Tracking an FDA advisory panel meeting on updating Covid vaccines

Meetings of the Food and Drug Administration’s vaccines advisory committee are never dull affairs. Drenched in data, maybe, but never dull.

And Tuesday’s meeting of the Vaccines and Related Biological Products Advisory Committee promises to hew to that tradition as the independent vaccine experts are asked to debate whether it is time to update Covid-19 vaccines.

It seems pretty evident the FDA wants to hear “Yes” when the committee is asked to conduct its sole vote on the question: Does the committee recommend inclusion of a SARS-CoV-2 Omicron component for Covid-19 booster vaccines in the United States?

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“I think, as we move into this coming fall when there will be a confluence of factors that make us more susceptible to yet another wave of Covid-19, we feel it’s important to potentially look at what we could do with giving additional vaccinations, that is booster vaccinations, to protect us,” Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, told STAT late last week.

The confluence of factors includes waning immunity, the possibility of the emergence of a new variant, and the looming arrival of winter, with weather that keeps people indoors more, in much of the country.

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“So those three things combined make us realize that we do need to think about a campaign for boosters sometime in the fall. And getting it right, thinking about what we might do differently than we’ve done now, is important,” Marks said.

An analogous committee that advises the World Health Organization recently declared that the vaccines should be reformulated to include a version of the Omicron variant, to broaden the immunity the vaccine induces.

It suggested that the manufacturers start making primary series that include both the original SARS-CoV-2 virus and the first version of Omicron that appeared, BA.1. (It has since been replaced by other strains of Omicron.) If manufacturers want to make an Omicron-only vaccine, it should only be used as a booster shot for people who have already been vaccinated.

My colleague Matt Herper and I will be live blogging the meeting, which starts at 8:30 a.m. EDT and could run to 5 p.m. The meeting will be webcast here.

We will be posting our updates and analysis below in reverse chronological order, so please check back often for updates.

— Helen Branswell

A final note

8:00 p.m.: Frequently, for an FDA panel, the result cannot be fully summarized by just a vote tally. That is especially the case today.

The panel was broadly in favor of telling companies to start manufacturing an Omicron-containing booster, with only two panelists voting that the data did not yet support creating such a shot.

But there was consensus on more than that. The panelists largely agreed that the booster should contain the BA.4 or BA.5 variants of Omicron. The data for shots containing these variants largely comes from tests on animals, not humans, but the panelists believed the new vaccine would be similar enough to previously tested variant vaccines that it is worth trying to get ahead of the next viral mutation, to go, as one panelist said, where the puck is going, not where it is now.

Despite data from Pfizer showing a better immune response from a so-called monovalent vaccine that contains antigen from only the Omicron strain, the panelists largely backed a bivalent vaccine, that is, one that contains both an Omicron strain and the original SARS-CoV-2 strain.

The panel had mixed ideas on whether to extrapolate from results in adults to children for new boosters, but all said that companies needed to collect data from children more quickly. There was unexpected interest in the vaccine being developed by Novavax, which has not yet been authorized, as a booster. Peter Marks, an FDA official, indicated that the discussions around the vaccine were complex.

During the public comment portion from the day, many speakers stated beliefs, often based on erroneous information, that the vaccine is harmful. Other speakers were mothers who believed that FDA had moved too slowly in making vaccines available to young children.  In his closing remarks, the FDA’s Marks seemed to make a plea to all sides to believe that the FDA and its panels are acting in good faith.

“Science is not always simple, but we will do our best to work our way through it to make sure that we do our best by public health and the country,” Marks said.

— Matthew Herper

The vote

4:45 p.m.: The FDA advisory committee voted on the following question:

Does the committee recommend inclusion of a SARS-CoV-2 Omicron component for COVID-19 booster vaccines in the United States?

Yes: 19
No: 2
Abstain: 0

The two “no” votes were cast by Paul Offit of Children’s Hospital of Philadelphia and Hank Bernstein of the Zucker School of Medicine.

— Matthew Herper

Will updating the vaccines lead to unintended consequences?

4:10 p.m.: Stanley Perlman, a coronavirus expert at the University of Iowa, raised an issue that is of serious concern at WHO headquarters in Geneva. If the U.S. opts for updated vaccine, what will that do to the willingness of other countries to use the large supplies of vaccine based on the original composition that are currently available?

“I’m uncomfortable with the U.S. having a vaccine that’s not accessible to the rest of the world,” Perlman said, noting there’s already a perception that the U.S. and other wealthy countries have put themselves first. “And if we’re saying that a bivalent vaccine is so much better, but it’s not accessible to much of the world, I think that’s ultimately a bad thing for getting vaccines out to the whole world.”

