When the Food and Drug Administration last month announced it would be holding another meeting of its panel of outside vaccine experts, it seemed like it would be a general discussion about a second set of Covid-19 boosters: whether they should be administered and, if so, to whom, and when.
That meeting is today, and the timing of it is now more interesting, to say the least. Last week, the FDA authorized another round of boosters for people 50 and older and those with certain immunocompromising conditions. Among the things we’ll be watching for at this meeting of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, is whether any panelists question that decision, or ask why they weren’t consulted before it was made.
There’s plenty else on tap today. There will be a presentation from Israeli researchers on their experience with second boosters — data the FDA cited when it authorized another shot for certain groups. And the experts will discuss the possibility of updating the vaccines to better match circulating SARS-CoV-2 strains and how to go about that process.
STAT will be live-blogging the all-day meeting. Posts are below, in reverse chronological order. And a livestream of the meeting is available here.
Final thoughts: a high bar for variant vaccines
5:07 p.m: As Drew noted below, the big message from the panel was that there is not a clear framework in place for approving vaccines aimed at new SARS-CoV-2 variants or deciding when people will need an additional dose of vaccine. But the panel was also clear that there is a real need to figure out what to do ahead of the fall and winter, when a surge is most likely.
Overall, this probably creates a high bar for new vaccines, either versions of the current mRNA vaccines from Pfizer and BioNTech that target different variants SARS-CoV-2 or combine more than one strain, or other technologies that might result in broader immunity. The FDA’s Peter Marks made clear that the agency does not see adding such a variant strain only as a booster – it would have to replace regular vaccinations in addition to boosters. And so that means the current vaccine would have to lose its effectiveness against hospitalization and that the new vaccine would have to be clearly better.
There are trials testing different strategies. Pfizer/BioNTech and Moderna both are doing studies of vaccines focused on Omicron. It could be that when data emerge, and this same panel meets to evaluate them, there will not be much to discuss.
But it’s also possible that the data will, as has happened so far, create as many questions as answers. CDC and FDA officials talked openly about the fact that we can’t just keep adding booster shots, and that new therapeutics that reduce hospitalization or mortality may be needed to keep the virus in check.
Ofer Levy, a panelist whose day job is at Boston Children’s Hospital, called on the FDA and the panel to remember that there may be a need for future vaccines that are better than what we have now. He called the mRNA vaccines “a godsend” but said “the political establishment” needs to realize that we still may need to develop other Covid vaccines. “I don’t think a lot of people have gotten that message,” he said.
— Matthew Herper
The meeting is adjourned
5:07 p.m.: There are a lot of concerns about the coronavirus next fall and winter, between the waning of immunity, the expected increase in transmission, and possible continued evolution of the virus. And yet, as today’s meeting has made clear, there’s not a good framework in place for deciding when to offer another booster and how to best update the vaccines.
If vaccines are updated, regulators will want to see some safety and immunogenicity data before they’re deployed (meaning, what kind of immune response do the shots elicit in people’s blood). And yet, experts aren’t really sure how to interpret the results of such lab studies in terms of what it means for people’s protection against the virus in the real world.
Those were among the issues that the panel was wrestling with today, but it was certainly not the end of the conversation. As the FDA’s Marks said, “We do anticipate holding another meeting on this topic,” likely by the early summer.
— Andrew Joseph
‘What is enough?’
4:22 p.m.: That was the question Amanda Cohn of the CDC raised when discussing booster strategy going forward. If we can’t keep boosting people every few months, and no vaccine can provide 100% protection, essentially what level of protection will we be satisfied with?
“Given that our effectiveness against hospitalization in immunocompetent individuals is over 80%, and that’s in older adults and in persons with chronic medical conditions, I think we may have to accept that level of protection and then use other alternative ways to protect individuals with therapeutics and other measures,” Cohn said. She added that she wanted to hear what other panelists thought, noting that different people might be comfortable with different thresholds.
The FDA’s Marks, who announced the agency’s decision last week to authorize second boosters for certain groups, said he agreed that boosting people every four months wasn’t a long-term plan. In fact, he called the latest round of shots “a stopgap measure” until there was a better system in place to consider booster strategy more broadly. He said health authorities wanted to provide older adults, who’ve taken the brunt of Covid’s damage, with an extra layer of protection in the interim.
