The Peter Attia Drive - #115 - David Watkins, Ph.D.： A masterclass in immunology, monoclonal antibodies, and vaccine strategies for COVID-19

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

00:00:15.480 my website and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.800 into something accessible for everyone. Our goal is to provide the best content in health

00:00:24.600 and wellness full stop. And we've assembled a great team of analysts to make this happen.

00:00:28.880 If you enjoy this podcast, we've created a membership program that brings you far more

00:00:33.280 in-depth content. If you want to take your knowledge of the space to the next level at

00:00:37.320 the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

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

00:00:47.760 here's today's episode. I guess this week is professor David Watkins. David is a professor

00:00:54.220 of pathology at the George Washington university medical school, where he recently relocated from

00:00:58.660 the university of Miami. There's an interesting story about his recent relocation, which we touch

00:01:03.140 on at the opening part of this interview. Dr. Watkins was elected a fellow of the American

00:01:07.100 Academy of Microbiology and was vice chair of research in pathology at the university of Miami

00:01:11.800 prior to this recent transition. His early work focused on the similarities between non-human primate

00:01:19.420 simian immunodeficiency virus, SIV and HIV. In fact, SIV is a great animal model for HIV,

00:01:25.900 which is where David has spent the bulk of his career. And we touch on that quite a bit in this

00:01:30.500 episode, because there's a lot you can learn about what may or may not work with coronavirus.

00:01:36.200 Obviously the purpose of this discussion was really to talk about coronavirus, but really what I find

00:01:42.340 great about this episode is the immunology 101 discussion that I wanted to open with, and we did

00:01:49.220 open with, but we went deeper than I expected we would go. I just can't say enough about that. I think

00:01:54.360 if you are trying to make sense of what you are hearing about this vaccine versus that vaccine

00:02:01.180 versus this test for antibodies versus that test for antibodies, if that stuff isn't crystal clear

00:02:07.140 to you, you're going to want to listen to this. And even if you don't care about some of the other

00:02:10.480 stuff we get into in the more nuanced science later on, I think the first part of this interview

00:02:15.260 will appeal to anybody who's trying to understand immunology and doesn't know the difference between

00:02:19.880 the innate system versus the adaptive system, the cellular system versus the humoral system.

00:02:26.480 I think the show notes for this are going to be really helpful because again, there's just so

00:02:29.940 much content here. David does just a great job explaining kind of the overall different categories

00:02:34.880 of vaccines, the inactivated viruses, the attenuated viruses, et cetera. And we go into what the examples

00:02:40.920 are of each of these. And then finally, David talks about what he is most excited about on this front,

00:02:46.060 which is the potential for monoclonal antibodies. So I hope you enjoy this episode and it's not going

00:02:51.380 to be the last one on this topic, but this one's an important one. If you want to understand anything

00:02:56.260 that we go into deeper. So without further delay, please enjoy my conversation with David Watkins.

00:03:07.660 David, thank you so much for making time to sit down after you just barely had a chance to settle

00:03:13.240 into Washington DC. My pleasure. I'm still not fully settled in and it's been a series of disasters

00:03:20.240 that have occurred in our move here to Washington, but hopefully we will get over those things pretty

00:03:28.180 quickly. Yeah. I didn't know about this until recently. Would you be comfortable sharing with

00:03:33.800 people the major disaster that is, I mean, if not for the fact that you were laughing, I certainly

00:03:39.400 wouldn't have a smile on my face because it's so sad, but. Well, our freezer truck traveling from

00:03:45.720 Miami to Washington DC. Maybe explain to folks that you've just left the University of Miami. Yeah.

00:03:52.340 Yeah. So I've been at the University of Miami for 10 years and recently decided to move to

00:03:58.540 GW Medical School. And so I needed to transport all of my samples that I've accumulated over probably 30

00:04:06.840 years of research. And they came up in a single truck in a variety of freezers that were plugged

00:04:13.400 into the truck. And there were a couple of liquid nitrogen freezers in that truck. And in North

00:04:18.540 Carolina, the truck caught fire and destroyed all of those samples. So over a hundred thousand

00:04:23.400 samples were destroyed in this truck. So we're now thinking and working with the insurance company

00:04:30.020 as to how to regenerate the most important samples in that truck. So yes, we had a little bit of a

00:04:38.420 setback. So David, you and I have met through this very interesting project. We're trying to get off

00:04:44.600 the ground, working with a bunch of really smart people, and we won't get too much into that project

00:04:49.720 specifically. But the point for the listener is some of my colleagues and I reached out to you

00:04:54.540 on the basis of your expertise in terms of understanding coronaviruses and specifically

00:05:00.560 around a question that pertains to how long could we expect the immunity of an infected person to last.

00:05:08.280 So if a person gets infected and is fortunate enough to survive, which fortunately is the majority of

00:05:12.900 people, what does that say about their ability to survive a subsequent infection? So a lot of paths and

00:05:19.900 roads led to David Watkins. So help me understand a little bit about your path. I know you were born in Uganda

00:05:25.600 and I know that you studied the Zika virus. I know you have a great interest clinically in HIV, but can I

00:05:31.480 connect some dots there for me in terms of where the interest in immunology came from?

00:05:35.480 So yes, I was born in Uganda and then I grew up in the West Indies until I was 11. And then I think it was in

00:05:42.900 the West Indies that I developed a keen interest in nature and all things tropical really, because it

00:05:50.840 was a very happy period in my life. My mother decided I needed to have a proper education. So I went to an

00:05:59.240 all boys British boarding school in South Wales, which was a pretty traumatic event coming from the color and

00:06:07.020 the beauty and the freedom of the West Indies to an all boys boarding school. However, I survived that. But I think that

00:06:15.880 what I got from my time in the West Indies was a deep appreciation of nature, and especially tropical nature, the

00:06:24.260 diversity. So I studied biology, and that was what was my great passion. And I did a degree, undergraduate degree in

00:06:33.820 botany and zoology, and then went to the United States to study immunology, really, the evolution of the

00:06:41.560 immune system, and then went to Boston and worked on the HIV epidemic in the long term. But initially, in the

00:06:53.140 short term, worked on the evolution of the immune response. So how did, first of all, frogs make an

00:07:02.000 immune response? And then how did monkeys make immune responses? So I was, I'm really an evolutionary

00:07:08.480 biologist. And then HIV came along. And this is the most dramatic example of evolution that I certainly

00:07:18.480 have ever seen, where the virus populations can change after infection in two weeks, where the

00:07:24.520 infecting virus can be essentially removed and a new virus appears under pressure from the immune response.

00:07:34.840 And then because of my roots in the West Indies, I had the occasion to visit Brazil about 20 years ago,

00:07:43.000 and realized that I was back in the West Indies because of the neotropical fauna, or exactly the same.

00:07:50.620 So I was back home. And since then, I've fallen in love with Brazil and learned how to speak Portuguese,

00:07:56.880 and now study many viruses that are tropical diseases like Zika and dengue. So I guess that's

00:08:05.920 how I came to develop my interest in tropical diseases.

00:08:12.100 Well, I share your love for Brazil, though clearly not your ability to speak the language, nor

00:08:16.740 probably the frequency with which you've been there, but it is a place I hold very special. And

00:08:20.820 I'm very bummed to probably not be making a trip this fall there. I was planning to take my wife,

00:08:26.540 potentially my daughter, to Sao Paulo. So I do look forward to getting back to Brazil, though, because

00:08:31.420 I agree with you. It is a very, very special place on this planet.

00:08:36.140 By the way, before we get into something, when you said the evolutionary thing, a question popped

00:08:39.840 into my mind that may or may not be relevant, but just out of pure curiosity,

00:08:43.240 when you think about our evolution as humans, people point to the development of language

00:08:49.040 as a big step function change in our development, or developmental changes in the brain, some of

00:08:55.520 which, of course, enable that change in language, or standing upright. All of these various things

00:09:00.300 that represented not just linear, but sort of logarithmic changes. Again, not that they occurred

00:09:06.160 very quickly in real time. Over a log scale, they look to have occurred more quickly.

00:09:10.860 What was the biggest change in the evolution of the immune system as you studied it?

00:09:17.460 I think probably the advent of the adaptive immune response, because many, many different animals have

00:09:25.920 innate immune responses that are incredibly important. But the evolution of T and B cells

00:09:33.000 that then allowed the immune system to have greater memory to respond to pathogens. And in the end,

00:09:43.100 is the basis for vaccination, which, as you know, is the public health measure that has saved more

00:09:50.980 human lives than any other public health measure. So yeah, probably the adaptive immune response. And of course,

00:09:58.420 that's what I'm interested in, too. So there's a little bit of bias here.

00:10:02.940 Well, when did that take place? How long ago did we acquire that out of just the innate system?

00:10:07.280 We certainly know that amphibians have T and B cells and make antibody responses and T cell responses.

00:10:14.640 So this occurred well before that branch of the animal kingdom.

00:10:20.380 That's amazing. I actually would not have guessed that. I would have guessed it was more recent than that.

00:10:24.160 But that's pretty impressive. And it speaks to, obviously, the importance of it.

00:10:28.860 So let's build up what you just said and give people a really good primer on immunology.

00:10:33.760 I love this topic as well, David. And I studied immunology, but in a different lens. I studied it

00:10:39.180 through the cancer lens. So mostly focused on the cellular branch of the adaptive system.