A number of countries are still relatively early in their vaccine rollouts. If there’s a perception that there is a better vaccine, they may object to using vaccines based on the original SARS-2 virus. That’s already been seen with countries holding out for mRNA vaccines, because of the view that they are the best Covid vaccines.

But the existing Covid vaccines are still doing a great job in protecting people against severe disease and death. As Kate O’Brien, technical lead on vaccines at WHO, told me recently: “There’s not a first class and a second class of vaccines, if these ones come out.”

— Helen Branswell

Notes from the VRBPAC discussion

4:05 p.m.: Ideas are flying fast and furious at this committee meeting. Here’s a snapshot of a few.

The FDA asked the panel to discuss three issues at once. Does it matter what Omicron sub-lineage is used, BA.1 or BA.4/BA.5? Should the vaccine be monovalent (just Omicron) or bivalent (Omicron and the original strain)? And should the data be extrapolated to different age groups?

Here are some issues that have been brought up.

Are we moving too fast? Paul Offit of Children’s Hospital of Philadelphia said he felt that the move to new-variant vaccines was happening too fast, with too little data.

“I think as a new product it should be handled as a new product,” he said. “I think we need a higher standard than what we’ve been given. I think it’s uncomfortably scant.”

He also added, though, that he is comforted that the panel is “jumping with a net.” The existing vaccines are protective against severe disease, he said, which means that the stakes of the decision are lower either way.

Some fans for Novavax. Two panelists spoke out in favor of the data shown by Novavax indicating that its shot against the original strain might work well as a booster against Omicron strains. James Hildreth, CEO of Meharry Medical Colllege, said the Novavax data were “the most compelling thing I’ve seen today” and that the data seem “more impressive to me than the data for Pfizer and Moderna.” Wayne Marasco of the Dana-Farber Cancer Institute made similar comments, wondering if the Novavax data were showing the limitations of the mRNA vaccines. Hildreth encouraged the FDA to consider Novavax’s emergency use application quickly.

How do we measure vaccines? One problem here is that there aren’t enough measures, outside of clinical data, to know if a vaccine is working. Ofer Levy of Boston Children’s Hospital implored the FDA to take the lead in finding one. “If we aren’t able to identify a correlate of protection, we are fighting with one arm behind our back,” he said.

Where’s the data for kids? Archana Chatterjee, dean of the Chicago Medical School, said that more studies of the vaccines in children need to be done — and they need to be done now. “I’ve asked the question several times, asking for pediatric data, and the response has been, well, we don’t have any,” she said. “And I think that is an inadequate response at this point in time.”

— Matthew Herper

ETAs for updated vaccines

3:30 p.m.: Committee members wanted to know how quickly updated vaccine could be available, if the FDA tells the manufacturers to include Omicron as a vaccine target.

Pfizer said it could have product available in the first week of October, if there is an agreement in place that provides a quick regulatory pathway for updated vaccines. Kathrin Jansen, head of Pfizer’s vaccines program, did not give an estimate of what quantity of vaccine it could deliver at that point.

Moderna said it could have updated vaccine available in late October, early November “at large scale.”

Novavax, which hasn’t yet received an emergency use authorization for its vaccine, said it could have updated vaccine available in the fourth quarter of the year, but noted that it believes its prototype vaccine, which includes an adjuvant, offers broader protection, and may not require updating yet.

— Helen Branswell

The discussion is underway

3:20 p.m.: The committee has started discussing a number of questions the FDA asked it to debate. There’s 100 minutes set aside for the VRBPAC to discuss a bunch of questions (see my first post below) before the group votes on one question — should Covid booster shots be updated to include an Omicron target?

At the rate this is going, it’s hard to envisage that they’ll get through all the questions the FDA asked them to discuss.

— Helen Branswell

Aiming for breadth of response, not matching the circulating strain

12:50 p.m.: As I reported Monday, it looks like the FDA and the World Health Organization may be heading in different directions when it comes to the aim of updating Covid vaccines.

Peter Marks, FDA’s director of the Center for Biologics Evaluation and Research, has been talking about trying to get updated vaccines to contain a viral target that is as close as possible to the strain of the virus that is circulating. (That’s how influenza vaccines are updated.)

But an expert committee that advises the WHO has chosen a different path. That group, called the Technical Advisory Group on Covid-19 Vaccine Composition, recently concluded that it probably is time to update Covid vaccines, either with a monovalent booster targeting Omicron’s BA.1 subvariant, or with a bivalent vaccine including the original Wuhan strain and Omicron’s BA.1. The monovalent vaccine could be used in people who have been previously vaccinated, as a booster, while the bivalent vaccine could be given to people who haven’t been previously vaccinated.

