The legendary vaccine researcher returns to answer a metric ton of our questions.

In this interview we discuss:

  • The safety data so far after 7 million vaccinations
  • The case of the OB doctor who died of a platelet-related illness after vaccination
  • Why the second dose of the mRNA vaccines is crucial
  • Why patients who’ve had COVID should still be vaccinated
  • The effect of monoclonal antibodies on vaccine efficacy
  • The situation with anaphylaxis/pregnancy/autoimmune disease and more
  • Whether new viral variants will “escape” the vaccine
  • Are there tests to check for real immunity after infection or vaccination
  • Whether you can mix and match the two vaccines
  • What new vaccines are coming down the pipeline
  • Do vaccinations prevent asymptomatic spread
  • Un-blinding and vaccinating placebo arms of the trials
  • The formula for herd immunity
  • Healthcare worker vaccine hesitancy, and much much more.

Here are all our prior shows with Dr. Paul Offit.

Full Transcript Below!

Dr. Z: Hey guys, Dr. Zubin Damania. Dr. Paul Offit returns for our usual update conversations on the vaccines. Paul, welcome back, man.

Dr. Offit: Thank you.

Dr. Z:  Man, so dude, there’s so much going on. It’s always great to have you back. You always teach us a whole lot. First off, it looks like CDC just came out with the recommendation that everyone 65 and over ought to be having access to this vaccine. What are your thoughts on that?

Dr. Offit: That’s a great idea. I think the struggle here is threefold. One, mass production, mass distribution, mass administration. Right now the hang up frankly, is mass administration. I mean, we only have about 30% of the vaccine that’s out there being given. And I think people are trying to sort of go 1A, 1B, 1C. You know, first we’ll do the people who are healthcare workers and people who live and work at long-term care facilities, then we’ll go to essential workers, then we’ll go to, and I think that we can’t do it that way. I think we just have to just get as much vaccine out there as we can, get as much herd immunity from vaccination as we can. So I’m all up for loosening them.

Dr. Z: Yeah, so this idea that then let’s just cut to the chase and vaccinate as many at-risk people as we can makes sense, which then again implies, and this is an ongoing conversation we’ve had since the beginning of the pandemic, which is you’re pretty confident now sitting on the FDA Advisory Committee, looking at the data, going through this and watching our conversation evolve over these months. Like, okay, what are we concerned about? Are we worried that this quote unquote, rush, to the vaccine and operation warp speed and all this. So it sounds to me now, like you’ve gotten vaccinated, I’ve gotten vaccinated, you’re comfortable with the safety and efficacy of the two new mRNAs vaccinations that are approved for EUA in the US?

Dr. Offit: Yes, the only thing I think we’re looking at, and now you have more than seven million doses of the vaccine that’s been distributed. And if you go by the sort of Maurice Hilleman law, Maurice Hilleman I think is the father of modern vaccines. Having done the primary research and development of 9 of the 14 vaccines we give to children, his law was quote, “I never breath a sigh of relief until the first three million doses are out there.” Okay, so we’re there. I do think we need to follow up on the Bell’s palsy issue. I mean, that was something that was seen in those two phase 3 trials. Haven’t heard about it since. So this may have just been a coincidental and not causal association in those phase 3 trials and that’s a relief if that’s true.

Dr. Z: Yeah, you know, it’s funny because you mentioned Maurice Hilleman’s three million statement early on in our conversations, and it’s good to see that that actually came to fruition and we can breathe a sigh of relief. You know, it’s a big deal. I mean, this is one of the great triumphs of modern science so far. Now, you brought up Bell’s palsy. What about the anaphylaxis issue that has been raised particularly with the Pfizer vaccine but I imagine with both?

Dr. Offit: Right, so the CDC just put out a missive three days ago in morbidity mortality with a report on an update on anaphylaxis. And what they said was that, there’s about 11 cases of anaphylaxis per million doses roughly. And, you know, that’s a little scary. The background rate is roughly one case per million doses of any vaccine. Although it may be that we’re looking a little more closely at this vaccine than other vaccines, because it’s under so much scrutiny. I mean, it’s a little, it’s frightening certainly to have a severe anaphylactic reaction. The good news is it happens immediately usually within 15 minutes. The other good news, it is a treatable phenomenon with epinephrin. So none of those people who’ve had an anaphylaxis reaction to the Pfizer vaccine have died. I haven’t seen a lot of anaphylaxis with the Moderna vaccine. There was one case in, I think, there was a physician in the Northeast and I’m not sure with Moderna’s vaccine. But I’m not sure that it was anaphylaxis. He brought an epi-pen with him, he’d had a history of anaphylaxis in his past, he was nervous. He had sort of some tingling in his hands. And so he gave himself an epi-pen which may have just been hyperventilation. I’m not sure that was anaphylaxis, but needs to be followed up.

Dr. Z: Yeah, it might be more than nocebo effect, right? The negative placebo effect and the anticipation of that. And yeah, it is interesting. And do you think that the anaphylaxis, like you said, it could be that we’re just really scrutinizing this vaccine. It’s probably one of the most scrutinized vaccines in history because all eyes of the world are on it. But the question is, you know, let’s say it’s real, 11X increase in rate of anaphylaxis. Do you think it’s the lipid nanoparticle or the polyethylene glycol? What is it in that vaccine?

Dr. Offit: Right, I think it’s the, at least the going feeling by allergists who know much more about this than I do is it’s the polyethylene glycol component of the lipid nanoparticle. It’s interesting that, although both the Moderna and Pfizer vaccines have the polyethylene glycol, it is in a different configuration. So if there’s a difference between those two vaccines in terms of anaphylaxis, that may be why.