00:10:46.540 Could you walk people through kind of a diagram that people might keep in their mind's eye,

00:10:51.740 which says you first would bifurcate the immune system as innate and adaptive, and then you would

00:10:57.080 further bifurcate the adaptive system as cellular and humoral? So maybe talk about what those two

00:11:02.200 branch points mean. Let's say people get infected with influenza virus or even coronavirus. What

00:11:10.960 happens is that the virus enters a cell through a reset, and the virus can't replicate by itself and

00:11:17.040 needs to get into that cell and replicate. And then the virus starts replicating, produces copies of

00:11:23.320 itself which are sent out into the blood and infects other cells. That infection event triggers the

00:11:31.540 innate immune response. There are sensors inside cells that will then trigger the production of

00:11:39.320 interferons, which will then start to turn on immune system, including the adaptive immune system. The

00:11:46.600 adaptive immune system really has two major arms, the T cells and the B cells. I'm going to talk a

00:11:54.080 little bit about the B cell response for the moment, because that is what has really fascinated me for

00:12:01.620 the last two or three years. And we get an influenza infection, our lymph nodes under our jaws swell up. And

00:12:09.340 the question is, what's going on? And what's happening there is that pieces of the virus are being presented to

00:12:18.980 the B cells. And the B cells have receptors on their surface, and they recognize this piece of the virus. And they

00:12:28.740 bind very weakly. But that stimulates the cell to divide. Every time the cell divides, it makes an

00:12:36.460 error in copying this receptor on the cell surface. And some of those errors make that antibody less able

00:12:45.260 to bind. And that B cell will die. But some make it better able to bind the antigen. And this process goes

00:12:54.600 on and on. And so the B cells start growing, and your lymph nodes start swelling. And during this process,

00:13:02.520 even though you're born with a set of B cell genes, by the time you're 60, you may end up with a

00:13:09.380 different set of B cell genes through this beautiful evolution. In fact, this after HIV evolution,

00:13:18.380 in the face of the immune response is one of the most beautiful examples of evolution that I've ever

00:13:25.540 seen. So what happens is this receptor on the B cell starts mutating, and then is selected for,

00:13:33.260 and you arrive at a antibody that now binds to the antigen with very high affinity.

00:13:41.640 And can you tell people the difference between an antibody and an antigen and what some of the

00:13:46.680 different antibodies are?

00:13:48.700 Absolutely. Antigen simply means a piece of a virus. So when the virus comes in to the body,

00:13:56.280 it starts replicating and be picked up by a macrophage, which will engulf it and then

00:14:01.840 put it back out on the surface of that cell or on dendritic cells.

00:14:07.140 It's all very mechanical, and I think it's important that people understand this, right?

00:14:10.980 These things you're talking about, like these are physical proteins. This is a virus that invades

00:14:16.360 a cell. I think for people who don't understand immunology, it seems like a bit of a black box,

00:14:20.560 but the way you're explaining it, if people understand that you're talking about a physical

00:14:24.060 piece of the virus, a tangible piece of virus makes its way into these cells that present the

00:14:30.140 antigens, I mean, it becomes actually a lot less intimidating, I think, to understand what you're

00:14:36.280 saying.

00:14:36.600 It's simply a piece of the virus. Antigen, perhaps, is a piece of jargon that we shouldn't

00:14:41.060 use. So just a small piece of the virus, and that's out on the surface of this cell.

00:14:46.940 But it's enough for us to know it's not us. That's the key point here is it's an antigen,

00:14:52.620 not just because it's a piece of the virus. It's an antigen because our body has some capacity to

00:14:57.720 realize, hey, that thing is foreign. Isn't that sort of the key piece of this?

00:15:03.180 Yes, it's a recognition of something that's not self. That is what stimulates these B cells to

00:15:10.100 start replicating. And then on the surface of the B cells is another protein, which you can think of

00:15:16.180 as a shape or a structure. And this interacts with the piece of the virus on the other cell,

00:15:25.200 which is presenting that to the B cell. And then the B cell replicates. And every time it does,

00:15:32.160 it makes a mistake. And it gets either a better or a receptor that's not so good. But those better

00:15:40.580 receptors then start binding to the piece of the virus with greater affinity and can basically now bind

00:15:51.940 very tightly to the piece of the virus. So then they circulate in the body, in your blood. And in a

00:16:01.060 year's time, you have another infection from the same virus. And this time, those antibodies are there

00:16:09.380 already pre-made. They bind to that virus. And they stop it infecting cells, and you're protected.

00:16:17.820 And again, that's the basis of vaccination. If I vaccinate somebody, I give them the virus.

00:16:26.500 And that gets presented to the B cells. They make these antibodies. And they make them better every

00:16:34.800 time they see a piece of the virus. And so even though you haven't been infected with the virus,

00:16:43.720 you've been vaccinated, the next time you see live virus, these antibodies will bind to the live

00:16:54.180 virus and prevent it infecting cells. Let's talk about a virus that doesn't really mutate much from

00:16:59.920 season to season. I don't know, pick a rotavirus or something like that. In that first round of

00:17:05.840 iterative replication of the B cell, where it's basically going through an evolutionary process on

00:17:11.160 its own to, quote unquote, naturally select for the best antibodies. How many times, what's the

00:17:19.040 speed with which it is able to replicate until it starts to converge on picking the optimal antibody?

00:17:26.060 These cells are replicating in a matter of hours. But with a new virus, maybe after a week or two,

00:17:35.960 you'll see antibodies that will be able to neutralize the virus. Now, neutralize is a bit

00:17:45.700 of a technical term, and I'm going to try to explain it now. You'll get many antibodies that

00:17:51.780 will bind to the virus, but they won't necessarily neutralize the virus because they won't stop it

00:17:59.680 infecting cells. They'll bind to it, but they won't affect its ability to infect cells.

00:18:05.960 And so the key antibody that most of us are most interested in are these neutralizing antibodies.

00:18:14.560 And that is that they will bind to a part of the virus and prevent that part of the virus

00:18:21.300 getting into a cell. So let's take an example of the new coronavirus. That has a spike on its surface.

00:18:29.820 Part of that spike is a region that binds to its receptor on a human cell. And if you have an

00:18:39.480 antibody that covers up that area, that will stop infection of a human cell. That's a neutralizing

00:18:48.640 antibody. If you have an antibody that binds to another region of the spike that's not involved

00:18:54.060 in binding to the receptor on the human cell, it won't necessarily prevent infection.

00:19:02.220 So David, let me pause you for a sec, because this is such an important point that I want to

00:19:05.900 make sure everybody understands it. And I want to throw in an orthogonal concept, which is most people,

00:19:12.560 when they start hearing about antibodies, they think about these serology tests because they're

00:19:16.480 all over the news. And they start to say, wait, antibody, I've heard of that. That's IgG,

00:19:20.300 IgM, or maybe they remember hearing about IgA. So I want to now have you explain a little bit,

00:19:26.720 what's the difference between IgG, IgM? Let's just keep those two simple. And then talk about how

00:19:32.920 knowing that you have those antibodies doesn't necessarily mean they're neutralizing and vice

00:19:38.400 versa. So how do we reconcile that nomenclature and explain, I guess, going back to the beginning,

00:19:44.520 what does immunoglobulin G or IgG refer to versus IgA, et cetera?

00:19:50.300 There are many different types of antibodies that can be used at different mucosal surfaces

00:19:56.720 and can be used for various different tasks in the body. So when you get infected, let's say you

00:20:03.880 get infected with dengue virus, the first antibody that comes up is an IgM antibody. So if you have a

00:20:10.500 test that says you're IgM positive for dengue, that means it's a very recent infection. Those IgM

00:20:16.840 antibodies tail off over time, maybe two months, three months, not everybody is the same. Then come

00:20:23.640 up your IgG antibodies. Now, these are the antibodies that will contain your neutralizing

00:20:29.680 antibodies eventually. Although IgM antibodies can also carry out neutralization. That is,

00:20:35.500 they can bind to regions of the virus and prevent infection. IgA antibodies are generally found at

00:20:43.660 mucosal surface, so obviously are very good for mucosal infections.

00:20:49.800 So let's focus mostly on the IgG and the IgM. So you said the IgM is the first antibody that typically

00:20:56.660 shows up and then the IgG comes up as the IgM is trailing off. What determines when a person makes

00:21:04.880 those in that first exposure, if they are neutralizing or not neutralizing? In other words,

00:21:10.220 could you take two people who are exposed to the same virus who both managed to successfully fight

00:21:16.480 off the virus, but do so with a different proportion of neutralizing antibodies and therefore maintain a

00:21:22.780 memory of different neutralizing antibodies that would render one more versus less successful

00:21:29.080 years later? There is actually an enormous variability in the way that people make neutralizing

00:21:36.200 antibodies. There's a paper under consideration, coronavirus at the moment from a very, very good

00:21:42.480 lab in Rockefeller. They looked at, I think it was 70 individuals and they looked for the presence

00:21:48.260 of neutralizing antibodies. And they found that almost 20% of them did not make neutralizing

00:21:56.880 antibodies. So there could be enormous differences in the way that we make neutralizing antibodies.

00:22:06.500 I'm sorry. I just want to make sure I understand that. Does that imply you're saying 20% of individuals

00:22:10.560 who were seropositive for exposure to coronavirus? So meaning on an ELISA test or some other point of

00:22:18.160 care test, they showed the presence of IgG or IgM in the blood. But when you did a special assay to

00:22:24.800 see if those antibodies would actually neutralize the virus, they did not neutralize the virus?

00:22:29.540 That's exactly correct. Furthermore, there was a great gradation in the ability of these individuals

00:22:37.480 to make neutralizing antibodies. One or two of them made neutralizing antibodies at very high titers.

00:22:44.440 And what that means is that you can dilute their sera and it will still neutralize the virus at a

00:22:51.540 one to 5,000 dilution. Whereas most people, it's one to a hundred dilution can still neutralize the

00:22:59.060 virus. So there was an enormous variation in the levels of neutralizing antibodies made.

00:23:06.920 Now, I know the sample isn't large, but did they speculate on whether that directly

00:23:12.040 factored into the clinical response of those patients?

00:23:16.160 Not sure. Not sure.

00:23:17.800 Because the next question it begs is those 20 patients that did not have neutralizing antibodies,

00:23:23.380 how did they thwart the virus? Or did they not? Is that the point?

00:23:27.380 Not necessarily. They could have had a lower inoculum of infection. They could have been

00:23:34.000 asymptomatic. I would have to go back to the data to make a correlation between those two things.

00:23:40.320 But I think what it says is that there's enormous variability in the B-cell response to this virus.

00:23:49.940 And that means for me, at least, those individuals that didn't make a good neutralizing antibody

00:23:56.600 response, can they be reinfected? And can they be reinfected how soon after their initial infection?

00:24:07.880 We know that people infected with other coronaviruses, like the cold virus, for example,

00:24:15.060 can be repeatedly infected with the same virus. So one of the big issues, for me at least, is

00:24:25.240 if you've been infected, can you be infected again? That ability to be infected, does it correlate

00:24:35.000 with neutralizing antibodies in the serum, which is a likely thought, but maybe completely wrong?

