A must-watch deep dive into some science!

Vaccine expert Dr. Paul Offit is less than impressed with evidence to support the Omicron BA.4/5 “bivalent” booster shots now rolling out for everyone 12 and older. We also talk polio and monkeypox and flu 👍

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Topics & Timestamps:

00:00 Intro

1:10 A brief history of the Covid vaccines, groups that benefit from boosting

5:12 Incubation periods and vaccination “goals,” preventing infection vs. severe disease

10:54 Bivalent vaccine, the FDA’s EUA approach, crucial dosing issues (ancestral strain vs. bivalent)

17:15 BA.4/5 booster immunogenicity data (or lack thereof), mouse data & vax safety profile

21:40 Why Paul himself would pass on the new booster, incubation periods, why Covid zero is a fantasy

24:28 Paul’s “perfect” bivalent vaccine

25:37 Yearly targeted boosters, myocarditis and the Thai children’s study

28:39 BA.4/5: MIS-C, boosters & long Covid, data from JAMA’s Italian study

31:28 Comparing BA.4/5 & the yearly flu vax, timing of the yearly flu shot

38:45 Polio’s resurgence, injected inactivated vs. live oral polio vaccines, the role of sanitation

48:05 Monkeypox and a history of smallpox vaccines

56:43 Reflection w/Dr. Offit: what he’s gotten right, what he’s gotten wrong and where to go from here

1:01:57 Final thoughts

Full transcript below!

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– P. Diddy, Paul Offit welcome back to the show, brother.

– Thanks for having me, it’s great to be back.

– It always fills my heart with joy throughout the pandemic. You’ve been a voice of rationality, reasonability and someone who’s willing to change your mind too, if like stuff emerges that is different. Let me ask you, let’s just start off with what everyone’s asking about, the new Bivalent, Omicron BA.4/5 booster dose that is been kind of pushed through and CDC says, yeah, give it to all the people just let’s start with that. Is there data to show that this thing is actually something that Americans need and if not, what data would you like to see? And would you take it and so on, there’s a million questions, but I’ll just toss it over to you ’cause you’re quite savvy at this.

– Okay, so right, so in the past few days, the CDC recommended that for that everybody over 12 could receive Pfizer’s vaccine that everybody over 18 could receive Moderna’s vaccine and that everybody should be vaccinated. So before I get to the bivalent vaccine, I just wanna answer that question. Is it true? I mean, does everybody benefit from a booster dose? I think to understand that, you kinda need to go back to the beginning. So in December 2020, our FDA Vaccine Advisor Committee considered the use of Pfizer/Moderna’s vaccine for use at the time in adults. And when that vaccine launched, it was taken up fairly well. And for the first year, the question was, did protection hold up against serious illness? ‘Cause that’s the goal. That’s the only reasonable goal for this vaccine. It’s the only attainable goal for this vaccine. You’re not gonna be able to protect against mild disease for this kind of virus for any length of time, so don’t so. So did it hold up? I mean, the vaccine was made to protect against the original strain, the Wuhan-1 strain, the ancestral strain, which wasn’t even the strain that left China, the strain that left China was the so-called D614G strain. But that’s what those vaccines do. Whether it’s Pfizer, Moderna, J&J, Novavax, all to protect against the Wuhan-1 strain. So did it protect well against these variants? So the very first variant was D614G, replaced by the alpha variant, ’cause it was more contagious, replaced by the Delta variant ’cause it was more contagious and that was the first year. So that was 2021. Those three variants. Did that Wuhan strain protect against severe disease with those three variants? Yes, that is was a CDC publication by Mark Tenforde, out of the Clinical Infectious Disease Journal. And whether it was Pfizer’s vaccine, whether it was Moderna’s vaccine, whether you had one or more comorbidities or whether you were over 65 years of age, you were still well protected through that first year. Then Omicron hit and Omicron was different. Omicron surprised people. I think people didn’t imagine me included that a coronavirus could drift if you will, in a matter that similar influenza, this big. I mean, there were 15 mutations just in the receptor binding domain, which is the kinda business end of the spike protein molecule that attaches to cell 15, so that’s a lot. And so even if you’d been naturally infected or vaccinated, you could still get mild disease. Even if you were relatively recently infected or vaccinated, you could still get mild disease. It was an immune evasive strain, but it wasn’t immune invasive for protection against severe disease, it wasn’t. And that the reason is, is that severe disease is the immunological component associated with protection against severe disease really is T-cells, especially cytotoxic T-cells, which are T-cells that kill virus infected cells. And those cells are generally long lived and more importantly, they recognize conserved regions. So for all the mutations that Omicron and these Omicron subvariants have, they haven’t really mutated away from protection against severe disease because that protection against severe disease isn’t mediated by neutralizing antibodies, it’s mediated by T-cell. So that’s good. But nonetheless, the CDC did critical studies, I think. They weren’t perfect, but at least they answered some questions. Were you better off getting a third doses compared to a second dose? And they found that you were less likely to be hospitalized if you got three doses than two doses. And then to a lesser extent, you were less likely to be hospitalized if you got four doses versus three doses, they weren’t perfect studies. But I think the critical question is, who was being protected? Who was it that wasn’t getting hospitalized because they hadn’t received a third dose or they hadn’t received the fourth dose? And the answer was not everybody. The people that really benefited were number one, far and away, the elderly or as Rochelle Walensky, God bless her, has said, the ELDERLY elderly. Which I appreciate as I get older. The second was people who had chronic lung disease or chronic heart disease, or chronic kidney disease, or chronic neurological disease because even a mild illness could cause them to land in the hospital. And then third were people who were immune compromised. So they benefited from that additional dosing. So I think it’s hard for me to embrace immunizing everybody, healthy young people when we haven’t really showed that they clearly benefited from boost dosing. So that’s that’s number one.

– So, okay. That’s a great resummary of even that first booster discussion that we had all those months ago is the third dose, something that’s necessary for everyone. And you just answered to the best that we understand and this question of like the elderly, elderly and people that are very high risk that are very frail, and that if they got a cold, they would be tipped over into decompensation, theoretically, having those higher levels, those boosted levels of neutralizing antibodies that the third dose might have given you in a time dependent way that decays over time, might be helpful. But your point that the T-cell immunity that’s long lived that really protects most people against the more severe disease that was causing havoc in 2020 and beyond, that the first two doses seems to really instill in a lot in most people that aren’t the ELDERLY elderly and the people with the chronic disease issues that you just pointed out. Is that a fair summary?

– Yes, exactly.

– Yeah, so now, and one other thing I wanted to repoint out that you pointed out, as Omicron and these new mutations emerged from the original ancestral strains, it seems like even incubation time is shorter, which would make it even harder to prevent because we’ve talked about this on the show before, and maybe it’s worth just readdressing real quick. If the incubation time is very short for an illness, you can replicate really fast, even before things like neutralizing antibodies and other defense mechanisms that the immune system can kick in. So you’re not gonna prevent an infection, but you will still prevent severe disease, is that fair?

