Faust Files: Paul Offit Vote Against Bivalent COVID Booster

In the first part of this two-part conversation, Jeremy Faust, MD, MedPage Today, with Medicine Dr. Paul Offit discusses his recent decision to vote against bivalent COVID-19 boosters at the FDA’s Vaccine and Related Biological Products Advisory Committee (VRBPAC) meeting.

Offit Yes Director of the Center for Vaccine Education at Children’s Hospital of Philadelphia (CHOP), attending CHOP Infectious Diseases Physician, Maurice R. Hilleman Professor of Vaccinology, Perelman School of Medicine, University of Pennsylvania.

The following is a transcript of their speech:

Jeremy Faust, MD: Hi, my name is Jeremy Faust, MedPage Today Medical Editor-in-Chief. Thanks for joining us.

Today we are joined by Dr. Paul Offit. He is a member of the FDA’s Vaccines and Related Biologics Advisory Committee, VRBPAC, which publicly discusses, debates, and ultimately votes on recommendations related to COVID-19 vaccines and their authorization.

PhD. Paul Offit, thank you so much for joining us.

Paul Offett, MD: I’m glad.

Faust: Let’s talk about an article you wrote in

*) New England Journal of Medicine , “COVID-19 Boosters – Where Did They Come From?” Essentially, you think these mRNA vaccines are specifically designed to do something very specific, prevent Serious illness and death, and they happen to temporarily do what other people want them to do, which is to reduce infection.

It seems to me that a lot of people are looking for boosters and they don’t realize it, but they see them as almost preventive, I think, In your opinion, this is not a sustainable way of doing things. How do you think this will play out?

Offit: I think you can probably trace the confusion back to December 2020.

In December 2020, the FDA Vaccine Advisory Committee was asked to consider both the Pfizer and Moderna vaccines. These are two doses of the vaccine given 3 or 4 weeks apart and provide 95% protection against mild, moderate and severe disease. These vaccines are about 95 percent effective in preventing serious and mild illnesses.

And then what happened was that 6 months later, the studies conducted by the CDC showed that prevention of severe disease persists, which is good, but protection from mild disease is waning – as you might have guessed – because protection against mild disease is largely mediated by neutralizing antibodies present at the time of infection, and those

then Why is it 95% protected against mild disease in December 2020? That was a 3 month study. These participants just got their second dose. So you have an unrealistic feeling about it all. That’s how it’s handled, not just the media, but I think public health officials do in many ways; when you see what you expect to see, they use “weakened immunity” or “breakthrough infection” ” and the like.

Even after 1 year, when Mark finished the study Tenforde came out of the CDC, with only two doses, you see that the protection against severe disease is still there.

Then came Omicron, an immune evasion strain that causes mild illness even in those who have been vaccinated. I think that led to a lot of confusion, which eventually led to the third dose, and then the fourth. I think we use terms like “fully vaccinated” rather than “fully vaccinated and up-to-date,” and I think it’s hard to find 10 Americans who agree on what it means to be protected from this virus.

Faust: I think that’s fair. Now, I actually think the next question is a bit messy, but I think it’s important that we do it first. That said, as I mentioned in the introduction, you’re a member of the committee VRBPAC that looked at these questions of what we should do next and make recommendations, and you voted against bivalent boosters. That is, use a booster that contains some old strains and some Omicron [strains]. You voted no in the fall. I want you to talk about your thought process and why you think it’s better to do it your way.

Offit: Submitted to us by Pfizer and Moderna on June 28, 2022 The studies are all correct, that is, they give people three doses of the ancestral strain vaccine and then the fourth dose is the ancestral strain vaccine, or the fourth dose is the bivalent vaccine. In both cases, Pfizer’s and Moderna’s bivalent vaccines were the ancestral strain plus the original Omicron strain, BA.1. They then looked at how these neutralizing antibody responses differed depending on whether you got an ancestral enhancer or whether you got a bivalent enhancer.

What they found was — depending on why the study was done because Pfizer did 30 mcg or 60 mcg, Moderna did 25 mcg for Ancestor, then Omicron The strain did 25 mcg – they found that the difference in neutralizing antibodies was 1.5 times greater for Omicron if you got the bivalent strain than if you just got the ancestral strain, either 1.75 greater, or 1.97 greater .

implies that this is enough; these statistically significant differences are also clinically significant differences, when we know back in December 2020 – when you look at When it comes to neutralizing antibody differences between Moderna and Pfizer — Moderna’s neutralizing antibody response is about twice as high as Pfizer’s, but that’s not important in preventing serious disease.

