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Follow the FDA advisory panel meeting on the J&J Covid vaccine booster – STAT

The booster-shot question that has been on the top of many minds for many months will be addressed today when the Food and Drug Administration’s vaccines advisory committee reconvenes to complete a two-day meeting. The question before it: Should people who got the one-dose Johnson & Johnson vaccine get a booster shot, and if so, when?

Another top-of-mind question, however, may end up not being addressed by the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC). If the highly active discussion on Twitter is any indication, people who got the J&J vaccine want to know if they should be boosted with one of the messenger RNA vaccines from Pfizer-BioNTech or Moderna.

That option doesn’t appear to be on the table for today.

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During Thursday’s online meeting to discuss Moderna’s application for a booster shot, the question — actually questions — that will be put to the committee during today’s discussion about the J&J application was temporarily posted by mistake. Nowhere among them was a question about whether J&J vaccine recipients ought to get a heterologous boost, in other words a boost with a different vaccine.

Data will be presented today on a study of mix-and-match boosting conducted by the National Institutes of Health. But according to the meeting schedule, it will be at the end of the day, after VRBPAC votes on the J&J booster application. There’s no provision on the schedule for a vote on heterologous boosting.

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People who got the one-and-done J&J vaccine have been in booster-shot limbo as the manufacturers of the mRNA vaccines have argued that an increasing number of breakthrough cases among fully vaccinated Americans and declining antibody levels signal a need for boosters.

If protection from two doses of the mRNA vaccines is already wearing off for people who were vaccinated early in the U.S. rollout, so the thinking goes, surely people who got only one dose of the J&J vaccine are also becoming increasingly vulnerable.

But available data don’t necessarily show a decline in protection from the J&J vaccine — or, for that matter, huge gains from a J&J booster shot. The vaccine’s protection against serious illness was never as high as the protection offered by the mRNA vaccines in the early days after vaccination. But it hasn’t waned either. The vaccine’s efficacy against moderate to severe disease was nearly 73% after one dose, and about 75% after two.

J&J submitted several studies to the FDA, evaluating both a second dose after two or three months and a booster given at least six months after the first dose.

For VRBAC, voting on a J&J booster will come in stages. The committee will first be asked to vote on whether the available evidence supports the safety and effectiveness of giving a dose of the J&J vaccine as a booster for all adults 18 years of age and older at least two months after their first dose.

If the committee votes “Yes” on that question, it will be asked if the data suggest that extending the interval between the first shot and the booster to at least six months might make the booster shot more effective. If the committee votes “No” to the first question, members will be asked if the data support a booster shot given six months or more after the first shot.

The vote places no restrictions — other than being age 18 and older — on who should get a J&J booster if one is approved. But given the vaccine’s safety profile — it has been linked to a small but real risk of serious clotting problems seen mainly in women under the age of 50 — there will likely be discussion about whether a J&J booster for anyone who got the vaccine is warranted.

There might be discussion about this regardless. Both the Pfizer/BioNTech and the Moderna boosters were greenlit for specific groups of people, albeit large groups that include people over 65, people 18 to 64 with medical conditions that increase their risk from Covid, and people who live in or work in places which increase their risk from Covid.

Matthew Herper and I will be live blogging the meeting, which you can watch here, starting at 8:30 a.m. EDT. We will be posting our updates and analysis below in reverse chronological order; check back often.

— Helen Branswell

Batting clean up, the FDA makes a mess

4:40 p.m.: The panel ended the day with a wide-ranging discussion about two of the biggest issues facing vaccines in the real world: whether to allow so-called “mix-and-match” boosters, in which people get a booster different than their original vaccine, and whether the age cut-off for getting a booster to the mRNA vaccines, the ones from Moderna and Pfizer, should be lowered from age 65 to 40.

Some panelists seemed open to both ideas, but it was unclear if there was a consensus and there was no formal vote on either topic.

Kirsten Lyke from the University of Maryland School of Medicine presented data from an NIH-funded study showing that, in general, a mix-and-match booster — the technical term is heterologous — increased antibody levels at least as much as getting a booster of the same type. However, she noted, there were limitations to the study, including not only that it wasn’t big enough to yield data on whether the boosters prevented infection but also that patients had not been randomly assigned to their groups and that the researchers did not control for differences in precisely how long it had been since people received their first dose.