– Yeah, and also, as you get shorter incubation periods and viruses that are progressively more contagious, you need even higher levels of neutralizing antibodies to really prevent a mild illness. So making it all the more difficult, but again, the goal is preventing severe illness. The goal is keeping people outta the hospital, outta the ICU, and outta the morgue. And again, I remain encouraged that there has not been a virus yet, a SARS-COVID-2 virus variant yet that has resisted protection against severe disease, which does happen with flu. And so that really hasn’t happened at least yet with this virus, so that’s good news.

– Can I ask one other question? So in the early data from those original trials with Moderna and Pfizer, there was a quite aggressive protection against infection as well, it appeared in those trials. Why do you think that was, why do you think that’s changed?

– Right, when we reviewed data in December 2020 with Pfizer/Moderna, they both had roughly 95% protection, not only against severe disease, but even mild disease. Remarkable, that was a remarkable level of protection. No way that was gonna last. I mean, and in fact, six months later, several studies showed that while protection against severe disease remained high, protection against mild disease dropped to as low as 50%. So why was it so good with those initial trials? And the answer is those were three month studies. Those participants had just received their second dose. So their neutralizing antibodies were high. And again, I think if you could go back in time, which you can do, actually, if you mix DayQuil with NyQuil, a lot of people don’t realize that you can do.

– There a little Tylenol PM in the mix. And then you’re really traveling through space and time.

– Yeah, I would wish we could go back in time. And when those data were presented, we could have said this protection against mild disease is not going to last given the nature of this infection. And given the way these trials were done, that’s not going to last. And we did the opposite. I think what happened was six months later when say there was an outbreak in Provincetown, Massachusetts, thousands of men get together, celebrate the July 4th holiday, there’s about 79% or 80% were vaccinated. But nonetheless, there’s an outbreak. And of the 346 men who got sick, four were hospitalized, a hospitalization of one point rate of 1.2%, that’s a win. That’s great. But the other 342 men had mild or asymptomatic infection, which the CDC unfortunately labeled as breakthrough illnesses and that was a mistake. Breakthrough implies failure, that wasn’t a failure. That was a moment actually to celebrate the vaccine, to celebrate how amazing it was working here with this outbreak in this basically close space or close together community in Provincetown, and we didn’t do that, we did the opposite of that, the opposite. And so the term breakthrough was born, and I remember just a few days after that was reported, Brett Kavanaugh, Supreme Court Justice gets an asymptomatic infection. If you watch the way that was carried on national television, you would’ve thought he was in the intensive care unit. So we didn’t communicate that well.

– So the full communication of that then led to a lot of mistrust and a lot of people feeling like, well, they told us one thing, and now they’re telling us another thing. And now they’re telling us another thing. And this whole idea that we can get vaccinated and actually get on with our lives is a lie. And so I’m just not even gonna do it. And I don’t trust anybody. And it was a huge problem. So then pulling that back now to where we are now with Omicron, we’re up to be a four and five, and now they’re onto a different type of booster. Tell us about that and where we are with that?

– Well, you could make the argument, that right now we’re vaccinating with the Wuhan-1 strain to protect against these Omicron subvariants BA.4/BA.5 does that make a bit of sense? Well, see, I would argue that to date, you’re still protected against severe disease because those immunologically distinct regions, i.e. epitopes that are on the SARS-COVID-2 spike protein are shared, and that’s been published. Those are published data. You have at least 80% homology between say Wuhan-1 and this BA.4/BA.5 Omicron subvariant in terms of T-cell recognition and T-cell are critical for protection against severe disease. So I would argue we’re still good, but nonetheless, even if you’ve gotten the Wuhan vaccines, you’re still at risk of mild illness because of these, how far the BA.4/BA.5 have mutated in terms of protection against neutralizing antibodies. So why not then put that in there? Okay, and so on June 28th, the FDA Vaccine Advisory Committee on which I sit, were presented data by Pfizer and Moderna on their bivalent vaccine. Now the bivalent vaccine data they presented weren’t on the vaccine that we’re currently using. They were on the bivalent vaccine was actually BA.1. So the original Omicron. So, and they did the studies the right way because remember, the hill that you’re trying to climb here is you have to show that the bivalent vaccine is better than the monovalent vaccine at inducing BA.4/BA.5 specific antibodies. There was a paper by Linda Safe that was published in the New England Journal of Medicine at the end of June. And what she did was she looked at hospital workers who had received two doses of the Pfizer/Moderna vaccine and found that the neutralizing antibody levels against BA.4/BA.5 was suboptimal. But when you got the third dose, it increased. So BA.4/BA.5 neutralizing antibodies increased just with the ancestral strain. So you have to make sure when you do these studies that you show that your bivalent vaccine is significantly better than what, in terms of BA.4/BA.5 specific neutralizing antibodies than it would be just with the ancestral strain alone. So in any case, that’s not the studies that were done, these studies were started like in February by Pfizer and Moderna. So it was still when BA.1 was predominant. And so that’s the bivalent vaccine they made, a BA.1 containing vaccine, Omicron, the original Omicron. Now the way they did the study was people, participants, so there’s about 300 in each group, got either three doses of the ancestral strain. And then the fourth dose was the ancestral strain or three dose of the ancestral strain, and then the fourth dose was the bivalent strain with BA.1. And so then they looked at neutralizing antibodies in the bivalent vaccine versus monovalent vaccine. And you had about it depended on which company you were looking at and which dose with Pfizer’s vaccine you were looking at, but about 1.5 to 1.75 fold increased level of neutralizing antibodies if you got the bivalent vaccine, while statistically significant, that is unlikely to be a clinically significant difference. And we know that because if you’re back to December 2020, there was about a twofold antibody difference, neutralizing antibody difference from Moderna versus Pfizer. But nonetheless, that didn’t pan out to be a difference in protection against serious illness. There were other problems actually with those studies, I think one, I think there were some assumptions that I think may well be incorrect. The first assumption was that, okay, take Moderna’s vaccine for example, normally if you’re an adult and you’re boosted with Moderna’s vaccine, you get 50 micrograms of mRNA. If you get the bivalent vaccine, you get 25 micrograms of the ancestral strain and 25 micrograms of BA.1, at least the data we were presented. And the thinking at the time was well, 25 plus 25 equals 50, which is true from an arithmetic standpoint. But I would argue isn’t true from a biological standpoint because those are two separate vaccines and you’re giving them at a child’s booster dose level. I mean, the 25 micrograms would not be an adult booster dose. So I don’t think you can fairly add them up. The second thing is, and Pfizer actually showed this, what Pfizer did was they did their studies several ways. One was, they took 30 micrograms, which is sort of the adult dose of the ancestral strain plus 30 micrograms of BA.1, or they just gave just BA.1 and you had a much better antibody response with just giving BA.1 than giving it as a bivalent vaccine, even at the same dose, which is interesting because what that tells you is that when you give it combined and you’re taken up in the germinal centers of the local lymph nodes, you’re competing for those same B-cells. Whereas when you give them at separate sides, you’re not. So really would be interesting to see if you just gave, you know, the bivalent vaccine instead of ancestral and BA.1, now BA.4/BA.5 in the same dose, whether if you separated and gave it in different arms, it would be different, I suspect it would be, that’s not a practical thing to do, but that is something that you’re up against.

