Fasten your seat belts, folks. We’re about to hit some turbulence.
If you’re reading this, you’re interested in the discussion on the future of Covid-19 vaccination that’s going to take place today in a meeting of the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee. We at STAT can’t predict the outcome, but we know enough to expect that this meeting will feature some heated debate.
At the start of year four of the pandemic — year three of the Covid vaccination program — the FDA is trying to chart a future path. Up till now, the effort has been to get first shots, the so-called primary series, into as many Americans as possible, and to follow them up with booster vaccinations.
But that is largely done. At this point, 81% of the country has had at least one dose and just under 70% has had the two doses that constitute a primary series. The 19% of people who haven’t had a single dose of Covid vaccine are unlikely to roll up their sleeves. So how do the country’s vaccine regulatory and public health leaders, the FDA, and the Centers for Disease Control and Prevention, redesign the vaccination program so that it is tailored to the needs of people who may need to have their immunity topped up from time to time, while making provision for the new people — young babies — who will continue to enter the need-to-be-vaccinated pool?
That’s what the FDA is asking the members of VRBPAC today. Should they — and how should they — transition a program that has seen pharmacy and doctors’ office fridges crammed with vials of various brands of vaccines, in various dose strengths designed for people of a range of ages into a more one-size-fits-all approach? Instead of one vaccine for first timers, containing only a single strain of the virus, and another for people being boosted, which has been updated with a more recent strain, would it be okay to have a single product to fill both functions?
The FDA is also asking the members of VRBPAC their thoughts on its proposal that Americans get an annual Covid shot, in the way they get a flu shot, one that is reconstituted regularly to try to target the strains in circulation at the time. In documents the FDA made public before the meeting, it proposed choosing new vaccine strains in June for a vaccine campaign that would begin in September.
Covid is clearly here to stay, so this may sound sensible. But there are concerns some of this is still based on a leap of faith rather than a data-led process. For example, the idea that everyone might need an annual Covid booster will not earn a unanimous “yea” vote out of this expert panel.
And recently a number of members of VRBPAC — including the acting chair, Arnold Monto of the University of Michigan — publicly chided the FDA for not presenting all relevant data to the committee at a meeting last year at which bivalent boosters were discussed. In advance of this meeting there have already been questions about whether all needed data will be presented.
My colleague Matthew Herper and I will be live blogging this VRBPAC meeting, which begins at 8:30 a.m. EST. You can watch the meeting here. Matt and I will be posting our updates and analysis below in reverse chronological order, so check back often. If you’re a vaccine policy nerd, this is likely going to be a very interesting day.
— Helen Branswell
5:45 p.m.: So I’m sitting here eating some humble pie. I promised heated discussion and there wasn’t heated discussion. Two thoughts. 1) I should leave the predictions to soothsayers and meteorologists; and 2) some cans were kicked down the road today.
There is not universal agreement among this group that two doses of vaccine, as currently formulated, would provide adequate protection for little kids who’ve never before been vaccinated; in fact, there’s probably agreement that isn’t enough, at least with one of the vaccines. And there are members of this group — Paul Offit is at the head of the line — who do not believe healthy adults need to be urged to get an annual Covid shot. Offit made that clear repeatedly.
Likewise some members seemed to question the schedule the FDA is proposing, the select-the-strain-in-June-and-roll-the-vaccine-out-in-September thing. But they seemed willing to tell FDA to give it a try. As Gellin said, “I don’t think we’re setting it in stone…. We may need to adjust along the way.”
So today was about VRBPAC giving a sort of high-level blessing to changing the approach to Covid vaccination. There will likely be active debates down the road about the details of the new approach. That said, some of that debate won’t happen at VRBPAC. When it comes to deciding who should get additional doses, how many and when, that will probably be the purview of the Advisory Committee on Immunization Practices, an expert panel that advises the CDC on how vaccines should be used.
Thanks for reading!