Still, many panelists were open to the idea. A few said they were open to making the “mix-and-match” boosters available now. Steven Pergram, of the Fred Hutchinson Cancer Research Center, suggested changing the language of the vaccines’ authorizations to allow people to get a different vaccine if they’ve had a reaction to the first. Right now, he emphasized, rules around emergency use authorization make it difficult for people to get a vaccine for an unauthorized use.

Arnold Monto of the University of Michigan, the panel’s chair, brought up a separate topic: whether the age at which people who don’t have risk factors can get a booster of the mRNA vaccines should be lowered to 40. Several panelists expressly said that they were open to the idea, but Peter Marks, the head of the FDA’s Center for Biologics Evaluation and Research, which approves vaccines, said an exact vote would not be necessary.

Jesse Goodman of Georgetown University, who previously held Marks’s job, called the discussion “imprecise in its structure and outcome” on a call with reporters and said such a topic would require much more structure from the FDA and that it would require the FDA to vote. Generally, throughout the past two days, Marks has seemed to be steering the panel in ways that are unusual for an FDA official, but not unheard of.

Outside experts and advisory committee members worried about another aspect of the meeting: the fact that the FDA had not, as it normally does, fully vetted the data from J&J’s studies, point by point. That did not happen, Marks said, because there just wasn’t time.

Panelist James Hildreth, the CEO of Meharry Medical College, made a point of publicly underlining the need to conduct those analyses.

“Dr. Marks, you’ve gone on record to say that the FDA team has not fully evaluated the data presented to them, and we voted to approve this without them having done so,” Hildreth said. “So I think it would be really really important that it be clarified that they’re going to do so and that if there are challenges that arise in that analysis that appropriate actions will be taken.”

Goodman said he was concerned about the precedent that was set by holding the meeting before data could be analyzed. Norman Baylor, a former head of the FDA office that reviews vaccines, echoed that concern on the same press call, saying the meeting may have been held too soon. “It does set a bad precedent,” Baylor said.

That’s a wrap. Thanks for tuning in. We’ll see you next time.

— Matthew Herper and Helen Branswell

That’s a wrap

3:30 p.m.: This two-day VRBPAC meeting is adjourned!

Matt and I are going to huddle and come back to you with a few wrap up thoughts shortly.

— Helen Branswell

The vote

1:30 p.m.: The panel voted on the following question:

Do available data support the safety and effectiveness of Janssen COVID-19 Vaccine for use under EUA as a booster dose in individuals 18 years and older at least 2 months after a single dose primary vaccination?

Yes: 19

No: 0

Abstain: 0

— Matthew Herper

Is boosting J&J with another brand of vaccine a looming option?

1:25 p.m.: This is turning out to be a bad meeting for J&J. It’s clearly the view of a lot of VRBPAC members that this vaccine should be a two-dose vaccine. And it’s also apparent that the FDA is thinking about whether the boost for the J&J vaccine should be another brand of vaccine.

There won’t be a vote on that issue this afternoon. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said FDA hasn’t yet had time to analyze thoroughly the data from the NIH’s mix-and-match study.

But VRBPAC chair Arnold Monto asked Marks if it’s possible that at some point there will be an emergency use authorization that permits heterologous boosting — priming with one vaccine and boosting with another.

“I would say it’s possible,” said Marks.

— Helen Branswell

Is this a two-dose vaccine trying to pass as a one-dose vaccine?

12:55 p.m.: The afternoon session has started. Something that came up just before the short lunch break is getting a serious airing now.

J&J is suggesting that its booster will be most effective if given six months after the first dose. But the company’s evidence for that is scarce — immunological readings from 17 patients, to be precise. That didn’t impress VRBPAC member Eric Rubin, editor-in-chief of The New England Journal of Medicine.

Rubin said what the company should be asking for is a booster dose at two months for everyone who gets the J&J vaccine. He didn’t use the term, but that’s a two-dose vaccine.

“If the vaccine isn’t adequate, then it should be boosted in everybody,” Rubin said, who called the evidence for a six-month interval before the booster thin. “I’m not sure why you’re asking for an indication that would apply to millions of patients with a data set that includes 17 patients.”

Paul Offit, a vaccine expert from Children’s Hospital of Philadelphia, was even more pointed in his remarks. “I think this frankly was always a two-dose vaccine. It’s hard to recommend this as a one-dose vaccine.”

J&J is not applying to change its authorization to turn this into a two-dose vaccine. The company wants to retain its one-dose standing, which is potentially a marketing advantage for some parts of the world.