– Well, so, that’s really interesting. So the question is why even make it bivalent? Why not make it monovalent new strain? Is it because some people haven’t gotten the third dose of the original ancestral strain, but what’s the reasoning?

– Good question. I think you could have reasonably done that, you could have reasonably introduced this as a BA.4/BA.5 vaccine, knowing that there are still those shared components with regard to T-cell so you’re still gonna be boosting T-cell responses. So I think that’s a perfectly reasonable question.

– And then, oh, go ahead.

– No, the other thing that was a little concerning is, there were really pretty good animal model studies done by Bob Sedar at his lab at NIH using non-human primates, rhesus macaques. And what he did was he sort of gave those animals two doses of the ancestral strain. And then either the third dose was, again, another dose of the ancestral strain or the Omicron only, and then challenged the animals with Omicron. But again, and what he found was no difference. There was no difference in protection of those animals against moderate or severe illness. So therefore, the animal model studies also didn’t make a case for what we’re trying to do here.

– Okay, so this is interesting because is there another immunological reason why mixing the two strains might reduce an overall response? Is there some other competition apart from germinal centers and things like that? Is there-

– Not that I can think-

– Not that you can think, and is there any effect of the sort of the… What do you call it? Original antigenic sin, where it was already exposed to the original?

– There’s always that. I think that’s always the hill we’re trying to climb here because I think if you took, say a 20-year-old who had never been naturally infected, never had been vaccinated and gave them just say BA.4/BA.5, you’d see a dramatically greater neutralizing antibody response than these folks, like me, who’s been sort of given three doses of vaccine, naturally infected you sort of lock in to that original response. And that’s right. So when you then go to the germinal center, the B-cells that have already seen sort of the epitopes on Wuhan-1 that are also contained on say, BA.4/BA.5, those will be expanded much more readily than will the new regions that you’re trying to promote, which is why you just don’t see that good of an immune response.

– Interesting, is it, and this is… We’ll talk about flu, but at some point I wanna come back and go the yearly flu vaccine. How does that sort of involve this sort of antigenic imprinting, but, so back to this, so one thing that you said was that the trials that you saw were the Omicron, first OG Omicron strain is what they were testing in the human trials, and that you had this 1.5 fold increase in neutralizing antibodies, which again, comparing to the original Moderna versus Pfizer trials, that was kind of the difference in the antibodies between those trials, but there was no clinical difference. So the concern is, is there really a clinical difference given that the T-cells are protecting against severe disease as it is. And that’s what we really care about in most people, maybe except for the elderly, elderly, and which we’ll talk about. So what is the bivalent version we’re actually getting now and what’s the data saying that that works?

– Well, there are no data. I mean, well, the bivalent vaccine you’re getting now for Moderna is 25 micrograms of ancestral strain and 25 micrograms of BA.4/BA.5. The bivalent vaccine you’re getting from Pfizer, and remember they presented data on 30 and 30 or 60 and 60, but they’re launching it 15 and 15. So there aren’t even human data, human immunogenicity data, even for BA.1 that is completely novel. It’d been nice to at least have immunogenicity data to show that you have at least twofold, you like twofold, threefold, fourfold, greater neutralizing antibodies against BA.4/BA.5, we don’t have those data.

– I mean, so do we have mouse data, is that all we have? What do we have?

– We have mouse data. So they’ve shown in mice, that you get, that if you give this bivalent vaccine, you get a dramatically greater increase in neutralizing antibodies against BA.4/BA.5, but again, I don’t think that the mouse data are always going to be predictive. I mean, the vaccinology people have a saying, which is mice lie and monkeys exaggerate, and that’s true.

– Yeah, and humans, I don’t know what they do, but it’s never good. But at least we should study it in them. Well, so this is interesting. So we’re now rolling out, they’re rolling this out, having skipped to the FDA Advisory Committee input, yeah?

– Yeah.

– Oh. And went right to CDC and CDC said, yeah, 12 and above bivalent, this fall, as a fourth dose or as a third dose if you’ve never been boosted, or as a original dose, if you’ve never gotten it, so one, two and three of this?

– Only a boost. So you would’ve had to have received at least two doses of the current ancestral strain before you would ever get this as a booster dose. It’s only being approved as a booster dose.

– Makes sense, ’cause the dosings different too. So now it actually increases complexity for administration because you’ve gotta store the ancestral vaccine for people who’ve never been vaccinated or haven’t gotten the two full doses, yeah? Got it.

– So the other thing the FDA did was they removed the emergency use authorization for the ancestral only booster dose, the monovalent booster dose. So that’s not available anymore. You really have to use this bivalent vaccine, which is a little sad because there’s a lot of that vaccine out there. I feel like at the very least we should send it to places that clearly would benefit. And I just think it’s wasteful.

– Now, so back to then, the BA.4/5, so we don’t have great immunogenic. We don’t have immunogenicity data in humans on this particular formulation. We don’t have any data saying that it actually improves our outcomes in terms of severe disease. Is there safety concern at all with this new formulation or do you think that would be overblown?

– So, I don’t know. I mean, I suspect that this bivalent mRNA vaccine, containing vaccines will have a similar safety profile to the current ancestral only vaccine. That would be my guess. I think that’s a fair guess. I think that’s biologically reasonable, but again, you have to be open-minded and I’m sure that the CDC will, through places like the vaccine safety data link, of the vaccine adverse events reporting system follow this up and follow it up well. And I suspect that by October we will have sort of human immune response data for the bivalent vaccine. I’m optimistic that will be true. And then we’ll see what those kinda data show, maybe it’ll be surprising. Maybe we’ll find that for BA.4/BA.5, given to people who’ve already received at least two doses and possibly three or four that it’s dramatically greater than what we saw with BA.1, that would be great, but we’ll see.

– So then when the rubber hits the road and CDC is saying, take this, would you right now, I imagine I’ve had two doses and a old school booster. Would you sign up to get this BA.4/5 with what we know right now at this time?

– Well, so I had three doses plus a natural infection in May. So I think I have high levels of memory B and T-cells. I don’t think that I will benefit from getting the booster dose because I think that what the benefit would be was I think it would give me sort of a few more months of protection against mild disease for say, for the winter months. But I guess I’m willing to suffer mild disease, I did once already and if anything, it just gives me broader hybrid immunity. In fact, I feel better actually that I had a natural infection and even better that I survived it, which is by definition true ’cause I’m on your show, but.

– That’s heresy Paul, you can’t talk about natural infection being a good thing at all, or you’re gonna be excommunicated from the Covidian church. But I mean, it’s interesting because for example, we don’t revaccinate patients who’ve had chicken pox with varicella typically do we? It’s a different scenario.

