The Peter Attia Drive - #160 - Paul Offit, M.D.： The latest on COVID-19 vaccines and their safety, herd immunity, and viral variants

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. I guess this week is Dr. Paul Offit. That may be a familiar name to

00:00:54.260 some of you because Paul was previously on the podcast in November of last year. At the time,

00:00:58.620 we spoke about the COVID-19 vaccines just prior to their first approvals. I wanted to have Paul back

00:01:04.840 to get an update on the vaccines and to get a sense of what the next year is going to look like.

00:01:10.040 As a refresher, Paul's a pediatrician specializing in infectious diseases and an expert on vaccines,

00:01:15.460 immunology, and virology. He is the director of the Vaccine Education Center and professor of

00:01:20.220 pediatrics in the Division of Infectious Diseases at the Children's Hospital of Philadelphia,

00:01:24.280 CHOP. And he is a professor of vaccinology at the Perlman School of Medicine at the University

00:01:30.000 of Pennsylvania. He serves on the FDA Committee for Biologics Evaluations and Research Vaccines and

00:01:36.500 Related Biologic Product Advisory Committee, evaluating not just the COVID-19 vaccines,

00:01:42.380 but vaccines for influenza and other infectious diseases. He is the co-inventor of the rotavirus

00:01:47.960 vaccine. In this episode, we start with an update of all four major classes of vaccines,

00:01:54.960 specifically talking about the two that are most utilized, which are the mRNA vaccines

00:02:00.020 and the adenovirus vaccines delivering DNA. We then talk about some of the safety concerns that

00:02:07.180 still remain around both of these. And Paul does a very eloquent job in my view of explaining

00:02:12.500 what is and is not a legitimate concern, both in the short term and the long term.

00:02:17.460 We talk about the variants and what the implications are of variants, and we get into

00:02:23.260 what herd immunity actually means. In other words, how much of it is going to require

00:02:29.560 a breadth of natural infection versus how much is going to require immunization. And we get into then

00:02:35.680 what's going to happen with respect to other populations being immunized, most notably people

00:02:41.560 under the age of 18. Something that I think many of you will find interesting in this discussion was

00:02:46.160 a deeper dive into the nature of immunology and how the short term immune response, usually mediated

00:02:53.580 by what's called the humoral system, differs from the longer term immune response, which we call the

00:02:58.920 cellular immune response, the memory immune response, how these two function together, and the

00:03:04.280 importance of the latter in providing durable immunity. We also talk a little bit about the origin

00:03:11.520 of this virus. I think there is a very interesting discussion around whether this virus originated in

00:03:18.140 a lab or it originated, quote unquote, naturally. And while a year ago, people who suggested it

00:03:24.260 originated in a lab were viewed as sort of conspiracy theorists, I don't think that's necessarily

00:03:29.520 the case today. And we talk a little bit about that. Finally, we talk about the future. I think most

00:03:34.580 people, Paul included, would agree that it is not a question of if, but rather when we see

00:03:39.680 another major coronavirus outbreak, given that this is the third one we've seen in 20 years,

00:03:45.060 what can we do to be better prepared for it? Neither of us pull punches on what we think went

00:03:49.640 wrong here. And most importantly, how would you need to remedy that in the future? So my hope is

00:03:55.740 that you'll find this podcast to be accretive to knowledge you've already gained through the recent

00:04:00.720 podcasts I've done on this topic, along with whatever else you're listening to on this topic. So

00:04:04.440 without further delay, please enjoy my conversation with Paul Offit.

00:04:12.540 Hey, Paul, it's great to have you back. Thank you so much for making time. Obviously, at the time

00:04:16.640 that we're recording this, I know you're busy with some news that we'll get to later. But nevertheless,

00:04:22.320 it seems like it's about the right time for us to pick up this discussion again, because the last

00:04:26.440 time we spoke, we were just on the cusp of watching a number of vaccines hit that first phase of early

00:04:33.860 use authorization. As we stand here today, I actually can't tell you the numbers, but

00:04:37.820 tens of millions of people have been vaccinated. And in some ways, there are still a lot of questions.

00:04:43.300 So let's start with just an update, the lay of the land for people. Broadly speaking, right,

00:04:48.500 four strategies, four scientific strategies in place to create vaccines. One of them is an mRNA vaccine,

00:04:56.420 which we'll talk about. The second, something that's a little more tried and true, at least

00:05:01.080 something that's been done a number of times before, using an adenovirus to deliver DNA. The

00:05:06.880 third is delivering directly purified protein of the virus. And the fourth, probably the oldest trick

00:05:12.680 in the book, is using live attenuated virus. Can you give us just a broad overview of where each of

00:05:20.200 those four are, and maybe what it says about the scientific challenges of the approval process for each?

00:05:27.820 At least in the United States, the messenger RNA vaccines are the farthest along. The FDA Vaccine

00:05:33.980 Advisory Committee approved the Pfizer messenger RNA vaccine on December 10th, the Moderna messenger RNA

00:05:39.420 vaccine on December 17th. And they then rolled off the assembly lines and into the arms of the American

00:05:46.080 public, such that now you have more than 120 million people who have received at least one dose of

00:05:51.320 an mRNA containing vaccine. So that's the farthest along, certainly in this country. In terms of the

00:05:57.320 adenovirus vectors, the replication defective adenovirus vectors, there's the replication defective

00:06:02.360 simian adenovirus vector, which is, that was put forward by the Jenner Institute at the University of

00:06:06.760 Oxford in the UK, that is partnered with AstraZeneca. And then the Johnson & Johnson product, which is

00:06:12.440 Janssen, that is the wholly owned subsidiary of Johnson & Johnson. And that's a replication defective

00:06:17.580 adenovirus type 26. The ad 26 vector had been used fairly extensively to try and slow the Ebola

00:06:24.260 outbreak in West Africa. So about 200,000 doses had been administered in West Africa of that vaccine.

00:06:30.700 Now we have more than 6 million doses of that that's been given in the United States. And then with

00:06:35.520 regard to the AstraZeneca vaccine, tens of millions of doses have been given in the United Kingdom as well

00:06:39.760 as in Europe. Certainly more than 20 million doses overall have been given of that vaccine.

00:06:44.640 In terms of the purified protein vaccine, probably the company that's the farthest along is Novavax.

00:06:51.120 They use a bacalovirus expression system. So basically you have a bacalovirus into which you

00:06:55.920 insert, in this case, the gene that codes for the coronavirus spike protein, and that's grown up into,

00:07:01.760 in butterfly cells, basically, spedoptera, fruggy peridocels. It's the exact same way we make flu

00:07:06.160 block. So there's a lot of experience using that technology to make a vaccine. Those studies have been

00:07:12.240 largely completed, but Novavax has been fairly slow to gain any sort of approval yet, to my knowledge,

00:07:18.720 anywhere yet. Live attenuated viral vaccines, they're still in the works. I don't know of any

00:07:23.520 live attenuated viral vaccine that is now being routinely given to anybody in any country in this

00:07:28.400 world, but I could be wrong. I haven't heard that. I know people were working, a number of

00:07:31.760 groups working on it. And then there's the whole killed viral vaccine, which is the product that's

00:07:36.240 used by China, which has been extensively given to now, again, tens of millions of people, which is

00:07:41.280 the way that we make the polio vaccine, the inactivated polio vaccine, or the hepatitis A

00:07:44.960 vaccine, or the rabies vaccine. So again, a lot of experience with that product. There's some

00:07:49.120 question about how effective it is. I should also add that the Russian vaccine is also a replication

00:07:53.200 defective adenovirus vaccine. In that case, AD26, human AD26, followed by human AD5. So those are the

00:08:00.080 strategies that are currently wending their way through the world.

00:08:03.200 And is it safe to say, Paul, that the whole killed is probably, I actually mistakenly said

00:08:09.760 that the attenuated, because I tend to lump that in with whole killed, but really whole killed is the

00:08:14.400 first play that's really initiated vaccination. Is that kind of the oldest trick?

00:08:20.080 Well, the oldest, oldest trick is a live non-human virus. I mean, the cowpox was the first vaccine in

00:08:26.080 the late 1700s. So basically, the thinking there was that, not that it was thinking at all,

00:08:30.960 since this was the late 1700s before we actually knew what viruses were. I mean,

00:08:34.400 it was just phenomenology. But now we know that the cowpox virus is antigenically related close

00:08:40.160 enough to human smallpox that immunization with one can protect you against disease caused by the

00:08:44.640 other. But you're right, the second strategy was the whole killed virus strategy. That was 100 years

00:08:49.040 later in the late 1800s in France with Louis Pasteur making the whole killed rabies virus.

00:08:55.120 For rabies, right?

00:08:55.760 Yeah, that's right.

00:08:56.400 Yeah. I remember my mom reading me that story when I was a little boy, actually. I could listen to that

00:09:02.080 story every single night because it had pictures of him taking the serum from the dog and killing the

00:09:09.440 virus and giving it to the boy. I can still actually see every part of that book. You know,

00:09:14.400 one of the things that I hear a lot of is that MRNA thing is crazy. This is totally sci-fi. It's

00:09:21.920 completely experimental. Why would anyone subject themselves to something that is so risky and so

00:09:27.840 unproven? A little while ago, I wrote something on this topic trying to make the point, I don't know

00:09:33.760 how convincing it was, that actually it's not as experimental as people think and that this

00:09:37.920 technology has been around for decades, plural, and that the only thing that's new is that this is the

00:09:44.160 first time the final step has been made, which is actually taking a virus that is of concern to

00:09:50.880 humans, sequencing it, and then putting it into a clinical practice. But this notion of using MRNA,

00:09:57.360 this didn't just come out of nowhere. This wasn't something that was developed in 12 months,

00:10:01.120 as one might believe if they weren't really following the science too closely.

00:10:05.920 Do you find yourself confronted with the same type of question?

00:10:08.560 Yes. And they're a reasonable question. It is a new era of vaccinology. I mean,

00:10:12.800 we just went through that briefly, but it's arguably the fifth era. I mean, you go to

00:10:16.720 initially sort of animal strains that are related to humans, then you go to the inactivated vaccines,

00:10:20.800 then you go to the live attenuated viral vaccines, then you go to purified protein vaccines. What all

00:10:26.000 those four strategies have in common is that you're giving the viral protein that you're interested in.

00:10:30.400 I mean, in this case, we're interested in the SARS-CoV-2 spike protein. And when you give that

00:10:34.640 protein in one form or another, whole virus or live attenuated virus, or just purified protein itself,

00:10:40.880 you're giving that protein, the viral protein, then the person makes an antibody response to that protein.

00:10:45.120 You're not doing that here. You're giving the gene that codes for the viral protein,

00:10:49.120 that's translated in the cytoplasm to the viral protein. So your body makes the viral protein,

00:10:54.000 then your body makes an antibody response. And you can see why people are concerned, because it's the term

00:10:59.040 that is used correctly as it's a genetic strategy. You're giving a gene. And the minute you say that

00:11:04.080 to people, that's often interpreted as something that could interfere with your genes or reorient

00:11:09.840 or re-engineer your genes. That's the way people hear that. They hear it as gene therapy. And in

00:11:13.840 a sense, it is kind of gene therapy, but not in the more traditional way that it's meant.