— Andrew Joseph
FDA: New strain would affect primary series and boosters
3:55 p.m.: One outstanding question about a potential change in the design of the vaccine is whether it would apply just to future boosters or all Covid-19 shots — including what’s included in the primary series.
The FDA’s Peter Marks made it clear Wednesday: If the vaccine design is changed, it’s for all vaccines.
If there’s a new composition, “that would have to become what we would use for primary series,” Marks said. “It would be too confusing and potentially dangerous to have different regimens.”
The comments from Marks came in response to a question from UCSD’s Mark Sawyer, who also argued that the vaccine manufacturers should be targeting the same strains, under the guidance of the FDA and VRBPAC.
“We clearly need a unified approach to manufacturing,” Sawyer said. “It would be impossible to keep track of multiple different vaccines with different compositions.”
A key issue that hangs over any discussion about when to offer people another booster or whether to update the shots relates to the goal of the vaccines themselves. Some experts, pointing to the fact that protection against infection seems relatively fleeting, say that as long as the shots are continuing to protect people against severe disease and death, most people don’t need another shot.
Or, as Sawyer said, “We need to continue to focus on the worst case, which is severe disease, and we need to change strains when we’re losing that battle.”
Other experts, however, argue we should put more emphasis on preventing infections — not only to protect people individually, but also because that can slow down transmission to a greater extent.
— Andrew Joseph
What the panel needs, but doesn’t have
3:41 p.m.: Jerry Weir, the director of the division of viral products at the FDA’s office of vaccines research and review, gave members of the panel a broad charge, basically throwing at them every open question about what would be needed in order to decide when a current vaccine is insufficient and when a new one, targeted against a different variant, is sufficient.
Stanford’s Hayley Ganz responded by laying out what the panel would need to know in order to make such a decision — data that haven’t been presented to the panel.
One problem, she said, was that a lot of the discussion is centered around influenza, where knowledge about the vaccines and the virus are settled. But what we know about SARS-CoV-2 is not settled at all. Here’s what Ganz wants:
- More information on “correlates of protection” beyond antibody levels. There is data being collected on T-cell response, she said. Those data need to be presented to the committee.
- Data on safety. The public comment session included remarks by many people who said they had been injured by the vaccines. There are several systems put in place in the U.S. and elsewhere that are closely monitoring the safety of the vaccine. Those data need to be presented for the new vaccines in a granular way.
- What’s in the pipeline? Right now, the committee is considering only data from vaccines that have been authorized. But to decide on new variant vaccines, experts need to know what products are in the pipeline, even if they are not yet authorized.
— Matthew Herper
How will we know?
3:26 p.m.: Members of the panel returned after public comment, and have turned their conversation to some of the heady questions about future booster strategy they’ve been called on to weigh in on.
These are complicated questions with lots of hypotheticals and unknowns about vaccine durability and viral evolution, the FDA’s Jerry Weir acknowledged. But, he added, “We would appreciate any input, any suggestions that the committee has in order to get this conversation started rather than wait until the next crisis to start talking about it.”
One issue that the experts are wrestling with is, as Cody Meissner of Tufts put it, “At what point will we say the vaccine isn’t working well enough?” That is, what kind of lab results will tell us we need to update the vaccines?
One way scientists test how well vaccines hold up against different forms of a virus is by testing how well the antibodies generated by a shot recognize and neutralize the variant in question. But researchers haven’t figured out yet what size drop in neutralizing activity in lab experiments corresponds to a dangerous loss of protection for people in the real world — essentially, when people are no longer protected against severe illness anymore.
Weir acknowledged the challenge of figuring out when to pull the trigger on an updated vaccine, but noted that real-world effectiveness data that researchers track over time would be part of the calculation.
— Andrew Joseph
Can you make it?
1:46 p.m.: Even if you have the perfect vaccine against a new SARS-CoV-2 strain, it’s not useful unless manufacturers have enough time to make it.
That was the major point to the panel from a presentation by Robert Johnson, a deputy assistant secretary at the Biomedical Advanced Research and Development Authority (BARDA). He presented a multitude of choke points along the path to a vaccine.
