown that the Moderna shot’s protection against mild infection wanes over time, but not yet to the same degree as has been seen with Pfizer’s vaccine. (For both vaccines, protection against severe illness appears to be holding.) And it wasn’t clear from the assessment FDA scientists wrote on the data Moderna submitted whether the agency believes a Moderna booster is needed at this time.

“Some real-world effectiveness studies have suggested declining efficacy of Moderna COVID-19 Vaccine over time against symptomatic infection or against the Delta variant, while others have not,” the FDA scientists said in a briefing document.

It is likely, though, that a Moderna booster will be needed at some point. And it is clear the administration is keen to push through with its boosters-for-all campaign. So turning down Moderna doesn’t seem like the likeliest of outcomes here.

VRBPAC meetings are never dull and today’s — which can be viewed online here starting at 8:30 a.m. ET — is unlikely to be an exception. Updates and analysis will be posted below in reverse chronological order.

— Helen Branswell

The panel doesn’t like universal boosters

5 p.m.: With the voting over, the panel’s work was not done. The FDA had also asked the committee to discuss when, if ever, it might be a good idea to expand the eligibility of boosters to everyone over 18.

Maybe never, said Paul Offit, the researcher from Children’s Hospital of Pennsylvania who helped develop the rotavirus vaccine.

“I’m uncomfortable with how we’ve sort of tripped down the line for the thought of universal booster dosing, which I just think is wrong,” Offit said.

The rest of the panel seemed to agree.

“We heard pretty loud and clearly that there was not a lot of appetite for moving down the age range very significantly if at all,” said Peter Marks, the director of the FDA Center for Biologics Evaluation and Research. 

One big reason for the panel’s skepticism: the risk of myocarditis and pericarditis, inflammation in or around the heart that both the Moderna and Pfizer-BioNTech vaccines appear to cause in rare cases, particularly in men aged 18 to 25. Those patients, several panelists said, are also at the lowest risk of Covid.

Earlier in the day, Hui-Lee Wong from the FDA’s Office of Biostatistics presented new data on the risk of heart inflammation with the Moderna vaccine. The condition mostly occurred for young men 18 to 25, and was similar between the Moderna and Pfizer-BioNTech vaccine. It’s so rare that it’s hard to know exactly how often it happens, but showed tens of thousands of people would probably need to get the vaccine for one case to occur.

The panelists said, repeatedly, that in order to make a call on boosters for other age groups, they would need to see good data on what the risk and benefit for those age groups would be. Right now, based on the data presented by Moderna in particular, they did not feel that data exists. Michael Kurilla, an NIH researcher, said that he wasn’t even convinced that, in the case of the data from Israel, that boosters would slow a wave of the pandemic. He noted that the decline of cases in Israel looked a lot like the decline in previous waves in places where people were not widely vaccinated.

Government officials seemed nervous that they will find themselves needing to expand booster availability without a mechanism to do it. The CDC’s Amanda Cohn referenced recent comments from meetings of the CDC’s Advisory Committee on Immunization Practices at which panelists said that using a hard line at 65 may be a disservice to people of color.  “The evidence for African Americans shows that their increased risk of death or hospitalization increases dramatically at age 50,” Oliver Brooks, chief medical officer of Watts HealthCare Corporation, said at a recent ACIP meeting.

It also appears that most people who are eligible for boosters are not currently getting them, Steven Pergam, a panelist from the Fred Hutchinson Cancer Research Center, said.

“It is a very challenging pandemic,” Marks said. He noted that some models say that the U.S. could face another wave of infections as people move inside for the winter, and said that the difficulty is that regulators have learned that they don’t know what they don’t know. Arnold Monto of the University of Michigan, the panel’s chair, suggested a future meeting regarding what would need to be known about booster shots in order to move to wider swaths of the population.

That’s it for today! The discussion will continue tomorrow as the panel considers whether there should be a second dose of the Johnson & Johnson vaccine and discusses data on “mix-and-match” boosters that combine different Covid vaccines.