– Or people, but see it’s… Chickenpox has a relative long incubation period disease, as is measles, as is mumps, as is rubella, so German measles. So when you get infected with those viruses, you generally have memory B and T-cells that are lifelong and that’s enough for you to be protected even against mild disease because there’s plenty of time for activation and differentiation of those memory B-cells or memory T-cells even to protect you against mild disease. That’s why you can eliminate long incubation period diseases from the face of the earth. I mean, smallpox has a long incubation period disease. Rinderpest, which is a sorta like cow measles has been eliminated from the face of the earth because it’s a long incubation period disease. And we eliminated measles from this country by 2000, it came back because a critical percentage of parents chose not to vaccinate their children. We eliminated rubella from this country in 2005, it hasn’t come back. So you can do that. You’re not gonna do that with this virus. This virus will continue to circulate and cause mild disease, even if a hundred percent of the world were vaccinated and even if it never mutated coming out of China, it would still circulate and cause mild illness and in some severe illness.

– Yeah, and it has animal reservoirs and you know, on and on, and on, and on, all the reasons you can or rather that COVID zero is a fantasy. But so, then this becomes a question because the government is already talking about, like for example, Bob Califf said, Hey, if you get this thing, you might be more likely to attend big winter gatherings if you get it by Halloween. I mean, do you think that’s a reasonable statement or is that wishful thinking?

– No, that that’s not fair. I mean, again, you can’t set yourself up at a goal of preventing transmission or preventing mild disease for a short incubation period disease. It’s just not reasonable. I think, if fantasies could come true, if I could get like the bivalent vaccine of my choosing, the bivalent vaccine, I would like to get, or just monovalent vaccine is one that contains mRNA against the SARS-COVID-2 nuclear protein because that is often richly expressed on infected cells, is definitely recognized by cytotoxic T-cells. So I think that would really boost my cytotoxic memory repertoire and probably give me longer lived protection against serious disease. So that’s the bivalent vaccine I want. By the way, there are studies now, that recently one that was published in Syrian hamsters, good news for the Syrian hamsters. And if we can get this into human trials, it would be good news for us, that it really, it does provide that sort of broad immunity that we’re looking for.

– So the nuclear antigen, that’s interesting. I would imagine you’d need new safety data trials and humans on that though, because there might be something, you just never know you’re using a different epitope. So this idea then of extrapolating to making this a yearly flu shot type thing, it might be worth kind of differentiating. Why would we need to do that for whom? In other words, who even now would you say should get this BA.4/5 bivalent vaccine? Is it the ELDERLY elderly, and the people with chronic disease, for whom even a mild infection, which we won’t fully prevent, but we might like lower the chances with the high levels of neutralizing antibodies out the gate. Are those the only people who should get it, do you think, and then, should we really be talking about doing this annually with the level of data we have currently?

– You know, I think, it’s certainly if we’re trying to have an impact on preventing hospitalization and ICU admissions and deaths, I think it makes sense to focus on those groups, the groups most likely to be hospitalized. The groups we’ve shown are most likely to be hospitalized if they don’t get, say a third dose or fourth dose, I think that’s perfectly fair. I also think pregnant women, by the way, in their third trimester will benefit from a dose of vaccine. And it doesn’t even have to be, I mean, if you said to me, would you prefer this sort of bivalent vaccine with BA.4/BA.5, or just getting the monovalent vaccine, the dose that is typically a booster dose, I don’t really distinguish those two. You could make a case for the fact that the monovalent vaccine was better for the reasons we talked about. It is an adult booster dose. You’re not competing at the level of the germinal center with two lower dose vaccines. But in any case, I think in some ways, it’s a saw of question. If a mother of a 12-year-old came into my office and said, look, I wanna get this vaccine, fine. I think it’s kind of low risk, low benefit. And at some level, it’s a personality issue. I mean, some people would argue if there’s any risk and then the benefits are small, forget it. And others would argue, well, if the risks are low, then if there’s any benefit, I’ll get it. So I wouldn’t discourage the one who are getting it, but I would wanna tell her about the potential side effects. I think on your show, Dr. Prasad talked about that Thai study that was done in 13 to 18 year olds in Thailand who had gotten sort of two doses of Pfizer’s vaccine. You saw sort of a transient elevation in heart muscle enzymes, like troponin, creatine kinase. It was short lived, it was self-resolving, but you are making immune response to your own heart for a brief period of time. And we’ll find whether or not there’s a spectrum of illness associated with that.

– Yeah, and that’s really interesting. And it just gets to the question of, if the benefit is very small, then any risk, even if small, is magnified relatively speaking and making that risk decision becomes something that you talk with your doctor, like you said, you’re not necessarily discouraging them, but you’re saying here’s what we know about this and the ins and outs of it, which again… By the way, I still can’t- I’m ready to cancel you, Paul because you said pregnant women, which is a no-no, it’s pregnant people, okay. Next, I actually got yelled at for saying pregnant women apparently. Yeah, the CDCs party line now is pregnant people. We won’t get into that ’cause we’ll both get canceled, but I’ll say this, when kids vaccine, one quick thing I wanna ask, do you think Omicron, there seems to be quite a bit less MIS-C now, is that because Omicron is different or because more people have overall immunity, or what do you think is going on?

– See, it’s hard to know. Because now, I mean, when say, D614G or after Delta came into the United States, we were a blank slate. And so now we’re not, we probably have 95% population immunity. So it’s hard to know whether there’s ameliorating effects of previous immunity with this strain. I mean, there was some data outta South Africa where they believed that Omicron was less likely because we’re certainly seeing less MIS-C. At our hospital, we’re seeing much less MIS-C then when this all started. But I suspect it has more to do with population immunity than the virus.

– And then let me ask another question because if you go on Twitter and you see people who are either in public health or around this space, tweeting things like, this new BA.4/5 bivalent vaccine, if you don’t wanna get long COVID, you should get this vaccine or any risk of infection is too much because of the risk of long COVID or the risk, you know, MIS-C now they’re not talking about ’cause we’re seeing much less of it in children, but what’s your thinking around this? Is there data that something like this would actually prevent long COVID?

– Yeah, so there are some data. There was actually just a paper and journal of the American Medical Association out in Italy. And what they looked at were people who had received either no vaccine or one dose, or two dose, or three doses. And what they found was that for unvaccinated people, at least Italy, the way they defined long COVID, there was a 42% incidence of long COVID and people who got COVID who were unvaccinated. For people who’d had one dose of vaccine that instance of 42% dropped to 30%. For people who had two doses of vaccine that 30% level dropped to 17%, so good. But for the third dose, it went from 17% to 16%. There was really no difference then between the second and third dose, which then makes the case then for boosters as a way of, if it’s gonna be your third dose or your fourth dose, at least those Italian data didn’t support the notion that’s gonna dramatically lessen the risk of long COVID.

– That’s fascinating, so the original series, yes. You might reduce risk and whether it’s due to less infection or whether it’s due to less severe disease, we don’t know ’cause we don’t understand long COVID, but the idea that an extra booster now is gonna somehow put a big dent in long COVID is, not supported by data that we have available, is that fair?

– That’s fair.