Dr. Z: Mm, interesting. Yeah. So that makes sense. Again, we can kind of science this up and try to get to the root of it and figure out, you know, and again, like you said, this is treatable, we’re watching people, you know. When I got mine, they had me sit there for 15 minutes and be careful, and I was talking to my daughter and telling her how to do CPR on me and stab me in the… I said I want it right in the heart, like in “Pulp Fiction”, you know, the full epi. So relating to that now that’s less humorous is this reports that have circulated on social media of an obstetrician who unfortunately died a few days after receiving I believe the Pfizer vaccine. And his wife had written a piece saying, we think this is vaccine related. So can you walk us through that and what you think about that? Because I think it’s making a lot of people nervous.

Dr. Offit: Yes, I recall, it was a middle-aged man who I think within three days of receiving the vaccine had a dramatic lowering of his platelet count, and despite intense therapy of trying to give him the platelets he needed, they were unsuccessful at doing that. And he ultimately succumbed. You know, I mean, the SARS-CoV-2 vaccines are designed to prevent SARS-CoV-2, not everything else that happens in life. So the trick is gonna be trying to sort out coincidental from causal associations. There was such a dramatic decrease in his platelets. And you wonder whether there was a complete shutdown of his body’s capacity to make platelets at the level of megakaryocytes in the bone marrow. Hard to know. I mean, I think that the only way we’re gonna really know about this is to see what happens when hundreds of millions of people are vaccinated, and see whether this comes up again. Otherwise I think it’s gonna have to be chalked up as a likely coincidental association.

Dr. Z: Right, you know, and isn’t idiopathic thrombocytopenic purpura which is a similar autoimmune low platelets particularly in children, but can happen in adults, is there an association with the MMR vaccination for that? And how does that differ from this situation?

Dr. Offit: Right, there is. So the measles containing component of MMR vaccine has been associated with thrombocytopenia. It usually happens 10 to 14 days after vaccination. It’s usually transient and without consequence. I get these calls occasionally from pediatricians who will say, you know, just did a CBC on this child, has a dramatically low platelet count. Everything else is fine, the child looks good, what could it be? And that’s the question. Did the child get a measles containing vaccine in the last couple of weeks? It depends on who you read, but the instance is estimated to be between 1 in 25,000 to 1 in 30,000. That said, measles, natural, wild-type measles virus also causes thrombocytopenia. So the vaccine is doing something that the wild type virus also does, the natural virus also does but at a much, much lesser rate, which is believable. Here, I mean it’s hard to understand why messenger RNA would shut down the synthesis of platelets because it happens so fast that it, in that case that you described that it’s hard to believe it was based on an immune response to platelets.

Dr. Z: Yeah, and again, like you said and we need to be very clear about this. It could entirely be that his platelets were dropping well prior to that. The vaccine, it has nothing to do, it’s just coincidental. Because like you said you vaccinated seven million people, incidentally you’re gonna have associations with bad events that were gonna happen anyways. And it’s very hard to tease out. I understand they’re doing an autopsy and things like that and it’s being investigated, which is very important. But I think like you said, I think we’ll have to watch, you know, again, this vaccine is under a microscope like no other. So I think it will be good to see that. One thing you mentioned that I wanna double down on a little bit is this idea that wild type virus, like getting infected with a normal virus in the world can cause some of the similar things that you see with other attenuated or inactivated virus vaccines. For example, the influenza vaccination, association with Guillain-Barre, So getting infected with natural flu has a higher association with causing Guillain-Barre. Is that right?

Dr. Offit: About 17 times higher. Therefore you could argue for that reason, that flu vaccine prevents Guillain-Barre syndrome.

Dr. Z: Wow, I’ve never even thought of it that way but that makes perfect sense. Because that’s used by a lot of people who are vaccine hesitant to say, you know, I don’t wanna get Guillain-Barre so I’m not gonna get the influenza vaccine. And the thing is, well, then if you actually come down with wild type flu, you’re 17 times more likely to get Guillain-Barre if you’re at risk for that anyway. So that’s very important. Now, the other, I think related question. Do you have any updates on other vaccines that are in the pipeline now or are we still really focused on these mRNA vaccines?

Dr. Offit: Well, so it looks like Johnson & Johnson’s vaccine which is a replication defective adenovirus type 26 vaccine, which again has in it the gene that codes for the SARSCoV-2 spike protein and it least has some commercial experience. And that that’s the vaccine that was used to try and eliminate the Ebola infection in West Africa. So it’s been in tens of thousands of people. That’s probably next up if I had to make a guess. I mean, I think that that probably is gonna be coming to our committee, the FDA Vaccine Advisory Committee in February if I had to take a guess, although I have no inside knowledge of whether that’s really true, that’s my guess. But my understanding also is that initially they launched a single dose trial. Now they’ve also launched a two-dose trial. So they’re doing both a single dose and two-dose trial which makes you wonder whether or not there was an interim analysis that suggested that one dose was not as good as two doses, and they wanna see whether the difference is dramatic. But again, I’m just trying to read tea leaves ’cause you don’t know, but I think that will be next. And then you have the UK AstraZeneca vaccine which is a replication defective simian adenovirus which is now in the midst of a two-dose trial in the United States. And when that gets completed I’m sure we’ll be hearing about that one.

Dr. Z: Right, so Johnson & Johnson’s is the one dose hope. Although, like you said they’re looking at two doses as well. So a couple of questions, and then we wanna make sure we talk about this two-dose controversy with the mRNA vaccinations and how we can think about that because people are quite concerned. And then I also wanna ask you just so people know what’s coming here, about what are the absolute contraindications for these mRNA vaccinations? Like, how do you think about someone who’s had COVID, who’s had monoclonal antibodies, who has a history of auto-immune or immune compromised, or is pregnant and lac, you know, breastfeeding. So we’ll talk about those things. But back to this piece, is there a concern with these adenoviruses and replication defective adenoviruses, these vectors, are they more complicationogetic? In other words, are we more concerned that you’re gonna get some odd things like the transverse myelitis signal you saw in the AstraZeneca trial or something relative to these new mRNA vaccinations, or what’s your thinking on that?