00:24:42.000 Remember, you also have T-cells that I haven't talked about.

00:24:45.620 I'm saving those guys in the back for a moment. We're not stopping the B-cell discussion yet.

00:24:49.380 I should say that I spent 15 years of my life working on T-cells and only more recently have

00:24:56.880 been working on B-cells. And I'm sure there's some B-cell experts that will be listening to this

00:25:01.240 and laughing at me, but this is my understanding of B-cell responses.

00:25:06.000 So another question, I think, digging deeper into this is, and not to put you on the spot,

00:25:09.760 but do you know if there has been a study done where they've taken a look at many,

00:25:14.200 many subjects who were vaccine naive, given them a vaccine, so human challenge vaccine

00:25:20.040 for a virus that does not have huge genetic drift. So that would exclude influenza vaccine.

00:25:26.080 And then done what you've proposed, which is followed those people post-vaccination for measurement

00:25:33.660 of neutralizing antibodies. Because at least in that situation, you would have a standardized

00:25:37.780 inoculum, presumably. And then you could sort of try to adjust for other host factors, such as age,

00:25:46.080 but you could maybe say, look, you have four different cohorts of neutralizing response,

00:25:51.380 but they generally correlate to factors X, Y, or Z. Do you know if that's been done?

00:25:56.700 It may well have been done, but I'm not aware of the results. But I can tell you of a study that

00:26:00.960 we've done in collaboration with Aspercalis in Sao Paulo and Myrna Bonaldo in Fiocruz in Rio,

00:26:08.480 we looked at the immune response to one of the most successful vaccines, and that is the 17D

00:26:15.140 yellow fever vaccine. So this is an attenuated vaccine that was derived from somebody in Africa

00:26:23.980 who had yellow fever, was then put into monkeys, and then cultured in the laboratory

00:26:30.480 for many, many rounds of tissue culture. And what emanated from this was a virus that was weakened,

00:26:38.260 and we call that an attenuated virus. This has many differences genetically from the original virus

00:26:45.900 in Africa. But if I inject this into a human, the virus will replicate, and it will do all of those

00:26:54.340 things that I talked about initially. It'll turn on the innate immune response, then the adaptive,

00:26:59.460 you'll have T and B cells generated, and you will have antibodies generated against the vaccine virus.

00:27:07.760 And in fact, the best way to make a vaccine is often attenuating or weakening the original virus.

00:27:15.300 Now, there's a few problems with the yellow fever virus vaccine. And that is that there are some

00:27:21.340 people whose immune responses cannot handle the attenuated virus. And some of these people will

00:27:28.960 actually, one in 300,000 will get sick from the virus. And some of those people will die from

00:27:36.560 the virus, especially if you're older. There is some risk associated with it.

00:27:43.360 And for perspective, I think measles, mumps, chicken pox would be other examples of live attenuated

00:27:48.040 viruses.

00:27:48.620 But this one is...

00:27:51.220 Something about this one, the 17D, its efficacy is great. What is the approximate efficacy?

00:27:56.860 The one thing about humans is they're all different. They're all different ages. And as you get older,

00:28:02.580 your immune responses are not as good. But the study that we did with Myrna and Asper shows that

00:28:11.420 all of those vaccinated individuals will make beautiful neutralizing antibody responses against

00:28:19.020 17D, one in 5,000. So I can dilute their serum, one in 5,000, it'll still stop the virus from

00:28:27.040 infecting cells. Beautiful immune response. But if we take a virus out of a dead monkey that's died

00:28:35.840 of yellow fever recently in Brazil, not the same. So one or two individuals didn't make any responses

00:28:44.320 against the wild-type primary iso. Because these viruses that come right out of a monkey, for example,

00:28:56.680 are incredibly well-adapted to replicating in the monkey and have not been adapted to replicate

00:29:04.720 in tissue culture. But was there anything special about the gentleman in Africa who was

00:29:11.520 the person from whom the yellow fever virus was first pulled? Or was it just that happened to be

00:29:17.680 a person there? Like, was there some characteristic about this person that's seated? No, I don't think

00:29:21.580 there was anything special about this individual. But the virus has so changed the vaccine virus from

00:29:27.620 that original virus. That it engenders immune responses that may not be able to recognize

00:29:34.420 a pathogenic primary isolate. And this primary isolate is incredibly important to test any vaccine

00:29:43.680 against. But what we found is that there was a large range in ability of these people that were

00:29:49.760 vaccinated to respond to the wild-type virus. So I want to come back to a really deep discussion

00:29:57.740 actually on viruses and take what you've just talked about, which is these attenuated viruses and

00:30:03.060 put them in the context of RNA and mRNA viruses, the inactivated viruses, and also some viruses for which we

00:30:11.380 have not yet come up with vaccines. RSV, at least not safely, HIV and hepatitis C. I want to come back and

00:30:18.060 talk about that. But I think to do so, we have to go back to these B-cells and these pesky T-cells.

00:30:23.900 So I think you've done an amazing job, at least to me, clarifying some of the nuances around B-cells.

00:30:31.080 And I just want to make sure I'm playing it back correctly, which is the B-cells arrive pretty soon

00:30:36.500 after that innate response takes place. And if anything, they're probably sped up by the cytokine storm

00:30:43.240 that follows the innate response. They go through this sort of evolutionary replicative cycle until

00:30:49.600 they converge on the perfect antigen. And if we're lucky, they preserve that memory. So the B-cells

00:30:56.540 that reside in our bone marrow for years and years later will always hold on to the dear memory of

00:31:02.420 what the final best antigen was. And if we get reinfected, it's a neutralizing antibody, if we're

00:31:08.720 lucky that goes back and gets it. But the risk that we don't yet understand is why do some people not

00:31:13.400 make neutralizing antibodies? And of course, what's the implication of that clinically? Is that a fair

00:31:17.600 synthesis? Yeah. I mean, the only addition I would make to that is that once the antibodies,

00:31:25.020 the B-cells are, we call it affinity matured, that is they get better and better at binding to the piece

00:31:32.000 of virus that they attach to. And this occurs in the lymph nodes where the architecture is very important

00:31:37.760 because you've got T-cells that are absolutely necessary to help them develop in those lymph

00:31:44.020 nodes. But then they exit the lymph nodes about seven to 14 days later. And then they become either

00:31:52.580 memory B-cells, which are very small B-cells that circulate, or they go into the bone marrow where they

00:32:00.080 become these big plasma cells, which essentially become the factories of antibodies.

00:32:06.640 So if you have laid down in your bone marrow a plasma cell, we call them plasma cells,

00:32:13.780 they are large cells that are spewing out antibodies. And if one of those cells is making

00:32:21.180 considerable amounts of neutralizing antibodies, you will be protected likely from an infection with

00:32:28.740 that virus that you've just seen for a long, long time. Now, that will vary from virus to virus.

00:32:36.020 But that's essentially the ontogeny and evolution of the B-cell response.

00:32:44.160 David, you've consistently referred to the dilutions that you do when you're actually looking for

00:32:49.700 basically a way to quantify neutralizing antibodies. I'm going to take it to mean then that when I

00:32:55.780 either poke a person's finger or draw blood and look at the quantification of IgG or IgM that we are

00:33:04.680 typically now seeing as common tests that people are doing for coronavirus, we are not distinguishing

00:33:10.180 whether or not neutralizing antibodies are present. That is not an assay that is capable of

00:33:14.980 determining this. Is that correct?

00:33:16.580 Absolutely. You're not looking at neutralizing antibodies at all. You're looking at the quantity

00:33:21.000 of antibody that is bound to the piece of virus that you're using in that assay. And that doesn't

00:33:29.640 tell you if those antibodies can bind to the region of the spike protein on the surface of the virus

00:33:38.620 that is critical in binding to the receptor on the human cells for entry. And the value of those

00:33:47.200 antibodies that are not neutralizing, not clear at all. But we do know that antibodies that neutralize

00:33:55.760 are really, really very important. That's really the goal of any of the vaccine efforts

00:34:01.360 that are underway at the moment is to generate neutralizing antibodies.

00:34:06.360 I'll admit something kind of embarrassing. I did not know that until I met you and Stanley Perlman.

00:34:12.840 So just to put that in perspective, up until two months ago, I did not know that the antibodies we

00:34:20.140 measured in a person's serum, whether it be to coronavirus, which we're doing now,

00:34:25.420 or those that I've looked at my entire medical career when I check a patient's antibody levels,

00:34:31.280 whether it be to see if they had varicella zoster and they're at risk for shingles or whether they

00:34:37.020 had Epstein-Barr or what, like you pick any virus. I had no clue that every time I ordered that lab test

00:34:43.820 on a patient and I was looking at their IgGs and IgM levels that I was not necessarily being assured

00:34:51.680 of immunity because I had no insight into whether those were neutralizing or not. And that must be

00:34:57.100 the analogy would be, you know, I'm making this up as I go, but like a cardiologist looking at a

00:35:02.000 patient's lipid numbers, but realizing that no matter what these numbers say, 20% of the time,

00:35:07.700 potentially, this has no bearing on anything because it's not actually the lipid that matters.

00:35:14.040 You're measuring the lipid level in a cell as opposed to the lipid level in a lipoprotein,

00:35:18.900 which is the one responsible for disease. Like it's such a stark wake up call to me.

00:35:24.340 I'm guessing I'm not the first person to be shocked by this. And the fact that we still don't have

00:35:28.540 clinical assays to do this, only laboratory assays, suggests it's very difficult to do this,

00:35:34.980 or at least not cost effective to just routinely screen patients for neutralizing antibodies.

00:35:39.440 It's quite a difficult assay that requires you incubating the patient's plasma or serum

00:35:46.120 with the actual virus, then plating it out over cells and then watching the virus infect the cells

00:35:56.100 over the next two, three, four, five, six days, depending on the virus. So what you're looking for

00:36:03.360 is a serum that will block the virus of interest from infecting the cells. So it's not trivial,

00:36:12.180 but we standardly do it for HIV, for Zika, for dengue in our laboratory, and we'll soon be doing it

00:36:21.200 for the new coronavirus. So let's now pivot to that second arm of the adaptive immune system,

00:36:29.840 this highly, highly advanced immune system, where you actually spent the majority of your

00:36:34.120 career, which is talking about these T-cells. First of all, how does a T-cell differ from a B-cell?