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, told the committee earlier in the morning that turning this vaccine into a two-dose vaccine is not on the table today.

— Helen Branswell

A public health imperative

12:30 p.m.: Both the FDA and the CDC want the advisory panel to know: The J&J vaccine is not as effective, given as a single-dose vaccine, as the Moderna or Pfizer vaccines.

Peter Marks, a top FDA official, went so far as to say that doing something about boosters is “a public health imperative.”

Several of the panelists seemed to be saying that, based on the clinical trial data, the J&J vaccine might be similar to the other vaccines, but more durable. Marks interjected to make sure it was clear that wasn’t true, referencing other data from the CDC. He also pointed out that the J&J vaccine, because it was one dose, was used as a way of reaching out to communities that were seen as more difficult to vaccinate, including the economically disadvantaged and people of color. Then he asked the CDC to speak about data regarding the vaccine in the real world.

The CDC’s Amanda Cohn didn’t mince words. Without a booster, she said, the J&J vaccine did not protect people as well.

“In our hospitalization network, so in our active surveillance that looks at vaccine effectiveness in hospitalized individuals, we demonstrated that the Janssen vaccine was only 68% effective against hospitalization, and this is in adults greater than 18 years of age without immunocompromising conditions,  which is both lower than what we saw from that real-world effectiveness presentation and it is also substantially lower than the mRNA vaccines are against hospitalization even with the waning,” Cohn said. 

“Additionally there was some other data to suggest that real-world effectiveness is hovering more in the 50% to 60% [range], and this is from some data from a different surveillance system,” she added.

“The overall perspective is that regardless of whether there has been waning or if this was the true effectiveness after a single dose, the effectiveness or protection with a single dose of the J&J vaccine is not equivalent to protection at this time with either two doses of mRNA vaccine and certainly not in those groups who have been authorized to receive a booster dose of the mRNA vaccine.”

Penny Heaton, a J&J executive, emphasized that the efficacy of the vaccine is “durable” but said that there is clearly “headroom” to improve the efficacy, and that the large 30,000-person study testing two doses of the vaccine shows efficacy in-line with the two-dose mRNA vaccines from Moderna and Pfizer.

— Matthew Herper

TTS, GBS and other vaccine reactions

10:50 a.m.: The Covid-19 vaccines have excellent safety records, but both classes of vaccines used in the U.S. and Europe — the mRNA vaccines and the viral-vectored ones — have rare but serious side effects. For the mRNA vaccines it’s myocarditis in young men. For the viral-vectored vaccines, like the J&J and AstraZeneca vaccines, it’s TTS — thrombosis with thrombocytopenia syndrome, a rare but dangerous clotting event that appears mainly to occur in women in their 20s and 30s.

J&J executives updated VRBPAC on the safety profile of their vaccine, noting that all reactions — mild and more severe — appear to occur at a lower rate after the second dose of their vaccine compared to the first. In fact, they didn’t see a single TTS case that met the case definition set by the Centers for Disease Control and Prevention in the booster trials they conducted.

Only about 14 million doses of the J&J vaccine have been used in the U.S., so the company pooled data on 33.6 million doses of viral-vectored Covid vaccines given globally to try to paint a picture of how common the serious adverse reactions to these vaccines are.

Macaya Douoguih, head of clinical development and medical affairs for Janssen Vaccines, told the committee that globally, TTS appears to occur at a rate of about 2.1 cases per 1 million doses of vaccine given. Guillain-Barré syndrome, a progressive but generally reversible paralysis, appears to occur at a rate of about 7.5 cases per 1 million doses of vaccine given, compared to a background rate of about 1 to 5 cases per 1 million people each year. (A number of illnesses and vaccines can trigger GBS.)

There have been seven cases of capillary leak syndrome after vaccination globally, with two of them occurring in the U.S., for a rate of about 0.2 cases per one million doses given. The syndrome is a rare disorder in which plasma leaks from the blood vessels, causing a sharp drop in blood pressure that can be fatal if not treated.

Narayan Nair, director of the FDA’s division of epidemiology, said that reports from the FDA’s Vaccine Adverse Events Reporting system do indicate a heightened risk of GBS and TTS, and that preliminary analyses may indicate a risk of myocarditis, pericarditis, and immune thrombocytopenia. However, in a bit of a surprise, the FDA’s BEST surveillance system, which monitors claims from Medicare and insurers, does not currently show safety signals for these events.