So why do we get a 1.5-fold or 1.97-fold difference when using Omicron augmentation, not ancestry? Why do we make it look like this is going to be the answer to all our questions? In addition, the BA.1 strain has essentially disappeared. It has been superseded by BA.5/BA.4 and now BA.2.12.1, which are only Omicron sub-variants, a little further away from BA.1.

So that’s the problem that’s addressed is, I think the [Biden] administration is interested in having a bivalent vaccine where one strain is the ancestral one and the other The strain is BA.5. We’ll wait and see, but I’m certainly hopeful that before they roll out this program for the American public, they’ll provide clear evidence of a dramatic increase in BA.5-neutralizing antibodies associated with this boost. Because keep in mind that even with the addition of ancestral strains, as Linda Saif and co-authors wrote in New England Journal of Medicine in June.

So I think it’s a burden that should be carried, otherwise it’s just marketing, right? Otherwise it’s like, “I’ll give you BA.5 because BA.5 is in circulation, so it’s going to get better”, which makes sense in theory, but you need to have clear evidence, preferably clinical data, but in the least convincing immunology data.

Faust: Will now turn to bivalent enhancers for “imprinting or antigenic sin” “Will the concerns generally progress? The idea is that whatever your body sees first, it will react narrowly to it. So, in the future, your body won’t react as well to what it first saw. For these reasons alone, is there really some benefit to giving something bivalent?

Offit: should be proven, but the imprinted stuff was originally created by a guy named Thomas As defined by researchers at Francis, who worked on influenza in the 1950s, he used the term “primitive antigenic sin”. The idea is that you can tell when a child is born based on how they respond to the flu—either by natural infection or by immunization—because they respond just as they did to the initial infection. Their primary infection as a child, and if they were subsequently vaccinated or had a secondary infection, they responded as if they were responding to the first infection without recognizing the nuances of the vaccine or natural infection.

That’s what you’re worried about here, you’re locking people into this kind of response to the ancestral strain and not having the opportunity for a broader response.

I would say that the ancestral strain is the original strain. It’s the Wuhan virus. The one that made its debut in Wuhan in October/November 2019 was very helpful to us. I mean, throughout, even including Omicron and Omicron sub-variants, it does seem to continue to protect against severe disease, which is the goal of this vaccine. At least that’s the stated goal of this vaccine, but I feel like we’re moving from preventing serious disease to trying to prevent everything.

I would argue that some people cannot handle minor illnesses. They can’t cope because they have severe heart disease or severe lung disease, or because they have uncontrolled diabetes or something, so when they have a mild or moderate infection, they’re more likely to get severe disease, or because they’re immune compromised.

So that’s different. It’s really not memory loss, it’s those who never had the People who have had a very good immune response, or because of their age, they don’t have a very good so-called cytotoxic T cell response, so they’re not able to crowd the infection and keep it as a mild or moderate infection. You can Arguing that, if you will, that group might benefit from boosting neutralizing antibodies so that they can make neutralizing antibodies for months when these viruses are in peak circulation, you can make that argument. But I think we Not making such an argument. We’re making the booster argument for everyone. First of all, I think people are getting a little tired of boosters at this point.

Faust: Yes. I mean, my view is that, as you mentioned, people with another risk factor for hospitalization may Need to keep what we call “up-to-date” vaccines so they don’t “don’t experience mild disease that affects them in ways that they don’t do to others.” It’s not that they’re going to get a serious illness; a serious COVID, is that mild illness that makes other things worse. This is what we keep seeing, and the data bears it out. So, absolutely, I think it makes sense to update for the older population.

I don’t think mRNA vaccines are optimized for this, but they are the best we have, so that’s what we’re stuck with right now. But I agree with you that instead of spreading effort, money and signals, we can spend all our efforts on that group and reap huge benefits with little in return.

When I think about young people, some young people obviously really want a dose. They have embraced the idea that these vaccines can eliminate the infection. I think you and I both agree that the benefits of uplifting young people are very short-lived, if anything, but over time I think arguments have been made like, ‘Well, look, there’s a lot of very Good reason to promote young people.’

Where are you standing now? Do you still think two doses of the ancestral vaccine is enough for most people, are you softening on the third dose for young people? I guess the third question of the three parts is: Who do you think needs more than two doses right now?

Offit: I still think that for a healthy young man, two doses seems like Serious illness can continue to be prevented. The effect of the third dose on Omicron (ie BA.1 and the Omicron sub-variants) is that you do have an increased response to those variants and sub-variants.