Among them: Who decides what strain to make a booster shot against? Do manufacturers keep making the previous vaccine, or switch over entirely to the new variant? And does the new vaccine include multiple strains, a so-called bivalent vaccine, or just one?
Two panelists, Harvard’s Eric Rubin and Tufts’ Cody Meissner, both pushed back here: Isn’t one of the advantages of mRNA technology that vaccines can be developed fast? “We hear that the pharmaceutical folks can make a new mRNA vaccine in a matter of days or a week,” Meissner said.
Johnson acknowledged that mRNA vaccines would likely emerge first, followed by recombinant protein and viral vector vaccines. But he emphasized that decisions made ahead of time would play a key role in when the variants to be targeted would be produced.
For instance, he said, assume clinical trials are required for new variant vaccines. Also, assume that we want to start giving boosters with the new variant vaccine in September. “If you’re not on your way to that clinical trial by the beginning of May, it’s going to be very difficult to meet demand,” Johnson said.
Johnson also seemed to suggest it would be better if manufacturers had more “alignment” on bivalent vaccines. “Manufacturers are working on a bivalent,” he said. “I think the challenge is a bit that they’re not necessarily working on the same category and the same types of bivalent.” As stated by Biegel, the NIAID researcher, earlier in the day, this could be even more complicated. Scientists might want to try to pick a vaccine against a previous variant that appears effective against an emerging one.
It would probably have helped to hear directly from vaccine manufacturers about what timelines they’d require to produce a vaccine. That question is going to remain unanswered as the panel discusses how the U.S. should think about boosters going forward. Right now, the panel is listening to an open hearing of comments from the public. Its discussion will start again at 2:30 p.m.
— Matthew Herper
Updating the vaccines: flu versus Covid-19
12:36 p.m.: So if the world decides to update the recipe for Covid-19 vaccines, how should we pick the new design?
Kanta Subbarao, the director of the WHO’s Collaborating Centre for Reference and Research on Influenza, is walking the panel through how choices for the flu vaccine are made every year. But Subbarao, a professor at Melbourne’s Doherty Institute (and who is calling in at like 2:30 a.m. local time), also made note of some of the potential differences should the Covid-19 vaccines need to be updated.
For one, it’s not clear if different regions will eventually want differently designed Covid-19 vaccines, or if a global approach can be maintained. And while there are regular flu seasons — meaning authorities can make a decision on that year’s flu shot design ahead of time — “we don’t know what the seasonality of SARS-CoV-2 will be yet.” There are also different platforms used for the Covid-19 shots, such as the mRNA vaccines.
Still, Subbarao said that influenza could serve as the “basis” for how Covid-19 vaccines are refined.
Subbarao also raised one point of caution that global health officials will have to consider if they were to update the vaccines to better match the Omicron variant. The other forms of the virus, like Alpha and Delta, were more closely related to the original strain, while Omicron is more of an outlier. What if future variants look more like those earlier variants, and an Omicron-designed vaccine lacks the breadth to provide protection against them?
— Andrew Joseph
Getting past “It’s complicated”
12:12 p.m.: Sometimes scientists give worrisome news in mundane technical language. Take this quote from Trevor Bedford, a professor at the Fred Hutchinson Cancer Research Center who is one of the leading experts on the evolution of the SARS-CoV-2 virus.
“Exactly assessing the probabilities here is quite difficult.”
Bedford was talking about whether the mutation of the virus would result in strains that are slightly different from existing ones, as happened for most of the pandemic, or whether another strain would come out of nowhere, as Omicron did. The second scenario is much worse, because it means that existing vaccines would take a bigger hit on efficacy.
His answer? Most likely, new strains will emerge from the Omicron variants. But it’s possible that an out-of-nowhere strain will appear anywhere from every 1.5 years to every decade. You can see this, dramatically, on this slide from Bedford.
That means that researchers need ways to predict whether an existing vaccine will work against a new variant.
John Beigel, the associate director for the clinical research division of microbiology and infectious diseases at the National Institute of Allergy and Infectious Disease, presented a plan for doing this. Blood samples are being taken from volunteers in studies of not only the current vaccines, but others in development. He proposed matching the response of sera, taken from those blood samples, against new variants. That’s what the below slide represents.