00:36:39.920 How do we define it as a different cell? They're clearly both very advanced types of immune cells.

00:36:45.380 Well, and last something that I know something about. I used to think that the most important

00:36:51.880 cell in the body was the cytotoxic T-cell. And worse than that, I used to think that the heart

00:36:59.080 had one function, and that is to pump T-cells around it.

00:37:07.700 I can see the immunology meetings now with pictures of hearts and just, you know, one function,

00:37:14.540 pump T-cells around. The lungs only function, provide cellular respiration for T-cells.

00:37:20.800 The kidneys only function, filter T-cells. There's a whole T-shirt industry for you here.

00:37:25.820 Yeah. So, but I have to admit that I love the cytotoxic T-cell. It's called the CD8 T-cell. It

00:37:32.520 is a cell of immense power, probably one of the most powerful immune cells you have. We can see its

00:37:42.220 awesome power in HIV. By the way, just for the record, I'm kind of partial to CD4. We'll come back to

00:37:49.780 it, especially CD4, CD25, but we'll get to that later.

00:37:53.000 I'm less interested in CD4 cells as an admission. The CD8 cells are really where the action is. So,

00:37:59.820 we made a discovery in the early days of HIV in the animal model of HIV infection, which is a SIV,

00:38:10.820 simian immunodeficiency virus. I remember this very clearly. We infected monkeys with a simian

00:38:21.900 immunodeficiency virus. And then we looked at the virus two weeks later. And two weeks later,

00:38:27.920 we couldn't find the virus we infected those monkeys with. There was virus replicating in the blood,

00:38:33.880 but it was a new virus. And it had changed at one site. And I remember when the student brought in

00:38:42.960 the sequence of the new virus and it had one change. And I said, you've made an error. We need to get

00:38:50.640 this checked by other labs because I couldn't believe it. But what had happened is that-

00:38:55.380 How many base pairs, by the way, just to put in-

00:38:57.180 It had two or three changes. It depends.

00:38:59.560 This is an RNA or DNA virus?

00:39:02.020 This is an RNA virus. So, this is HIV, which is a RNA virus. And it's notoriously error-prone when it

00:39:10.300 copies itself. But what we discovered had happened is that the monkey had made a massive T-cell response

00:39:19.260 directed against eight amino acids. And an amino acid is a, you think of it like a string of pearls.

00:39:25.840 And this was eight pearls. This T-cell response had wiped out the initial infecting virus. So,

00:39:34.720 that all that was present replicating in that animal now was a virus that had mutations in that area.

00:39:43.340 So, when you see dramatic effects like this, you understand the power of a cytotoxic T-cell. So,

00:39:51.300 basically, these CTLs had been generated, and I use CTL, cytotoxic T lymphocyte is the abbreviation.

00:39:58.980 They had wiped out the virus that I put into these monkeys. And more recently, you've seen this in

00:40:05.780 cancer. There was a paper published in the New England Journal where, if I remember the paper

00:40:11.880 correctly, this patient had a melanoma, she tried every treatment, and she had a massive tumor under

00:40:21.740 her left breast, I think it was. She was treated with an antibody that turns the T-cells back on.

00:40:31.120 And in a matter of weeks, she now had a hole in her chest because the T-cells had just gone and wiped

00:40:37.200 out the tumor. So, to me, this is the awesome power of these CD8 T-cells. And that's what I initially

00:40:47.820 fell in love with, was CD8 T-cells in the immune system. But after spending 20 years trying to make

00:40:56.120 a vaccine against HIV based on inducing T-cell responses, and failed spectacularly at that,

00:41:04.600 and then recently discovered the power and the beauty of B-cell responses and antibody evolution,

00:41:13.340 which is the same way that the virus had evolved in the face of this CD8 T-cell onslaught,

00:41:21.440 is the same way that an antibody evolves when an affinity matures to become the perfect fit binding

00:41:31.080 antibody. There's two sides of the same coin. Let's explain a little bit to how that CTL works.

00:41:37.580 The cancer example, of course, is near and dear to my heart, but let's use another viral example

00:41:42.920 to explain how the CTL or the CD8 T-cell is basically instructed to destroy in the same way

00:41:53.240 that the B-cell makes neutralizing antibodies that ultimately destroy the virus. So, this is a different

00:41:58.760 method of killing. So, let's walk the listener through that.

00:42:02.220 It's a completely different method of killing. So, again, a virus, let's use HIV as the example.

00:42:09.220 A virus will enter a cell and within 24 hours will make thousands of copies of itself and will burst

00:42:18.460 the infected cell. And in the case of HIV, these are CD4 cells. The virus enters the cell,

00:42:24.220 24 hours later, hundreds and thousands of copies of this virus are now released into the blood.

00:42:32.780 Now, an antibody can interact to stop the virus from getting into the cell, although that's proven

00:42:41.720 to be very difficult in HIV and we can talk about that later. But once that virus is in the cell,

00:42:48.140 it cannot do anything. The antibody cannot get inside the cell. So, the game's over as far as an antibody

00:42:55.520 is concerned. This is where CD8 T-cells come in. Sorry. And is that just because HIV has so much

00:43:03.960 replicative power or is it because just by some stroke of horrible, horrible luck, the cell that HIV

00:43:11.960 uses to replicate happens to be the general of the cellular immune system, the CD4 cell? What is it

00:43:19.620 about that that is so ironically bad? Well, I mean, most viruses will get into any cell that has their

00:43:28.640 receptor on the surface of it. But in the case of HIV, this receptor, the CD4 receptors on the surface

00:43:37.700 of CD4 cells, these helper cells. But in any event, an antibody, whether it's an epithelial cell

00:43:47.380 that's been infected or a CD4 cell, once that infection event is over, an antibody can do nothing

00:43:54.940 because the antibody can't get into that cell. So, what we need is a cell that can recognize an infected

00:44:03.720 cell and kill it before it releases all the progeny virus. So, I like to think of an infected

00:44:10.340 cell as a virus factory. You need to shut that virus factory down. So, how do you get another cell

00:44:16.840 to recognize an infected cell? Because that cell can't go around killing cells indiscriminately in

00:44:28.040 your body. It has to be able to recognize an infected cell. And that is what a CD8 T cell does in a very

00:44:37.420 elegant way. When the virus binds to the receptor and gets into the cell, it starts to make its own

00:44:47.980 proteins in that cell. Then we have these buckets called MHC molecules, major histocombatibility

00:44:58.080 complex molecules. These buckets sample what's on the inside of the cell and they put it up on the

00:45:06.500 surface of the cell. And in the buckets on the cell's surface are pieces of the virus in an infected

00:45:15.900 cell. In a normal cell, they're normal proteins of normal cellular machinery that goes on inside the

00:45:25.320 cell. So, a killer T cell will come along and it will see, let's say it has 10 cells in front of it.

00:45:33.960 Five of them have been infected with HIV and five of them have not. So, it'll move over them. It has on

00:45:40.160 its surface a T cell receptor that looks like an antibody. It'll move over and look at the buckets

00:45:45.520 and say, okay, I've got five uninfected cells here. I'm not going to kill these guys. But then it comes

00:45:52.740 to an HIV infected cell and it sees a piece of the virus in one of these buckets and it goes crazy.

00:45:59.540 It binds to that and then it blows holes in that infected cell and it closes the factory down. So,

00:46:08.040 these buckets full of pieces of HIV are like flags on the surface of an infected cell that say, kill me

00:46:17.560 because if you don't, I'm going to release a thousand or two virus particles into the infected

00:46:26.620 person's blood. So, that is what a CD8 T cell does and it plays a critically important role in almost any

00:46:36.140 viral infection. And in fact, you need both arms of the immune system. Although I've waxed lyrically

00:46:44.280 about the B cell response and the beauty of antibodies and their ability to neutralize,

00:46:51.080 sometimes they don't neutralize every virus that comes in. You need your CD8 T cells, which are such

00:46:56.780 efficient killers, to come in and kill those virus factories. And so, as with anything, you need

00:47:03.700 multiple approaches to control an infection. And it also depends on the quantity of virus that's in

00:47:11.840 the system as well. But the CD8 T cells are really exquisitely good at closing down virus factories. And

00:47:22.400 that's really their main job. Now, we can't generate beautiful neutralizing antibodies or these incredibly

00:47:31.460 powerful CD8 T cells without helper cells that are critically important in providing a milieu for the

00:47:41.120 development of the CD8 killer cells and for the B cells. And of course, the most dramatic example of

00:47:49.780 the importance of CD4 cells is HIV. When a person gets infected, what happens is we get massive virus

00:47:58.560 replication initially, because there's no immune response. And what's happening during that first

00:48:03.760 two or three weeks is the innate immune response is being turned on, and that's generating the adaptive

00:48:09.920 immune response. About day seven to day 40, in come the CD8 T cells, and they destroy everything they can.

00:48:17.660 But unfortunately, they destroy the first virus they saw, but the virus has been making errors.

00:48:26.160 And so now, by the time you're two weeks out, you have so many copies of different viruses in that

00:48:35.320 infected individual. And it's simple Darwinian evolution. The CD8 T cells will search and destroy

00:48:41.880 every infected cell that they can. But there'll be one that has a mutation in that string of eight pearls

00:48:49.520 that the CD8 T cells that the CD8 T cells are seeing in that bucket on the surface of the infected

00:48:55.040 cell. Those CD8 T cells cannot recognize that. That cell will start spewing out thousands and thousands

00:49:02.740 of copies of virus, and that will become the new virus in the individual.

00:49:08.780 And so does that mean that every patient who's infected with HIV will ultimately converge to a mutation

00:49:14.320 that at least that contains that section? It would, if everybody had the same buckets.

00:49:22.780 Ah, so it's different for different patients. Right. So the MHC is incredibly interesting because it has

00:49:30.860 so much diversity. So your MHC didn't a different than mine. And if you needed a skin graft, you couldn't

00:49:41.960 have a skin graft for me for active reasons, including the fact that your T cells would

00:49:47.900 recognize my skin as foreign because of the MHC molecules on the surface and just slough it off.