00:11:17.920 What is the best answer you have to someone that says, look, I'm not worried about acute toxicity

00:11:25.040 toxicity. Because given how many tens of millions of people have received both the Moderna vaccine and

00:11:34.560 the Pfizer vaccine, I think anybody can say unequivocally, there can't be any complications

00:11:41.200 in the short run that are clinically relevant. I mean, we just, there've been too many people

00:11:46.000 vaccinated to know that, oh my gosh, you know, 0.001% of people are going to suffer some horrible

00:11:52.160 complication. But it's not necessarily clear that there can't be some really long-term

00:11:58.880 complication that doesn't show up for a year or two years or three years. And therefore,

00:12:03.760 I think to your point, it is a reasonable point of concern to say, well, this is still very new,

00:12:11.600 and we don't have 10 years of data the way we would if this strategy were deployed through a

00:12:17.680 traditional non-emergency use approach for something like influenza, where we didn't have to rush,

00:12:23.520 because we have so many other strategies. So my question is, what would you say to reassure somebody

00:12:29.280 that in five years, we're not going to learn something horrible about inserting coronavirus

00:12:35.840 mRNA into our cells? All right, so there's two ways I would answer that. The first is,

00:12:41.440 can the messenger RNA in any way alter our DNA? Because I think that's at the heart of what people are

00:12:47.280 worried about, and then that comes up later in some form or another. That's not possible for

00:12:52.000 three reasons. First of all, when the messenger RNA is taken up by cells in our body, it's primarily

00:12:57.120 something called dendritic cells, which is the major antigen presenting cell in your body that presents

00:13:01.440 cells, presents antigens to the immune system, to the rest of the immune system. So it's taken up,

00:13:06.560 it's in a lipid nanoparticle, the lipid nanoparticle is taken up in the cell, it's stripped away,

00:13:10.320 and then that messenger RNA enters the ribosomal system, where like the other couple hundred

00:13:14.560 thousand copies of messenger RNA that are in your cytoplasm, it's then translated to a protein.

00:13:19.520 And that happens over days. And then the messenger RNA, like all messenger RNAs, breaks down and is no

00:13:25.440 longer making that protein. So the question then is, can the messenger RNA get into the nucleus and

00:13:30.720 in any way alter the DNA, which it cannot do for three reasons. First of all, it has to be able to

00:13:35.440 cross the nuclear membrane, which requires a nuclear access signal that it doesn't have.

00:13:39.760 Secondly, even if it got into the nucleus, it's RNA, it's not DNA. So in order to affect DNA,

00:13:46.160 it has to be converted to DNA, which requires an enzyme like reverse transcriptase, which it also

00:13:51.280 doesn't have. Even if it was converted to DNA, which it can't because it can't cross the nuclear

00:13:56.240 membrane and it can't be basically reverse transcribed back to DNA, it still has to insert

00:14:00.720 itself into the DNA, which requires an integrase enzyme that it also doesn't have. So it's not

00:14:06.640 possible. You have a better chance of developing x-ray vision after you've gotten this than you

00:14:11.280 have of the mRNA in any way altering your DNA. Although I never understand why people, when

00:14:15.440 they say that it alters your DNA, doesn't think it can alter your DNA for the good, you know,

00:14:19.440 like making you Spider-Man, for example, or something like that. People never talk about that.

00:14:23.200 So that's one thing. I think that's not possible. The second thing is long-term effects. I guess I

00:14:28.480 would challenge, we have these discussions at the CDC a lot with people who have a lot of experience with

00:14:33.120 this. Name that serious adverse event that's associated with vaccines that has not been

00:14:38.960 picked up within two months of getting a dose. And there are. I mean, you know, vaccines like

00:14:42.880 any medical product that have a positive effect can have a negative effect, including a severe negative

00:14:46.800 effect. And so, for example, the squalene adjuvanted influenza vaccine that was used in Europe

00:14:52.480 for the 2009 pandemic, one of those vaccines, so-called Pandemrix, could actually cause narcolepsy.

00:14:58.720 I mean, it was rare. It was about one per 55,000 people, but it was real. And it, again,

00:15:02.880 occurred within six weeks of getting a dose. The oral polio vaccine that was created by

00:15:07.760 Albert Sabin to basically eliminate a polio from this country could itself cause polio.

00:15:11.920 It could actually revert to essentially neurovirulent or wild-type virus and cause polio again,

00:15:16.160 what happened within a few weeks of a dose. The influenza vaccine is a rare cause, roughly one

00:15:21.440 per million. And for polio, it's about one per 2.4 million doses. But influenza, about one

00:15:25.600 per million doses, can cause Guillain-Barre syndrome, which is an ascending paralysis,

00:15:30.080 which can be severe and occasionally fatal. Again, occurs within six weeks of a dose.

00:15:34.560 The yellow fever vaccine, in roughly one per million people, depending on which strain you use,

00:15:39.440 can cause something we call viscerotropic disease, which is a nice way of saying yellow fever. I mean,

00:15:44.400 the yellow fever vaccine can cause yellow fever, much the same way the oral polio vaccine could cause

00:15:48.560 polio, again, within a week or so of getting the dose. So I don't know of that serious side effect that

00:15:54.000 causes long-term problems. Now, it is true that some of these, most of these side effects,

00:15:57.760 all of these side effects are so rare that when they occur, they only occur when they're in

00:16:02.080 tens of millions of people, and then you can see that. But that's why for every vaccine,

00:16:06.240 you have to wait for two months after the second dose or whatever the last dose is to make sure

00:16:11.120 it's still safe. And that was true of all these vaccines going out. I mean, we're going to get to

00:16:14.560 the issue, I think, later in this broadcast with Johnson & Johnson vaccine. But again, that issue came

00:16:19.360 up within two weeks of a dose. Yeah. I just want to make sure that for

00:16:23.040 the listener, we really highlight the salient point here, which I think is actually the first

00:16:27.520 point that you made. Because I do think that for most people who are, I think, hearing a lot of

00:16:34.240 misinformation, it's coming through the channels of people who don't really understand enough biology

00:16:41.120 to sort of explain exactly how messenger RNA is translated into protein. And of course,

00:16:49.280 that's what we want here. And how we don't have any of the machinery to enable the reverse.

00:16:56.400 Let's talk a little bit about HIV as a virus, because HIV actually can undergo some of this process.

00:17:03.120 So maybe use HIV as a counterpoint. And also, let's dovetail that into how failed attempts

00:17:10.800 to create a vaccine for HIV. Why is that not possible? And what has that taught us about

00:17:16.240 the current strategy here? A lot packed into that question, I realize.

00:17:19.600 Yeah. I would say if I had to pick what I think is the most heinous virus that was ever created,

00:17:24.240 it would be HIV. Because it does two things. First of all, when you're first infected with

00:17:29.040 human immunodeficiency virus, and it begins to reproduce itself, you make an antibody response to that

00:17:34.800 virus that neutralizes and kills that virus. It does. It kills it effectively, efficiently.

00:17:40.800 But what happens is it continues to evolve during a single infection so that the surface protein,

00:17:47.520 the so-called glycoprotein of that virus, to which you make an antibody response to prevent

00:17:51.440 the virus from binding itself, continues to mutate again and again and again. Here we talk about how

00:17:56.720 influenza virus, for example, mutates so much from one year to the next that natural infection or

00:18:02.000 immunization from the previous year does infect you, hence the need for a yearly vaccine. This

00:18:06.640 virus does that during a single infection. It just continues to mutate and mutate and mutate and mutate,

00:18:12.720 number one. Number two is, where does it grow? It reproduces itself primarily in something called T

00:18:17.760 helper cells, which is the major orchestrator of your immune system. It's T helper cells that help

00:18:22.640 B cells make antibodies. It's T helper cells that help stimulate cytotoxic T cells, which kill virus

00:18:28.080 infected cells. So it paralyzes the orchestrator of your immune system at the same time that it

00:18:33.200 continues to mutate so that your immune system never catches up to it. It is a remarkably effective

00:18:39.760 virus at being able to kill us. I mean, we have, you know, in the late nineties, we had finally

00:18:44.800 developed a highly active antiretroviral therapy as a treatment. So we were able to do what we wanted

00:18:49.360 to do, which was to make HIV a chronic disease. But that vaccine has remained elusive and it is not

00:18:55.760 because of lack of money or lack of effort. I know Merck put several billion dollars into that project

00:19:02.080 and was unsuccessful, again, with actually with a adenovirus vector into which they then inserted

00:19:08.480 either the group antigen or the envelope protein or the glycoprotein genes. And it didn't in any sense

00:19:14.800 work. In some ways it was actually worse for those who were vaccinated. Yeah. I used to sort of explain

00:19:19.600 it to people as, imagine you were up against a foe, you know, an army was up against another army

00:19:27.520 and the army knew how to strategically target the general. I mean, and the general being the CD4 cell,

00:19:35.840 the helper T cell. And all of a sudden you could just sort of abolish any chance of there being a

00:19:40.560 coherent strategy to fight back. But you're right, that those two things, the constant mutation

00:19:46.640 and the ability to infect, again, at least if you come at this from the cellular side,

00:19:50.640 the most important cell in the arsenal is pretty remarkable. What is it about those failures that

00:19:56.320 maybe actually sped up the development of vaccines against SARS-CoV-2, if anything?

00:20:02.720 No, I think you always learn. I mean, the replication defective adenoviruses that were used,

00:20:08.640 it was an adenovirus human serotype five that was used in the Merck trial. Certainly we learned about

00:20:13.840 replication defective adenoviruses for the Ebola vaccine, not only the J&J vaccine, but also there

00:20:18.960 was a replication competent of viral vector using something called vesicular stomatitis virus,

00:20:24.320 which is sort of a cousin in many ways of rabies, but obviously doesn't cause any of the symptoms

00:20:29.120 of rabies or symptoms at all. So yeah, sure. I mean, we've learned as we've gone here and with HIV,

00:20:36.480 it's like Jonas Salk's strategy was to try and take the whole virus and kill it. That obviously was never

00:20:40.320 going to work. That was the strategy he had used. He thought it could apply to other things that

00:20:44.400 clearly doesn't apply here. That vaccine has failed and failed and failed. I put that sort of in the

00:20:49.520 same category as like the universal flu vaccine. I mean, it's not for one of money and is not for

00:20:54.400 one of effort. I trained in a flu lab actually in the early 1980s at the Wistar Institute here in

00:20:58.720 Philadelphia. I was working on rotoviruses, but I was trying to make monoclonal antibodies to

00:21:02.960 rotavirus surface proteins. And I was learning to do it in a flu lab. And it was just these brilliant

00:21:07.600 researchers, you know, people like John Udell and Walter Gerhardt and Lew Stout all in one place.

00:21:11.760 I don't think I realized how lucky I was at that time to be around such amazing scientists. But

00:21:16.480 the head of that lab at the time said something to me I'll never forget. And now 40 years later,

00:21:20.880 it's still true. He said, quote, if you want to research career that lasts for the rest of your

00:21:25.040 life, study influenza. I think that's a virus where it's going to take a long time to catch up to.