Dr. Offit: I think we’re learning. I mean it’s sort of the good news and bad news about replication defective viruses. The good news is they’re replication defective, so they can’t reproduce themselves and cause disease. The bad news is they don’t amplify themselves. So you give a lot of viral particles in the vicinity of 50 billion viral particles. And you wonder, I remember, I mean, you know, at the University of Pennsylvania where in 1999 we had the Jesse Gelsinger experience. This was the first gene therapy death where this is a boy who had an enzyme deficiency that allowed him to effectively eliminate urea from, I’m sorry, effectively eliminate ammonia from his body, ammonia being a product of protein metabolism. So in order to provide him with the gene he needed, they used a replication defective human adenovirus type 5, given at a dose much higher than we’re giving these vaccines. But he had an overwhelming cytokine response, so called cytokine storm from which he died. So that’s sort of always in my mind when I think about these vectors. And I think, you know, we just need to keep our eyes open. We are an outbred population, we will respond to things differently. So we need to keep our eyes open for that. And then, yeah, there was with the UK vaccine there were two clinical pauses; one in July, the other in September, both associated with essentially, diseases that were associated with a similar pathogenesis. One was what was called undiagnosed multiple sclerosis. The other one was so-called transverse myelitis which was inflammation of a segment of your spinal cord, both of which are based on essentially immune responses against myelin basic protein which forms kind of the sheathing of nerve cells. Hasn’t happened since. So we’ll see as we move forward, but those were always in your head as something that might be a rare, but real problem.

Dr. Z: Yeah. Yeah. And so then getting back to this question of the two vaccine, so the two-dose regimen of these mRNA vaccines, both Pfizer and Moderna. Actually even before we get into that, what are the real, like people ask, I want the Pfizer one, or I want the Moderna one. It’s funny, like a lot of nurses who are hesitant about vaccines are like, I don’t want either until more people have gotten it. I’m tired of being the Guinea pig. A lot of doctors who are hesitant that talk to me are like, I don’t want the Pfizer one, I’m waiting for the Moderna or vice versa. So, I mean again, help me understand this.

Dr. Offit: I remember once I was waiting in line at the grocery store and in that grocery was an Acme grocery store. They were giving flu vaccines in the back. I remember one of the women, two middle-aged women in front of me, one of them said, “Are you gonna get the flu vaccine here?” And she said, “You know, I don’t want the Acme brand,” which made me think, how do people think these vaccines are made? I think they think they’re made back there in like, you know, frozen food section?

Dr. Z: It’s like brand loyalty, like any like consumer product, is like, I don’t think that’s how this works.

Dr. Offit: What do people want? I mean you have two large clinical trials with 30,000, 44,000 person trials showing that these two vaccines are 95% effective against disease. 95% effective at least in people over 65 years of age. Very effective, arguably 100% effective against severe disease, effective across all racial and ethnic backgrounds. In fact, effective all comorbidities, have now been given to more than seven million people and still they’re hesitant? I mean, what are they waiting for? If you asked people a year ago, look, here are the characteristics of this vaccine, you would you think this is a vaccine you would get. I don’t know what piece is missing that make people hesitate at this point.

Dr. Z: Yeah, you know, I actually put out one of our earlier talks back on Facebook where it was like, don’t rush a vaccine. Like here are the things that we don’t wanna see happen. And those things didn’t happen. And actually, you know, again, the safety signal, the efficacy signal, quite high. Let me play devil’s advocate for a second though. So Doshi, I think one of the associate editors at BMJ had written a piece about, he looked at the data and he’s like, you know, I don’t know that they’re characterizing the efficacy correctly in these trials because of how they’re defining symptomatic cases and positives. Can you walk us through that controversy, and explain kind of what you think?

Dr. Offit: I don’t have a lot of faith in Peter Doshi because he does speak at anti-vaccine conferences.

Dr. Z: Oh, I didn’t realize that. Okay. Sorry, didn’t mean to interrupt.

Dr. Offit: He’s in, I think the division of pharmacy or Department of Pharmacy at the University of Maryland, but there are many people, I know there are a number of people who have written to the British Medical Journal and said, you know this is the guy who is an associate editor, really, you’re sure you want this to be the guy? And he’s certainly spoken, I think at both of our FDA vaccine advisory committees. He was in into public comment. But he certainly speaks at anti-vaccine conferences. So for that, he kind of loses me. But no, his arguments are, you know, are we fairly characterizing disease and severe disease? But I think that, I don’t see it. I think that both Pfizer and Moderna although have somewhat different rules for what they consider to be severe disease. I think that as a general rule, if you look at the Pfizer data, there weren’t a lot of people with severe disease under their guidelines. There were only about five, all in the placebo group. In the Moderna trial, there was 30 again all in the placebo group. I mean, it’s just ridiculous nitpicking at this point. You can’t ask actually for better. Now that said, I mean, be humble. We don’t know what we’re gonna see as we’re moving forward. Certainly these are novel vaccine strategies and we may find something that surprises us. So be open-minded to that. But at this point, there’s just nothing that one sees. It’s also, well, this is a novel vaccine strategy. People have been working on mRNAs vaccines, you know, for HIV and flu and malaria, really for 15 years. It’s not really a novel research strategy. And actually it was done at Penn. I don’t know if you knew that, but Drew Weissmann and Katelyn Croakey I think is how you pronounce her last name are the ones that figured out how to stabilize messenger RNA using these sort of nucleoside analogs, like pseudouridine and make it so that it was a more stable molecule. Also that it didn’t then induce innate immunity. It didn’t act as an adjuvant.