– Yeah, so I don’t think that’s a good rationale for say an 18-year-old to go run out and get the BA.4/5 bivalent vaccine. And you’ve already kind of talked about why, even though it makes intuitive sense to update for Omicron, they’re the reasons why that may be less effective than we think have already been established by what you’ve talked about, and we’ve talked about on previous shows. So then what’s the comparison to influenza because now a lot of people are talking about going and getting the BA.4/5 vaccine along with the flu shot and the same visit, et cetera. Why is it, we annually vaccinate for flu, what’s flu’s incubation period, what’s the deal with severe disease protection and waning, and how can we compare these two things since comparing flu to COVID is already another way to get us canceled?

– So here’s what I would say. So a couple years ago, when the FDA Vaccine Advisory Committee picked flu strains, we missed on H3N2, there was a mismatch. And as a consequence, H3N2 was spread throughout this country pretty much unchecked because we didn’t have a vaccine to prevent it. If flu was like coronavirus, then it should have been true that there are say T helper cell epitopes that are present on other H3N2 strains that would’ve protected its against severe disease, but it didn’t. I think with flu, it’s much more strain specific. And so you need those new strains every year, those strains that are circulating in Australia or South America before they come into the United States, that matters. I still think it’s amazing since we’ve had flu vaccines since the 1940s, there’s still much not to know, much that we don’t know about sort of human T-cell epitopes, much that we don’t know about sort of the difference between protection against mild disease and protection against severe disease, where we actually have a lot of data on that with coronaviruses that we don’t have as clearly defined with flu virus. Whether these two viruses are similar enough, that one could say that you could reasonably give a yearly coronavirus vaccine in the same manner that we give a yearly flu vaccine. There’s much that that’s not known, but I do think that with coronavirus to date, it does look like if you’ve been naturally infected or vaccinated, you appear to be protected against severe disease, and then the critical question is, and CDC needs to answer this question along with academic immunologists. If you’re say a healthy young person, who’s gotten two dose of vaccine, three doses of vaccine, or four dose of vaccine, how long does that protection against severe disease last? So the epidemiologist can answer that question and should, and the immunologist can also at the same time, look at the frequencies of memory B and T-cells, one year later, two years later, three years later, they’ve already looked one year later, and now you’re starting to get sort of one and a half year later, but let’s, let’s look over time and see somebody like me, who’s had three dose of vaccine. I’ve had a natural infection, do I ever need another dose of vaccine again? I think those those are answerable questions and I think we deserve those answers.

– Okay, so it’s very important, I’m gonna go back to everything you just said and try to summarize it because I think this is key. When you’re comparing cor- it’s funny, you’re not allowed to compare coronavirus to influenza in the early days because that was taboo. But now, actually the officials are saying just like flu, we’re gonna need an annual coronavirus vaccine and we can give it with the flu vaccine. But the difference is, as you’re saying are that influenza, it is so strain specific as to whether it causes severe disease. So a different strain will cause severe disease even if you have antibodies to the other strain. Whereas with coronavirus, we have yet to see that in fact, we might be seeing the opposite and more data is needed for both obviously, and that it may be actually time to even look back at flu and go, okay, so what is it in our approach that actually works and what can be modified and so on, but influenza is quite different and the severe disease in influenza actually affects people of all ages, typically although, typically they’re very young and old, and immunocompromised worse. Is that a fair summary of what you’re saying?

– Yes, I mean, I think the other thing is that, ’cause we talk about like Pan-Sarbecovirus vaccines, let’s do what makes sense, let’s find those shared epitopes of those conserved regions among these different viruses, SARS-COVID-1, the four strains of circulating human coronaviruses, strains that are currently circulating in bats that have pandemic potentially, I mean, let’s do that. Let’s make a Pan-Sarbecovirus vaccine. And I think, I guess my enthusiasm is tempered somewhat because I trained in Walter Gerhard’s laboratory in the 1980s at the Wistar Institute in Philadelphia, who was a flu research was actually where John Hudel also trained. And he said something to me, he was working at the time 40 years ago on a universal flu vaccine. And he said, if you want to research career that lasts the rest of your life, study influenza. And I think that’s true. These are much, much harder things to do than you would imagine. Same thing with HIV. I mean, when you’re infected with HIV, you make an antibody response that neutralizes that strain, but the virus continues to mutate during the same infection, it mutates and mutates, and mutate. So those original antibodies don’t work anymore. All right, so it doesn’t make sense then, you look at conserved regions on one of the proteins and make a vaccine out of that, which is what Merck did essentially, and it didn’t work. It’s much easier to say this than to do it.

– So interesting. And with influenza, the other thing that people wonder about is, well, if I get this dose too early, people say that the immunity wanes and is that again, is that a coronavirus type thing where the influenza incubation period is short, and so you can still get infected and you need high levels of neutralizing antibodies to ward it off or is there something else going on, and is that even true? Does influenza shot immunity wane over the months? What’s your understanding?

– It does. I mean, I have people who are vaccine experts who choose to get two doses of influenza vaccine during the winter season. So yes, I think is the answer.

– So you can either get two and there vaccine experts said do that, or you can get one and try to time the market, so to speak and say, okay, we’re not seeing a lot of influenza circulating, I’ll get it in October instead of August when CVS is marketing it, pushing it really hard. And it’s like, well, by the time, if there’s a second phase of influenza, of course, no sense what’s gonna happen with influenza this winter.

– No, you know, we always make our best guess, we pick strains in March because six month production cycle, the vaccines were all out in September and we’re usually pretty good at getting it right. And you should come to those meeting, actually, they’re open to the public. You can come as my guest, although, I don’t need to have you as a guest. You can definitely come.

– Yes!

– Come to the FDA. And you’ll be really impressed. I mean, you get presentations from the Department of Defense, from the CDC, from the World Health Organization from this, and you have this map of the world with all these different strains and substrains, and clades that are circulating. And you wonder, how we ever prevent this disease at all in anybody given how much this virus mutates. And this is not coronavirus. I mean, coronavirus is not that. And so we’ll see, I do think the critical question the CDC has to answer in constant with immunologists is how long are you protected against severe disease if you’ve begotten three doses, if you’ve gotten four doses, knowing that to date, there has not been a virus yet, that has a variant yet, that is so mutated that escapes protection against serious disease because when that happens, then we have to get, take a step back and vaccinate everybody. Then it’s a little more like a flu shifted strain. I mean, like in 2009, when the H1N1 swine flu appeared, essentially no one had immunity to that virus. And that may happen with this virus too. We’ll see, I doubt it. But we’ll see.

– Really interesting. It’s the naivete of the human immune system to a particular virus. So, okay, so speaking of this, now, all this talk about vaccines and everything that’s sort of divided us during pandemic and all the kind of communication from public health officials and from scientists, and then from people that have decided that they’re gonna snort ivermectin or whatever it is, we’re in a situation now where I think that trust is, Hey, don’t knock it till you’ve tried it, Paul. Snorting ivermectin, I mean, in the ’80s, it was cocaine. Nowadays, it’s anti-parasitics. I am worm free, I’ll just say that. I’ve not snorted ivermectin or taken it. The ancillary effect is, even our regular childhood vaccines now are suffering, uptake a suffering, partially because of shutdowns, partially ’cause people are afraid to go to the doctor, but partially, I think there’s a growing distrust of expertise and what you just pointed at which you, Hey, you come to the FDA meeting and you look at this data as it’s presented from around the world and you see, you need experts to be able to parse through something that complex. And the fact that we’re able to do it at all is a testament to the fact that teams of people who study for years are able to come together and they have their own biases, but science is supposed to try to clean up and see through bias. Now we’re seeing resistance to even childhood vaccines and what’s going on with polio? The news coming out about seeing vaccine derived polio strains showing up in New York and an actual paralytic case showing up in a younger person in their 20s I believe, what’s going on there and how do you think about this?