00:21:30.000 So let's actually talk a little bit about influenza because there's something sort of strange about

00:21:36.240 this coronavirus that fits in between the one and done viruses and influenza. And let's just put HIV

00:21:44.640 in its own category because I think you've appropriately described it as the single worst

00:21:49.200 virus that's ever been shat into the civilization of mankind. I mean, it is truly, fortunately,

00:21:55.120 an anomaly with regard to how difficult it is. But on the one end of the spectrum, you have influenza,

00:22:00.640 which has so much genetic drift that every year you have to get a new vaccine if you want to have

00:22:09.440 any chance of being vaccinated. Of course, you could say, I don't want to be vaccinated because,

00:22:14.080 you know, it's generally not a very lethal virus, but it's bad enough. And certainly in high risk

00:22:18.720 populations, a vaccine makes a ton of sense. But, you know, we can't hold our natural immunity to it

00:22:24.800 from year to year to year. At the other end of the spectrum, you have polio, smallpox,

00:22:31.760 pertussis, pick your favorite of these things where they don't seem to mutate. Or if they do,

00:22:37.920 I shouldn't say they don't seem to mutate. Whatever mutations they have don't seem to impact

00:22:43.120 our body's immune system from reacting to them. So far, am I correct on those two ends of the spectrum?

00:22:50.800 Yes. Okay. Now we have this coronavirus, which seems to be neither of those. It's not clear that

00:22:58.240 it has the genetic drift of an influenza, where every year it's basically a new virus. But it also

00:23:04.640 appears that it ain't one of the other guys too, where you're going to be one and done strategy with

00:23:09.520 your vaccine. In fact, even though B117 looks like it is going to be managed through current

00:23:18.080 vaccination strategies, it is not clear that the South African variant, the South American variant,

00:23:24.320 Brazilian variant, are going to respond in that way, given significant changes in their binding

00:23:30.720 properties. What does that say about this virus, if anything? Or is that simply just the luck of the

00:23:35.520 biologic draw? Right. So I'm not sure I can explain why these viruses act the way they act. But your

00:23:42.320 assessment was exactly right. And on the one hand, once at the end of the spectrum, you have flu,

00:23:46.960 which you said correctly, year to year, probably you could argue minute to minute. I mean,

00:23:53.360 I'm on the FDA's vaccine advisory committee. The first week in March, we always pick flu strains.

00:23:57.120 And the way that works is we, the Department of Defense, the World Health Organization,

00:24:01.440 the CDC, all present data about these flu strains that are circulating in all areas of the world.

00:24:07.360 So we can see how these clades of influenza and subclades and sub-subclades are constantly sort of

00:24:13.840 moving around so we can try and predict which strains to include. And we certainly work hard to

00:24:18.400 try and get the strains right. We usually get them right, but it's amazing we get them right, given how

00:24:23.040 much this virus mutates. And flu is a single-stranded RNA virus. Therefore, like all single-stranded RNA

00:24:28.400 viruses, its replication isn't highly faithful. But then you have a virus like measles, which is

00:24:33.040 also a single-stranded RNA virus, which also mutates, but mutates in such a confined way

00:24:38.560 that the vaccines that you introduced or we introduced in the early 1960s continue to work.

00:24:43.120 Now, you know, 50 plus years later, that virus has never mutated away from the vaccine, even though

00:24:48.080 it is also a single-stranded RNA virus. So then you have this virus, also the SARS-CoV-2 virus,

00:24:53.760 also a single-stranded RNA virus, and also does mutate, but much more slowly actually than

00:24:58.640 influenza. And in many ways, in a manner that is between those two, between, say,

00:25:04.080 measles and influenza. So it does mutate, all for the purpose primarily of becoming more contagious.

00:25:09.600 That's really the main goal of viruses is to continue to reproduce themselves. They don't

00:25:13.440 necessarily want to make themselves more virulent, more likely to kill you because then they can't

00:25:17.120 reproduce anymore. So they really, their goal is to be more contagious. So the bat virus, which was

00:25:21.920 largely a bat virus that sort of first started in China and swept through China, was not the virus

00:25:26.320 that left China. The virus that left China was the first variant, the so-called D614G variant.

00:25:30.960 That was the first variant. That's the virus that swept through Europe. That's the virus that swept

00:25:34.080 through the United States. That's the virus that's killed 570,000 people. That's the virus to which all

00:25:39.680 vaccines are made to try and prevent the D614G strain. But now these other variants come up. You know,

00:25:45.520 the B117 UK variant, the Brazilian variant, the South African variant, now the New York variant,

00:25:50.640 the California variant. So there's always going to be variants that are made as the virus tries to be

00:25:54.320 more contagious. And so the critical question then is, to what extent will it drift away from

00:25:58.640 immunity caused by vaccination? And the answer so far is that the B117 is close enough to that

00:26:04.480 initial virus, the left China, the D614G variant, that immunization with one protects against the other

00:26:10.240 well. I mean, really well. They're close enough where there's not really a critical immunological

00:26:16.320 distinction between those two viruses. But the South African and Brazilian strain, now the New

00:26:20.640 York strain, all the so-called variants of concern are different, but not so far critically different

00:26:27.200 in this sense that I think natural infection or immunization still protects against severe

00:26:33.280 critical disease, meaning still protects against hospitalization and ICU admission and death.

00:26:38.960 That's still true. When we've crossed the line with these variants is when you see,

00:26:43.920 when you see, and we haven't seen this yet, people who are either naturally infected or fully immunized

00:26:48.400 that nonetheless are hospitalized or killed by a variant virus. That line hasn't been crossed yet.

00:26:52.800 Now we're looking because now as people are getting hospitalized and dying of this virus,

00:26:57.760 we always have to look at the virus they're getting infected with. And there's an NIH group that's

00:27:01.520 specifically designed to do that, to make sure that we have, these people aren't being infected with

00:27:06.640 variants and they're critically different that now you're not even protected against severe critical

00:27:11.040 disease. How do we know in the situation you just described where someone who's been previously

00:27:16.320 infected or vaccinated becomes infected with a variant of concern and goes on to have a bad adverse

00:27:22.480 outcome, either ICU and or death, how do we know that it's because their existing immunity was

00:27:29.360 incapable of responding versus they simply had lost immunity? Are you also checking for some

00:27:35.920 quantitative or qualitative assessment of their existing immunity?

00:27:40.800 What you can say, if you isolate a virus, sequence it and realize it is just the D614G strain or the

00:27:46.560 B117 strain, something that should have been fully susceptible to immunity induced by natural

00:27:50.960 infection or immunization, then one of those two things is true. Either you had an adequate immune

00:27:54.960 response and lost it, or you never really developed an adequate immune response. I'm not sure how easy

00:27:59.920 those two things would be to figure out at that point.

00:28:02.160 Right. It's tough to distinguish those two.

00:28:03.840 Yeah. That's the issue.

00:28:05.600 Right. But then what happens if they are confronted with the Brazilian variant? How will we know if

00:28:14.960 indeed it's the latter problem, which you just described, or frankly, the more frightening problem,

00:28:21.440 which is actually no amount of current immunity either acquired from D614 or through any of the

00:28:28.880 vaccines is going to save you. And basically we are back to square one of a pandemic.

00:28:33.760 Right. So I think when we isolate those variants, the question is, you take it to the laboratory and

00:28:39.680 see whether or not then the number of mutations that have occurred have occurred to the point that when

00:28:45.040 you take sera from people who are adequately immunized or people who are naturally infected,

00:28:49.760 that it doesn't neutralize that virus in the lab. I mean, that'll be the first clue that it's now

00:28:54.000 escaped recognition by natural or vaccine induced immunity.

00:28:57.680 And we're confident that an in vitro assay to look at neutralizing antibodies in the presence of

00:29:03.920 a new variant is pretty sufficient to give us that insight. We won't have to rely on epidemiology to

00:29:09.680 give us the answer.

00:29:09.760 No, I think it's pretty sufficient. I mean, it does ignore T helper cell responses, which tend to be

00:29:15.280 broader and are of value in that they do offer that sort of broader immunity where even though

00:29:20.240 there have been mutations in the receptor binding domain or the interminal domain, that you still

00:29:24.480 would get some evidence of immunity. That's why T helper cell responses are so critical here.

00:29:30.000 But no, I think we can figure, for the most part, figure that out.

00:29:33.520 Okay. So the good news about what you're saying, Paul, is you're holding us to a higher and more

00:29:38.000 conservative standard? Because what you're basically saying is I can test in vitro what a B cell can do

00:29:45.200 through neutralizing antibodies. I can't test what a T cell can do, but if it passes the B cell test,

00:29:50.960 I don't need to worry about it. Now, if it fails the B cell test, we still don't know about the T cell

00:29:56.080 test and that can only be played out in the real world. But if it's failing the B cell test, we're going

00:30:02.640 to take action. Presumably, we're not going to wait and assume that this is going to be worked out on

00:30:07.760 the side of T cells. I think that's right. I mean, I think that's right. Yeah. I mean,

00:30:11.680 if you look at the work that was done by Shane Crotty and others in La Jolla, looking at people

00:30:15.760 who are naturally infected and then, you know, if we're exposed to a virus again, we're protected.

00:30:20.640 They did find that while antibody responses fade over time and can fade over five, six, seven months

00:30:26.320 later, that memory B cells are still there and memory T helper cells or memory cytotoxic T cells are

00:30:32.160 there. And that's good. Now, you know, you have, this is a virus that has an incubation period of around

00:30:36.800 six days, meaning from the time you're first exposed to when you develop symptoms is about

00:30:40.400 six days. That's between sort of the typical mucosal infection like rotavirus or influenza,

00:30:46.160 where incubation periods are very short, one to two days, and a virus like measles or German measles,

00:30:51.360 which have, or chicken pox, which have incubation periods of 10 to 14 days.

00:30:55.040 The longer incubation period diseases are better in the sense that you really can induce

00:31:00.000 sterilizing immunity and therefore you really can eliminate those viruses. We eliminated measles from

00:31:04.640 this country by the year 2000. We eliminated rubella from this country by the year 2005.

00:31:09.200 The only reason measles has come back is because a critical number of parents have chosen not to

00:31:12.480 vaccinate their children, but those are eliminatable viruses. This is not because it's virus in the

00:31:19.040 bloodstream is not an important part of pathogenesis. So when you have long incubation periods, all you

00:31:24.080 need is immunological memory because there's plenty of time for activation and differentiation of

00:31:27.680 memory B cells to become effector cells, meaning antibody producing cells, and therefore you're good.