— Helen Branswell and Matthew Herper

“The data have not been independently verified by the FDA”

10:21 a.m.: What’s the difference between emergency use authorization and approval? It can, as with the authorization for convalescent plasma, be a lot. Emergency use authorization just requires a treatment be “reasonably likely” to help during a public health emergency.

But when it comes to the vaccines, the FDA has chosen to make emergency use authorization look a lot like the traditional approval used by vaccines, called a biologics license approval. That’s why all the vaccine makers have tested their vaccines in trials involving tens of thousands of patients.

There are differences. One sacrifice for speed is being stated by FDA reviewers again and again today: “The data have not been independently verified by the FDA.” FDA reviewers normally go through a company’s data with a fine-tooth comb, and it’s not unlikely that they find problems — a trust, but verify, approach. That step was apparently skipped in order to make it possible to hold these meetings so quickly.

— Matthew Herper

J&J moves early to try to block a heterologous boost

10:15 a.m.: One of the key questions facing vaccine regulators and their advisory committees — though maybe not today — is whether people who got a single dose of J&J vaccine would be better off being boosted with one of the mRNA vaccines. Data from a small National Institutes of Health-run study that will be discussed later this afternoon suggest that approach, called a heterologous (i.e. different) boost produces higher levels of antibodies.

As I explained earlier, there isn’t going to be a vote today on whether to offer people who got a J&J vaccine a heterologous boost. But J&J executives clearly see that train barreling down the track, and they tried briefly during their data presentation to sidestep it.

As he closed the company’s extensive presentation, Johann Van Hoof, managing director of Jannsen Vaccines (J&J’s vaccines division) reminded VRBPAC members that important questions remain about how safe heterologous boosting is and how durable the response to a heterologous boost will be.

The subtext of his remarks: The J&J vaccine’s protection seems so far to be very durable. Boost J&J with J&J.

— Helen Branswell

J&J makes its case

9:54 a.m.: It was a changing-of-the-guard moment as Penny Heaton, who joined J&J as the global therapeutic area head for vaccines in September, made the case for the vaccine. Two of the main faces behind the vaccine, Paul Stoffels, J&J’s chief scientific officer, and Johan Van Hoof, a top vaccine development executive, are retiring.

Heaton laid out the company’s  argument with a clarity that is rare at FDA advisory panels. The J&J vaccine, whose use has lagged behind the Pfizer/BioNTech and Moderna vaccines, has important advantages that are only heightened by adding a second dose. These advantages are because the vaccine uses a virus, called Ad.26, as a vector to lead cells to make protein, not mRNA, as the Pfizer and Moderna vaccines do, she said.

J&J is hammering home that while the protection from those other vaccines seems to wane, it does not believe that is true for its vaccine. However, as FDA reviewers noted, efficacy for the single-dose J&J vaccine has been consistently lower than the efficacy of the mRNA vaccines.

“More than 14 million individuals in the U.S. have received Johnson’s vaccine,” Heaton said. “And while the efficacy has been stable, it’s been consistent. We think that the data we’re going to share today will highlight the opportunity that we have to further increase the efficacy and the protection with the booster dose.”

However, Heaton noted, when a second dose was given two months later in a 30,000-patient study, the vaccine’s efficacy increased from about 74% to 94%. (She appeared to use the numbers from the U.S. portion of the study; they were lower internationally.) She emphasized the vaccine’s “unique profile” that she implied allows the vaccine to protect more widely against variants. (Vaccine efficacy did seem to wane in the pivotal study; that may be due to variants.)

That was followed by a presentation by Sebastian Schneeweis, the founder of real-world evidence company Aetion, offering more evidence that the J&J efficacy is not waning, and a scientific talk from Dan Barouch, a Harvard professor whose lab was key to the early development of the vaccine. Barouch showed data explaining why the J&J vaccine response might be more durable.

J&J is asking for something very different than what Moderna and Pfizer/BioNTech did: not a booster to return a vaccine’s efficacy to normal, but one to up its efficacy to be in the realm of the other vaccines.

— Matthew Herper

J&J’s vaccine is different than the mRNA vaccines

9:00 a.m.: The subhead above may seem self-evident. But it’s important to remember as today’s discussions begin that the Johnson & Johnson vaccine (sometimes called the Jannsen vaccine, because that’s the name of J&J’s vaccine division) is made differently than the Pfizer-BioNTech and Moderna vaccines. It is a viral-vectored vaccine: a weakened cold virus has been modified to carry genetic information about the SARS-CoV-2 spike protein.