— Helen Branswell
We’ll be doing this again…
5:30 p.m.: The meeting is now concluded. The FDA asked a lot of big questions about its future plans for Covid vaccines, but in the end got one clear answer: that it’s OK to go from having two different types of Covid shots — the original shots and the bivalent boosters matched to new circulating strains — to just one. From now on, it seems clear, there will be only vaccines matched to current circulating strains and, for now, the bivalent shots will be used as the primary series, too. Of course, the FDA will actually have to make that official for it to happen.
There also seemed broad agreement that it is a good idea for the FDA to move toward making it so most people will get one more Covid shot next year, although it’s not exactly clear who will need more. The group getting two or more vaccines will likely include young children, the immunocompromised, and the elderly. But Peter Marks, the director of the Center for Biologics Evaluation and Research at the FDA, said that this does mean that the FDA will be doing at least one of these meetings in June.
And the panel wasn’t unanimously behind committing to annual Covid shots for everyone, forever. In the words of Eric Rubin, the Harvard infectious disease expert and New England Journal of Medicine Editor, “It’s hard to say it’s going to be annual at this point.”
Several panelists also said that they are hoping for a better vaccine to come — and some of them worried about the fate of Novavax’s vaccine, which seems to constantly get lost in the proverbial shuffle. But Novavax also has a tough argument to make: it needs people, their doctors, and public health officials to choose it despite the lack of some of the harder, more rigorous data that exists for the other shots, which have been given to many, many more people. The problem of how to develop a better vaccine will have both scientific and commercial components, and neither part of that equation is close to solved.
— Matthew Herper
The meeting continues
5 p.m.: The single vote of the meeting is out of the way, but that’s not the end of the agenda. FDA asked the committee to discuss two questions it wants some help thinking through. The committee is completing discussion of the first right now, which is should the Covid vaccine schedule now become one dose for most people and two for people who are immunocompromised, older adults, and young children who haven’t yet been vaccinated against Covid?
A number of members of the committee have raised concerns about the proposal as it pertains to young kids. The Pfizer vaccine for the littlest kids has been a three-dose shot because two shots at the low dose that Pfizer used did not generate enough protection. Archana Chatterjee, dean of Chicago Medical School, stressed more data are needed for decisions about little children.
But there will be no vote on this question. Likewise there won’t be a vote on the next question: How does the committee feel about the idea of regularly updating the vaccines timed to a fall vaccination program? Based on what was said earlier in the afternoon, the committee will probably support that idea.
— Helen Branswell
4:40 p.m.: The advisory panel voted on the following question:
Vaccine composition: Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (Original plus Omicron BA.4/BA.5)?
Read the full story.
The T-cell conundrum
4:15 p.m.: One thing that panelists keep asking about: Is it possible to develop “correlates of protection” – measures of whether vaccines are effective – other than just levels of neutralizing antibodies?
At one point in the discussion, Jerry Weir, the head of the FDA’s division of viral products, acknowledged that as time passes, it is going to get more and more difficult to get better measures. But another exchange Weir had may have shed even more light.
Hank Bernstein of Northwell asked for more data on how the vaccines provide immunity due to T-cell response. Weir responded that “T-cell response is a broad term” and that we don’t even know whether it is, for instance, a CD4 response or a CD8 response, referring to different types of immune cells. But then, Bernstein replied: “I do think it’s making a difference,” saying that T-cell response is probably why the vaccines are continuing to protect people. Weir replied that nobody disagrees with that; we just don’t know their specific contribution. In other words, we don’t know why the vaccines are working as well as they are.
— Matthew Herper
When is the optimal time to vaccinate for Covid?
3:50 p.m.: The committee is asking last questions, mainly of the FDA and CDC experts, before they start to deliberate on the issues they’re meant to discuss. That discussion was supposed to start at 3:30 p.m., so they’re running a little late.