00:31:31.600 For the shorter incubation periods, your hope is to modify disease. Because a disease like rotavirus,

00:31:37.120 which has an incubation period of two to four days, you can stimulate then those memory cells,

00:31:41.600 which are long lived to become antibody producing cells, but you've already started to sort of

00:31:46.000 replicate because the incubation period is so short and it takes about three to five days to get

00:31:49.200 activation and differentiation of memory cells. So when incubation periods are short,

00:31:53.440 the best you can hope for is to modify disease associated with infection. So that's true of flu,

00:31:57.680 it's true of respiratory disease. Incentral virus is true of rotavirus. For measles, on the other hand,

00:32:02.800 where you have this long incubation period, as long as you have memory cells, which are generally

00:32:06.800 long, you have plenty of time for activation and differentiation of those cells to become

00:32:10.720 antibody secreting cells. And that's why you can eliminate those diseases. This is actually somewhere

00:32:14.880 in between. It's about a six-day incubation period. So, and again, virus in the bloodstream is really

00:32:20.480 not an important part of pathogenesis, so IgG memory cells become a little less important. But I do think

00:32:26.080 that we can control this infection. But I think that like all mucosal infections, your two choices,

00:32:31.280 basically, as we move forward are immunization or natural infection. Those are your two choices.

00:32:36.400 So, Paul, that's actually an amazing insight about how the SARS-CoV-2 has that sort of gestation

00:32:43.920 period that puts it into kind of an intermediate zone between the short and the long. Maybe let's

00:32:50.560 take a moment to just explain to people how the cellular immune system comes into play here. So,

00:32:56.240 I think by this point, folks who have been paying attention to this understand how the neutralizing

00:33:01.520 antibodies can work on first contact and how that can provide immunity in the weeks and months

00:33:08.320 following an infection. But to your point, at some point down the line, call it six months later,

00:33:14.240 12 months later, a year later, or whatever, 18 months later, those neutralizing antibodies may not

00:33:20.240 be there in sufficiently high enough titers. What is the actual process by which that virus now gets

00:33:27.120 presented to the cellular immune system such that we can re-engage B cells to come out and make more

00:33:35.040 neutralizing antibodies under the instruction of T cells? Maybe walk people through how

00:33:39.360 that works through antigen presentation, et cetera. The virus would be then picked up by

00:33:44.560 major antigen presenting cells in the body, like dendritic cells, macrophages, and to some extent,

00:33:49.600 B cells, broken down into small sort of 10 to 15 mer peptides put on the surface of the cell of these

00:33:56.320 antigen presenting cells. And then they travel to T helper cells where they then stimulate T helper cells to

00:34:01.520 do two things. One is to stimulate B cells to make antibodies. Two is to stimulate cytotoxic T cells to

00:34:07.760 kill virus infected cells. But as long as you have immunological memory, as long as you have memory

00:34:12.800 B cells, memory T helper cells, memory cytotoxic T cells, and those are generally longer lived, then you

00:34:19.120 can at least have activation and differentiation of those memory cells to become effector cells in the

00:34:24.400 case of B cells, antibody producing cells. In the case of cytotoxic T cells, T cells that kill virus

00:34:29.680 infected cells. So memory is what you want. And I think, I guess I was encouraged by the work of

00:34:35.120 Shane Crotty and others that memory cells here do, at least after natural infection, appear to be

00:34:39.680 fairly long lived. I'm also encouraged by the messenger RNA data, where after that second dose,

00:34:45.680 you clearly get stimulation of T helper cells and cytotoxic T cells, which suggests that you'll have

00:34:51.120 also somewhat longer lived responses. I mean, I'd like to think that these responses would be durable

00:34:55.760 enough after natural infection or immunization to protect you for a couple years, three years,

00:35:01.040 four years. I'd like to think that's true. I mean, we'll see whether or not it ends up being true.

00:35:05.040 But the good news about the mRNA strategy is it's a powerful immunization. I mean, I'm amazed at how

00:35:12.240 effective it is. And one thing that the people at least can notice is that many people get shots in

00:35:17.680 their arms for a variety of vaccines. This vaccine often causes lymph node enlargement under your arm,

00:35:23.440 so-called ipsilateral lymphadenopathy. That's not common. You see it with the smallpox vaccine,

00:35:29.520 which is another powerful immunogen. And you see it with this vaccine. Those antigen presenting cells

00:35:34.240 travel to the local lymph node and then stimulate that response to the extent that your lymph node

00:35:38.800 actually enlarges. It is a powerful immunogen, these mRNA vaccines. It's so funny that you bring that up,

00:35:44.080 Paul. I was going to bring that point up later. So both my wife and I had whole body MRIs. We do this

00:35:49.440 every once in a while for sort of a cancer screening protocol. And we had them four days ago. And the

00:35:55.760 radiologist said, hey, I assume you guys have been vaccinated. And we said, yep, both vaccinated

00:36:02.160 at such and such a time. He said, okay, let me show you something on the MRI. The radiologist is a very

00:36:06.160 close friend. And he said, look at the extent of lymphadenopathy under your arms. This is normally

00:36:12.720 something that in a case of a woman would make me think she potentially had breast cancer.

00:36:17.520 That's how inflammatory, how concerning these nodes are. He said, look, I've now looked at enough

00:36:23.200 of these in the past couple of months to realize that it's almost always people responding to the

00:36:27.920 vaccination of this virus. And he said he is seeing it more with the RNA viruses, the Moderna and Pfizer.

00:36:36.240 I didn't ask, and I should have asked, to what extent is he seeing it with the adenoviruses?

00:36:41.760 But I think what you said is very interesting. And I only knew of it literally four or five days ago.

00:36:46.080 I want to ask you another question about this, which is, why is it that the J&J

00:36:50.480 virus is able to provide such a benefit after only one injection, whereas the RNA viruses needed that

00:36:57.760 second injection? Right. And if you look at these replication-effective

00:37:00.960 similar human adenoviruses, the J&J vaccine, the replication-effective AD26, human adenovirus 26,

00:37:06.720 they induce cellular immunity after a single dose. That's really not true with the mRNA vaccines.

00:37:10.640 You need that second dose. I'm not sure why one is more powerful in terms of one dose versus two doses,

00:37:15.280 but that is true, which is why it's all the more important to get that second dose of mRNA vaccine.

00:37:20.880 There are a lot of people, people who I actually really respect and are well-known in the field of

00:37:26.800 epidemiology or virology, who have written op-ed pieces that have gotten a lot of national play

00:37:32.080 on why it is that one dose of mRNA vaccine gives you 80% effective protection, whereas the second dose

00:37:37.120 gives you 90% or 95%, and that let's get as much first dose out there as we can. I think as long as

00:37:43.760 people realize you need that second dose, I mean, I just worry that people are going to hear, well,

00:37:48.240 80% protective after one dose, 90% after two doses. That's not that big of a deal. I know that with

00:37:54.080 the second dose, there's more side effects, so I'm just going to go with one dose, and then confuse

00:37:58.080 it with the fact that J&J's vaccine, Johnson & Johnson's vaccine is one dose. This is a two-dose

00:38:03.120 vaccine, the mRNA vaccines, and the choice not to get that second dose is a choice probably to get less

00:38:08.240 durable immunity, less pleat immunity, and likely less effective immunity against these variants that

00:38:14.640 have drifted farther away from the original strain. One other point on that, Paul, that I think is a

00:38:20.960 real mistake that the press has made, and frankly, I think that the vaccine companies have made,

00:38:25.600 is they have not communicated clearly the difference between relative risk reduction and absolute risk

00:38:31.520 reduction. So when the J&J vaccine received its emergency use authorization, I think the headline

00:38:37.840 grabbing statement was, hey, we just heard that Pfizer is 96% effective and Moderna 95% effective,

00:38:46.480 but J&J looks like it's only 66% effective. Those numbers are probably off by a couple of percent,

00:38:52.080 but directionally, they are correct. And at the surface, you would say, why in the world would

00:38:57.600 you take the J&J vaccine, even though it's only a single shot? Or you might ask another question,

00:39:02.560 which is, well, what happens if you took two shots of the J&J? Wouldn't that put it on par,

00:39:06.880 et cetera? And it turns out, I actually had to go back and look at the data to actually see what the

00:39:13.360 true risk reduction was. Now, I won't go into it here for people because it would take too long,

00:39:17.600 but we'll link to it in the show notes. We have an entire post I've written about the difference

00:39:22.400 between absolute risk reduction and relative risk reduction. But you must talk about this in terms of

00:39:27.520 absolute risk reduction. And when you look at the absolute risk reduction, it turns out that the J&J

00:39:33.200 vaccine has a 1.7% absolute risk reduction versus a 1.2% absolute risk reduction for Moderna. And I

00:39:42.240 believe Pfizer is actually less than 1% risk reduction. These are all great vaccines,

00:39:48.480 but it turns out that J&J gets the most bang for its buck. Now, I wanted to talk with you about why

00:39:54.080 you think there is that discordance between the lowest relative risk reduction in the mid-60s and

00:40:00.720 the highest absolute risk reduction, which is the number that matters, approaching 2%. Do you believe

00:40:05.600 that the Pfizer and Moderna vaccines were tested on less susceptible populations and that J&J was

00:40:12.240 just tested on a sicker population that was therefore going to benefit more greatly?

00:40:16.640 Well, so there are different strategies. So it is interesting how both mRNA strategies had very

00:40:21.200 similar, at least relative risk reduction. But you're right. I mean, it is interesting how

00:40:26.000 we don't talk about it that way. We also don't talk about that way with regard to safety issues.

00:40:30.160 So if you look, for example, I'm trying to remember the specific numbers for the Pfizer trial,

00:40:33.600 but there were like 165 cases of disease in the placebo group and like eight cases in the vaccine

00:40:40.480 group. So that's 165 cases per, in the case of the Pfizer trial was a roughly 40,000 person trial.

00:40:47.280 So you're roughly, it's like 165 cases, you know, per 20,000 people that got placebo as compared to

00:40:53.040 like eight cases per 20,000 people who got the vaccine. So when you actually divide that all up,

00:40:58.320 the absolute difference is much less dramatic than is, you know, the sort of the relative risk.

00:41:03.360 Right. The Pfizer absolute risk difference was like 0.9%. And you're right. The total number of cases

00:41:10.800 was about 170 total cases in 20,000 or 40,000. I'm sorry. But you're right. The difference was

00:41:20.480 eight versus like 165 or something like that. Right.

00:41:23.680 Which again, makes me just think like, these are people who were either less exposed,

00:41:27.840 more healthy. There was something in these populations that differed dramatically from the

00:41:33.040 J and J population where, I mean, we're talking about 500 infections versus a hundred infections

00:41:40.080 directionally. So the relative reduction wasn't as high, but the absolute reduction, like I said,

00:41:45.600 1.7%, which we're going to come back to in a moment. It's worth keeping in the back of your mind.

00:41:50.960 When you have a 1.7% absolute risk reduction, that means your number needed to treat to prevent

00:41:59.200 a negative, a bad outcome is very low. I mean, we're talking about what, 60 for an NNT?

00:42:05.680 No, you're right. It's interesting that, I mean, the way I think of it, just because it's easier for

00:42:11.600 me to conceptualize it, is if I walk on the street in front of my house, I have a certain risk of being

00:42:16.880 hit by a car, just stand in front of my house, in the lawn in front of my house. I have another

00:42:21.600 risk of being hit by a car. The risk is much greater if I cross the street than if I just

00:42:25.200 stand on the grass in front of my house. But I cross the street all the time and never get hit.

00:42:31.840 So still the chances of my being hit are still extremely small, even though I cross the street,

00:42:37.280 even though the relative risk is much higher, the absolute risk is still very low of being hit by a

00:42:42.720 car. And I think that's what people don't quite understand.