00:49:54.060 Yeah. I mean, the T cells are really, I mean, not just as you've described it, their role in treating

00:49:59.720 viruses or combating viruses, but their role in treating cancer and transplantation, human

00:50:05.100 transplantation. So organ rejection, their role can't be overstated. The example you gave of the woman

00:50:09.840 with melanoma is a very extreme one, but there's reasonable evidence that most people walking

00:50:14.440 around have cancerous cells in them, i.e. cells that do not respond to normal cell cycle growth.

00:50:19.900 And yet they will not go on to develop cancer anytime soon. And that's a great testament to the CD8 cell,

00:50:26.820 which is able to recognize those cancer cells as non-self, which is the key determinant and to eradicate

00:50:33.920 them. And of course, this is exactly the reason we have to give patients who have been given a

00:50:38.480 transplanted organ, immune suppressing drugs. It's really suppressing this arm of the immune system

00:50:44.860 to prevent them from doing their job, which is saying, hey, that kidney or that skin graft or

00:50:50.600 whatever is not me. And therefore it needs to be eradicated. I share your enthusiasm for this,

00:50:56.040 David. I find this to be some of the most interesting biology in the human system. And so it's kind of

00:51:01.580 remarkable. It's funny. I still don't think I really understand why certain viruses,

00:51:06.400 in particular HIV and hep C are not vaccinated against. And I think maybe naively, I assumed that

00:51:13.340 the problem with HIV was the rate of mutation and the fact that it was primarily targeting the CD4

00:51:22.460 cell. Are those effectively the two reasons that we don't have a vaccine against HIV?

00:51:27.880 Most of our vaccines are based on immunizing an individual so that they develop neutralizing

00:51:38.260 antibodies. There are very few T cell based vaccines, although it's likely that T cells play

00:51:44.960 a very, very important role in the vaccination process. But it's those neutralizing antibodies that

00:51:52.260 when you first get infected, they come in and they stop infection. Your T cells can come in then and

00:51:58.220 clean up afterwards. But they are really the basis of almost all licensed vaccines. So the first attempt

00:52:08.400 was to make neutralizing antibodies by vaccination. And the problem is it's very difficult to make a

00:52:18.980 neutralizing antibody against HIV and HIV. Just for structural reasons, meaning?

00:52:28.300 I'll explain that. That's not to say that neutralizing antibodies aren't generated. So

00:52:32.780 let's go back to this infected person or a monkey. Massive virus replication, you can have 10 to 100

00:52:42.960 million copies of virus per ml in those first two or three weeks. It's a massive population size.

00:52:52.280 And almost all of them are different. So you've got enormous variability. And that's the basis for

00:52:58.680 selection. So in comes your CD8 T cell response. It kills everything it can. And now what you're left

00:53:05.500 with growing out are these new viruses that have CTL escape mutants. Your antibody response then kicks

00:53:13.940 in along the lines that we discussed. And patients will make a neutralizing antibody response. But guess

00:53:20.200 what happens? The virus escapes. So you go through these cycles of escape generation of new antibody

00:53:27.620 responses. But there are rare individuals. Well, the point also is that there is enormous variability in HIV.

00:53:37.980 Reason for the enormous variability you've already guessed. And that is this error prone mechanism of generating

00:53:48.960 new variants, coupled with the fact that HIV, unlike most viruses, is a chronic virus. So the virus

00:53:56.980 constantly gets selected upon by the immune response. And we've done these experiments. We can infect a

00:54:06.140 monkey with a clone virus. So we know entire sequence. We can then get that virus a year later and look at

00:54:15.080 the variation in the virus. An outside envelope, which is the piece of the virus on the surface of the virus

00:54:23.320 for entry. All of the variation is selected for by CTLs, by killer cells. On an envelope, it's all selected for

00:54:30.560 by antibodies. So this virus, because it's chronic, is so variable. So when you talk about HIV, you're basically

00:54:39.360 talking about lots of different HIV. So here's the question for a vaccinologist. How am I going to make

00:54:45.240 a vaccine that I'm going to give to 100 people in Boston? But those 100 people are all going to be

00:54:52.800 exposed to different viruses? If I vaccinate them in yellow fever, I know pretty much what the sequence

00:54:59.040 will be. But here, I've got a hugely diverse set of viruses that I'll be challenged with. The second

00:55:08.380 problem is that, to date, nobody has been able to generate, by vaccination, a neutralizing antibody

00:55:15.780 against HIV. Meaning every vaccine that has been given to patients, even if it generates antibodies,

00:55:24.360 they fail to actually neutralize the virus. Exactly. That's the big problem. I can vaccinate

00:55:30.980 monkeys and generate huge levels of antibodies. The bind, none of them neutralize. The virus said,

00:55:37.640 I'm going to challenge the monkeys with. That's another huge problem. The reason for that is

00:55:41.680 that this virus, this envelope, first of all, there are very few copies of envelope on the surface

00:55:47.500 of a HIV virion. That envelope is a protein, but it's covered in a shield of sugars. So it's hard to get

00:55:56.960 in to bind to the regions of the envelope that are important for binding the CD4 and getting into the

00:56:05.060 cell. So this virus is unlike anything I've ever seen. It is so, so difficult to generate

00:56:14.940 neutralizing antibody responses because of the biology of the virus. And the biology, by that,

00:56:22.780 I mean both the fact that it's covered in this sugar shield, and if I vaccinate with one envelope,

00:56:30.240 humans, they're going to be challenged with a bunch of different viruses that have all gone through

00:56:36.700 selection and mutation and a different one from the other. And this can be as different as 30% of

00:56:43.920 their structure. It's a very, very difficult issue. And the fortunate news here is that on a drug

00:56:52.320 development standpoint, the progress has been remarkable. I mean, the advent of highly active

00:56:58.260 antiretroviral therapy in the mid-90s is a game changer. I mean, it is unbelievable if you just

00:57:04.980 take a retrospective look for 40 years at HIV mortality matched against exposure to or capacity

00:57:13.800 to receive heart, highly active antiretroviral therapy. I don't want to say overnight, but it's

00:57:19.060 like within a span of two years, you took something that was uniformly fatal and you've rendered it a

00:57:25.760 chronic disease that is to no way diminish the struggle of it. But having friends with HIV and

00:57:32.220 watching how long they can live with T cell counts that would have in the past rendered them dead within

00:57:41.620 months. It's on the bad news, I think you came up against a virus with the most superpowers of any

00:57:47.720 virus. The good news is it's a very chronic killer. On the medicine side, there were opportunities

00:57:53.860 to keep it at bay. Am I being overly optimistic there?

00:57:57.280 No, no, no. And I think the bigger point you raise is that as we stand here with the coronavirus

00:58:03.760 epidemic three months old, I think we should have faith that science will find a solution to this.

00:58:10.380 And I'll go back 30 years and I'm in a lab at Harvard at the Primate Center there. And I'm hearing

00:58:17.760 about these people in San Francisco with these lesions and they're dying. And I remember, we don't know

00:58:25.920 what's causing this. Bacteria, is it drugs? Is it a virus? Nobody could isolate virus from these

00:58:32.880 individuals. And I'm at the Primate Center and monkeys are dying as well. And Rhonda Rossi is at the

00:58:38.780 Primate Center, the New England Primate Center, isolated a virus that looked very similar to HIV.

00:58:46.220 And that was the birth of the animal model that we were able to pass therapies on. So we discovered

00:58:52.560 it was a virus. We thought, well, okay, then we can use condoms to protect from it. Okay, that's good.

00:58:59.200 That's a behavioral measure. Then came AZT.

00:59:03.060 And that was not until the late 80s that that insight?

00:59:06.360 I can't remember the exact timeline.

00:59:08.720 Maybe a bit earlier, right? Potentially mid 80s, but okay.

00:59:11.220 But so now we have the first measure against the virus. We have social distancing.

00:59:17.120 That's right.

00:59:17.560 So, and then AZT was a repurposed drug. And I remember where you could see the virus loads coming

00:59:25.060 down and then they came back up, of course, because the virus escaped. Then Ray Shinazi at Emory

00:59:30.600 discovered a couple of drugs that if you put these together or in combination with other drugs,

00:59:38.420 you now had a treatment. And this was the game changer. The rest of us are working on vaccines

00:59:45.020 and immune responses. And what we're learning is that it's so difficult, this virus can escape from

00:59:51.040 just about any immune response we throw in it. And then you have the groundbreaking PrEP studies,

00:59:59.400 pre-exposure prophylaxis, where people take a drug, Truvada in this case, every day, and they

01:00:08.640 simply don't get infected. And if everybody who's sexually active takes Truvada, the epidemic of new

01:00:17.380 infections is over. We still have a large number of people already infected and they need to get on

01:00:24.480 treatment. But in that example, science found a solution to the epidemic. Although it wasn't a

01:00:35.600 vaccine because of the unique nature of the virus. And I think it's important to understand that every

01:00:42.020 virus presents its own particular set of challenges. And HIV presented us as vaccinologists with a set of

01:00:49.980 challenges, which I think, frankly, are going to be insurmountable. And thankfully, we have these

01:00:55.960 drugs that are highly effective. That's not to say that we don't need an HIV vaccine. We need an HIV

01:01:03.180 vaccine. And this virus has infected 75 million people. To give you some perspective on the new

01:01:11.900 coronavirus virus infection numbers, it's killed 32 million people. Again, we're not even close to that

01:01:18.720 with coronavirus. But I think the general lessons that we learned from the HIV epidemic and many of

01:01:27.060 us that worked in the HIV epidemic are now better able to deal with the coronavirus because we've

01:01:34.820 learned a lot of valuable lessons from HIV. Now, how much do you know about hepatitis C?