— Matthew Herper

A chilling postscript

3:40 p.m.: Committee member Michael Kurilla raised some interesting — and potentially rather concerning — questions about how long protection from the mRNA vaccines last during today’s meeting. If people who got mRNA vaccines need to be boosted so soon, what does the future hold?

The evidence so far for both mRNA vaccines points to “very limited durability” — in the range of four to eight months, said Kurilla, director of the National Institutes of Health’s division of clinical innovation in the National Center for Advancing Translational Sciences.

Whether that’s related to the fact that both doses of the both vaccines are spaced closely together — three weeks for the Pfizer and four for the Moderna — or the size of the dosages used isn’t clear, he said, even raising the question of whether short-lived protection might be “a fundamental, inherent issue with the mRNA platform.”

The answer is currently unknown, he said, but is crucially important. “And it’s going to be very critical to understand whether or not a six-month boost actually does change the trajectory of the antibody response and provide some better durability,” Kurilla warned.

The fact that the Moderna’s booster contains half the antigen of their regular shot may have a big impact on how quickly the protection it generates wanes, he added.

— Helen Branswell

The vote

3:15 p.m.: The advisory committee voted on the following question:

Do available data support the safety and effectiveness of Moderna COVID-19 Vaccine for use under EUA as a booster dose (50 mcg mRNA-1273) at least 6 months after completion of a primary series in the following populations:

• Individuals 65 years of age and older,
• Individuals 18 through 64 years of age at high risk of severe COVID-19, and
• Individuals 18 through 64 years of age whose frequent institutional or occupational
exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19
including severe COVID-19.

Yes: 19
No: 0
Abstain: 0

— Matthew Herper

Getting down to business

2:30 p.m.: The committee has started to discuss the voting question, which is (in shortened form):

Do the currently available data support the safety and effectiveness of Moderna’s vaccine for use as a booster at least six months after the primary series for the following populations: People aged 65 and older; people 18 to 64 at high risk of severe Covid; people 18 through 64 who live or work in situations where they are at increased of severe Covid?

These are the same groups of people who are eligible for a Pfizer booster.

— Helen Branswell

Moderna evades the hot seat

2:10 p.m.: Moderna has taken a lot of heat lately about the fact that it sells its vaccine doses almost exclusively to wealthy countries. David Kessler, the Biden administration appointee who took over running what used to be called Operation Warp Speed, the government’s vaccine and drug fast-tracking and acquisition program, has gone so far as to publicly warn that the company needs to “step up.”

Who Moderna sells to isn’t the purview of VRBPAC. But Randy Hawkins, a pulmonary and internal medicine doctor from Inglewood, Calif., who is on the panel today as a temporary voting member, asked about it anyway.

Chair Arnold Monto can be quick to cut off questions he deems off-topic, but he let this one go. In a meeting that has been kind of lackluster so far, it seemed like VRBPAC was on the verge of having a moment.

There were no fireworks, however. Jacqueline Miller, Moderna’s infectious diseases therapeutic area head, seemed prepared for the question, pointing to an open letter CEO Stéphane Bancel recently published in the company’s website. It talks of major supply commitments for low-income countries — in 2022 — and a promised production site in Africa to produce vaccine for the continent.

Hawkins asked for a timeline on the African manufacturing plant. Miller didn’t have one. He let the issue lie and that was that.

— Helen Branswell

The Israeli case for boosters

11:30 a.m.: Israeli scientists presented more data from their experience giving Covid boosters to the entire adult population in order to head off a fifth wave of the pandemic.

The data from Israel are probably the most important argument for a wide rollout of boosters, and several panelists who had questions on the dataset all agreed that the Israeli researchers had presented a compelling case. That’s notable because a month ago, when the same FDA advisory committee met to examine the case of giving boosters broadly, the panelists largely felt that they should be limited to older and at-risk individuals.