00:42:45.680 Yeah. Let's talk about the kind of the elephant in the room today, at least, which is as of

00:42:50.160 yesterday. And by the time this podcast come out, this might even be irrelevant news. So I don't

00:42:53.920 want to dwell on it too much. But as of yesterday, the news came out that J&J's vaccine, which as of

00:42:58.880 this moment has been given to 6.9 million people in the United States, has resulted in six serious

00:43:05.680 clotting episodes, all in women, interestingly, probably not a coincidence, but it's too soon to tell.

00:43:11.600 And one of whom has died. So obviously, very easy to believe that these side effects are the result

00:43:19.120 of the vaccine, given what we saw in the AstraZeneca case. Not clear if it's a coincidence that it's also

00:43:24.960 in an adenovirus vector. But regardless, let's just think about this for a moment through the numbers.

00:43:31.200 Six out of 6.9 million people have had a side effect that is completely undesirable,

00:43:38.400 one of whom has died, which is the ultimate undesirable side effect. But contrast that with

00:43:43.920 the NNT. Now, the data in the JAMA paper that I looked at, which is where I saw the most robust

00:43:52.560 data on the vaccine, at least I couldn't extract from it what the NNT was to save a life. Do you know

00:43:59.680 that? So the NNT data that I quoted, which is about 60, based on the reciprocal of the ARR.

00:44:06.880 So if you take 100 divided by 1.7, whatever that number is, I'm doing the math in my head,

00:44:12.320 it's about 60. That's for all reactions. So serious reactions, hospitalizations, death.

00:44:19.360 But if you just do it on death, I don't know what that is. Do you?

00:44:22.960 I think it's something like, let's assume just for the purposes of this discussion that

00:44:27.760 it's roughly one case of this so-called cerebral vascular sinus thrombosis, or blood clot in a vein

00:44:35.440 of the brain, per million people who got this vaccine. For a million people who would get the

00:44:41.280 vaccine otherwise, something like 1,850 or so would be prevented from dying. This was presented this

00:44:50.560 morning. Okay, that's the number I'm asking for. Yeah, what's the difference? So we can do it for

00:44:54.960 how big that number is will be prevented from going to the hospital. But to actually be prevented from

00:45:00.160 dying, if it's about 2000, you're talking about a trade-off of 2000 to 1. And that's why I've got

00:45:05.120 to be honest with you. I looked at the reaction of the federal, if I read it correctly, Paul,

00:45:11.120 the federal government basically said, we're going to stop this and let states decide. And New York and

00:45:18.400 California immediately said, we're going to stop it. And again, that's not the worst thing in the world

00:45:22.800 if we have enough other vaccines in the pipeline to keep going. But my thinking is, that's an

00:45:28.320 overreactive strategy if it's going to actually prevent people from being vaccinated, isn't it?

00:45:34.640 Oh, and it's going to prevent people from being vaccinated. I mean, I just think that the minute

00:45:38.880 you did that, the minute you pause that vaccine, you sent a chill through people in this country.

00:45:45.040 I think that would affect not only this vaccine, but I think even it would spill over to any COVID vaccine,

00:45:50.640 which is, I think, what worries me the most about this pause. I mean, I understand why they did it.

00:45:55.280 I think they wanted to say to people, at the very least, this is an unusual phenomenon. And

00:46:01.200 typically when you see, for example, thrombotic events, you invariably treat them with heparin,

00:46:05.120 don't treat this with heparin. So thinking maybe is that intravenous immunoglobulin is the best

00:46:09.760 treatment, but heparin is the worst thing you could do for this. And so to alert the physicians of that,

00:46:15.680 also to alert physicians of the fact that if anybody's gotten the J&J vaccine,

00:46:19.120 and within two weeks of getting that vaccine had signs and symptoms of severe headache,

00:46:23.520 chest pain, shortness of breath, leg pain, to pay attention to that. I think that all makes sense.

00:46:28.480 But by pausing it, now the city of Philadelphia is not giving that vaccine anymore. I think in San

00:46:33.440 Francisco, they've decided not to give that vaccine. And I just think that the point you

00:46:37.920 made earlier is exactly right. If it doesn't matter, meaning if we have enough of the Pfizer,

00:46:43.040 Moderna vaccine, that this is not going to, in any sense, slow our ability to vaccinate this

00:46:47.520 population and get to the level of population immunity that creates herd immunity, then it's

00:46:52.000 not that big of a deal. But I think that there's two ways to look at that. One is that we have

00:46:55.600 enough vaccine that makes it not a problem. But the other thing is that people may now be scared.

00:47:00.000 That's what scares me the most of this. If you ask me the question, what do I fear most about this

00:47:03.440 whole pandemic? It's actually not the variants. It's not. It's that there would be a significant

00:47:07.760 percentage of the population that is going to choose not to vaccinate, so much so that we can't get to

00:47:12.800 that 80 plus percent of population immunity. We need to slow this virus. And then what do we do?

00:47:17.600 And we're going to know that by the middle of the summer when we have enough vaccine.

00:47:20.960 And then we're going to figure out just what percentage of this population doesn't get

00:47:24.320 vaccinated because it's not small. I mean, I was at the doctor's office yesterday.

00:47:27.920 The nurse who checked me in told me she was not going to get a vaccine. This is a nurse. You know,

00:47:32.400 these are people in the medical profession. So you can imagine what it's going to be like out there

00:47:37.040 in the real world. And we already know those numbers to some extent. You know,

00:47:39.840 we know that for example, 46% of Republican men say that they don't want to get a vaccine. 30%

00:47:44.720 of Christian evangelists say they don't want to get a vaccine. 14% of those in the black community

00:47:49.200 say they definitely don't want to get a vaccine. So there are groups out there that are going to

00:47:52.960 be making this choice. We'll see how this plays out. So let's talk about what herd immunity means,

00:47:58.640 because even something that conceptually makes sense when it comes to the details, we're seeing lots of

00:48:06.400 experts disagree on what it's going to take to achieve herd immunity. What is your best explanation

00:48:13.600 for not what it means conceptually, I think we understand that, but for specifically what is

00:48:19.360 going to be required. And that includes both among children, adults, very susceptible populations.

00:48:26.880 Like what is it, what does a world look like in which we have herd immunity?

00:48:30.400 Right. So I define herd immunity for mucosal viruses like rotavirus, for example, as a thing

00:48:36.640 from non-mucosal virus, systemic viruses, where the virus spreads into the bloodstream like polio and

00:48:42.480 measles and rubella, where you can eliminate that virus. We're not going to eliminate this virus. I

00:48:46.960 think the best we can hope for is to significantly slow its spread as we did for rotavirus. I mean,

00:48:51.760 when the rotavirus vaccine was introduced in the United States, there would be several million cases

00:48:56.800 every year of rotavirus. There would be about 75,000 hospitalizations and roughly 60 deaths

00:49:01.200 every year from rotavirus. But no child got to age five without being infected with that virus. That

00:49:04.880 virus came into the United States in 2006. And within a few years, you started to see a dramatic

00:49:11.280 drop in the spread of that virus. It's still out there, but it's much, much less. And many residents

00:49:16.320 have never seen a case of rotavirus-induced diarrhea and dehydration, whereas it dominated my residency.

00:49:22.640 So you can control it, but you're not going to eliminate it. So I think that's number one.

00:49:27.680 Number two is, if you look at sort of the contagiousness index and the efficacy of the

00:49:31.520 vaccine, there's a formula for this. You would figure that you probably would need at least 80%

00:49:36.640 of the population to be immune, either from natural infection or immunization, to slow the spread of

00:49:41.760 this virus. But this virus, I think it's going to be with us forever. I don't see it going away. I think

00:49:47.040 it's just going to slowly get under control, assuming we can get the 194 countries in this

00:49:52.320 world to get a significant percentage of their population vaccinated. But know this,

00:49:56.720 we're going to be giving a coronavirus, a SARS-CoV-2 vaccine, continually until it happens

00:50:02.640 that other countries have gotten it under control. Because, you know, we give a polio vaccine every

00:50:06.400 year to children in the United States. We haven't had a case of natural polio in this country since

00:50:10.000 the 1970s. The reason we do that is polio still exists in Pakistan and Afghanistan,

00:50:14.640 and so international travel is common, so polio could always come back in this country.

00:50:18.560 And I think that's going to be true here, too. We're going to see how long immunity lasts. We're

00:50:22.080 going to see whether the variants get to the point where they escape immunity from natural

00:50:26.320 infection or immunization. But all that is going to play out over years, and we're going to be

00:50:29.600 dealing with this for years. But I do think we can get control of this virus if we can get at least

00:50:34.320 80% of the population immune to the point that we can go back to the things we normally do,

00:50:38.480 like going to Eagles games and screaming and booing without a mask. That is my goal.

00:50:42.720 Well, as a person who really can't stand the Eagles, you'll have to forgive me that I have

00:50:48.560 no interest in you going to Eagles games unless you are booing because your team is doing poorly.

00:50:53.120 Now, that said, let's go back to the person like this nurse who you saw at the doctor's office the

00:50:58.560 other day who says, I'm not going to get the vaccine. Now, my view is there's going to be a

00:51:02.800 subset of the population that will never be convinced that that is the right strategy,

00:51:07.440 or more to the point that getting a vaccine is a safe alternative to getting COVID. So,

00:51:13.040 that's fine. I think we do live in a world where medical freedom for adults exists, and I support

00:51:17.680 that. So, I do support a person's right to choose to not get a vaccine. Can't we still get to herd

00:51:24.320 immunity when enough healthy people who have refused vaccination survive the infection? Because we

00:51:31.600 we certainly have seen that natural infection is going to be a great way to develop immunity.

00:51:37.920 So, I don't know what the numbers are, but is it safe to say about 30% of American adults

00:51:43.360 don't want to get vaccinated?

00:51:44.640 I don't know. If I had to guess, I think it's probably that, about 30%, maybe more. And you're

00:51:51.680 right in terms of natural immunity in that, if you look on the reports, you know, on this COVID

00:51:56.640 tracker, it says 32,000 people, sorry, 32 million people have been infected with SARS-CoV-2 and have

00:52:02.480 COVID. But that's only people who've been tested and found to be infected. If you do antibody

00:52:06.960 surveillance studies, that number is probably all five.

00:52:09.120 That could be much higher.

00:52:09.840 It's probably more like the CDC estimate last I saw, which was a few weeks ago, was 85 million.

00:52:14.320 It's probably close to 100 million people who've been infected with this virus and are naturally

00:52:18.160 immune. And then we don't know the overlap between those people and then who's been vaccinated.

00:52:22.080 There's obviously going to be a Venn diagram. You can't add these things up. I guess the way I look

00:52:26.240 at it is, even with a modest success of the vaccine and those, let's just say those 30% of people

00:52:33.520 who say, I'm not going to be vaccinated, someone's got to be able to come up with a reasonable

00:52:37.120 estimate for how many of those people were knowingly infected in the past, were unknowingly

00:52:42.000 infected in the past. And in other words, those people you could argue don't need a vaccine.

00:52:46.320 Then you've got the group who have not been infected, who don't want to get vaccinated. Well,

00:52:51.280 a subset of those people are going to get infected and therefore will develop natural immunity.