01:01:40.940 It has a similar story in that I remember 20 years ago or a little longer than that, maybe 22,

01:01:45.240 23 years ago. I'm in medical school. I'm sitting in my immunology 101 class. And they're saying,

01:01:50.520 just so you understand, there will never be a vaccine for this virus. Don't think about that

01:01:55.760 anymore. And not going into that field, I never did think about it anymore. But I did notice that,

01:02:00.960 by the way, a couple of years ago, we got a drug that now eradicates hep C. And it's a lot like the

01:02:06.160 HIV story, which is we still don't have a vaccine. I don't understand why. I'm hoping you might be able

01:02:10.700 to offer an insight there. But there was a pretty successful workaround because prior to that, David,

01:02:15.220 it was predicted that hep C was going to be accounting for something to the tune of 70% of

01:02:20.200 liver transplants. Absolutely. Hep C is a virus that replicates to enormous levels, even higher than

01:02:27.000 HIV, generates lots and lots of variants. And it's going to be very, very, has enormous variability,

01:02:34.780 even though it's a different family of viruses. But it's a virus that's going to be very, very

01:02:40.140 difficult to find a vaccine for. But luckily, the same man, Ray Shinazi, PhD biochemist, who

01:02:48.180 discovered the first two drugs, he was involved in the discovery of these first drugs that not only

01:02:55.060 treat hep C, but they cure hep C, which is the key. The virus is gone. Now, even with our best

01:03:02.620 antiretroviral drug therapies, we're still not curing the infected individuals. And of course,

01:03:08.500 that's a huge and important area of research. My view on this is, I want to be careful I don't

01:03:15.420 say something that I'm going to think sounds really stupid after the fact, but I'm going to go ahead

01:03:19.300 and say it anyway. It's quite possible there has been no greater advancement in medicine in the past

01:03:25.160 10 years than the drugs that cure hep C. When you think about the scale of what that has done,

01:03:31.820 it is enormous. And to put this in perspective, when I was in residency, I did my training in

01:03:36.620 surgery. So we were always exposed to sharps and things like that. I was far, far more afraid of

01:03:43.760 hepatitis C than HIV for the following reason. Hep B. So the big three are hep B, hep C, and HIV.

01:03:51.760 Those are the things that are bloodborne transmission. You're going to be worried about

01:03:55.680 them. All of them have devastating consequences. Hep C probably having the quickest consequences if you

01:04:01.740 are untreated. Hep B we could vaccinate against. HIV was a lousy virus in terms of transmission.

01:04:09.280 A solid needle going through a double glove is pretty low transmission. But hep C was a very

01:04:15.580 transmissible virus. If my memory serves me correctly, it's at least an order of magnitude

01:04:20.540 more transmissible than HIV and no treatment, no vaccine. So, I mean, I remember being scared

01:04:28.060 senseless of hep C and to think that, as you said, today, I think it's about a 30 to 60 day course

01:04:34.380 of a medication, albeit a very expensive one. And you take somebody who's got a 40 to 50% chance of

01:04:40.780 dying of liver failure in a decade and you cure them. I mean, this is unbelievable.

01:04:46.240 Science is truly wonderful.

01:04:48.240 I want to bring it back to your point, which is we are still early in this coronavirus situation.

01:04:52.460 And there's probably a greater effort on this than there is on anything else that we've talked

01:04:59.540 about, at least relative to the moment in time when it was perceived to be an issue.

01:05:05.620 I completely agree. And I think we have to put it into context of other pandemics like HIV,

01:05:14.100 like the 1918 flu, for example, where 50 to 100 million people likely died from influenza.

01:05:21.500 I think we're much better able to mount a rapid response. I think that this virus will be easier

01:05:32.900 to develop a vaccine against. But I should put in a disclaimer here, and that is that I have been

01:05:41.120 wrong about every prediction I've made about this new coronavirus since January, where I thought that

01:05:48.800 maybe this would be like a very, very bad flu. And I was completely wrong about that.

01:05:55.000 But do you think you are wrong about that, David? I mean, it's still not entirely clear to me that

01:05:59.100 this isn't just three to five times worse than a flu. How much worse do you think it is?

01:06:05.380 I don't think that a really bad flu has closed down the world economy like this.

01:06:10.440 I'm sorry. Yes. No, no. Okay. I'm speaking from a purely biologic standpoint, not from a sort of

01:06:17.660 policy standpoint. But from a biology standpoint, my reading of the data is that when you really look

01:06:23.900 at the IFR and not focus on the CFR, and you age stratify, this is a disease that, depending on your

01:06:31.520 age, is maybe twice as bad as the flu, is maybe five times, maybe eight times as bad as the flu,

01:06:38.180 but it's not 25 times as bad as the flu. How do you read the literature?

01:06:43.280 Again, remember the caveat. When I first started looking at this, and I looked at some of the

01:06:47.520 crucial data, I thought, yeah, this is going to be five to 10 times worse than seasonal flu.

01:06:54.260 I think it's more likely 10 times worse, but I think it also depends on what sort of preexisting

01:07:00.440 conditions that you have, diabetes, obesity. And I think there are lots of things that we don't

01:07:06.020 understand that can predispose you to this. I mean, what about the amount of virus that you see

01:07:11.680 initially? So I think there's a lot of things that we need to have a lot of humility about

01:07:16.340 understanding in this new virus. But I am buoyed by the fact that the evidence for escape, there is

01:07:25.920 some, but it's logs less than we see with HIV. This is not a chronic virus. So that means that

01:07:34.020 it is possible to generate a antibody response. It's been difficult in the monkey studies to

01:07:40.920 understand the exact titer of the neutralizing antibody response. But the key experiments are

01:07:49.120 putting these vaccine concepts into humans and looking at their neutralizing antibody response.

01:07:59.060 But we don't know what levels of neutralizing antibody responses will be sufficient to prevent

01:08:08.320 infection. And I think that's a very important issue.

01:08:12.540 We don't know that. So we don't know what percentage, we don't know the frequency of people

01:08:16.280 who would develop them, and we don't know the duration that they will last.

01:08:19.480 Duration, I think, is a key issue with respect to infected people and with respect to vaccines.

01:08:27.500 Because you've got to make a neutralizing response. And then you've got to keep that

01:08:31.460 neutralizing response up to a level where it will prevent infection. But for me, the most exciting

01:08:40.440 hope that we have for treating this virus is neutralizing antibodies delivered as monoclonal antibodies.

01:08:50.500 And maybe I should explain that concept because it really is a beautiful concept. So let's go back to

01:09:01.720 the example I gave of yellow fever. If I vaccinate 100 people with this yellow fever virus that's

01:09:11.640 attenuated, let's say 90% of them will make a response against the vaccine virus.

01:09:16.500 20% of them won't make a response against the wild-type virus, the virus that's circulating.

01:09:24.640 So they're going to be susceptible to infection. But at the other end, you're going to have three

01:09:29.160 or four individuals that are going to make wonderful antibody responses against the vaccine

01:09:34.100 virus and the wild-type virus. So those individuals, what if I could take their blood and give it to

01:09:39.520 everybody else? Well, there's lots of problems with that.

01:09:42.880 And that was proposed very early via the lingo of convalescent serum, right? Which is we give

01:09:49.280 concentrated amounts of convalescent serum to people who are sick. Maybe we give diluted amounts

01:09:54.640 of convalescent serum to people who are not sick, but at high risk because they presumably wouldn't

01:09:59.080 need as many antibodies to fight off the initial response if exposed.

01:10:03.720 Right. So I've got these three people that are super responders that are making beautiful antibody

01:10:08.700 responses that neutralize the virus. Well, what I'm going to go in and do is I'm going to get their

01:10:14.420 memory B cells and I'm going to clone the genes of those antibodies that, remember, have been through

01:10:21.920 this beautiful process of affinity maturation and changed and now bind very well to the piece of virus

01:10:30.000 that prevents the virus from getting inside the cell. So they neutralize. So I'm going to get

01:10:37.880 these neutralizing antibodies and I'm going to clone them. And then I'm going to test them

01:10:42.920 against the virus. And then I'm going to test them in animal models. And then I'm going to grow them up

01:10:50.220 in large vats. And I'm going to go into a nursing home. Let's say it's a hundred people. And I'm going

01:10:58.120 to give them each an injection of this monoclonal antibody. And that is going to prevent infection.

01:11:06.280 How long will that last?

01:11:07.940 It depends. It depends on the dose you give. And it depends on how you genetically engineer that

01:11:17.620 antibody. So you can put mutations into that antibody where that antibody will last for three

01:11:23.220 to six months at levels that should prevent infection. To me, this is the most exciting

01:11:30.340 aspect and the most hopeful treatment for coronavirus. And it's a new type of vaccinology,

01:11:40.560 if you will. And it's, I think, the way forward for the vaccine field is to get those individuals

01:11:48.640 that make the best antibody responses, clone their best antibodies, grow them up in vats,

01:11:55.060 and then distribute that to the people that need it. And this can be used for prevention

01:12:01.240 and it can be used for treatment. And one of the things that we're doing at the moment

01:12:05.640 is in the setting of yellow fever, there'd be yellow fever outbreaks in Brazil. And my colleague

01:12:12.000 Esma Callas has been managing patients in Sao Paulo and they come in and you don't know if they're

01:12:19.920 going to die or they're going to live. And 40% of these people are dying and there's nothing we can do

01:12:25.980 about it. So the exciting idea is to inject them with an antibody that neutralizes the virus and

01:12:32.260 stops it replicating. Can we save their lives? And as you saw from what happened with Ebola

01:12:39.920 last fall, simple injection of a monoclonal antibody that neutralizes the virus after infection

01:12:47.520 saved many, many people's lives. Dropped the death rate from, I think, 50% to about 15%.

01:12:57.620 And that's the part I want to actually double click on here a little bit. So let's go back

01:13:02.120 and review. We spent a lot of time talking about vaccines and the goal of a vaccine for the most

01:13:07.000 part is a B cell strategy, which is put in some form of attenuated inactivated virus, or maybe just

01:13:15.220 it's RNA. We'll come back to all the full means, but you do something that elicits an immune response

01:13:21.600 that is appropriate. If we're lucky, we not only get the appropriate immune response, but it generates

01:13:26.860 these specific antibodies called neutralizing antibodies. They're the ones that matter.

01:13:31.180 We go off. And if we're, again, if we're lucky, we get beautiful, big fat effector B cells that

01:13:37.060 turn into plasma cells. They hang out in bone marrow. They are just sitting there primed and ready.