The question is, does it really matter? Because it still looks like you can prevent serious disease, does it really matter to get a third dose? I would argue “no”. [But] I think that ship has sailed. I think it’s mostly a three-dose vaccine right now because that’s how the media and the public handle it, that’s how public administrators handle it.

But I would still argue that if you look at Mark Tenforde’s paper published in Infectious Diseases, what he did It was he who looked at two doses in 1 year until December to 2021, so the vaccine has been out for a year – so you’re looking at the D614G variant, the alpha variant and the delta variant – he found the effect on severe disease Protection still exists. This is for…80% of this group had at least one comorbidity, and a significant proportion were over [age] 65. So this holds up pretty well.

But then Omicron came along and we clearly showed that three doses of Omicron were better than two doses in preventing hospitalizations. My question is: who are those people? And I don’t think everyone is like that.

I still think a breakdown of the CDC would be helpful. To some extent they have; they’ve shown us that at least 75% of people who are still hospitalized after two doses are in these high-risk groups that we just talked about. So focus on them. I think that makes the most sense to me.

Faust: Yes. If you look at the CDC readings — I think we’ve discussed this before going offline, but I’m not sure we’ve discussed it publicly — it’s actually hard to tell the difference between someone who received a second dose a year ago and People who received their third dose a year ago. So the idea of ​​a three-dose vaccine only makes sense in the time period when the third dose increases these neutralizing antibodies.

So yes you can tell the difference between someone who just got the third dose, but you also can’t tell the difference between someone who just got the third dose and who just got the second dose difference between people.What really matters is the dose closest to you How far, I don’t think the general public will continue to do this, except in high-risk groups. Is this a fair read?

Offit: Very fair. And I think when we compare vaccinated versus unvaccinated or two-dose versus three-dose, you also need to consider people who are naturally infected at the same time, because that does change things. It’s knowable, I mean, you can tell that by looking at say antibodies against nucleoproteins, which only happens if you’re naturally infected. So I think that’s one of the issues as well — controlling natural infections, which are pretty common these days.

I remember a few months into this pandemic, Jon Udall, head of virus research at the National Institutes of Health, said that in 3 years you will have two Options: Natural infection or vaccination.

If you look at some of these recent seroprevalence studies, there was a recent study in JAMA that showed more Up to 90% have been naturally infected or vaccinated. Thousands of people donate blood. Now, it’s limited by who chooses to donate blood, but I still think it’s amazing.

Faust: Correct. I think maybe the cognitive shift I made at some point was that you may not necessarily have to choose between infection or vaccination, but you have to choose between infection with protection or infection without protection. In other words, you obviously want to do that regardless of whether you’re carrying a vaccine into that infection or exposure.

I want to make sure we don’t not post incorrect information here. You say you think it’s a three-dose vaccine, but you say that because you think basically the scientific debate is over because nobody has it. Not because of the science-backed stuff, but basically because of the marketing, right?

Offit: Yes. I just got an email today from a mother of a college student who is upset about her child not being able to go to a school on the east coast because he hasn’t gotten his third dose yet. Her arguments are sound – he’s a healthy young man, he’s had two doses, he’s a boy in the risk age range for myocarditis, and I don’t think the benefits here outweigh the risks. A perfectly reasonable argument. I agree. I agree with her.

Faust: But I also think that as my friend Carter Mecher when We pointed out to me a year ago when we were discussing this that most people who get a third dose, even in the young, healthy group of men, are mostly happy with their decision to get a third dose because 99% No difference. For a small group of people it helps;

So most people will be happy with their decision because no matter what they do, they’ll think, ‘ Well, I got the third dose. I tried my best. ‘ So the government said, “Well, look, if we break even, we might as well keep everyone happy.”

Offit: Yes. There was an old study done at Canadian racetracks where they asked people to rate their horses during the betting process, and then they asked another group of people to rate their horses after they had already placed bets. Obviously, after you bet, you rate it much higher.

But I like the title of that article, it’s “Post-Decision Discord.”

Faust: Yes. After vax something or other – we can do it.

Mix and match, start with one of Pfizer’s formulas, then boost the idea with Moderna, how about you? Think it’s important? Sure, it has more antibody responses and more side effects, but at the population level, do you think that matters? If someone asked you, “What should I do?”, what would you tell them?

Offit: Waiting for data. I mean, it’s interesting now to see some early reports of boosting with Novavax, which is a purified protein vaccine in the same adjuvant that’s used in Shingrix, which is a specific vaccine.

If you’ve had two or three doses of the mRNA vaccine, and then you’ve had this dose of Nova, the antibody studies, at least the small studies reported so far, see It looks promising.

But again, you end up needing clinical data and hopefully the CDC can help generate those.