This vaccine underwhelmed initially, because its efficacy was substantially lower than that of the messenger RNA vaccines. But where the efficacy of those vaccines — at least the Pfizer one — has declined substantially in the first six or eight months after administration, the J&J vaccine’s efficacy hasn’t.

A letter published this morning in the New England Journal of Medicine briefly charts the different ways the three U.S.-authorized vaccines engage with the immune system. The senior author is Dan Barouch, an immunologist at Beth Israel Deaconess Medical Center who led development of the modified adenovirus platform that the J&J vaccine uses.

“The [J&J] vaccine induced lower initial antibody responses, but these responses were relatively stable over the 8-month follow-up period, with minimal-to-no evidence of decline. These findings have important implications for waning vaccine immunity, although correlates of protection from SARS-CoV-2 are not yet defined,” Barouch and colleagues noted.

These features — lower initial efficacy but no evidence yet of decline — may create a dilemma in today’s discussion. There has been concern for some time among VRBPAC members and members of the CDC’s vaccine advisers, the Advisory Committee on Immunization Practices, that people who received the one-dose J&J vaccine should probably get a second shot. The evidence may actually suggest it isn’t urgently needed. But given that boosters for both Pfizer and Moderna were authorized, it seems likely J&J’s booster or second shot will be approved too.

The big question will be around the timing of the second shot — at two months after the first shot, or at 6 months?

— Helen Branswell

A cheat sheet for today’s panel

7:00 a.m. Yesterday’s panel regarding the approval of booster shots for the Moderna vaccine brought some drama but also ended with a unanimous vote backing the boosters. What’s in store for today? Here’s a handy list of questions that may arise.

Should all J&J recipients get a booster?

A second shot of the J&J vaccine has been tested in two studies. One was a study in which 30,000 patients received two shots two months apart. They had fewer cases of moderate or severe Covid-19 than those who received a placebo. The second study showed antibody levels rose after a six-month booster. Unlike Moderna, J&J is asking for authorization for everyone who has received its single-dose vaccine to get another shot.

Was the J&J vaccine always going to be a two-dose vaccine?

In the FDA briefing documents posted Wednesday, the J&J vaccine doesn’t appear to be showing waning efficacy. Instead, the FDA staff said the effectiveness of the single-shot J&J vaccine appears to always have been lower than that of the two-dose mRNA vaccines.

At the time the J&J vaccine was authorized, some members of the VRPAC were already wondering whether a second dose would be needed. Paul Offit, a vaccine researcher from Children’s Hospital of Philadelphia, wondered aloud how to communicate to the public that a second shot might be needed. So one argument for granting J&J’s request for authorizing a booster is that it always seemed as if two doses might be needed.

Should J&J recipients get a J&J booster, or something else?

One of the most anticipated parts of the two-day meeting will come at the end of the day, when the panel will discuss a study by the NIH on mixing and matching booster shots. These data show higher levels of antibodies for those who got the Moderna shot after a J&J shot. But the study is small and has other flaws.

How should we think about safety?

Thursday’s panel about the Moderna vaccine was filled with discussion about one rare side effect: myocarditis. Dozens of cases appear to occur for every million men between the ages of 18 and 24 who receive the vaccine. The J&J vaccine has a different safety profile, but may cause a condition called thrombotic thrombocytopenia, a condition that causes both excessive bleeding and dangerous blood clots. That condition is also rare, occurring in perhaps three people with Covid-19 per million, and in data presented during the spring seemed most common in women in their 30s. The vaccine has also been linked to several cases of Guillain-Barré syndrome.

There was little discussion of this in FDA briefing documents. For every case of either side effect, the CDC has estimated that the vaccine prevented thousands of Covid-19 cases. The panel may discuss how to balance these rare risks in younger people, who are at lower risk from Covid-19, too.

If you’re watching the panel and want to think about the state of medicine, consider this: the Covid-19 vaccines are a tremendous success, based largely on the efforts of pharmaceutical companies. But relying on companies to conduct clinical trials can mean some questions don’t get answered. For instance, what happens if we want to mix and match booster shots? The question of how one could change the system so questions like that get answered is left as an exercise to the reader.

— Matthew Herper



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