Bruce Gellin, a temporary voting member, asked a key question: If you’re hoping to get maximum benefit from a Covid vaccination program, when does it make sense to vaccinate?
Covid hasn’t really settled into a seasonal pattern yet. Unlike flu, respiratory syncytial virus, or the panoply of viruses that cause colds, there are still spikes of Covid activity at various times of the year. Covid peaks are not exclusive to winter.
Peter Marks, the director of FDA’s Center for Biologics Evaluation and Research, jumped in, saying there is some evidence SARS-2 is developing a seasonal pattern. (That comment would not be met with universal agreement.) And he insisted the idea of vaccinating against Covid in the fall — in conjunction with the delivery of flu shots — makes sense.
“When do we have to worry about the worst overwhelming of the hospitals? It will be when we have influenza, RSV, and potentially covid at the same time,” he said.
This year that trifecta definitely swamped hospitals in a series of waves that began in late summer. Will that be an annual thing? Not clear.
— Helen Branswell
How long does it take to update vaccines?
1:50 p.m.: Before I get into what this post is going to be about, an unrelated observation: An extraordinary amount of time at this meeting has been devoted to issues that are at best tangential to what the committee is going to be asked to advise the FDA on. Updates on what is going on with Covid and the SARS-2 virus, on the safety and effectiveness of the vaccines, on that the manufacturers are studying. It’s all interesting, but it’s not what the FDA gathered these experts to talk about.
Now, to the point of transitioning to a system where vaccines would be updated annually: The FDA is proposing to model it after the way flu vaccines are updated. Twice a year experts gather at the World Health Organization and pour over the data about which virus strains are waxing and waning around the world. In February, the experts propose the strains for the vaccine for the following Northern Hemisphere winter; in September, they pick the strains for the Southern Hemisphere vaccine. The long lead time is needed because it takes months to make and bottle flu vaccine.
With Covid vaccines, the FDA hopes to narrow that window. Scientists there would like to select strains in June and see delivery of the vaccine in time to start vaccinating in September. Can the manufacturers do that?
Pfizer, which makes an mRNA vaccine, said it can deliver vaccine in 100 days, even if the vaccine contains multiple strains. (The current booster contains two.) Moderna hasn’t yet been directly asked that question, but Antonella Lozito, executive director of regulatory affairs for infectious disease, said the company supports the FDA’s proposal, so presumably Moderna, which also makes an mRNA vaccine, believes it can deliver on the FDA’s timeline.
But Novavax, which does not produce an mRNA vaccine, may have trouble meeting the FDA’s expectations. The company, which has not yet produced a bivalent booster shot, proposed that new strains be chosen by the end of the first quarter of the year — so March rather than June.
— Helen Branswell
Where are the fireworks?
1:04 p.m.: The committee just got a 26-minute lunch break.
In our intro I predicted heated discussion. There hasn’t been any yet. Was my prediction off base?
It may turn out to be, but it’s early yet. This meeting has a super-stacked agenda. Presentation after presentation after presentation; there were nine in the morning session with short intervals in between where committee members got to ask a question or two.
Late this afternoon, though, there is a two-hour block in which the committee will debate these issues before voting on a single question: Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (original plus Omicron BA.4/BA.5)?
I still think there could be some pointed questions raised then. That part of the meeting starts at 3:30 p.m. ET.
— Helen Branswell
Does the world have to take what the U.S. orders?
12:50 p.m.: Temporary VRBPAC member Bruce Gellin just addressed one of the elephants in the room. (Yes, elephants plural.)
As the U.S. designs a program to update Covid vaccines annually, do U.S. choices dictate what vaccine is available to the rest of the world? Gellin, who is chief of global public health strategy at the Rockefeller Foundation, asked that question during a Q &A that followed the Pfizer presentation.
Gellin noted the FDA’s briefing document for the meeting mentioned coordinating updating of vaccines with the World Health Organization. [Note: It did, but very briefly.] “If the United States orders this … vaccines in June, does that mean the rest of the world’s going to get it without having a chance to order something different?”