– Right, so again, sort of starting from the beginning. So Jonas Salk made a polio vaccine by taking polio virus, growing it up in culture, purifying it and killing it with a chemical, a whole killed viral vaccine. We used that vaccine in this country from the mid 1950s till the early 1960s. That was then replaced by a vaccine made by Albert Sabin, which was made by taking poliovirus weakening it by passing it in monkey kidney cells and monkey testicular cells in a variety of other cell types. So that now you had a live virus, but a live weakened virus. And that’s the vaccine that we used from the early 1960s up until the year 2000. Now we eliminated polio from this country in the 1970s, but throughout the 1980s and throughout the 1990s, every year in this country, 8 to 10 children would get polio from the polio vaccine because that virus like this virus, like SARS-COVID-2, it’s a single stranded RNA virus. It’s about 7500 base pairs in length, but it’s possible for that virus because it’s really not attenuated or weakened for growth in the intestines, it’s attenuated for growth in the nervous system. So when you get the oral polio vaccine, that virus can reproduce itself for weeks and months. And if it happens to be that because single strand RNA viruses, replication is not terribly faithful, you have a mutation or mutations that essentially cause the virus to essentially revert to neurovirulent type or wild-type, then you get polio from the polio vaccine. That was rare, it occurred in about one per 2.4 million doses, but it was real. And once that happened, once you were shedding, essentially a vaccine virus that had reverted to neurovirulent type, it was clinically indistinguishable from the polio caused by wild-type virus, natural poliovirus. And so countries that use the oral polio vaccine and we haven’t used the oral polio vaccine here for more than 20 years. When they use that vaccine, that’s the Faustian bargain that they’re making, which is that, you know that you have a cheap and easy way to prevent polio. Its also, I think the attraction of the oral polio vaccine was something called contact immunity, not herd immunity, meaning if you vaccinate somebody in the home that virus can spread throughout the home and essentially immunize other people, which, especially low resource countries was attractive. And it was attractive here. Actually, you look at Scandinavian countries, never used the oral polio vaccine, eliminated polio from their country. So we could’ve done that. We could’ve stayed with the inactivated vaccine and never asked those children, those 8 to 10 children every year to get polio from the polio vaccine. I was actually on the advisory committee for immunization practices from like 1996 to 2001. And I was made head of the polio working group. And it was my mission to get us away from the oral polio vaccine because I just thought it was unconscionable to give a vaccine that you knew caused 8 to 10 children to get polio every year, knowing you had a safer way of doing this. And it to make that happen, to make it easier to happen, I brought up man named John Salamone onto the committee. I mean, he was this wonderful man whose son had suffered polio from the oral polio vaccine. And he was actually, I think, Head of the Italian American Foundation. So he was used to dealing with Congress all the time. He would, to me, was a true vaccine safety activist. I know the anti-vaccine people often label themselves vaccine safety activist, but often what they advocate for has nothing to do with vaccine safety. He was right. He wanted the oral polio vaccine to have a black box warning on it. His son was paralyzed by that vaccine because he had no idea that the oral polio vaccine could do that. And he was really angry, his son actually died a few years ago. So I brought him onto the committee, and he was a powerful voice that helped moved us away then from the oral polio vaccine to the inactivated vaccine, which we’ve had now for the last 20 plus years. If you go to Scandinavian countries and you look in wastewater, presumably you won’t find any polio virus because the inactivated vaccine shouldn’t be detected in wastewater. But in New York City, what happened was there was a man I think a 27-year-old man in Rockland County who was part of an ultra-orthodox community that was under vaccinated, who got polio from the polio vaccine caused by this type-2 revertant virus. Now, what percentage of people who are infected with this virus develop paralysis? A very small percentage. I mean, some estimated as few as one in 2,000 thousand people who are infected with this virus, actually are paralyzed by it. Those are true with the natural virus. The natural virus, I mean, polio was common, but not everybody who got polio, which was really mostly a mild summer gastroenteritis, got paralyzed by it. And that’s true also for these reverent strains. So when you see a case of paralysis and assume is the type of a much tip of a much bigger iceberg. Also assume that these type two reverent viruses have been circulating in the United States for a while. I think if you looked in Las Vegas or San Francisco at the wastewater, you would also find polio virus there because I think those strains always circulate. The reason I think this happened likely reason it happened in that community, it was in an under vaccinated community. And that’s the lesson. The lesson is maintain high levels of vaccine because these kinds of viruses are out there and we’re not gonna ever eliminate polio from this world until we stop using the oral polio vaccine.

– Wow. Oh my gosh, Paul. That is an amazing story. So what is the disadvantage of the inactivated, apart from the inability to shed and create close contact immunization? What’s the downside of inactivated, it’s an injection instead of oral?

– Yeah, it’s more expensive. It requires paramedical personnel to give it, that’s it. It is a highly effective vaccine that has the capacity to eliminate polio from this world.

– Wow. So if we had unlimited resources, everyone would get that and we’d eliminate polio, but we have limited resources. So some get the oral polio vaccine, which can mutate and revert in rare instances and then be shed, and infect people who would normally even one in 2,000 or 2,000 of ’em would do fine even normally unvaccinated, but that one could get paralyzed. Now vaccinated, you dropped that to negligible?

– Yeah, you know if people, the term infantile paralysis, which was an old term that we used to describe polio, misrepresents what that disease was. I mean, the polio was incredibly common. What happened was, is in this say 1920s, 30s, polio wasn’t as common as it is now. It became a common as a result of increased sanitation and hygiene because what happened there was, normally what would happen is because polio was everybody got polio, usually, an asymptomatic infection. And so mothers therefore had antibodies, polio antibodies that they would passively transfer to their newborn. And in that first year or two of life, that’s when the child would be exposed because sanitation and hygiene wasn’t very good. Once we improved sanitation and hygiene, and people weren’t exposed then in that first year of life, then it became a disease of the 5 to 9-year-old. I mean, that’s why. And so the term infantile paralysis was never right. It was really a disease of the 5 to 9-year-old because of sanitation and hygiene. That’s what happened.