Dr. Z: Right, right.

Dr. Offit: So it’s really a remarkable break. It may in the end be a Nobel prize winning breakthrough-

Dr. Z: I mean it’ll give you goosebumps. And I remember when I was lucky enough to receive the vaccine I was in the right tier as a healthcare worker. But I was lower than say, somebody who’s seeing patients all day every day and now they’ve opened it up even broader. And actually I was actually hesitating to get it because I didn’t want to take it from someone. There was no way I was going to take a vaccination from someone who’s seeing patients every single day in the ICU. And then I’m reading about 20, 30, 40% hesitancy rates in healthcare professionals and these vaccines sitting in refrigerators. And I said, you know what? There’s no way I need to. First of all, I need to set an example. Second of all, I want this vaccination because I don’t want COVID and I don’t wanna give it to my family, and I don’t want to give it to someone else. Now, relating to that, and we can talk about hesitancy, but relating to that again, and we will get to this two-dose question I promise. But the asymptomatic transmission after vaccination has come up in many forums as well. Listen, do we really know? We don’t know whether, vaccination, it prevents symptomatic disease, it prevents severe disease, but does it prevent asymptomatic infection and transmission? Because then how are we gonna ever have herd immunity if we can still get infected with vaccines? So, how do you like to talk about that?

Dr. Offit: So, true, we don’t know. The two studies that were done looked at prevention of disease, not prevention of infection. So it’s possible that people could be asymptomatically infected to shed. But the way I see this is, even were that true, were there still asymptomatic infection, I would bet that in people who are immunized, the degree to which they shed would be much less than someone who wasn’t immunized. So I think they would be less contagious. I mean, you know, I was fortunate enough to be part of the team at Children’s Hospital Philadelphia that created the rotavirus vaccine. I mean that vaccine does not prevent asymptomatic infection. Nonetheless, as it was introduced in the United States and now it’s used by most, we’ve virtually eliminated that disease here even though that vaccine does not prevent asymptomatic infection. Because I think that in those children, those babies who were immunized, although they can still be asymptomatically infected, they shed less virus is my guess is what’s happening.

Dr. Z: Wow, man, every time I think about that rotavirus vaccine that you were part of the development of, I just think I’m really standing in the presence of someone who’s saved countless lives and yet will be vilified by anti-vaccine people into perpetuity. So no good deed goes unpunished at all.

Dr. Offit: Yeah, twice this week. I’ve had two threats this week, so-

Dr. Z: Oh, good, just two, that’s a downgrade from your baseline. I mean, you came to my studio that time and there were people banging on the windows making threats. So , so back to this idea. So yes, I agree with you that I think this asymptomatic transmission thing, most of the vaccines we have again, just by creating immunity, lowering viral load, lowering shedding are gonna produce that. So this idea, then I think that people are saying you need to still wear a mask, you still need to distance, you still need to do those other things after the vaccine, why are they saying that?

Dr. Offit: Well, first of all, it’s not 100% effective. It’s 95% effective. So you may be one of those one in 20 whose, get sick. Secondly, there still may be asymptomatic shedding and we don’t know that. I think it’s a belt and suspenders approach. I think if you had to answer the question, do I think people who are vaccinated that then wear masks and social distance, do I think that that would have a big impact on the transmission of this? That’s probably not, but that’s the current recommendation by the CDC.

Dr. Z: Right, right, right. And I think they have to say that. You know, what I’ve been telling people is, if we get enough people vaccinated, I think we can start changing that recommendation but it needs to, we need to get it out. So now that gets to the second question, this idea of, hey, let’s stop holding back the second shot and release them all and get as many people the first shot as we can with the hope that we’ll scale up manufacturing to get the second shot. So that’s the framing of the question. And then the question is, first of all, why two shots? Second of all, why are you shaking your head thinking that’s a bad idea? So walk us through this. And I heard you on PBS News Hour. By the way, it’s always crazy, Paul, when I’m driving and I’m listening to the radio and it was the Capitol riot week and everybody’s focus was on that. And then I hear Paul Offit and I’m like, wait, what? And I’m listening to you and you give this eloquent thing. And I’m like, “Hey, I know that guy.” It’s kind of cool to know really amazing people. But also realize that the older I get, the more talk radio I listen to which may, I don’t know if that’s a good thing, but anyways, back to the question.