This is an issue that a number of experts have wondered about in the lead-up to this meeting. Is the U.S. going to be setting Covid vaccine update policy for the world, effectively, if it entrenches a system of choosing new strains for the vaccine every June for use in the fall?
There’s already a bit of a precedent for this concern. Last spring, the WHO’s Covid vaccine advisers recommended updating the vaccine to target Omicron’s BA.1 strain as well as the original virus. But the FDA decided the U.S. wanted an updated vaccine that targeted BA.4/5, which was the strain then circulating. The manufacturers had made some BA.1-containing vaccine on spec, but then switched production to BA.4/5.
Bill Falstich, Pfizer’s vice president for global supply chain, responded to Gellin’s question: “Not necessarily.”
“This past year we delivered BA.4/5 bivalent to the U.S. We delivered a BA.1 bivalent elsewhere in the world. It was on separate decision cycles and we were able to manage that with no concerns and fulfill all the global demands. So we can be flexible like that again if we needed to,” Falstich said.
— Helen Branswell
Moderna did the booster study we needed — in the U.K.
12:30 p.m.: One of the big problems with talking about the updated bivalent boosters has been that, generally speaking, there have not been big clinical trials that randomly assign people to the new booster and the original one. Moderna did conduct that study, and presented the results.
The study was conducted in the U.K. As I’ve noted before, though the U.S. is a global hotbed of clinical research, the U.K.’s clinical infrastructure is increasingly making it the home to some important research.
Here are the results to that study. Importantly, it used a BA.1 booster, not the BA.4/BA.5 booster that was used in the U.S. (those are all names of Omicron variants). But the results should comfort anyone who was worried about the booster switch.
— Matthew Herper
Safety: that stroke analysis, and where is myocarditis?
11:20 a.m.: The FDA panel just spent nearly an hour and a half discussing data on potential safety concerns with the vaccines.
Most of that time was spent on a new analysis that could mean that older patients who receive the Pfizer/BioNTech vaccine might be at a higher risk of stroke. When the FDA disclosed this analysis on Jan. 13, it said it is “very unlikely” that there is a true clinical risk.
The presentation, by Nicola Klein, director of the Kaiser Permanente Vaccine Study Center, revealed some of the reasons for that. The strokes appeared to occur clustered together, and the overall increase in incidence seems to be waning with time. As the FDA previously emphasized, other safety databases have not turned up the same risk. One worry that did seem to affect some panelists: that concomitant administration of the Covid vaccine with influenza vaccine might increase this risk. But Arthur Reingold, of the University of California, Berkeley, said that even if the signal was clear it would need to be put in the context of whether there is an increased risk of stroke from Covid as there is from influenza.
One topic that was not covered much in the CDC or FDA safety presentations: myocarditis and pericarditis, the inflammation of the heart tissue that has been clearly linked to both the Pfizer/BioNTech and Moderna vaccines in adolescent boys and young men. The risk from the disorder has been presented at past FDA advisory panels as being very low. But it also occurs in a population that seems very unlikely to die or be hospitalized due to Covid.
Panelist Hayley Gans, a Stanford pediatrician, asked for more discussion of other safety signals, seeming to hint at the myocarditis issue. Michael Nelson, a University of Virginia immunologist specializing in vaccine side effects, also said that more data on myocarditis would be useful, especially because the issue has become “very public with respect to concern and vaccine hesitancy.”
— Matthew Herper
How well are Covid vaccines working in kids?
10:05 a.m.: Ruth Link-Gelles, a Covid vaccine expert at the CDC, has just presented some data on how well Covid vaccines appear to be working in young children, the segment of the population least likely to be vaccinated. CDC’s most recent estimate is that only 11% of kids aged 6 months to 4 years have received at least one dose of Covid vaccine.
Link-Gelles said data on Moderna’s two-dose pediatric Covid vaccine suggests the vaccine effectiveness is 47% after one dose and 57% after two.