00:52:56.160 For those of us who choose to get vaccinated, Paul, is it really that big a concern at the number

00:53:01.760 of people who don't want to get vaccinated?

00:53:03.520 Well, first of all, we're also assuming that natural infection induces a durability and

00:53:08.240 completeness of protection that is the same as vaccine. That may not be true. I mean,

00:53:12.080 the vaccine, there are certainly a number of vaccines. The human papillomavirus vaccine is

00:53:15.680 one example. Tetanus is another. The conjugate Hib and pneumococcal vaccines are another example

00:53:19.920 where the vaccination is better than natural infection in terms of the immunity that's induced.

00:53:23.680 That may also be true here. Well, I think it's perfectly reasonable to give them a dose of vaccine,

00:53:28.160 dose of the mRNA containing vaccines.

00:53:29.920 Sort of the booster strategy for those who are naturally infected.

00:53:33.600 You and I are going to differ on one thing, which is a person's right to choose not to be

00:53:37.040 vaccinated. I think if I cut my foot on a rusty nail, for example, go to the doctor's office,

00:53:42.080 get it washed out, and the doctor says I would recommend a tetanus vaccine, and I choose not to

00:53:46.240 get a tetanus vaccine, that only affects me. I mean, if I get tetanus, nobody's going to catch tetanus

00:53:50.400 for me. That's not true here. I mean, when you make a choice not to get a vaccine, you are making a

00:53:55.200 choice potentially to catch and transmit a potentially fatal infection. And see, I don't

00:53:59.120 think that's your choice. I think that should not be your inalienable right as a U.S. citizen

00:54:04.400 to affect others. I mean, if you're going to stay in your house and the only time you ever

00:54:09.680 walk outside is you're going to be really good about wearing a mask and making sure you're

00:54:12.960 four to six feet away from somebody else, great. But that's not the way it's going to play out.

00:54:16.160 And I think we're dealing with that in our hospital now is the issue of mandating a vaccine.

00:54:20.400 You know, we have a population of vulnerable hospitalized children. Certainly viruses like

00:54:25.280 this can spread in a hospital. And is it your responsibility as someone who works in a hospital

00:54:30.320 in a group of vulnerable hospitalized children to get a vaccine? We think the answer is yes.

00:54:34.000 Well, I would agree with you on that. So I mean, obviously, these things are nuanced. I'll tell you

00:54:37.920 where my view is. There are going to be some people for whom there is a privilege that comes from

00:54:43.760 your existence. So for me, healthcare is a privilege. To be a doctor or a nurse is a privilege, not a right.

00:54:50.000 And so I would agree with you. If you're going to work in a hospital and take care of patients,

00:54:54.880 I do not believe you should have the right to refuse vaccination for exactly the reasons you've

00:54:59.120 stated. Furthermore, I would agree that, and this is getting way off topic, but when it comes to MMR,

00:55:05.600 I don't think the parents should be able to refuse that for their child because I don't think it's

00:55:10.800 fair to the children. In other words, I don't think a parent should be able to make a decision

00:55:14.640 that's going to negatively impact a child. I will go one step further. This is going to,

00:55:19.360 I'm sure make, I'm sure every statement I'm making is making a newer and newer faction of people

00:55:24.240 irate. So the last one I'll say is, I think that society may have to make decisions about who

00:55:30.720 can and can't have other certain privileges such as travel. So I think that there should be a day when

00:55:38.240 if we decide, you know what, like people who haven't been vaccinated or haven't conferred natural

00:55:42.880 immunity through some other means and can demonstrate it, maybe we don't want to have all those people

00:55:47.520 traveling on airplanes or maybe certain countries are going to say you can't enter unless you've

00:55:52.080 done those things. So I think you and I would probably be aligned on everything I just said.

00:55:56.880 I think where we do differ is if John Smith, who works in whatever he does, doesn't want to get

00:56:04.800 vaccinated provided his society, his network is okay with that, you know, and he's not lying about

00:56:12.720 it or something, which again, I think there are ways around that. You have to live with the consequences

00:56:16.480 of your choice. When people say to me, why would you, Peter, as a healthy, you know, roughly 50 year

00:56:23.200 old get vaccinated when your odds of dying are so low from a natural infection? I say, frankly, my concern

00:56:30.160 is not death. I think my odds of dying from this virus are so low that, you know, I'm more,

00:56:36.240 I'm much more afraid of dying in a car accident. What I'm afraid of are the long-term consequences

00:56:41.200 of this that don't seem trivial, even in young people. And, you know, there was an article in

00:56:46.640 JAMA maybe two months ago that talked about some of the long-term neuropsychiatric complications that

00:56:52.800 are being seen in up to a quarter of people six and 12 months out. And to me, those are the things

00:56:58.800 that are of grave concern. And again, when you weigh the risk of that versus the risk of vaccination,

00:57:04.560 which I think you very eloquently spoke to at the outset, to me, it's personally a no brainer.

00:57:10.000 But that said, there are gray areas in between. That said, of course, I agree with you about in

00:57:16.080 the hospital. I think it's a tragedy that a high risk patient would be cared for by someone in a

00:57:20.800 hospital who has willingly or knowingly chosen not to be vaccinated. This is probably the one area

00:57:25.680 we're going to disagree. But I think, see, I see the hospital as a microcosm of society. I mean,

00:57:29.920 if I, there are probably about 500,000 people or so in this country who can't be vaccinated because

00:57:34.960 they're getting biologicals for their chronic disease, because they're getting chemotherapy for their

00:57:38.960 cancers, they depend on those around them to protect them. I mean, I remember when, when

00:57:43.280 California suffered its measles epidemic and Richard Pan, who was a democratic state senator

00:57:48.720 out of Sacramento, basically eliminated the philosophical exemption, leaving California

00:57:53.200 with only medical exemptions. They'd never had a religious exemption. Now that you only had

00:57:57.360 medical exemptions, if you went to school in California, you had to be vaccinated or you could

00:58:01.680 homeschool. There was a little boy who showed up at those meetings and certainly the anti-vaccine

00:58:05.440 folks were all over those meetings. They didn't want this, this exemption eliminated. And this,

00:58:10.160 he was great. I just wish there was a videotape of him because I've heard what he said and I've

00:58:14.320 seen pictures of him, but he's a little kid named Luke who was five years old and he was in the

00:58:19.040 induction phase of his chemotherapy for acute lymphoplastic leukemia. And he would get up to

00:58:23.280 the microphone. They'd have to give him a stool so he could reach the microphone. And he would say,

00:58:27.600 what about me? I depend on you to protect me. Don't I count? And I think that that's how I see,

00:58:33.680 I see the hospital in some ways as society, you know, you don't know who you're running into when

00:58:37.200 you're getting on a subway or a bus or whatever. And that could be, those could be the Luke's out

00:58:41.600 there. So I just don't think if it's, it's a contagious disease that that's, that's where I

00:58:45.840 sort of draw the line. So love to discuss this more over a meal. Let's talk about the implication

00:58:52.800 of it though. Do we believe, cause I don't think it's going to happen from a practicality

00:58:57.600 standpoint. Is there any chance this is going to be mandated? At the private level, there's already

00:59:02.480 is at some level and in a carrot, not stick sort of way where, you know, a number of universities now

00:59:07.200 said, want to come back to campus. Great. Love to have you get vaccinated. If not, you're going to

00:59:10.960 continue to do remotely. Sure. And just as travel restrictions may only open up to those who are

00:59:17.920 vaccinated. I mean, I completely, I think that's exactly the right way to do it. But my point

00:59:22.720 is we'll never do what California did, which is say, you don't get to send a kid to school without

00:59:27.760 vaccination, which by the way, I think was the right thing to do a hundred percent,

00:59:30.640 but I don't see how you would enforce or make something like that happen in society. So assuming

00:59:35.920 we don't, what do you think is the duration of time from now until we achieve herd immunity,

00:59:42.560 based on what you know about the speed with which the vaccines are rolling out and the limited

00:59:47.680 information we have about the rates of natural infections, which are obviously challenging to

00:59:52.880 comprehend. Right. So let's assume the following. Let's assume that about 25 or maybe as many as 30

00:59:58.560 percent of the population has been naturally infected. We know that about 22 to 23 percent

01:00:04.480 of the general population has also been now fully vaccinated. With the adult population,

01:00:09.600 so it may be a little more than that. And you're right, there's overlap in terms of having been

01:00:13.360 infected or having been vaccinated. So let's assume we're getting close to 40 percent. To get to 80

01:00:18.480 percent, you're probably going to need to fully immunize another 120 million people. We're vaccinating

01:00:23.280 more than three million people or three million doses of vaccine a day. These are mostly two-dose

01:00:27.680 vaccines. So if you just play out the math, it's possible that if we continue to get three million

01:00:33.440 doses a day out there, that within three or four months, we could have vaccinated that other 120

01:00:38.240 million people. I think by mid-summer, when there's enough vaccine for everybody, that's when you're

01:00:42.560 going to really find out how many, what percentage of the population doesn't want to get vaccinated.

01:00:46.320 And then we'll see what we're going to do. And the way that you'll test, you'll know whether or not

01:00:50.240 we've succeeded with herd immunity is what happens next winter. This is still at its heart, largely a

01:00:54.960 winter respiratory virus. And if you look at what happened when the virus came into the U.S. in early

01:00:58.880 March and started to kill people, it quickly shot up. You would have 2,000, 2,500 deaths. So just

01:01:03.600 look at deaths, deaths a day. And then it started to come down. As you went to sort of April, May, June,

01:01:08.320 you started to see the number of deaths per day come down. This was in a wholly susceptible

01:01:13.040 population without a vaccine. And then for the summer months, you were sort of at hundreds of

01:01:18.000 deaths a day. Then once you hit November, December, it took off again. 2,000 deaths a day, 3,000 deaths

01:01:23.760 a day, 4,000 deaths a day, 4,500 deaths a day. And then now it's started to come down again. And I

01:01:29.200 think that there's several reasons. One, because a larger percentage of the population is immune from

01:01:33.440 natural infection because a larger percentage of the population is immune now with vaccination. But

01:01:36.880 I think also the weather has something to do with this. So it's now starting to come down. What

01:01:41.360 happens then next winter, if we're at population immunity that is effective, then you will see a

01:01:47.440 bump in the winter month. If we're not, you are going to see a surge just like we saw this winter

01:01:51.840 in the winter month. And that's how you'll know. But we're going to be vaccinating this population

01:01:56.160 for my lifetime because I just think this is a virus that's not going to go away. We're going to

01:02:01.200 continue to need to keep up that population that's immune. And that's also going to involve

01:02:05.760 children. So now, you know, we've got an approved vaccine down to 12 years of age. I think by early

01:02:10.720 next year, we'll probably have it down to six years of age. And then we're going to need to,

01:02:14.080 I think, vaccinate children as well. Will that be because children are vectors

01:02:18.880 or because we actually fear harm to the kids themselves? Both. But I was on service for two weeks in

01:02:25.680 a row about a week ago. And it's the same thing that you mentioned earlier in terms of like

01:02:31.200 fear of long-term disease. You should see what MIS-C looks like up close. I mean,

01:02:35.840 this so-called multi-system inflammatory disease in children, which is not uncommon. And they all

01:02:40.880 tell the same story, a very similar story, which is that they had an incidental infection,

01:02:45.520 something that was picked up often because a family member or friend got sick. And so then they

01:02:49.280 had, they were tested to be PCR positive, but were asymptomatic. A month later, they come now to our

01:02:53.920 house with high fever, involvement of heart, liver, lung, kidney, you know, heart enzymes spilling

01:02:58.800 out into the bloodstream with high fever. And they're PCR negative and they're antibody positive.