“There is no question in my mind that the break of the curve now was due to the booster dose,” Sharon Alroy-Preis, director of  public health services at the Ministry of Health, Israel, told the panelists.

There is a major caveat to applying the Israel data to the main question of the day: boosters for those who received the Moderna vaccine. Israel has mostly used the Pfizer-BioNTech vaccine, although it has given Moderna boosters and noted in one case of a potential side effect that the recipient had gotten both vaccines. A request for more discussion on the Moderna point was tabled by Monto until later in the day.

The data could also influence the panel’s discussion, expected later today, of at what point, if ever, the recommendations for boosters should be expanded to all people over 18.

The Israeli researchers presented a barrage of data, using different comparison groups, indicating that people who received the booster dose were far less likely to catch Covid or become severely ill compared to those who did not.

Here are two slides that particularly capture the arguments. The first shows the protection against severe disease among people over 65 and also those over 40, compared to the rates of the disease in the same population before the vaccine took effect. 

Alroy-Preis said that in younger people, there were not enough cases of disease to get a clear result. “It could impact even younger than 40 years old for severe disease and mortality,” she said.

A second graphic shows how cases in people over 60 declined after they received a booster, even while rates in younger people who were not yet eligible for a booster continued to climb.

One important question that remains unanswered: Does this mean people will need a booster every six months, or does the third shot grant long-term protection? Alroy-Preis called this “the $1 million question that I don’t have the answer to.”

— Matthew Herper

This could get confusing

9:40 a.m.: Kurilla has asked a question that immediately made clear that there is plenty of room for confusion about who should get boosted, when, and with which dose of Moderna’s vaccine.

Kurilla, who is director of the National Institutes of Health’s division of clinical innovation in the National Center for Advancing Translational Sciences, asked whether, if the Moderna booster is authorized, it will supplant an earlier emergency use authorization allowing people who are severely immunocompromised to get a third dose of the Moderna vaccine. (A third dose for severely immunocompromised people who got the Pfizer vaccine is also allowed.)

This question is important because the third dose previously authorized is a full dose of the Moderna vaccine, the 100-microgram shot, one month after someone’s second dose. The booster VRBPAC is being asked to advise on today is the 50-microgram booster Moderna has proposed for the general population, given six months or later after the last dose in the series.

It appeared from the answers of FDA staff that the answer to Kurilla’s question is “No.” Sudhakar Agnihothram, from FDA’s Division of Vaccines and Related Product Applications, said that people who are severely immunocompromised may opt to get a fourth dose, the half-dose booster shot, when the appropriate time has elapsed after their third shot.

But then Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, jumped in. Marks seemed to suggest it wasn’t clear if people who are severely immunocompromised will be eligible to get a fourth shot. “This is far enough in the future that I don’t want to make a definitive statement,” he said, adding he’d welcome it if the panel discussed this issue later in the meeting.

— Helen Branswell

Looks like people 65 and older who got Moderna’s vaccine are getting a booster

8:50 a.m.: The FDA has posted the question it is asking VRBPAC today, and it makes clear that the FDA’s mind is probably already made up about people aged 65 and older who got the Moderna vaccine. It looks very likely that the FDA has decided they should get a booster.

The agency asked the committee whether adults under the age of 65 should be given a booster six months or later after receiving their second dose. It states that for the purposes of the vote, people under the age of 18 shouldn’t be considered. That’s not surprising as the Moderna vaccine is currently only authorized for people 18 and older and the company’s application for a booster was for people 18 and older.

That the FDA hasn’t asked for advice about people over the age of 65 suggests that for the agency, this question has already been answered.

When VRBPAC votes later today, it will be asked if the available evidence supports issuing an emergency use authorization for the Moderna booster for people 65 and older, people 18 to 64 who are at high risk of developing severe Covid-19, and individuals 18 to 64 who live or work in situations that increase their risk of serious complications from Covid.