– That is fascinating, because it’s funny because anti-vaccine activists will often say, oh, the reason polio got better was not the vaccine. It’s because of improved sanitation and hygiene. And what you’re saying is no, actually when we were dirtier, everyone would get infected and the mom would pass those antibodies and the kid would then have at least some passive protection when they were very young. And that is absolutely fascinating. So this is an interesting story that again, gets back to why it’s important to actually use safe and effective vaccines in childhood to prevent these diseases. And like you said, when you have a safer opportunity than one that’s less, like the oral polio vaccine, you wanna take that and scale up to do that. So then that brings us to monkeypox ’cause everyone’s talking about monkeypox. And they were saying, oh, if it’s not one pandemic, it’s another, the government just wants to control us by creating pandemics. I did a video on monkeypox recently and I’m just curious, so. What’s interesting, the questions for you are, and this affects children as well. So it’s a kinda broad, it’s in the sort of pox virus family, teach us a little about monkeypox and let’s talk about vaccine options ’cause I think it’s interesting.

– Right, so many different species have their own infections with so-called orthopoxviruses, pox viruses. So there’s, cowpox, monkeypox, rabbitpox, horsepox, human smallpox, and the good news is they’re antigenically similar. So, and that was the first vaccine, right? Edward Jenner made the observation or actually it was made before him that milkmaids had fair skin. That if you looked in Southern England, every two to three years where Edward Jenner worked, the virus would sweep through the Southern English countryside and cause the devastation that comes with smallpox, which has a mortality rate of like 30% and for those who survive many are left blind. It is a terrible infection, but milkmaids and when you’re infected, and survive, you have these sort of residual pox marks because it’s a very, deep-seated blister. But milkmaids didn’t seem to get that. Hence the term milkmaids have fair skin because what he observed and was actually observed by a guy named Benjamin Jesty, a couple decades before him. But Jesty didn’t do the experiment and Jenner did, and so Jenner gets credit, but what Jenner realized then was, well, maybe there’s an association between these blisters that these milkmaids are getting on their hands and wrists. Though and we now think of as, we know as cowpox and the fact that they don’t get human smallpox, and so he then just took the blisters from a woman who was in his employee, a milkmaid named Sarah Nelms, and then inoculated people, including his son. And then what he did was he variolated them because, you know, really back from in the early 1700s, Benjamin Franklin regretted the fact that he didn’t give his son this essentially a smallpox vaccine, which was you would give them smallpox, you would sort of take these dried blisters and you would make them into a crust, and then you would either inject them or inhale them. And that was variolation. But when you got injected that it caused a really intense blister. So what he did was he inoculated his son of what we think now is cowpox and then he variolated him, but didn’t see that intense reaction. So he said, okay, I think there is protection here. It’s interesting, if you look back, I’m not sure it actually there was cowpox. There was recently a study in New England Journal of Medicine, suggesting that might have been horsepox that we were using as a vaccinia virus to protect against human smallpox, which is interesting, ’cause that’s where the word vaccine comes from. The word vaccine comes from V-A-C-C-A, in Latin there’s no hard V in Latin. So Vacca means cow, vaccinae is the generative form of the cow and that’s where the word vaccine comes from, was cow, but maybe we’re gonna have to go back and change that all, and make it like “equines”

– I just had a nerdgasm listening to that story. That was amazing, Oh man. So, alright, so we kinda have the history of this smallpox, the history of vaccines. We have interesting immunology in there. So now bring us up to monkeypox, which is in that family. And people will say, well, if you’ve had the original smallpox vaccine, which by the way, Paul, I was born in 1973, so I missed the American tail end of smallpox vaccination. We’d eradicated it by, I think, 1970, I believe. But my mom took me to India when I was six months old and I stayed there for six months with the family. And they were like, we have all vaccines and I got the smallpox vaccine, and I still have a big ass scar from it, from that, I guess, variolation reaction. I don’t know if it’s the same thing, but you know-

– That was vaccination, that wasn’t variolation.

– That’s right. That was vac-

– You got vaccinated.

– Yeah, ’cause I didn’t get the crust and inhale it or inject it. And so am I, the cross-protection you said is pretty good, do you think I would still be protected against monkeypox having had that?

– You know remember the… Well, I think the answer is yes. For the most part. So the number that you hear people talk about is that the protection again is about 85% protection against monkeypox. But I think the answer to the question which you really care about is yeah, ’cause monkeypox like all pox viruses can be fatal. Are you protected against potentially fatal or serious disease like, encephalitis or you get a sepsis like syndrome, or pneumonia. And I think the answer is yes, for the same reason. Remember the current monkeypox vaccines are still vaccinia. I mean, they’re still like the original smallpox vaccine, the two that are available and one we don’t use, one is called ACAM2000, which is essentially just kind of a purified version of that vaccinia virus vaccine. And then the other is the JYNNEOS vaccine, which basically you just take this, the Ankara strain of what was the vaccinia virus vaccine that we use and then modified. So it’s a modified vaccinia Ankara strain, and it’s modified by basically passing it like 500 times in chick embryo fibroblast cells. So it really can’t reproduce itself anymore. So it’s like live virus, but it really can’t reproduce itself. A similar in a sense to the Johnson & Johnson, SARS-COVID-2 vaccine, it’s a live virus, but it can’t reproduce. And so interestingly, when we decided to give it, to sort of because we didn’t have enough vaccine to give it say via the intradermal root. I like that idea because remember, the vaccine you got when you were in India, I got, because I was born well before 1972, when we stopped using smallpox, that was an intradermal vaccine. The scarification technique is an intradermal vaccine. And the area in your skin is a rich source of so-called antigen presenting cells like dendritic cells. So that’s a great way to give a vaccine. I mean, we still lack a critical amount of data, but there’s every reason to believe that it would be effective.

– So we don’t… Okay, so couple questions. Why do we do intramuscular at all then?

– No, you can argue, you can argue that we should use more dendr- that we could use more intradermal vaccine. It’s not as easy to give intradermal vaccines as compared to subcutaneous intramuscular vaccines, but we could certainly use it more. And there’s always a talk about these so-called microneedles, where you have like a hundred little needles and as a patch, and you put that patch on that’s essentially an intradermal vaccine.

– Got it. And so we don’t have a fully inactivated killed smallpox type vaccine? Is it just because you need-

– For all intensive purposes, the virus doesn’t replicate, the JYNNEOS vaccine doesn’t replicate. So that’s why it’s much safer. The original vaccine, the smallpox vaccine had euphemistically say a difficult safety profile. I mean, it could cause pericarditis, myocarditis, there are people who would occasionally die from the smallpox vaccine. And when we launched the smallpox vaccine in this country, which we did back in early 2000s, right before we invaded Iraq, there was an interest in, by the Bush administration of initially vaccinating everybody and then sort of talk down to just vaccinating first line responders. I never thought that was a good idea. I actually voted, no. I seemed to be always the only no vote on these things, but I voted no, when I came up for many reasons, I didn’t think we needed to launch that program. I thought we should get ready. I mean, make sure people knew how to give the vaccine was if there was just one case somewhere in the world, you could basically connect a case was starting, but I didn’t think we needed to start doing that yet.

– Yeah, and so we were seeing some myocarditis in military personnel, correct? Young people?

– That’s right.

– Yeah, and now, one thing I was reading about the old smallpox vaccine was occasionally, you would get, was it a disseminated smallpox case or a replication?