Unfortunately, as Harvard’s Eric Rubin, an FDA panelist, noted, these figures are “complex” and “very hard to judge.” In a follow-up, Paul Offit, another FDA panelist who works at the Children’s Hospital of Philadelphia, noted that measures of T cells, not antibody levels, might be a better correlate of protection for vaccine efficacy. This is one time where it would be better if the answer wasn’t “it’s complicated.”
— Matthew Herper
Looking to Israel
11:32 a.m.: The meeting is back, and in full volume. Though we seemed to have skipped, at least for now, the Q&A with the researchers from Israel about the data they presented. That was what was beginning when the audio issues began.
Before the sound cut out, however, we did get presentations from Sharon Alroy-Preis of Israel’s health ministry and Ron Milo of the Weizmann Institute about the safety and effectiveness of fourth doses of the vaccines. Israel authorized second boosters for people 60 and older early this year in anticipation of an Omicron surge and as they saw some waning of the protection offered by the initial booster. About half of the eligible population received fourth doses, the Israeli researchers told the panel.
There have been several studies from Israel showing that second boosters led to improved protection against not only infections, but severe disease and deaths as well. One study, published Tuesday in the New England Journal of Medicine, found that another shot elicited stronger protection against infection and severe illness, but that the protection against infection waned quickly. The protection against severe disease did not wane, but the study only followed participants for six weeks.
“Overall we see somewhere between two-fold and four-fold further protection against mortality” with the fourth dose, Milo said.
The FDA cited Israeli data when it announced its second booster decision last week, and other U.S. health officials have similarly pointed to the data to justify the need for an additional shot for certain populations. At a White House briefing Tuesday, Tony Fauci walked reporters through the findings in the Israeli studies, though he acknowledged that they were based on short-term data.
Experts have noted, however, that there are limitations to some of the findings. Perhaps people who rushed out to get another dose are more cautious about their health generally, and are thus less likely to have severe outcomes from Covid-19 versus people who stuck with three doses.
— Andrew Joseph
Houston (er, Rockville), we have a problem
11:27 a.m.: Ever since the FDA advisory committee process went virtual at the beginning of the pandemic, there have been hiccups in the audio. Speakers have cut in and out. Last September, Pfizer, the company with the technical expertise to develop the first vaccine, had repeated audio issues.
.@US_FDA What’s the point of having public #VRBPAC hearings if the public can’t hear the discussions?
— Tilde Cafe (@TildeCafe_) April 6, 2022
But up until now, the process has been able to move forward admirably despite the squawks and hiccups. Some aspects of the virtual panels – notably the voting – have even seemed more streamlined than they were in person. Which is to say that right now the panel has had some serious audio issues. The webcast (and, we presume the panel discussion) have been turned off twice today, and now listeners have been treated to a full sampling of the FDA’s hold music. Several songs have repeated. There’s the one that sounds like a Mumford & Sons outtake, a generic blues song. And, I think, some whistling. When the meeting stopped, the panelists were going into an important topic: questions and answers on the Israeli vaccine data. Hopefully we can get back to that before too long.
We’ll be back when the panel is.
— Matthew Herper
CDC TLDR: the boosters worked during Omicron
10:30 a.m.: That’s short for “too long, didn’t read.” Ruth Link-Gelles, the CDC’s program lead on Covid-19 vaccine effectiveness on its epidemiology task force, presented a deep dive into observational data on vaccine effectiveness in both children and adults. This slide basically sums it up. On this graph, you want to be as far to the right as possible — that means vaccine efficacy is highest. Note how much further the purple dots (3 doses) are than the green ones (2 doses).
— Matthew Herper
Covid is changing. Are boosters keeping up?
10:00 a.m.: The first presentation of data to the panel came from Heather Scobie of the Centers for Disease Control and Prevention. It went deep into the changing epidemiology of Covid in the U.S. and discussed some data on the effectiveness of the vaccines. Here’s a quick rundown, with a few of Scobie’s slides.
First, the Covid landscape has been constantly shifting as new strains emerge. This image makes that very clear: look at that big orange area taking over the entire graph. That’s the Delta wave. And then see the Omicron wave, in purple, taking over.
Another key point was that Omicron, despite generally causing less severe symptoms, has resulted in a lot of hospitalizations. You can see them peak in the graph below.