01:03:04.240 I mean, their immune system has been induced to make an inflammatory response against themselves.

01:03:09.600 I mean, primarily against the cells that line vessels. And so this is a largely a vasculitis.

01:03:14.560 And because every organ in your body has a blood supply, virtually every organ can be affected.

01:03:18.720 It's pretty frightening to see. And do I think that some of these kids are going to have long-term

01:03:22.960 problems? I absolutely do, for the same reason Kawasaki's did that. I mean,

01:03:26.560 also another multi-system inflammatory disease that could cause long-term heart problems. I think

01:03:31.440 that is likely to be true here. We're going to learn as we go. But if a parent sat across from me

01:03:36.480 in my office and asked me, why should I vaccinate my child? These are the stories I would tell,

01:03:41.120 the Miss C story. Yeah. I mean, I wish I had a crystal

01:03:44.160 ball that would show us the data we're going to have a year from now. Like when you think about how

01:03:48.000 much we have learned in 12 months, it has been a geometric outflow of knowledge. And the next 12

01:03:53.920 months will offer, I think, even more insight. Because as you said, we're going to be laying

01:03:59.280 over the natural infection. The vaccine immunology will also, as you basically alluded to, really

01:04:06.960 have a true sense of what steady state is going to look like societally with respect to vaccine

01:04:11.200 refusal. And so we will be able to incorporate that into models of how close we are going to get

01:04:17.120 to that herd immunity. But let's talk about it through the two scenarios. There's a scenario clearly

01:04:21.840 where enough people refuse vaccination that we never truly achieve herd immunity.

01:04:26.240 And in that sense, the real tragedy is for the vulnerable people who can't be immunized,

01:04:30.720 correct? I mean, I think that's a very clear thing to acknowledge is there's going to be a subset of

01:04:35.040 people who, because of their cancer treatment or rheumatologic treatments, can't be vaccinated.

01:04:40.480 And the disease is still spreading like crazy. Then there's a scenario under which we get to herd immunity

01:04:46.160 on the backs of people who are naturally infected and or are willing to be vaccinated, inclusive of

01:04:53.120 children. And have you done the math on how far down you need to go in kids' ages to almost assure

01:04:59.600 that happens? In other words, if you go down to six years of age, is that pretty much a fait accompli?

01:05:05.520 Oh, for sure. You may not even have to get down that far. I mean, it's something like 20% of the

01:05:10.880 population is less than 18 years of age. So you assume that all adults got vaccinated, which isn't

01:05:15.600 going to happen. You know, you're already talking about 80%. But the other reason I think that deaths

01:05:20.240 are down, you look at Michigan, for example, clearly there's been a surge of cases in Michigan,

01:05:23.920 but not really a surge in deaths. And I think the reason is, is that it's something like 55% or 57%

01:05:29.360 of people over 65 now have been vaccinated fully and something 75% have gotten at least one dose of

01:05:34.560 vaccine. So we're starting to pull out of the group, the group, those that are most likely to die.

01:05:40.480 It's something like 92% of those over 55 or those over 55 account for 92% of the deaths.

01:05:46.320 So, you know, we're now pulling them out. And so that's, I think it's one of the several reasons

01:05:51.120 why the deaths are clearly coming down now. Paul, how long do you think it'll be before we

01:05:55.360 know the frequency with which people need to be given a booster shot? And is this going to be a

01:06:01.440 single booster shot that should be more than enough to make sure that the memory T and B cells are

01:06:08.320 rocking and rolling? Or do you think that, and by the way, I'm putting aside for a moment,

01:06:12.640 mutation. So let's put that aside for one second, but just on the basis of B117, D614,

01:06:21.920 is it your immunologic expectation that if you've had your two RNAs, you'll need one more. If you've

01:06:28.640 had your one ad, no, you'll need one more and that should be it. Or is it, are we talking about

01:06:33.200 an annual or biannual process? I think we'll know in two years. I think we'll have a much

01:06:37.760 better idea in two years how this plays out. There were studies done with human coronaviruses,

01:06:41.360 human challenge studies done with human coronaviruses in the early 1990s, where they

01:06:45.040 would, you know, someone would be infected with a serotype, one of the four serotypes of human

01:06:48.960 coronavirus that circulates. And then a year later, they were experimentally challenged with that virus

01:06:53.040 to see, answer the question, were they protected against symptoms associated with illness? And they were

01:06:58.880 a year later, but they never did those studies beyond that. I'm optimistic that it would be for

01:07:04.960 a few years, but I don't think that we're talking about decades. Okay. Let's pivot to another question

01:07:10.560 that has come up a lot. And when it first arose, which was a year ago, if not more than a year ago,

01:07:17.520 the people who were raising it sounded crazy. And today it doesn't sound so crazy, which is the

01:07:23.200 origin of this virus. So there are largely two competing theories. The first is the theory that

01:07:28.800 was proposed at the time of the pandemic's arrival, which is that this was a virus that escaped from

01:07:37.200 a bat or left a species of a bat via some intermediary mammal and made its way to humans.

01:07:43.920 This originated in a wet market in China. And that's kind of the story everybody knows. But with

01:07:50.400 increasing, I don't want to say veracity, but certainly with more and more reason behind it,

01:07:57.680 there are lots of people offering explanations for the idea that this was actually an accidental

01:08:02.800 escape of a virus in a lab that happened to be near Wuhan. So I guess there were three labs near

01:08:09.120 Wuhan that would do this type of research. This theory does not suggest biological warfare,

01:08:14.240 that this was deliberately unleashed, but rather that any lab can have a breach in

01:08:19.520 protocol that could result in a virus leaving. How much have you examined this theory?

01:08:24.480 I mean, certainly it is not unheard of that laboratories have done so-called gain-of-function

01:08:28.880 studies to see what would happen if they alter a virus and then cause it to be able to do things

01:08:34.560 it couldn't do before. So for example, you could take rabies virus. I'm not saying you should do

01:08:39.280 this or how easy it would be to do this, but you take rabies virus, which is essentially a universally

01:08:43.280 fatal virus, but not easily transmitted. I mean, in order to get rabies virus, you usually have to be

01:08:48.240 bitten by a rabid animal and make it such that it is spread by the respiratory route. So now you have

01:08:54.400 a contagious virus that is highly fatal, which I think was basically the story behind the movie

01:08:59.520 Contagion. I think it was a Nipah virus that killed Gwyneth Paltrow in that movie and others,

01:09:05.760 because they showed an electron micrograph of it. And I think this was a Nipah virus, which is

01:09:11.440 not easily transmitted. And they made it easily transmitted. It's something that affects the brain,

01:09:15.840 they made it easier. So certainly gain-of-function studies have been done. Is it possible that

01:09:20.720 somebody in Wuhan was doing these kinds of gain-of-function studies? I'm telling you,

01:09:24.720 though, this is like the world's smartest human. I honestly don't think humans were smart enough to

01:09:28.240 make this virus, given all the things that it can do. The only way to really know the answer to the

01:09:32.720 question, because I think this is a knowable question, is to go back and look at all the

01:09:37.440 sequences of those early strains and go back as early as you can and look at, you know,

01:09:41.600 CIRA from people in China, you know, from well before this virus was said to have spread. I mean,

01:09:47.520 think about it. We really depended on a whistleblower in Wuhan to tell us what was going on,

01:09:52.400 which was China not acting like a good neighbor here. And that's the way we did it with HIV. I

01:09:57.440 mean, when we finally got all the sequences that we needed with HIV, we'd go back further and further

01:10:02.800 and further to see when exactly it evolved from so-called simian immunodeficiency virus. I mean,

01:10:08.160 the chimp virus. You could see that it happened in Cameroon in the 1930s, presumably when a hunter

01:10:14.240 cut the chimp and then cut himself and introduced the virus into himself. But so it's knowable. I

01:10:19.520 just don't think we know. So now we're left with sort of postulates as to how it happened. My bias

01:10:24.160 is that it jumped from a bat to humans, presumably from an intermediate host that remains unidentified.

01:10:30.160 You know, people have suggested maybe it's pangolins, but that's knowable if we can just have all

01:10:34.800 the sequence data we need. And China has not been great about opening its doors and letting us see

01:10:39.520 all that information. If you assume that it occurred naturally, it begs the question,

01:10:48.640 if versus when this occurs again, because coronaviruses have been around longer than we have.

01:10:55.440 There's no reason to believe that SARS-CoV-2 is the last of them. So what is the implication for SARS-CoV-3?

01:11:04.800 Oh, we can assume this is going to happen. I mean, you know, we had SARS-1, which was largely

01:11:08.800 a bat virus. We had MERS, which came out of Saudi Arabia, which was also at least in part of bat

01:11:13.440 virus. And now you have, you know, SARS-CoV-2, three viruses all within roughly 20 years, right?

01:11:18.880 SARS-1 was around 2002, MERS around 2012. It'll happen. I mean, I'd like to think what we've learned

01:11:25.600 from this is that it will happen, that we need a level of international collaboration, that with the

01:11:31.040 minute there's evidence that this is going on, that there's an international surveillance system

01:11:35.680 where all countries are open to this, where we can identify it, you know, do the kinds of works we

01:11:41.040 need to do, not just to make a vaccine, but to have, you know, personal protective equipment

01:11:44.560 and ventilators or anything else that you're going to need so that we're not overwhelmed by this.

01:11:49.120 I mean, this, unless you're 130 or 140 years old and lived through the 1918, 1919 flu pandemic,

01:11:54.960 no one has lived through this. And I'd like to think this has sobered us up as to what needs to

01:11:59.760 be done moving forward. Do you think that there's a chance that if the next variant of this comes

01:12:05.600 along, which is even worse than this one, so pick, so either it's more virulent, but has the same degree

01:12:11.760 of transmissibility, or it's similar virulence, but an even greater transmissibility, either of those

01:12:16.960 would make for a much worse pandemic. Do you think that there's a chance that such a virus emerges,

01:12:22.720 let's just say it originates in the United States, that a given population locally could be shut down

01:12:28.720 enough to identify quickly patient zero, you know, the first 50 people, and immediately quell this

01:12:35.280 thing? Or do these types of things never result in a local shutdown that is effective and they will

01:12:43.920 always turn into something bigger? Because the difference between SARS-1 and MERS is not so much

01:12:49.280 that the response was amazing. I mean, in the case of MERS, I think the thing was just such a deadly

01:12:54.000 virus that it didn't have a high enough reproductive rate because it was killing people too quickly.