– Yeah, especially people who had like, psoriasis or sort of skin disorders where it allowed for more that- I thought when I was a fellow, I remember seeing a case of disseminated smallpox or disseminated vaccinia in someone who was a physician who had decided to give the smallpox vaccine this way sort of boosting immunity, this sort of paraimmunity thing, which was a terrible idea. And it’s pretty frightening.

– Really interesting. Yeah, I’m sorry, I misspoke. It’s not disseminated smallpox, like you said, it’s the vaccinia is the virus that you’re using in a similar family, so. Okay, fascinating. Thank you, Paul. So one quick question that I wanna ask, you know, we’ve been through this ride together, it continues. What are some things that you think you may have gotten over the path? Because part of science is figuring out when you’re wrong and correcting, or incorporating that knowledge, and getting better instead of entrenching, defending and rationalizing, which seems to be what the public discourse is often. What are some things that you might have gotten wrong during this whole course that you’ve changed your mind about or things that you’ve changed your mind about? And what are some things that you think you kinda nailed right and you’re still really advocating we do?

– Well, I certainly was wrong about how devastating this virus would be. I mean, when it firstly raised its head in China and then seemed to settle down, initially, there were like 3,000 deaths in a population five times greater than that. Now same goes to Italy, which has arguably, especially in Northern Italy, a healthcare system is not necessarily as good as ours, whereas good as we’d like ours to be, and I sort of just figured, okay, Italy smaller than us. China is bigger than us here. If you look, I think we’re gonna have, fewer than 60,000 deaths here and said that actually on CNN International in the early March of 2020. So I was only off by like a million plus deaths. So I was definitely wrong about how bad this was gonna be. I’m curious to see whether how it works out with two dose- initially, I felt like two doses. Well, let me take a step back. When in December 2020, we recommended that Moderna and Pfizer’s vaccine be launched as a two dose vaccine. Some very smart people, vaccinologists, called me and said, this is a three dose vaccine. It is because if you look at polio and inactivated polio vaccine, you look at an activated hepatitis A vaccine, or you look at purified protein vaccines. The only way you can get adequate frequencies, high frequencies of memory B-cells or memory T-cells is to have a four to six-month window between doses. So you’re gonna have to have that third dose later at some point to get those levels up, you know? And so, I believe that, but sort of waiting to see it and didn’t see it at the end of the first year ’cause remember, these mRNA vaccines were something with which we had no experience. So be open-minded, wait to see what you see. I’m curious to see whether over time, if you just gotten two doses and you were otherwise healthy young person, whether you really are at risk of serious illness, it’s certainly true with that third dose, you get a boost in some, you get some more affinity maturation, you get a broader immune response against BA.4/BA.5, that all true. But does that also mean that you’re not as well protected against serious illness? We’ll see what happens. I just really hope that the immunologists and epidemiologists get together to answer those questions who really needs these booster doses because like anything in medicine, whether it’s a biological or a drug, if you have clear evidence of benefit, then you’re willing to take the risk. But if there’s not clear evidence of benefit, then don’t ask people to take any sort of risk, even if it’s small or theoretical. So just make the case, make the case for it, is all I’m saying.

– Yeah, so quick lightning question kind of related to that, that I meant to ask earlier, would you mandate a BA.4/5 booster for healthcare professionals?

– No, I mean, I can tell you, we were not mandating it at Children’s Hospital of Philadelphia.

– Yeah, got it. For all the reasons we talked about. And how about the last thing I’ll ask is for young children, let’s say 2 to 11, that sort of range. We have pretty abysmal uptake of vaccine. Do you think more people should be vaccinating kids in that age or do you think we’ve reached enough general zero prevalence now that it’s not necessary? What are your thinking on the young kids that say, without comorbidities?

– Right, I actually, and I get a lot of hate mail for this. If you look at children who are hospitalized or go to the ICU with COVID, only about a third have underlying comorbidity. And I work in a hospital where I see this. So I would really encourage people to vaccinate their young children. I think you’re right and I’ve heard Dr. Prasad say this on your show that there definitely is more population immunity. I think that that protects us all, but if you look at what’s happening now, the answer to the question, what group is the least vaccinated? It’s people less than 18 years of age. They’re going back to school now and you’re starting to see an increase in hospitalization. Dave Rubin at our child policy lab, has now put out these data showing, you are starting to see more hospitalizations in children because we have this network of children’s hospitals we follow, you know, not for serious ones, but for bronchiolitis, for croup, for fever in a young child. So if you can avoid that safely, which I think vaccines do, then I would say, get a vaccine. Then the question becomes, well, how long does it last? I mean, if you get that vaccine, are you going to be obligated for boosters sooner and for longer? I mean, because you’re younger, are you not responding as well? Time will tell. But I do think that if that I would, I certainly encourage vaccines even in young children, but because I think the less than 5-year-old, I think it’s fewer than 5% of that group is getting vaccinated.

– Yeah, it’s very, very small. I just always love hearing your perspective. I know my audience does. I learned so much during this talk. If maybe when I edit it, I’ll cut away to my face during some of your conversation ’cause I’m just like… It’s really, the insights on BA.4/5, on the boosters, on influenza, on polio, on monkeypox on all of that, really, really tremendous Paul. Anything else you wanted to tell the audience that you can’t say on CNN, drop any F-bombs, anything you want, the platform’s yours, just spill it.

– No, I think we’re getting there. I think it’ll be really interesting to see what happens this winter. I mean, you hear some pundits saying, this is gonna be awful. There’s gonna be a BA.4/BA.5 is gonna sweep across because we’re now gonna be indoors again. And it’s gonna be just like, it’s been the last two winters, that would really surprise me. And we have such a high level of population immunity. We have monoclonal lab, we have Paxlovid, we have antiviral agents. I would really be surprised if you saw what we saw the last two winters, where you’d see 3,000 deaths a day, 4,000 deaths, I can’t imagine that would happen. So ’cause I think we are getting there and you know people, it’s different from where we were early because if you define pandemic, as it changes the way you live, work or play, you would argue in most areas of this country, we’re past the pandemic. I mean, most people are just doing what they normally do now. And we’ll see, whether by doing that, knowing that the virus is still circulating, knowing that there’s still population in this country that’s not vaccinated or under vaccinated, we’ll see what happens. But I would think that if you look at the last two winters and then this winter, you would not see that same level of bump, but we’re gonna learn a lot this winter.

– Yeah, that’s awesome. Paul, thanks a million. Guys who are watching the show, Paul, this is where I have to do the YouTube thing in order to stay afloat, I have to say, guys, smash that subscribe button. If you like, what Paul said, hit share, hit like and leave a comment. Tell us what you think, what style should we be canceled in for saying pregnant women instead of pregnant people? Hit that like button and if you wanna support the show, ZDoggMD.com/supporters or PayPal.me/ZDoggMD. And I respond to all those and I will send Paul a tip for every donation I get the next time when I go to visit him to go to the FDA meeting on influenza stuff, which he invited me to, and I’m gonna hold him to it. You guys will help fund that trip. So Paul, thanks a million. Guys and gals, and non-binary pals, we are out. Peace!

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