01:13:42.120 And if you see this infection again, it's not even going to be a blip on the radar because the

01:13:47.500 antibodies are right there right away to neutralize. You're saying, great. In parallel, here's another

01:13:52.520 strategy. We figure out who the Olympic champions of making neutralizing antibodies are and using

01:13:59.140 recombinant engineering, recombinant DNA technology. We basically make copies of these things, effectively

01:14:04.900 synthetic copies of these things and inject them into people so that even if their B cells are out

01:14:09.980 to lunch, it doesn't matter because it's the substrate or it's really the product of the B cell

01:14:15.280 that is sitting there waiting. Now, the issues with this are as follows. One, they don't last

01:14:21.120 forever. So you said get three to six months out of this. So if we said, look, this will be something

01:14:26.660 that we would use to target the most high risk people, presumably the elderly, those with the

01:14:31.980 greatest number of comorbidities and healthcare workers. And I think then that there's also tiers

01:14:36.760 of other people who are working in close proximity to others, et cetera, et cetera. You would come up

01:14:41.780 with a list of people who probably need to receive these monoclonal antibodies on some regular

01:14:46.460 frequency, say two to four times per year. How feasible is that in the context of what it takes

01:14:53.900 to basically scale and deliver vaccines? Is it on par with that in terms of challenge? Is it more

01:15:01.360 difficult? Where does it rank? No, I mean, let's not forget that a cheap vaccine is really the best way

01:15:09.600 to go with all of this. And we need this for HIV. There's not a doubt in my mind that we need this for

01:15:14.780 HIV. And if we can get that for coronavirus, that'll be great. And I think one of these vaccine

01:15:22.380 approaches will result in durable neutralizing antibodies. And then you can do a prime boost

01:15:28.840 with a different vaccine to boost your immune responses. But there are certain people who don't

01:15:36.520 do so well with vaccines, and that's the elderly. They don't make such robust immune responses.

01:15:42.880 And in fact, it's this population that you might vaccinate with these new vaccines against

01:15:50.000 coronavirus, but they may not make such robust responses. So using a monoclonal antibody,

01:15:58.520 I think, or a combination of monoclonal antibodies would be the way to go in this population.

01:16:04.560 If we can increase the herd immunity in the younger people by vaccination, therefore reducing the number

01:16:10.960 of transmission events, then that would decrease transmission to the elderly. But as we've learned

01:16:18.920 with HIV, we need to use lots of different approaches to defeat this virus. So initially,

01:16:25.500 we use condoms, we have drugs, and we can use drugs to prevent infection. So the same thing will be

01:16:32.820 with coronavirus. We need drugs, we need social distancing, we need vaccines. But the point with

01:16:41.180 regard to is this feasible, is the follows, is as follows. Humira is one of the most prescribed drugs

01:16:50.000 that we have today. That's a monoclonal antibody that's repeatedly given to people. So I think that the

01:16:57.540 advent of monoclonal antibodies is going to be very, very important to treat infectious diseases. And

01:17:06.560 in fact, it may be the way of the future. There's a trial going on now using monoclonal antibodies

01:17:13.960 that neutralize HIV to see if it can prevent infection in Africa. And it's going to be very,

01:17:20.500 very interesting.

01:17:22.120 Where did they get the neutralizing antibodies in the first place, given that so few people,

01:17:25.980 if any, would generate them?

01:17:27.840 Absolutely right. That's an excellent question. So one of my colleagues, Dennis Burton,

01:17:34.300 at Scripps was instrumental and a pioneer in this area. So they developed these huge cohorts. So after

01:17:42.000 about five to 10 years, a small number of individuals make antibodies that can neutralize

01:17:51.000 not only their own virus, but they neutralize many other different viruses. And what this

01:17:59.880 is, is that they'll bind to conserved regions on the envelope. And by binding to those conserved

01:18:07.840 regions on the envelope, they'll prevent infection. So that's how these very rare antibodies were

01:18:16.440 isolated. And Dennis was amongst the first to clone and express these and test them in monkey

01:18:22.800 animal models. And then subsequently, many different antibodies that are what we call broadly

01:18:30.840 neutralizing. So it's important to understand we have neutralizing antibodies. And people infected

01:18:35.500 with HIV will make neutralizing antibodies, but the virus, it escapes. And that neutralizing antibody

01:18:40.800 will be peculiar to their own virus. But then later on, as the virus evolves, and the antibody evolves

01:18:48.620 along with it, they will generate what we call broadly neutralizing antibodies. And those are the key

01:18:55.420 antibodies. Those can not only neutralize their own virus, but everybody else's. And so that's how

01:19:02.780 they isolated those. And that was a massive breakthrough for the HIV vaccine treatment field.

01:19:09.260 So David, coming back to this vaccine issue, you've touched on kind of one of the pillars of vaccine

01:19:15.160 development, which is using the attenuated virus. It's weakened. And again, the example that you used

01:19:21.020 there of yellow fever being a very successful one, and again, other very successful ones would be

01:19:25.560 measles, mumps, and varicella zoster. On the inactivated virus side, so these are viruses that can't do

01:19:32.480 anything, but you still have the entire coat of the virus that's given. Polio, hepatitis A,

01:19:39.000 and rabies would be the sort of flagship stories there. Those two categories of either inactivated

01:19:46.260 or attenuate are the lion's share of our vaccines. I mean, I know that spike proteins did hep B,

01:19:52.760 and I think maybe HPV. I think so. But most of the current approaches to coronavirus vaccines are

01:20:01.540 not looking at the inactivated or attenuated strategies, are they? Or am I just misreading

01:20:06.640 it? Because all of the stories that we're reading about the companies, whether it be Pfizer, the

01:20:11.620 Oxford example, Moderna example, which I think is getting far more attention than it deserves.

01:20:16.420 I mean, they're all looking at other sort of newer approaches of taking DNA or mRNA from these viruses,

01:20:22.340 or spike proteins directly. So is it just that that's the way technology is going, and this is

01:20:28.020 the first time we're seeing an all-hands-on-deck fire drill for a vaccine development? Or is it that

01:20:34.580 there's something about inactivated versions of coronaviruses or attenuated versions that scares us?

01:20:40.660 Yes. And I'm going to give you an example. Very early on, Ronda Rosias at Harvard Medical School,

01:20:48.240 the man who isolated the first simian immunodeficiency virus and the subsequent clones of

01:20:55.000 that virus, and really is a pioneer in this field and has done some tremendous work. He discovered

01:21:01.160 that if you attenuate that virus, SIV, by knocking out a piece of meth, and you vaccinate, you infect

01:21:10.620 animals, the virus replicates, but it's weak. It then goes away to a very low level of replication.

01:21:17.120 But if you come back with a wild-type virus 20 weeks later, those animals are protected. I mean,

01:21:24.980 this is the best vaccine that we have. And so the argument would be, well, let's go into Africa and

01:21:33.040 vaccinate everybody with us. Well, there's a couple of problems. It was noticed that monkeys that were

01:21:39.880 given this neph-attenuated virus many years later started developing some clinical signs of SIV

01:21:47.660 infection. It had repaired itself and was now pathogenic. In fact, we did an experiment where

01:21:57.680 we took attenuated virus-infected monkeys, and then we challenged them with a different virus.

01:22:05.880 And we got some level of protection. But what we saw was a few animals that had very,

01:22:13.680 very high virus loads and were not protected at all. The incoming virus had recombined with a

01:22:20.740 vaccine virus to form an entirely new virus that was highly pathogenic. A remarkable story.

01:22:29.520 We couldn't understand why a couple of these animals had these huge virus loads. And when we

01:22:33.780 sequenced the virus, there was a chimer between the incoming challenge virus. And then I think this

01:22:40.180 also bears on the issue that development of vaccines is very, very difficult. And you have to be very,

01:22:46.200 very careful before going to thousands and millions of people with whatever vaccine construct you might

01:22:53.960 have. And that is part of the problem in developing vaccines. But every way to make a vaccine is being

01:23:02.080 trying at the moment. The Oxford approach is to use a chimp adenovirus to express the spike protein

01:23:09.980 of the coronavirus. And it's going to be very interesting to see what sort of neutralizing

01:23:18.700 antibodies that vaccine generates in humans.

01:23:22.320 Do they test that, David? Sorry to interrupt you. Do they test for that in phase one, even though the

01:23:27.940 purpose of phase one in humans is safety, given what's at stake, do they at least use the phase

01:23:34.280 one to confirm that when I stick a piece of spike protein into this defective adenovirus and give it to

01:23:41.560 even a hundred humans just to make sure it doesn't cause any acute toxicity, oh, by the way, I can at least

01:23:47.980 find a couple of neutralizing antibodies. And if I can't, I better question whether we're going to

01:23:52.220 move ahead.

01:23:53.660 I guess what I would say is I would hope that they would be doing that. But again, it depends

01:23:58.820 on what sort of titer is being induced by these antibodies, by these vaccines. What's the neutralizing

01:24:07.040 titer? And not necessarily just in monkeys, in humans, because in the end, that's the only experiment

01:24:13.520 that we truly care about. And then how long does that antibody titer stay there? But in this case,

01:24:22.240 remember, what we're trying to do is not necessarily provide sterilizing immunity, which is what we

01:24:29.520 really needed to do in the case of HIV. We're trying to knock down initial virus inoculum to a level

01:24:37.200 where it doesn't cause symptoms and also reduces the amount of transmission. And so the goal for

01:24:47.400 this vaccine is not the same as an HIV vaccine, if you will, where we were trying to provide

01:24:54.180 sterilizing immunity because once HIV starts replicating, it spawns the necessary mutations

01:25:00.360 to escape from any sort of immune response. But if we can knock down the amount of virus in people

01:25:07.940 that are challenged with the virus after vaccination, and it prevents them from going to the ICU,

01:25:14.600 prevents them, reduces the days that they are infectious, that for me is a gain. And so the goal

01:25:23.000 of an HIV vaccine and the coronavirus vaccine are quite different.

01:25:27.060 You've also studied Zika extensively, and I know that that ties into your love of Brazil. Is there

01:25:34.280 anything that you've learned through your years of studying Zika, both in its epidemiology and its

01:25:40.700 immunology, that factors into how you think about coronavirus, either optimistically or pessimistically?

01:25:46.680 Zika virus had its own special set of issues. And that is that Zika virus infecting you and me

01:25:54.480 is not really going to cause much of an issue. The problem is, is if it infects pregnant women.