The picture is less impressive for the three-dose Pfizer-BioNTech pediatric vaccine. The CDC data suggests that after one dose, the vaccine effectiveness is 12%. But the confidence intervals on that estimate cross zero, so that’s not a statistically significant finding; the effectiveness could be lower or even nil. After two doses, the vaccine effectiveness is 39%. Link-Gelles said it isn’t currently possible to estimate the vaccine effectiveness of the Pfizer vaccine after three doses, saying the estimates “don’t meet precision thresholds for interpretation.” She offered no further explanation.
Remember: As part of its effort to simplify the Covid vaccine administration schedule, the FDA is proposing that all young children get two doses of vaccine. From the data presented so far, the evidence doesn’t suggest two doses of the Pfizer vaccine would give young kids robust protection.
— Helen Branswell
Who is getting sick and dying from Covid now?
9:45 a.m.: As the panel decides whether everyone should get an annual Covid vaccine and whether those vaccines should match the current booster shots, it’s going to need to consider who gets sick from Covid right now and who dies from it in the U.S. The answer, according to data presented by Heather Scobie of the CDC, is that older people are most likely to be hospitalized and to die, but that there is also an increase in the number of hospitalizations of infants who have not yet been vaccinated.
You can see below that deaths during the Omicron surge have been clustered in older people, particularly those older than 75.
But when Scobie looked at hospitalizations, not deaths, there was also a surge among very young children who had not yet been vaccinated.
The cumulative rate of hospitalizations in young infants is higher than that for people between the ages of 50 and 64, and approaches that of those between 65 and 74. The highest rate of hospitalization by far is in those over 75 years.
What remains true is that the vaccines are highly protective. People who have received all vaccines including the bivalent booster are 13 times less likely to die from Covid than those who are not vaccinated at all, Scobie said. Those who received the bivalent booster are also less likely to die from Covid than those who have received only the primary vaccine series — that is, the original two doses.
What’s problematic is that people are, for the most part, not getting the updated booster. Some 229.5 million people, or 75% of those over age 5, received the original vaccine series, Scobie said. But only 50.6 million, or 16% of those eligible, have gotten the updated booster. That is something else the panel will need to consider.
Another reaction to the data that seems important: The panelists may be increasingly skeptical of neutralizing antibody titers, one of the easiest-to-get measures of vaccine efficacy. The vaccines seem more protective than these would indicate, said Stanley Perlman, the panel’s acting chair.
“I wonder if using neutralizing antibodies as the sole correlate of protection, which is what we kind of do, needs to be upgraded or changed because it seems like people are still pretty well-protected, even though the antibody titers are variable.”
— Matthew Herper
Another looming issue: Why include the Wuhan strain?
8:50 a.m.: The meeting is getting underway with roll call and a reading of the rules for the day. The presentations will begin in a few minutes. A quick note: Arnold Monto, the University of Michigan vaccine expert who was to chair the meeting, is not in attendance. University of Iowa coronavirus expert Stanley Perlman is acting chair.
While this is underway, I thought I’d alert readers to another issue that will likely come up today. A number of vaccine experts, including at least one member of VRBPAC, are questioning why Covid vaccines still target the original strain of SARS-2, which came out of Wuhan, China in early 2020.
That version of the virus hasn’t been seen for quite some time; it has been overtaken by a series of variants of concerns, the latest of which is the current version, Omicron.
The argument I’ve heard for continuing to include the original virus in the vaccine relates to concerns that a new variant of concern could emerge, one that looks more like earlier versions of SARS-2 than Omicron. A vaccine targeting Omicron wouldn’t protect well against such a virus, the thinking goes.
But a number of vaccine experts think if that were to happen, a new version of the vaccine could quickly be developed to address that new threat. The messenger RNA platform Pfizer and Moderna use has proven to be particularly nimble in that regard.