The Omicron wave, this shows, resulted in the sharpest peak in hospitalizations of the entire pandemic.
Hayley Ganz, of Stanford, asked Scobie perhaps the key question: Do we know if booster shots help? “Those who have a booster dose – there was clear benefit for quite a while,” Scobie said, referring to the hospitalization data shown below. However, this did seem to wane over time. She said it is possible this is because many of the people who did not receive the booster shot may have been infected in the Omicron wave.
Another key fact to consider, per Scobie: 217 million people are vaccinated, but only 90 million have received a booster dose.
— Matthew Herper
What about VRBPAC?
9:17 a.m.: Well, that was fast.
We’re not far into this, and James Hildreth, a temporary voting member of the VRBPAC and the president of Meharry Medical College, brought up the FDA’s decision last week to expand eligibility for boosters for some groups without asking for the panel’s thoughts.
“You’ve already made a decision about boosters recently, to give them to [50+] and those with underlying conditions, so I’m just wondering why this discussion is being held now when you already made some major decisions about boosters,” Hildreth asked FDA officials. “What was the reasoning for not convening the VRBPAC to make that decision?”
In response, Peter Marks, a top vaccine regulator at FDA, said the expanded authorization last week amounted to giving an option to certain groups “to essentially restore levels of protection” based on data from the United Kingdom and Israel that indicated the immunity from a third shot could wane. The decision was made with some evidence suggesting the United States could be in the early stages of another wave of some size, as the Omicron BA.2 lineage has become dominant.
“We consider that as not a major expansion or a major change, but something that we looked over the data and felt was reasonable to do at the time,” Marks said. “This discussion today is a much larger discussion. It’s a discussion of what do we do for the entire population, and what do we do when we think the virus may have evolved further?”
For the larger discussion — including about how broadly to extend a booster campaign ahead of an expected Covid-19 wave next fall — the FDA wanted input from the VRBPAC, Marks said.
— Andrew Joseph
On the vaccine experts’ agenda
6 a.m.: Good morning from STAT’s Matt Herper and me. We’ll be your live-bloggers today.
Get ready for a lot of talk about boosters: who should get additional shots and when, and how regulators should go about deciding when to rework the design of the vaccines.
As a refresher, recall that there are two main reasons people may need a booster shot (and they can occur simultaneously). For one, the effectiveness of the shots can wane over time. Or, the virus can evolve in ways that undermine the power of the vaccines.
That raises the question of whether the Covid-19 vaccines — which were designed based on the strain of the coronavirus that first appeared in Wuhan, China — should be updated at some point to better match the virus as it’s evolved over more than two years.
In a briefing document released ahead of the meeting, the FDA laid out the pros and cons regulators would have to consider when making that call. What kind of delays would ensue if manufacturers had to shift production to an updated version of the vaccine? Should companies try to make vaccines that target more than one strain — making a multivalent or bivalent shot instead of a monovalent one?
Some studies have also indicated that another dose of the existing vaccines elicit such a strong and deep immune response that it can offer robust protection even in the face of a highly mutated virus, as was the case with the Omicron variant. What if an updated vaccine doesn’t have such versatility? And what happens as the virus keeps evolving?
Or, as the FDA wrote: “While modification of a monovalent Covid-19 vaccine to be more closely aligned to a specific variant may improve vaccine effectiveness against that variant, it is not known whether such modification might come at a cost of reduced breadth of coverage and potentially decreased effectiveness against variants that might emerge in the future. Depending on the evolution of the virus and the epidemiology of circulating variants, a multivalent vaccine … may offer benefit over a monovalent vaccine.”
Global health authorities already have experience updating the composition of the flu vaccine, and the FDA document raises the idea of adopting a similar approach should that be necessary for the Covid-19 vaccines. The agency also said that “ideally, when appropriate, any change in vaccine composition would be implemented broadly and coordinated by the World Health Organization with national regulatory authorities.”
However, the FDA did leave open the door to the U.S. acting on its own in updating its vaccines in certain situations, including when there’s sufficient data to suggest there’s a need for a better vaccine, when there’s evidence to suggest a new variant-specific vaccine will be superior to existing vaccines, and when manufacturers have capacity to produce those vaccines in sufficient quantities for use in the U.S.
— Andrew Joseph
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