Dr. Offit: So I think that what the Biden administration wants to do is they want to get as much vaccine out there as possible. I think the way they initially announced it was a messaging problem, because what it sounded like was, let’s just get people the first dose and then we’ll get them the second dose, if they can. That’s not what they meant to say. And I’ll give you the evidence for why. Well, first of all, here’s where it comes from. It comes from a number of, there was an op-ed piece written in the Washington Post by Dr. Ashish Jha and Bob Wachter, saying, look, if you look at the first dose, I mean, you do have efficacy. There’s whatever, about 80 to 90% efficacy in the Moderna trial. The problem with that is that, it’s several fold. One is, if you look at the Pfizer trial, which was you know, where you get those one times zero and then three weeks later, you get the second dose, there’s that period of time between when you get the first dose before you get the second dose where you can look to see whether people got sick. And the efficacy there was about 52%. For Moderna where now it’s four weeks, so it’s a little long between the first dose and second dose, again, you can look to see whether people were protected depending on how you sliced it. Do I include the first week? Do I include the first two weeks? It’s 80 to 90% effective for four weeks. That’s what you know, you know it’s for four weeks. There was some dated people who didn’t get that second dose that it could last as long as a couple months. But what you do know from the phase 1 trials, the so-called dose ranging trials is that the first dose induces an immune response that doesn’t compare all that favorably to that induced by, that found in human convalescent serum meaning people who were naturally infected and survived. With the second dose on the other hand, you get a dramatic increase in neutralizing antibodies. Plus you get detectable T-cell responses which is consistent with memory, and therefore likely long lived immunity. So I think with the first dose, all you can say is that the vaccine is likely effective for a few weeks, and that the vaccine likely doesn’t induce long-term immunity. So the fear is, now you have all these people who think great, 80 to 90% effective with one dose, you know, I had some symptoms with that first dose, 80 to 90%, 95%, no big difference, I’ll just skip the second dose. That’s what worried me the most in this. Or that people would, you know, there’d be such a delay in getting the second dose that people either just didn’t get it because there was such a delay, or that they were at risk because there was such a delay. I just thought the messaging was terrible. So hence what I said on on PBS News Hour. The next day, I talked to someone who was central to the Biden transition team, who basically we had a discussion. He said, this is not what we mean. We just think we have a better way of getting people two doses. And then that day, there were two people from the Biden transition team; Celine Gounder and Michael Osterholm who both went on TV and said, no, two-dose vaccine, three weeks or four weeks later, that’s what we’re doing. We just think this is a better way to get two-dose out there because it really made it sound like, you know, hey, one dose is good enough. I was actually on the “Dr. Oz Show” talking about this with Dr. Jha who’s great. I mean, I think Dr. Jha who’s on TV, he’s the dean of public health at-

Dr. Z: Ashish, yeah.

Dr. Offit: Exactly, Ashish. And he’s great, he’s very good at explaining things simply. And when I read that op-ed in the Washington Post, et tu Dr. Jha? really. But he was great, and we had a conversation and I think, I think he actually, I think he softened his position a little bit on this. ‘Cause it would be very bad if people thought one dose was good enough.

Dr. Z: Oh man, so much to say here. Okay, first of all, I need an epi pen right now because I’m breaking out in hives because you mentioned he who shall not be named, the MD who shall not be named, Dr. Oz, all right. Why? Why? I know why, because you can reach a lot of people and that’s lovely. Number next, I wanna restate what you said, which is in that phase 1 dose ranging trial, there was evidence. And I’d mentioned this in a separate video after hearing you on PBS, which is, you get a response but it’s not as robust as getting infected with COVID after one dose and the T-cell memory response that may be our key to durable response long-term happens after the second dose. So there’s no guarantee you have good or lasting immunity after one dose. And there’s a reason we’re giving two doses based on the phase 1 trial, which is a dose ranging trial to figure out what’s the dose? What’s the frequency. They did that. And again, this whole idea that this thing was rushed, no, they did the phase 1. They just took the risk out and didn’t have to go through all that phase 2, right? And then they did the full phase 3, am I misunderstanding that?

Dr. Offit: No, that’s exactly right. I mean, it would be great if we could do it with one dose. I think Johnson & Johnson may have an advantage of having a single dose vaccine, but it didn’t work out that way. That’s why you needed that second dose. That’s why we do phase 1 trials, and then translate them to phase 3 trials. And you can’t make it up after that. You then can’t go, yeah, yeah, sure. I mean, we know two doses, 95% effective but let’s just get one dose and see what happens. You can’t do that. Plus there is a fragile vaccine confidence in this country. If you gave one dose, and you had people say four or five six months later, getting sick, you will have shaken that confidence and you can’t afford to do that. Stick to the science and the Biden administration to their credit has consistently said, we will stick to the science. And when they came out with that unfortunately badly messaged statement, you know, Dr. Fauci stood up and said no, the FDA stood up and said no, this is a two-dose vaccine. So I think people responded quickly and well, and ultimately the Biden team to their credit has now gotten on TV and said, no, this is not what we meant, so all good.

Dr. Z: Good, good, good, good. Thanks for clarifying that, you know. And then relating to this, let’s say we did do a one-dose, people stopped taking the second dose, does that increase the risk of vaccine escape? To clarify what that is, you know, we have these new variants emerging of coronavirus, SARS-2 coronavirus that have changes in spike protein. Now you can tell us how likely it is that they’re gonna actually develop resistance to the existing two mRNA vaccines. But regardless of that, would getting just a single vaccination increase the risk of getting these escape mutations selected for?

Dr. Offit: Yes, you want a powerful, strong, virus-killing immune response. The extent you have a less powerful immune response, you allow the virus to sort of limp along and figure out a way to escape. That’s how you create escape mutants. So that was another potential concern. But again, just, you know, it’s two-dose vaccine. This administration is committed to that. And frankly, you know, if you look at, you know, this business about we need to get more first doses out there. In the mass production, mass distribution, mass administration, the problem really is administration. We’ve only given about a third of the vaccine that’s out there. So the problem isn’t as much getting more vaccine out there as administering more vaccine.

Dr. Z: Yeah, so getting it into arms, and that’s not easy either because people have to wait 15 minutes, there’s a process, but it can be done. We just have to put effort and money into it. And it seems like we’re putting lots of effort and money into other things, so we should really do this. How much concern do you have that these variants that are emerging are gonna ultimately display or develop vaccine escape and be resistant to the current line of mRNA vaccinations?