The chair of that advisory committee, Kanta Subbarao, who is also the director of the WHO Collaborating Center for Reference and Research on Influenza, in Melbourne, Australia, presented data to explain the committee’s decision. Some of it has already been presented by the vaccine manufacturers (see Matt’s post below) and I’m not going to repeat it here.

Subbarao — who used to work at the National Institute of Allergy and Infectious Diseases — said the WHO expert panel decided the goal should be to broaden the immune response the vaccine induces rather than trying to keep pace with a rapidly changing virus.

“Our goal here is to achieve broader immunity against circulating and emerging variants and it is not so much to match what is likely to circulate, because there is so much uncertainty about the trajectory of this evolution,” she said.

For that reason, the WHO group recommend that BA.1 should be the Omicron variant included in any updated vaccine. Evolutionarily it is the most distinct of the variants and subvariants vis-à-vis the original Wuhan virus, Subbarao explained. Adding it to the vaccine should expose immune systems to a broader range of epitopes — parts of the SARS-2 spike protein — which should then help the immune system recognize the viruses, even if they’ve evolved further.

Subbarao noted the data her group worked with were all based on messenger RNA vaccines (i.e. the Pfizer and Moderna products), so there are question marks hanging over vaccines made with other platforms. And she acknowledged that the committee doesn’t have a good handle on how easy or hard it would be for manufacturers of non-mRNA vaccines to update their products.

— Helen Branswell

Three vaccine makers take three very different approaches

12:30 p.m.: Through most of the pandemic, different vaccine makers have approached testing Covid vaccines in much the same way. The only big outlier was Johnson & Johnson’s insistence that its vaccine should be given as a one-dose vaccine.

But three different vaccine manufacturers — Moderna, Pfizer/BioNTech, and Novavax — presented data on their booster shots to the committee, and each had a distinct and different approach.

Moderna, represented by the company’s president, Stephen Hoge, went first. Moderna tested a bivalent Omicron booster. That means that the booster shot included equal amounts of antigen from the original Covid strain and from the BA.1 Omicron variant. Using the bivalent Omicron booster meant that there were higher levels of antibodies that could fight the virus.

But the real interesting data came after Hoge had presented, when he was asked why Moderna chose a bivalent booster, not a monovalent one that only contained Omicron antigen.  Hoge presented data showing that with previous variants, a bivalent booster meant that antibody levels stayed higher longer.

Moderna showed data indicating that a bivalent booster might lead to smaller decreases in antibody levels.

That’s a particularly interesting argument for Moderna to make, because Pfizer presented data on both monovalent and bivalent boosters — and the monovalent Omicron boosters appeared unequivocally better.  That will leave the panel to try to make its own call on whether boosters should be monovalent or bivalent. Even if a monovalent booster is more effective, a bivalent one might provide protection against a broader range of strains.

Pfizer and Moderna also both asked to be able to move forward with new boosters without clinical data, and Pfizer presented its own surprise — data from animal studies of a booster containing newer variants of the Omicron strain, BA.4 and BA.5. The data show that, in mice, the newer strains result in higher antibody levels.

In mice, Pfizer says a BA.4 booster performs better than the original strain.

The FDA asked Pfizer if there were data comparing this new booster to the Omicron booster. Those data are not available yet. So that’s more uncertainty for the panel to weigh.

Novavax, which was late to deliver phase 3 results and so has not seen its vaccine used in the U.S., presented its own booster data arguing that its vaccine, which uses a different way to deliver the spike protein that all the vaccines use as an antigen, provides broader  protection against SARS-CoV-2 strains than would be expected. In particular, Gregory Glenn, the company’s president of research and development, said that giving a booster dose of the existing vaccine gave antibody against the BA.5 Omicron variant that are comparable to what were seen against the original SARS-CoV-2 strain in the company’s phase 3 trials. It’s a tantalizing idea, but will either the FDA or the panel be willing to bet on it based on the data available? Novavax is also developing its own variant vaccine; that study began in May.

— Matthew Herper

‘Substantial possibility of resurgences’

10:50 a.m.: VRBPAC just heard a presentation from Justin Lessler, a professor of epidemiology at the University of North Carolina at Chapel Hill. Lessler was presenting modeling data that tries to project where the pandemic is going.

Confession: Interpreting modeling isn’t my strongest skill. But I’ll give it a shot.

Lessler said the 20 modeling groups that feed into the Scenario Modeling Hub looked at several scenarios — fast versus slow waning of vaccine protection, no new variants versus the arrival of a new variant that has a 30% escape potential (i.e. it is different enough that it can evade a portion of antibodies generated by vaccination or previous infection).