01:12:58.880 It's not like we did such a great job with those viruses. It was really the biology of the viruses,

01:13:04.000 right? Right. I think both SARS-1 and MERS were, did not have this level of asymptomatic

01:13:09.600 transmission. I think that's what makes this virus so awful. And that when you walk past somebody in

01:13:14.480 the street who's perfectly fine, they could be shedding this virus. That really wasn't true

01:13:18.400 with SARS-1 or MERS where most of that disease was either moderate or severe. So it was much easier

01:13:23.440 to put a moat around those infections than you can here because everyone could be infected. This

01:13:27.680 actually in many ways reminds me of polio. I mean, I am a child of the 50s. I'm much older than you are,

01:13:32.080 but I remember polio. But part of the heinousness of polio was that only about one of every 200

01:13:36.720 people who was infected with polio virus was paralyzed. I mean, there was a lot of asymptomatic

01:13:40.720 transmission of that virus. So what does that mean though,

01:13:42.880 Paul? How confident are you that 10 years from now, we're not going to have another worldwide

01:13:47.600 pandemic that, you know, the analogy I used to describe this to somebody the other day was,

01:13:53.040 when you're driving a race car, the worst thing you can be doing is braking too late because then

01:13:59.120 you have to brake much harder than you want to. And the dynamics of the car become really unstable

01:14:04.320 and you're probably going to crash. And in some ways, I sort of feel like that's what happened

01:14:09.040 in the United States, which is we didn't brake soon enough. And when we did brake,

01:14:15.680 we had to brake way harder than we should have, and we crashed. And I want to believe we could learn

01:14:21.600 from that. For such a great analogy. I do think that at the heart of that question is how much do I have

01:14:27.280 faith in human nature that we can learn from these things, that we will have the kind of heart,

01:14:33.120 big heartedness that will allow us to have international collaborations and more open

01:14:37.200 borders regarding sort of scientific inquiry. We haven't been very good at that so far. If we

01:14:42.480 don't learn our lesson here, I mean, we're never going to learn it. So I don't know. I don't have

01:14:46.400 an enormous amount of faith in human nature that we're going to learn from this, but I hope you're

01:14:50.080 right. Yeah. I wasn't suggesting I was right. I was just, I was wondering what would need to happen,

01:14:55.760 right? What would, let me pose it to you this way, Paul. If someone came to you and said,

01:15:02.880 hey, I want to put you in charge of thinking about the next pandemic. You're doing a great job

01:15:07.920 helping us with this one, but we've got a lot of people thinking about this one. I want you to go

01:15:11.760 on vacation for two weeks, recharge, shake the dust off a little bit, and I want you to come back.

01:15:17.120 And the only thing I want you to do is think about how we're going to prepare for the next one.

01:15:21.200 What would be some of the ideas you'd put forth? It's an international collaboration. That's an

01:15:25.680 international question. So you have to get the governments and the scientists from every nation

01:15:30.320 in this world in line with what are we going to do collectively to monitor for the next pandemic

01:15:36.160 potential virus. And there will be a next pandemic potential virus in terms of surveillance. How are we

01:15:41.200 going to do that? How are we going to do the sequencing? Who's going to do it? And then once in

01:15:45.920 hand, when we see that that's true, how are we going to collaborate to do this to make sure we all

01:15:50.960 have what we need because we're all dependent on each other, because we're only as strong as our

01:15:54.480 weakest nation out there? How are we going to do that? But even with the vaccines, you see a

01:15:58.960 certain level of nationalism, right? The Chinese have their vaccines, the Russians have their vaccines,

01:16:04.080 we have our vaccines. The fact of the matter is, I think Dr. Fauci is amazing. He's a phenomenal

01:16:10.400 science communicator. He's a brilliant man. The only time he's ever said anything that bummed me out a

01:16:16.320 little bit was when somebody asked him about whether or not there would be another vaccine

01:16:20.400 that would be submitted for licensure, like the UK AstraZeneca vaccine being submitted for

01:16:24.800 UA approval here. And his response to that was, we don't need another vaccine. We have enough

01:16:28.560 vaccine for our country. But I think our country has a responsibility to all countries in this world,

01:16:33.680 who are economically and technologically advanced, to provide vaccine for everyone if we can. And we can.

01:16:38.720 You know, the Pfizer, look at these mRNA vaccines. They're given at 30 micrograms or 100

01:16:43.600 micrograms a dose. A microgram is a millionth of a gram. That's 10 to the minus six, right?

01:16:48.480 You can make kilograms. That's 10 to the third, right? That's a nine log difference. That's a

01:16:53.360 billion fold difference. Can you make billions of doses of mRNA vaccine? Absolutely. Should you?

01:16:58.800 Absolutely. And if it means restricting sort of the intellectual property and allowing that to happen,

01:17:04.640 it should happen because it's the right thing to do for these companies and for the world.

01:17:09.760 So this is an unrelated question to where I want to go. But while we're here on the topic,

01:17:14.000 do you have any idea what vaccine hesitancy rates are like outside of the United States? I have

01:17:18.080 actually haven't looked at those data. Right. So there's a woman named Heidi Larson

01:17:22.480 at the London School of Public Health who does this. She has something called a vaccine confidence

01:17:27.760 project. So she goes throughout countries in this world to see sort of what she measures vaccine

01:17:32.720 confidence. She recently had a book out that came out called Stuck. But interestingly,

01:17:36.560 we're not the least confident country in this world. The least confident country in this world

01:17:41.680 for vaccinations is France. Don't know why. Yeah, France is number one. So we're not actually

01:17:48.000 that bad. But see, I sort of divide this into two categories. I think there's the skeptics and I'm a

01:17:54.800 skeptic. I think you should be skeptical of anything you put in your body. I think you should want to see

01:17:57.920 the data to make sure that what you're being given has been adequately tested and vetted. I think

01:18:03.280 skepticism at this point, certainly for the mRNA vaccine, should melt away. You've got a highly

01:18:08.160 effective vaccine that doesn't even appear to have a rare serious side effect problem,

01:18:12.000 and it's been in 120 million people in the United States. Skepticism should be gone. And I think

01:18:16.400 largely among that group, it has. When you look at sort of percentage of people who said they would

01:18:21.040 definitely get a vaccine, they say last September, it was about 30 percent. Then by December, it was 40

01:18:26.720 percent. The University of Washington came out with recently a survey that suggested it's about 70

01:18:31.760 percent that said they would definitely get a vaccine. And then there's the second group,

01:18:35.200 which are the vaccine cynics. And they just don't trust the government or trust pharmaceutical

01:18:40.240 companies or trust the medical community. They just don't believe you. They don't believe you.

01:18:44.640 It's amazing to me that some of those people are also in the medical profession,

01:18:47.920 but that's been the experience. So you can't convince them. Neil deGrasse Tyson has just a great

01:18:53.360 quote on this, which is, if people don't use reason or logic to come to a specific conclusion,

01:18:57.760 reason and logic are not going to talk them out of it. So then what do you do? And then this is what

01:19:01.680 we were talking about earlier. Do you compel them either with the carrot or the stick to get

01:19:06.160 vaccinated because what they do affects others? When I think back, looking at the past year,

01:19:10.720 Paul, this is my opinion, which I'm only stating so you can contrast it with something that's probably

01:19:15.200 much more thoughtful. My view of the greatest single failure in the past year was how long it took to

01:19:21.680 get testing up and running. When I think about the absolute buffoonery on the part of, I think it

01:19:30.560 was frankly, mostly on the part of the government, but I'm sure there were others at hand. It was the

01:19:36.160 inability to make testing readily available. Now, I don't think it was at the obvious level. I mean,

01:19:42.240 I think there are things that probably weren't in place. In other words, how much reagent existed for

01:19:48.000 PCR to begin with? But you'd like to think that in a future pandemic or in preparedness for a future

01:19:54.080 pandemic, you would have enough PCR machines, you would have enough reagent, you would have enough

01:20:00.720 other critical infrastructure such that the moment you had a sequence, because getting the sequence of

01:20:06.880 this virus was not the right limiting step. The moment you had a sequence, you would be able to

01:20:11.600 rapidly deploy tests to contain this thing. And I think a lot of the things that have happened since

01:20:18.640 that time have been actually pretty good. Like, I mean, the speed with which the vaccine has been

01:20:22.480 developed has been remarkable. I think the evolution of insight into critical care has actually been

01:20:28.320 pretty darn impressive. So I think a lot of things have gone kind of well, but boy, that testing thing

01:20:35.040 is really what goes back to my analogy of coming, you know, waiting way too deep in the corner to hit the

01:20:40.800 brakes and then slamming on the brakes and crashing the car. What's your assessment of where we really

01:20:49.040 lost things this time around and therefore where we'd want to really make sure we had it right the

01:20:53.920 next time around? Right. I completely agree with you. I mean, we had the sequence in hand by January

01:20:58.240 of 2020. The virus started to kill people in this country two months later. Was that enough time to be

01:21:03.760 able to create, produce, and distribute enough tests that we could have done what South Korea did? Now,

01:21:08.560 we're not South Korea in many ways. I think we are a much more diverse population that is much less

01:21:15.680 corrallable, if you will. And so, but I do think that we put all our eggs in the CDC basket. It was

01:21:21.440 just CDC that was making the test, whereas it should have been many, many groups that were making those

01:21:25.600 tests initially and quality controlling for them. Because what happened was then CDC screwed up.

01:21:30.880 They did. They screwed up the testing so that their negative control ended up being positive.

01:21:34.800 Therefore, those tests were useless. And so, by the time that all got sorted out,

01:21:38.400 South Korea had done 500,000 tests when we had done fewer than 5,000. It was pathetic,

01:21:43.360 pathetic. And if we had done that, and again, I just don't think we didn't have great federal

01:21:48.800 leadership either. That's today's understatement in terms of this, where you could have said,

01:21:52.720 let's get things in place to do the testing, do the quarantining, do the restriction of international

01:21:57.120 travel that would have allowed us to be much better off. I mean, we are roughly,

01:22:01.600 roughly at 4% of the world's population and 20% of the world's deaths when we have a technologically

01:22:06.480 and economically advanced society. So there's really no excuse for doing it as badly as we did

01:22:12.000 it. But I think the testing was one big reason. I agree. Well, Paul, there are actually several

01:22:16.960 things I want to talk with you about more, but I also know that given that the news of J&J's vaccine

01:22:22.080 just hit, you are probably being dragged in a million different directions. So I want to let you

01:22:28.080 get on with those obligations. And I'm incredibly grateful that you made time to still speak with me

01:22:34.080 today, obviously far less important than speaking with all the other people that are clamoring at

01:22:38.480 your door today. So thank you again for making time as it was the case last time, just a phenomenally

01:22:44.480 interesting discussion to me. I learned a lot and I know that the folks watching this did as well.

01:22:48.560 Well, no, thank you. I can tell you that you'll be the most interesting,

01:22:51.440 smartest person that was clamoring at my door as I go through the rest of my day. But no,

01:22:55.280 I really appreciate this. It was a lot of fun. Thank you. Thank you for listening to this week's

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The Peter Attia Drive - May 03, 2021

#160 - Paul Offit, M.D.： The latest on COVID-19 vaccines and their safety, herd immunity, and viral variants

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