Dr. Offit: Right, so you probably should never make any prediction about this virus ’cause it’s you’re like always wrong. But certainly, the UK variant, the B117 variant is not an escape virus. I mean both looking at convalescent sera as well as sera generated from people who were inoculated with Pfizer’s vaccine, that those sera neutralized this virus. So it is just like the variant in terms of its ability to be neutralized by either being naturally infected or being immunized. The South African variant, the data that I’ve seen, I still haven’t seen really that study. You want to see that study when we look at convalescent human serum and you look at people who were inoculated with either Pfizer or Moderna vaccine. Does that clearly neutralize this virus in a neutralization assay? I spent a lot of time growing up in this world of vaccine research doing neutralization assays, plaque reduction neutralization assays, they’re not that hard. I don’t understand why when they do, get these viruses in hand, they can’t within a week let us know those studies. They do the monoclonal antibody studies, but that’s not really what you want to see. ‘Cause we are generating polyclonal not monoclonal antibody responses. And I believe there can be an escape for one or two, you know, one or two so-called epitopes immunologically distinct regions on that receptor binding domain, but those are the data you want to see. And they’re not quick to generate them. We need to be better at this. We need to just be able to sequence these viruses much quicker in the US. When we identify variants, we need to then within days know whether or not there’s any evidence of escape because if that’s true, that’s a problem. I mean, if we really do need to make a different vaccine for a different virus, imagine how hard it is just to get this one vaccine out there much less having to do more than that. And when we identify those viruses, we need to really quarantine them, isolate people, and look for spread, because that would be a problem.

Dr. Z: Yeah, you know, we use the term on this show, science the crap out of it. Like that’s what we ought to be doing with these things, right? And it’s funny, that you said that these things are not hard, these neutralization assays are not that hard to do. We oughta be doing that. You know, one related question to that. So, you know, when you make the spike protein, there are multiple epitopes on the protein, right? That can generate antibody response. And this is vaccine generated spike proteins. So it would take multiple sites before you develop escape, correct?

Dr. Offit: Exactly, right.

Dr. Z: Right, but the virus is being selected for, if you’re putting that pressure on it. So in other words, if there’s a bunch of people that are kind of partially vaccinated and the virus can still replicate in them, you’re selecting for virus that is resistant to what you’re generating with the vaccine. That is a disaster waiting to happen in the sense that you’re gonna need a new vaccine, new mRNA email to send to the cells. And again, like you said, it’s so hard to do one vaccine, now we gotta spin up a variant of it. So, the other question that’s related to that is a lot of people ask me, well how will I know if I’m like a non-responder to the vaccine? Is there an antibody test commercially available that people can test their immunity? Like for hepatitis or something?

Dr. Offit: There is a problem is there’s not yet in hand a clear immunological correlate, meaning where you can say, look, if I have this antibody response, I know I’m protected. I mean, usually the key information there comes from the so-called breakthrough cases. Meaning in the case of the Pfizer trial, there were eight people who got the vaccine yet still got sick from the virus. In the case of the Moderna, there was 11 people who got the vaccine, but still got sick. You’d like to look at their antibody response to see whether or not they had a lesser antibody response after that second dose, and those who were protected. Then you can say, look, if you have this antibody response then you’re gonna be protected. That question was asked both times and both of those FDA vaccine advisory committee meetings, they were at, that was asked of the sponsors, meaning the companies. And both times they said, look, we’ll have those data in January. It surprises me they didn’t have those data, but not that hard to do, love to see what those data are. And then let’s suppose that the answer is no, they had the same neutralizing antibody responses as everybody else. Maybe that’s not what we need to be looking at. Maybe we need to be looking at frequencies of memory B or T cells or something other than what we’re looking at to get a correlate. There are a number of vaccines on the market that don’t have immunological correlates. It’s not as easy as people think. I mean, I think it’s likely that this would be the correlate but it doesn’t always work out that way.

Dr. Z: Interesting, yeah, that’s really helpful. ‘Cause I’ve been trying to wrap my head around that. A lot of people asking that question. The other thing people are asking is, I had COVID recently, I’m currently infected with COVID, I’m positive, can I get the vaccine? What’s your thinking on that? Should they even get it? What’s going on?

Dr. Offit: So yes, for two reasons. One first of all, programmatically it’s very hard to say, okay, we’re going to screen everybody and see who’s been infected, who isn’t. Then we’ll just gonna give the vaccine to people who haven’t been infected. Secondly, the Pfizer trial, not the Moderna trial but the Pfizer trial actually included people who were or were not previously infected. And so they actually got to see whether or not there was any advantage to being vaccinated. There were 162 case, well, there were eight people who had been previously infected that then either, well, for the people who’d been previously infected, they got the vaccine, there were seven people who got sick in the placebo group, and one in the vaccine group. So therefore there was a booster response associated with that vaccine, so there was actually an advantage to getting that vaccine. The numbers were small, but it was encouraging.

Dr. Z: So certainly no disadvantage, potentially an advantage. So whether or not you’ve had wild type infection, good idea to get the vaccine is the punchline?

Dr. Offit: Yes, I think that’s right.

Dr. Z: And is there any temporal reason like you just had coronavirus infection, is there any reason you can’t get vaccinated now?

Dr. Offit: Right, so the CDC’s recommendation is if you’ve been infected, wait till your symptoms are gone and then get the vaccine. Or if you are in quarantine, for example, wait till you’re out of quarantine and then get the vaccine. That’s the CDC rec.

Dr. Z: That makes sense. I mean, I imagine that’s partially just because you don’t want to confuse symptoms of the coronavirus infection with vaccine adverse event.

Dr. Offit: Exactly, right.

Dr. Z: Yeah, that makes sense. And then relating to that, people who’ve gotten the monoclonal antibody treatments, I guess CDC was saying three months before you can get the vaccine or am I wrong and why would they say that?