These groups are the same as those currently eligible to get a Pfizer-BioNTech booster.

— Helen Branswell

Key questions to watch during the panel

8:45 a.m. The next two days will bring a lot of data about whether booster shots are needed, whether they are effective, and for whom. Here are some key questions that could become hot topics for the panelists.

First, remember the situation is very different from the one a month ago, when the same group of panelists met to consider whether to recommend a third booster shot of the Pfizer/BioNTech Covid-19 vaccine for everyone over the age of 16. The panel said that the shots should not be given that broadly, and instead recommended boosters for those over 65, for those with risk factors for severe Covid, and those, like health care workers, whose jobs put them at risk of contracting severe disease.

Now, instead of having to push back against the expectations of the Biden administration, the panel will essentially be playing by the rules it set with the Pfizer vote as it evaluates the proposed booster shots for the Moderna and Johnson & Johnson vaccines. But there are also some key differences between the data available for the three shots.

Why were FDA scientists neutral about boosters? With all three vaccines, the FDA’s reviewers have tended to be skeptical about data showing that the efficacy of vaccines is waning — such data come from observational studies. What will be interesting is the degree to which the panelists share this skepticism.

Is the efficacy of either the Moderna or J&J vaccine waning? Part of the argument for booster shots is the idea that the vaccines are becoming less effective as protection against severe Covid-19 and death. A big point of discussion at the panel for the Pfizer vaccine was that some panelists seemed unconvinced that the vaccine’s efficacy was waning so much that a booster was needed for all. So how the panel reacts to data showing that the vaccines may become less protective over time is important.

When are antibody levels enough evidence? A lot of evidence for both the waning of vaccine efficacy and the effectiveness of the boosters comes from studies measuring the antibody levels, known as titers, in volunteers. One of the big things the panel has to wrestle with is whether these numbers are enough without proof that waning causes more cases of severe disease, or that, say, a 66-fold boost in antibody titers from the Moderna vaccine means recipients are less likely to become sick.

Was Moderna right to reduce its vaccine dose? The dose of the Moderna booster is half that of the normal vaccine dose, a contrast to the other vaccines, which boost with an additional dose of the same vaccine. Moderna decided to do this because early data showed that side effects like fever were more common with the higher dose but not with the lower one, but antibody titers increased about as much. As with many decisions made in vaccine development, the panelists are likely stuck with this whether they like it or not.

What role should side effects play in the booster decision? One of the big reasons the panel wasn’t excited about giving a Pfizer/BioNTech booster to younger adults was the risk of myocarditis, a rare inflammation of the heart. The question is: Does the small incremental risk of myocarditis outweigh the potential benefit of extra protection in people whose risk from Covid is already low due to youth and lack of other risk factors? The same calculus is likely to play a role with the Moderna shot.

— Matthew Herper

Mixing and matching isn’t on today’s agenda

7 a.m. Good morning. Grab a coffee or tea — it could be a long day.

A key question about Covid vaccines is whether they could be more effective if used in combination. There’s good reason to believe the vaccines — because they aren’t all made using the same design or platform — won’t all generate the exact same immune response. In theory, giving an mRNA vaccine after one that uses a modified virus to deliver genetic material from the SARS-CoV-2 virus — as the J&J vaccine does — might provide broader protection.

The National Institute of Allergy and Infectious Diseases has been studying this question, and a preprint containing the earliest data from that so-called mix-and-match trial was posted online on Wednesday. The data look good for the Moderna booster; it seems to work well as a booster for itself, for the Pfizer vaccine, and for the J&J shot.

But the dose studied in the mix-and-match trial was not the half dose Moderna is hoping the FDA will authorize — the study used the full, 100-microgram dose.

At any rate, mix-and-match use of the Moderna booster isn’t on the agenda for today. The NIAID data won’t be presented until tomorrow. Today’s vote — the wording of which has not yet been revealed — will be about whether people who received Moderna’s vaccine should get its booster.

— Helen Branswell