01:26:02.900 The legacy of Zika virus in South America is far greater than we could have ever envisaged.

01:26:09.080 There are many children walking around today that don't look as if they're unusual, but because this

01:26:19.260 virus infects brain tissue, they will have many, many deficits, neurological deficits.

01:26:28.820 So that had its own set of issues. I think a vaccine against Zika virus, again, faces the same problems

01:26:37.380 that you need to induce neutralizing antibodies that can be durable. But in the end, we decided to take the

01:26:47.580 approach to make antibodies, and this is a collaboration that we had with Dennis Burton,

01:26:53.660 to make antibodies that we could inject into monkeys and prevent infection. So if you're a

01:27:01.580 pregnant woman and you wanted to have a baby when there's a Zika outbreak, if we gave you these

01:27:09.060 antibodies, neutralizing antibodies, would that prevent infection? And in fact, we were able to

01:27:14.780 show in monkeys that a combination of antibodies completely gave sterilizing immunity to those

01:27:22.800 monkeys. They couldn't be infected with Zika virus. Now, we did the same experiment on pregnant monkeys

01:27:29.860 that were already infected. So we treated them at day three with our monoclonal antibody,

01:27:34.300 and it was a very small number of monkeys, but we did not prevent transmission to the fetus.

01:27:43.780 So in that case, we failed. So again, it depends on the biology of the virus, what you need to do

01:27:52.060 to ameliorate suffering from that virus as to the approach that you might take.

01:27:59.140 Yeah, I think that's actually a very helpful explanation, David, because it really frames for me

01:28:03.080 and the listener why you don't need a vaccine here that is perfect. It has to be good enough. It has

01:28:09.900 to have neutralizing antibodies. That's non-negotiable. If you don't have that, it's all for show and so

01:28:14.920 what? Who cares how many IgGs you have if they can't neutralize? But what you have to do is reduce

01:28:21.120 the viral load because one, it reduces the transmission, and two, the viral load is proportional

01:28:26.540 to the damage. So more virus is more entry through cells that bear the ACE2 receptor, presumably is

01:28:33.360 more of a cytokine storm. So you get more of the immune modulation. And let's assume either through

01:28:39.160 some combination of monoclonal antibodies or effective vaccines, you can reduce the viral

01:28:44.040 load upon first contact by 70, 80%. That could have a commensurate reduction in mortality and spread.

01:28:51.480 All of a sudden, I want to come back to something that you brought up earlier, which is I think it's

01:28:55.820 unfair to compare SARS-CoV-2 to influenza because influenza, meaning the resistance to influenza,

01:29:03.980 has many advantages. And that is that healthcare workers are all vaccinated against it. And so are

01:29:10.420 the elderly each year. Now that doesn't mean it's necessarily always an effective vaccine, but you

01:29:15.280 know your enemy, you know where they are, and you're ready for them. And I think a lot of the damage

01:29:20.240 we saw out of the gate with coronavirus was nosocomial. It was transmission within hospitals,

01:29:25.460 which also probably means higher viral loads. And so that becomes yet another advantage to a

01:29:31.480 coronavirus vaccine, even if it is not perfect, because the flu vaccine is never perfect, but it's

01:29:37.560 good enough to do all those things you said. And I like this idea of you've got a few patients that

01:29:43.700 are extra high risk and you bolster onto the vaccine with the monoclonal antibodies, especially

01:29:50.040 if this ends up having a seasonal component to it, which I guess we're not going to know for a while,

01:29:55.320 then even be more targeted in your therapy.

01:29:58.080 I'm a huge fan of monoclonal antibodies. In fact, that's what we're doing in our lab is trying to

01:30:03.500 develop monoclonal antibodies against both this virus. And you know that they're going to be

01:30:10.140 new viruses down the road. So I think that we have to be a bit smarter now. This is not the first

01:30:16.160 SARS virus we've seen in the last 20 years. So need to try to anticipate the next one. And I think that

01:30:25.640 monoclonal antibodies for me are the way forward to treat almost all infectious disease, to prevent

01:30:33.340 and treat. And they're a logical extension of a vaccine. We're simply taking from the best responders,

01:30:41.220 the best antibodies. And we're now distributing that to everybody because everybody genetically

01:30:47.740 were not able to make those robust and highly specific and high binding neutralizing antibodies.

01:30:55.320 So there's an internal beauty to the idea as well. It's just the new vaccinology, if you will.

01:31:01.460 Well, I'm glad to hear that these approaches are going on in parallel. Again, I'm not privy to all of

01:31:05.780 it. I certainly see sort of the five to 10 large vaccine efforts. But again, they're generally on

01:31:11.380 the DNA or mRNA side. But hopefully there is at least some effort on the inactivated side. As you

01:31:18.640 point out, the attenuated is the diciest of them all, though it has probably the potential to do the

01:31:23.520 best. And I agree with you completely, David, that my greatest hope in all of this is that people

01:31:28.440 don't forget about it. I think it's left a big enough shock that people aren't going to forget about it.

01:31:32.140 But lots of smart people were sounding alarms on this after some of the recent pandemics where

01:31:37.420 they were near misses. This one obviously was not a near miss. In some ways it is in terms of,

01:31:42.380 you know, this could have been a lot worse, right? You pointed it out. If SARS-CoV-2 was 10 times more

01:31:47.920 deadly, if it was on par with the H1N1 of 1918, I mean, it's hard to imagine what that would do in a

01:31:56.700 world that is this connected. It's not something I give a lot of thought to because it's so devastating.

01:32:01.220 No, I completely agree with you. If this virus had the W-shaped curve of the 1918 flu, that is it

01:32:09.280 killed the young and then went down and then came up between the ages of 20 and 40, came down and then

01:32:16.520 went up again with older people, this would, for me, have been a horrendous, horrendous pandemic.

01:32:26.460 So we're very lucky in that sense. The other message that I think I'd like to give, when I was

01:32:35.000 a young scientist, I always thought, oh, this is the approach. This is the single approach.

01:32:40.680 And as I age, I think the message is, guys, try everything that you can. We need everybody's

01:32:49.460 approaches. And one of them is going to work better than another, but we need a combination of

01:32:55.600 all of these approaches. So for example, I used to think, oh yes, a T cell-based vaccine is the way

01:33:00.820 for it because a neutralizing antibody vaccine is not going to work against HIV. Well, I was completely

01:33:06.760 wrong as usual. But in this sense, let's try all the different vaccine approaches. And in the end,

01:33:14.260 the ultimate purveyor is putting them into humans and then seeing if they're effective.

01:33:22.280 A very famous vaccinologist once stood up at a meeting. We were talking about monkey data. And of

01:33:26.980 course, I was working in monkeys and I thought it was important. And it's not really. And he said,

01:33:31.860 look, David, human data trumps everything. And he was correct, right?

01:33:37.800 I couldn't agree more. And I think that extends beyond immunology and vaccinology and to

01:33:42.580 every aspect of human health. With that, David, I want to thank you for your generosity,

01:33:48.000 not just of course, with this interview, which has been great, but also the work that you've been doing

01:33:52.580 on the project that we're working on collectively with that huge team. And obviously in the midst of

01:33:58.620 such a, what can only be described as very disappointing and upsetting loss of your life's

01:34:03.700 work as you transferred your lab from Miami to Washington DC, one, to maintain your sense of humor

01:34:10.520 about it. And two, to just keep sort of working on the problem. It's really a remarkable example

01:34:16.340 for someone like me who can easily get frustrated, frankly, when existential crises hit.

01:34:22.060 It's a real pleasure to talk to you. And hopefully that we can embark upon this study and see

01:34:28.520 whether a person that has had a coronavirus can be reinfected. And that to me is a very,

01:34:35.640 very important issue.

01:34:37.560 Thanks so much, David.

01:34:38.320 All right. Cheers.

01:34:41.140 Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper

01:34:45.540 into any topics we discuss, we've created a membership program that allows us to bring you

01:34:49.960 more in-depth, exclusive content without relying on paid ads. It's our goal to ensure members get

01:34:55.440 back much more than the price of the subscription. Now to that end, membership benefits include a bunch

01:35:00.960 of things. One, totally kick-ass comprehensive podcast show notes that detail every topic, paper,

01:35:06.660 person thing we discuss on each episode. The word on the street is nobody's show notes rival these

01:35:12.080 monthly AMA episodes or ask me anything episodes, hearing these episodes completely access to our

01:35:18.740 private podcast feed that allows you to hear everything without having to listen to spiels like

01:35:23.640 this. The qualities, which are a super short podcast, typically less than five minutes that we

01:35:29.000 release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on

01:35:33.820 previous episodes of The Drive. This is a great way to catch up on previous episodes without having

01:35:39.160 to go back and necessarily listen to everyone. Steep discounts on products that I believe in, but for

01:35:45.060 which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in

01:35:50.040 as time goes on. If you want to learn more and access these member-only benefits, you can head over

01:35:54.480 to peteratiamd.com forward slash subscribe. You can find me on Twitter, Instagram, and Facebook,

01:36:01.700 all with the ID peteratiamd. You can also leave us a review on Apple Podcasts or whatever podcast

01:36:08.200 player you listen on. This podcast is for general informational purposes only and does not constitute

01:36:13.760 the practice of medicine, nursing, or other professional healthcare services, including the giving of

01:36:19.260 medical advice. No doctor-patient relationship is formed. The use of this information and the

01:36:24.960 materials linked to this podcast is at the user's own risk. The content on this podcast is not intended

01:36:31.140 to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard

01:36:37.620 or delay in obtaining medical advice from any medical condition they have, and they should seek the

01:36:43.780 assistance of their healthcare professionals for any such conditions. Finally, I take conflict

01:36:49.240 of interest very seriously. For all of my disclosures and the companies I invest in or advise,

01:36:54.980 please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of such companies.

01:37:19.240 Thank you.

The Peter Attia Drive - June 15, 2020

#115 - David Watkins, Ph.D.： A masterclass in immunology, monoclonal antibodies, and vaccine strategies for COVID-19

Episode Stats

Length

Words per Minute

Word Count

Sentence Count

Misogynist Sentences

Hate Speech Sentences

Summary

Transcript