Dr. Offit: Yeah, so 90 days is the recommendation. The thinking being that when you’re given these antibody preparations, so now you have a high quantity of virus neutralizing antibodies in your bloodstream. When you then get the vaccine, and then you make the messenger RNA, you excrete the protein, or put that spike protein on the surface of your cells, those antibodies will sort of, you know, kind of sop it up so that your immune system doesn’t get to see it as easily. So just wait three months. So, for example, when Donald Trump got his Regeneron, his monoclonal antibodies, and that was about three months ago. So he then could now get this vaccine around the time of Biden’s inauguration.

Dr. Z: Got it. Now that makes a lot of sense. ‘Cause you’re basically blocking with these administered antibodies, your body’s own ability to, to yeah, makes perfect sense. So relating to that, are they unblinding now the placebo group in these big trials and giving them vaccine?

Dr. Offit: So they’re unblinding them. The issue of who gets vaccine and who doesn’t, I think pretty much where people have settled out on this is that if you would get the vaccine normally, like you’re in, you know, you’re living or working in a long-term care facility or you’re a essential healthcare worker, if you would be up to get the vaccine, then get the vaccine. The question is, I think one of the companies actually said, had made the promise that if you are a part of this trial and then you’re unblinded and you didn’t get the vaccine, you will be getting that vaccine. If that was the promise that was made, then keep it. Because you know, people, when they admit to, when they submit themselves to these trials, they go through a lot. You know, they get tested frequently, they get their blood tested frequently so that’s a lot to do that. So I think that’s fair.

Dr. Z: Right, right. From a fair standpoint, it is. I think from a pure science standpoint, wouldn’t you love to see a persistent placebo group moving forward months and years. But it is what it is. It makes sense. Now the other people, I don’t know if this came up in the UK or where it came up with the idea of, oh, you got a Pfizer first dose, the Moderna is available, take the second dose as Moderna. What’s your thinking on that?

Dr. Offit: So, no. So you can’t mix. These are two different molecules as as expressed by the fact that one’s given at 30 micrograms, the other is given at 100 micrograms dose. So these are different, different molecules. So no, the CDC is clear on this. You don’t mix those two vaccines.

Dr. Z: Don’t mix them together. And your thinking on pregnancy and breastfeeding?

Dr. Offit: So it’s interesting, normally the CDC in the absence of data will say contra-indicated. So there were 23 people who became pregnant, they were, became pregnant during the Pfizer trial. There were 13 people who either were, became pregnant during the Moderna trial, not many people. And they pretty much broke down as placebo or vaccine. There were two cases of spontaneous abortion, one in each trial. In both cases, it was a placebo recipient. There’s no reason to believe biologically that this vaccine would be detrimental either to the pregnant woman or to her unborn child. And so the CDC did something they don’t usually do. They said, if you’re pregnant, you may choose to get this vaccine. Or if you’re breastfeeding, you may choose to get this vaccine because certainly women who are pregnant are more likely to suffer severe infection with SARS-CoV-2 than women of the same age who weren’t pregnant. That, you know, so that’s the known. The unknown is whether there would be a problem. I can tell you that’s the most frequent question I get asked including by doctors in our hospital who know what the CDC is recommending, but they just want a little hand-holding ’cause they’re nervous about this. And it’s understandable. I think, you know, you’re responsible for that little life growing inside you, and you want to make sure you don’t do anything. When you’re injected with a biological, no matter how much you know, it still just feels wrong. I mean, when our son was born, well, you know, and he got his hepatitis B vaccine at a day of age, you know, just feels bad. I mean, you know, just no matter how much you know about virology or immunology, it just feels bad to watch that happen. It’s like the first scratch on your car.

Dr. Z: It’s a great analogy, actually, ’cause I remember when my kids, my first child got the, you know, first series of vaccinations, including hepatitis, it was. It was this like visceral fight or flight. Like what are you doing with a needle? And, you know, I actually have this idea, this theory that needle fear is actually much more prominent and in a conditioned response than we give it credit for and it doesn’t manifest as, oh, I’m scared of needles. It manifests as I did research on the internet and I found Doshi saying stuff about the vaccine trial, and I believe him. And I do wonder where that’s a… And that brings me up to this question of hesitancy in healthcare professionals, because we can talk about the public another time probably but I think healthcare professionals have expressed quite a bit of hesitancy. What’s your thinking on why that is, and how we might understand it and maybe overcome it?

Dr. Offit: No, it’s really heartbreaking. I think that if they’re hesitant because they just don’t feel there’s enough data out there yet, or they don’t know the data, then they are convincible. If they’re hesitant because they don’t trust the system, that they think that the pharmaceutical companies are lying to them, or the government’s lying to them, or the medical professionals lying to them then you’re not gonna get very far. There are definitely people, even at our hospital who’ve chosen not to get the vaccine because they just don’t trust it. And it’s not the first thing. It’s not lack of knowledge. It’s not gonna be handled by providing information. It’s just a general distrust of the system. And I don’t know how you handle that.

Dr. Z: It’s pure, unconscious and conscious bias against that whole structure. It’s tough because I’ve told people, you know, if you’re in healthcare and you elect not to take the vaccine, then I don’t wanna hear you complaining about your PPE, I don’t want to see pictures of you on social media showing the marks from your PPE. We have a solution that’s highly efficacious that uses the structure and tools that we use in our profession, which are randomized control trials and large amounts of data. And if that’s something you don’t want, then I don’t want to hear about the other stuff. And also, I don’t wanna hear you going on social media telling patients I didn’t get the vaccine because I don’t trust them or whatever, because then you’re also modeling behavior that’s gonna be harmful to patients. I think everyone has a right to make decisions but that’s my concern is, is we have a certain sacred trust in our profession, especially nurses who have more trust than us, Paul. Like the public values their opinion almost more than they, definitely more than they value us which I think is actually generally a good move ’cause they actually are there with the patient, right? Whereas we’re a little bit, you know, we’re us. And so that piece, you know, I think approaching with love and understanding and compassion can help. I think in my platform, we’re trying to do that. Getting really smart people on to talk about it I think is important. But that deep distrust requires an understanding of their what I call their elephant, their unconscious bias and frontal attacks never seemed to work with that. I’ve tried, it doesn’t work. So we have to think that through a little bit more but one thing I’ll say is, as many people as we can convince that this is the right thing to do, it’s now becoming, COVID is now a preventable disease. And to not prevent it, seems to me you’re costing lives that are absolutely unnecessary to cost when we have 370,000 dead already.