“I don’t know why we have the Wuhan strain in the booster. I think it’s a complete waste,” Anna Durbin, director of the Center for Immunization Research at the Johns Hopkins Bloomberg School of Public Health, told me Wednesday. “If Wuhan comes back, we can make an mRNA vaccine to contain that. But to keep it, I don’t think it’s adding anything whatsoever.”
VRBPAC member Paul Offit shares that view. This will likely be a topic of discussion today.
— Helen Branswell
Some things to watch for
7:40 a.m.: Designing effective Covid vaccines turned out to be a far easier task than people dreamed at the start of the pandemic. The first were ready to use within 11 months.
But that’s where easy ended.
So as VRBPAC tries to give guidance to the FDA on the issue of simplifying the Covid vaccine schedule, here are a few wrenches that might find their way into the works.
- The FDA is suggesting that going forward, most people will need only one shot a year, though some high-risk people — older adults, people whose immune systems are compromised — might need two. But do most people need an annual booster? At least one member of the committee, Paul Offit of Children’s Hospital of Philadelphia, is on record saying that he doesn’t see the need for healthy younger adults to get repeat boosters. Others may agree.
- And there’s the issue of young children. The FDA proposal suggests children who haven’t been previously vaccinated against Covid should get two doses. But the Pfizer-BioNTech vaccine, one of two approved for use in young kids in this country, is currently given as a three-dose series — because two doses weren’t adequately protective. (The Moderna vaccine is given as a two-dose regimen for young children.) The FDA documents released before the meeting did not include a justification for why Pfizer’s three-dose pediatric vaccine could now be given as a two-dose series.
- Then there’s the issue of the size of doses. The bivalent boosters — the two-in-one shots that were cleared for use last fall — contain lower amounts of antigen per targeted strain than the initial Covid shots did. The original Pfizer vaccine included 30 micrograms of antigen targeting only the original strain; the Moderna vaccine contained 50 micrograms. Each company’s bivalent boost contains the same total amount of vaccine as the original, but divided in half because they now target two strains. If the bivalent becomes the first Covid vaccine a person gets, is half the tested amount of antigen enough? Maybe, Phil Krause, a former deputy director of the FDA’s Office of Vaccines Research and Review, told reporters on Wednesday. But is there evidence to support that move, he asked?
“From the big picture, I’m worried that we don’t have the data needed to make these kinds of decisions tomorrow,” said Krause, who is not a member of VRBPAC.
— Helen Branswell
There’s one place missing at the table
7:15 a.m.: There are four Covid vaccines either licensed or authorized under emergency use provisions in the United States. The companies that make three of them will be presenting data at this meeting — Pfizer, Moderna, and Novavax. One company, though, is not scheduled to appear.
Johnson & Johnson, whose vaccine division, Janssen, produced a Covid vaccine that was the third to market in this country, is not on today’s agenda.
The J&J vaccine was the product of a bold — and ultimately ill-fated — move by the company to try to produce a Covid vaccine that could be given in a single dose. Had it worked, it would have had an enormous market advantage. But while the vaccine received an emergency use authorization, the FDA later recommended J&J recipients get at least one additional dose, two months after their first. And the vaccine was found to be associated with a rare but dangerous clotting disorder.
In late 2021, the FDA effectively benched the J&J vaccine, saying it should only be given to people who cannot or will not take one of the other vaccines, which at the time were the messenger RNA vaccines made by Pfizer and Moderna. (The Novavax vaccine, which isn’t made using mRNA technology, was later authorized for use in the U.S.) Earlier this month the Wall Street Journal reported J&J was scaling back production of its Covid vaccine in the face of dwindling demand.
The company did not produce a bivalent or an updated vaccine. Given that it isn’t part of today’s discussion, it would seem the J&J Covid vaccine will not play a significant role in future U.S. Covid vaccination efforts.
— Helen Branswell
Create a display name to comment
This name will appear with your comment