Based on their work, it looks like the fall could be difficult. “Incidence is tracking with the more pessimistic scenarios,” Lessler noted.

“We see that faster waning leads to higher likely … hospitalization numbers, particularly in the nearer term. And particularly with a variant, we see resurgences. In both cases, we do see a substantial probability of resurgences in the fall.”

Lessler said that in the most optimistic scenario, there could be 95,000 additional Covid deaths in the U.S. between March 2022 and March 2023. Under the most pessimistic scenario, that number could be 211,000.

A couple of caveats: Lessler started his presentation by stressing that in the past this group has found its modeling is most accurate when it looks out a few weeks; Covid has been so unpredictable that longer-term projections are challenging. And the confidence intervals on the death estimates are very wide.

— Helen Branswell

The CDC shows snapshots of the pandemic

10:10 a.m.: Presenters from the Centers for Disease Control and Prevention started the day with presentations about the state of the Covid pandemic and the efficacy of the vaccines over the course of the pandemic. Here are some things that stood out.

First, vaccines continued to reduce the risk of infection and death. There were more nuanced analyses shown, but perhaps this is clearest from the raw data below.

Even during the Omicron pandemic, vaccination reduced the risk of death — and booster doses added protection.

But there has also been considerable vaccine fatigue among the public. Most people got their first two-dose series. But fewer have gotten boosters, even though they add protection. Hard numbers: 71% of eligible people have received a primary series, but only 26% of those over 50 have gotten a second booster (that is, a fourth shot).

People have not been getting boosters at the same rate that they got the original vaccine.

It’s also a reality that the efficacy of both vaccines and boosters has dropped with time and as new strains emerge. The drop-off is very fast, measured in months.

This slide shows how effective the vaccine is in periods where different variants are prominent. It’s better if the dot is further to the right.

As you can see, people who received boosters are better protected against being hospitalized than those who only received two doses, no matter what the strain. But the effiacacy of even three doses wanes after 120 days. An additional booster dose (that is, four doses) does return the efficacy to levels of 80%.

The question: will boosters better matched to the strains protect people better?

Another interesting note, that came out of discussion between the panel and Ruth Link-Gelles, a CDC researcher: The efficacy for series including the J&J vaccine has generally remained lower than that for the two mRNA vaccines, made by Pfizer/BioNTech and Moderna.

— Matthew Herper

Charge to the panel

9:20 a.m.: The meeting has opened with Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, explaining the situation the FDA is seeking guidance on. Specifically, Marks said the agency is concerned that with waning immunity, the onset of winter weather, and the continued evolution of the SARS-CoV-2 virus, the U.S. could see a rise in serious Covid illness in the autumn and winter.

The committee is being asked to indicate whether it believes it’s time to update the vaccines. From Marks’ comments, it seems pretty obvious the FDA thinks the answer is yes. And it also seems clear that the agency is hoping to hear support for the idea of updating the vaccines to target one of the Omicron subvariants, BA. 4 or BA. 5, which are becoming the dominant viruses circulating in the country.

Marks said decisions about whether to update the vaccines and how to do that need to be made quickly if vaccine is to be available for the fall.

VRBPAC 6

— Helen Branswell

Looks like FDA is giving itself some leeway

6 a.m.: As I mentioned in the introduction, there’s only one voting question slated for today. It’s on whether an Omicron strain should be included in Covid boosters.

But the FDA is asking VRBPAC to consider a number of other questions; they are just not, it appears, going to be asked to vote on them. That means the agency gets to hear the views of their advisers, but doesn’t face the thorny issue of ignoring their recommendations, should the FDA decide not to follow that advice.

And the questions the FDA wants discussed but not voted on cover a lot of important ground. Like: Which version of Omicron should be included in the updated vaccine, if updates are called for? The FDA’s analysis for the meeting, found here, acknowledges there currently are no data on how well boosters based on BA. 4 and BA. 5, the subvariants that are now surging across the country, would actually work. And yet it’s clear the FDA is considering instructing manufacturers to make updated vaccines using one or the other of them.

VRBPAC will also be asked to discuss but not vote on whether updated vaccines should be monovalent — targeting only Omicron — or bivalent, retaining the original vaccine and adding an Omicron strain to it. It is being asked to opine on whether the existing primary series vaccines — the ones that have been in use since late 2020 — can still be used for people who’ve never been vaccinated before if the booster shot composition is changed.

With no votes on these questions, policy setting may be easier for the FDA.

— Helen Branswell

Source: STAT