Dr. Offit: Right. It’s awful.

Dr. Z:  It really is. Do you have any other things you wanted to discuss in terms of distribution rollout? Anything else, Paul?

Dr. Offit: Yeah, I would like to offer this message of hope. I think things are gonna get better, and I think they’re gonna get dramatically better and here’s why. First of all, we now have two vaccines that are highly effective, that now have been given thank goodness to more than seven million people without an apparent evidence of a rare, serious adverse event. That’s great. And we have a clear interest on the incoming administration in trying to figure out how to vaccinate us. We’re not gonna have to go through this cult of denialism anymore, where we just have to shut our eyes really tight and hope it all goes away. That’s good. We have likely two more vaccines that are gonna be coming out within the next month or two in all likelihood. So that should make it even easier in terms of getting vaccine out there. And I think that the weather will get warmer, as it gets warmer and more humid and hotter, I think that makes it less easy for the virus to be transmitted. So all of that’s gonna happen over the next few months and then one thing that’s true, and we never talk about it because it’s so awful, the price that we had to pay for it. You know, it’s listed, roughly 23 million people are listed as having been infected in the United States. But what that means is those are people who have been tested and found to be infected. I mean there are a lot of people who haven’t been tested. And when you do sort of serological surveys to try and better answer the question, how many people have really been infected? When they did that study in November, they showed that that figure was probably off by a factor of four. But let’s just assume it’s off by a factor of three. So 22 million is probably 66 million which is roughly 20% of the population who are immune. You know, we paid a ridiculously high price for that, but they’re immune. I think it’s very unlikely that when re-exposed to this virus, they’re gonna get sick so you already have a base of 20%. If you look at, there’s a formula actually for the number of people, percentage of the population you need to vaccinate in order to stop spreading the virus. There’s a book called “Plotkin’s Vaccines”. It’s in a chapter called Community Immunity by Paul Fein, but the formula is this, so I’m gonna really bore your listeners. Depends on two things, just what you would expect it would depend on; contagiousness of the virus. Obviously the more contagious the virus the higher percentage of people you need to inoculate. And vaccine efficacy. Obviously the higher the vaccine efficacy, the fewer people you would need to vaccinate. So the formula is R0 which is the contagiousness index minus one over or not divided by the percent efficacy. Okay, so if they R0 let’s say for the purposes of this discussion, two minus one over two is 0.5. If you take the vaccine efficacy at 0.95 and divide, so 0.5 divided by 0.95 is roughly 0.55. That’s 55%. If you can vaccinate 55% of the population, in theory, you could stop spread. Now that doesn’t include, it really should be efficacy against contagiousness. So we don’t really know that yet, but let’s assume that even if you’re contagious, you’re much, much less contagious. So let’s say 60%, you need to vaccinate 60% of the population. 20% is already probably immune. And they’re gonna be in your 60%, your people that you’re vaccinating. But I think if you really can vaccinate a million to a million and a half a day, and I think we can do that, we’re already up to over 500,000. I think we’re starting to get it in terms of the mass vaccination thing. Pennsylvania Convention Center now is a mass vaccination site. And I think that’s going on spouting up across this country. We can get to a million, a million and a half a day. Then you can get to half the population, 60% of the population by May or June. And then I think we could stop the spread by early summer. I think that’s really possible.

Dr. Z: Man, that is exactly what we need to hear right now is this hopeful message. ‘Cause I think that’s it. There’s an escape here. I think we’re reaching a tipping point in general. I think things are gonna wake up and we’ll get through this. And like you said, I think the temperatures are a key component. I think the existing community immunity is a big component. I love the fact that you guys have this, like this guide. You know, you remind me of Egon from “Ghostbusters” and Tobin’s spirit guide just to make sure you understand the different slimers and vapors that can attack, and make a formula to understand how to prevent it. That’s great. And that also speaks to these kinds of ideas that like Fauci throws out different numbers for what existing herd immunity should be, right? And there’s actually ways to calculate this, and it really depends on contagiousness. Now, do you think these new mutant variants are gonna increase R0 and make it a little harder?

Dr. Offit: Could, it’s certainly true that the the UK variant has increased the R0 by about 0.4 which is not trivial when you’re talking about populations of people, so yeah.

Dr. Z: Yeah, yeah. Man, Paul. Oh gosh. I could literally talk to you for another three hours but I know you’re running out of time. This was a gift as always to the audience. Again, I can’t express how grateful I am that you teach us, and all the work that you’ve done and do continue to do educating the public and making vaccines yourself, and teaching. So thank you, thank you, thank you. You’ll come back, right?

Dr. Offit: Yeah, for sure. Thanks for asking me. This is my most fun interview. I love this. You get to talk about things like “Ghostbusters”. I mean can’t do that on CNN.

Dr. Z: You know what? It’s just that you won’t do it on CNN, Paul. I think you need to just lay down the gauntlet. Listen, if you want me to be on James Earl Jones on your network, I will make a “Ghostbusters” reference, right? Offer him a Snickers, go, “Ah, you’ve earned it.” All right, Paul. Thanks a million. You guys share the video and we out, peace.

Dr. Offit: Thanks man.

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