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

Episode Date: June 15, 2020

In this episode, David Watkins, professor of pathology at George Washington University, shares how insights from his HIV and Zika virus research could apply to SARS-CoV-2 protection strategies. David introduces monoclonal antibodies as an intervention to prevent and treat COVID-19 infection, and also discusses how they could be used as a hedge to vaccine development. Additionally, David’s immunology tutorial explains the innate and adaptive immune systems and their differentiated responses to viral infection.   We discuss: Background and current interest in immunology [4:30]; Immunology 101—The innate and adaptive immune system [10:15]; Defining antibodies, importance of neutralizing antibodies, and serology testing for COVID-19 [19:00]; B cells—How they fight viruses, create antibodies, and fit into the vaccine strategy [25:00]; T cells—Role in the adaptive immune system and ability to kill infected cells to prevent viral spread [36:15]; Valuable lessons from HIV applied to SARS-CoV-2 [51:00]; Lessons taken from the hepatitis C success story [1:01:30]; Monoclonal antibodies, vaccines, and the most promising strategies for preventing and treating COVID-19 infection [1:04:45]; COVID-19 vaccines in development [1:19:00]; How David’s work with Zika virus informs his thinking on SARS-CoV-2 [1:25:20]; Why a vaccine for COVID-19 doesn’t need to be perfect to be effective [1:27:45]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/davidwatkins Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Professor David Watkins. David is a professor of pathology at the George Washington University Medical School where he recently relocated from the University of Miami. There's an interesting story about his recent relocation, which we touch on at the opening part of this interview. Dr. Watkins was elected a Fellow of the American Academy of Microbiology and was Vice Chair of Research and Pathology at the University of Miami prior to this recent transition. His early work focused on the similarities between non-human primate, simian immunodeficiency virus,

SIV and HIV. In fact, SIV is a great animal model for HIV, which is where David has spent the bulk of his career. And we touch on that quite a bit in this episode because there's a lot you can learn about what may or may not work with coronavirus. Obviously, the purpose of this discussion was really to talk about coronavirus, but really what I find great about this episode is the immunology 101 discussion that I wanted to open with and we did open with but we went deeper than I expected we would go. I just can't say enough about that. I think if you are trying to make sense of what you are hearing about this vaccine versus that vaccine versus this test for antibodies versus this test for antibodies, versus that test for antibodies. If that stuff isn't crystal clear to you, you're going to want to listen to this. And even if you don't care about some of the other stuff we get into in the more nuanced

science later on, I think the first part of this interview will appeal to anybody who's trying to understand immunology and doesn't know the difference between the innate system versus the adaptive system, the cellular system versus the humoral system. I think the show notes for this are gonna be really helpful because again, there's just so much content here. David does just a great job explaining kind of the overall different categories of vaccines, the inactivated viruses, the attenuated viruses, et cetera.

And we go into what the examples are of each of these. And then finally, David talks about what he is most excited about on this front, which is the potential for monoclonal antibodies. So I hope you enjoy this episode, and it's not going to be the last one on this topic, but this one's an important one if you want to understand anything that we go into deeper. So without further delay, please enjoy my conversation with David Watkins. David, thank you so much for making time to sit down after you just barely had a chance to settle into Washington, DC.

My pleasure. I'm still not fully settled in. It's been a series of disasters that have occurred in our move here to Washington, but hopefully we will get over those things pretty quickly. Yeah, I didn't know about this until recently. Would you be comfortable sharing with people the major disaster that is, I mean, if not for the fact that you were laughing, I certainly wouldn't have a smile on my face because it's so sad.

Well, our freezer truck traveling from Miami to Washington, DC with over half of the folks that you've just left the university in Miami. Yeah, so I've been at the University of Miami for 10 years and recently decided to move to GW Medical School. And so I needed to transport all of my samples that I have accumulated over probably 30 years of research. And they came up in a single truck in a variety of freezers that were plugged into the truck and there were a couple of liquid nitrogen freezers in that truck. And in North Carolina the truck caught fire and destroyed all of those samples.

So over 100,000 samples were destroyed in this truck. So we're now thinking and working with the insurance company as to how to regenerate the most important samples in that truck. So yes, we had a little bit of a setback. So David, you and I have met through this very interesting project we're trying to get off the ground working with a bunch of really smart people, and we won't get too much into that project specifically. But the point for the listener is some of my colleagues and I reached out to you on the basis of your expertise in terms of understanding coronavirus and specifically around a question

that pertains to how long could be expect the immunity of an infected person to last. So if a person gets infected and is fortunate enough to survive, which fortunately is the majority of people, what does that say about their ability to survive a subsequent infection? So a lot of paths and roads led to David Watkins.

So help me understand a little bit about your path. I know you were born in Uganda and I know that you studied the Zika virus. I know you have a great interest clinically in HIV, but can I connect some dots there for me in terms of where the interest in immunology came from? So yes, I was born in Uganda and then I grew up in the Western bees until I was 11. And I think it was in the West Indies that I developed a keen interest in nature and all things tropical really, because it was a very happy period in my life. My mother decided I needed to have a proper education,

so I went to an old boy's British boarding school in South Wales, which was a pretty traumatic event coming from the color and the beauty and Freedom of the West Indies to a all-boys boarding school. However, I survived that, but I think that what I got from my Time in the West Indies was a deep appreciation of nature and especially tropical nature the diversity deep appreciation of nature and especially tropical nature, the diversity. So I studied biology, that was what was my great passion and I did a degree, undergrad degree in botany and zoology and then went to the United States to study immunology really, the evolution of the immune system and then went to Boston and worked on the HIV epidemic in the long term, but initially in the short term worked on the evolution of the immune response. So how did first of all frogs make an immune response and then how did monkeys make immune responses.

So I was a really an evolutionary biologist and then HIV came along and this is the most dramatic example of evolution that I certainly have ever seen, whether virus populations can change after infection in two weeks where the infecting virus can be essentially removed and a new virus appears under pressure from the immune response and then because of my roots in the West Indies, I had the occasion to visit Brazil about 20 years ago and to visit Brazil about 20 years ago and realized that I was back in the West Indies because of the Neatropical foreigner or exactly the same.

So I was back home. And since then I've fallen in love with Brazil and learned how to speak Portuguese. And now study many viruses that are tropical diseases like Cacur and dynchid. So I guess that's how I came to develop my interest in tropical diseases. Well, I share your love for Brazil, the clearly not your ability to speak the language, or probably the frequency with which you've been there, but it is the place, I hold very special, and I'm very bummed to probably not be making a trip this fall there. I was planning to take my wife, potentially my daughter, the cell Paulo. So I do look forward to getting back to Brazil though, because I agree with you. It is a very, very special place on this planet.

By the way, before we get into something, when you said the evolutionary thing, I questioned popped into my mind that may or may not be relevant, but just out of pure curiosity. When you think about our evolution as humans, people point to the development of language as a big step function change in our development or developmental changes in the brain, some of which of course enabled that change in language or standing upright, all of these various things that represented not just linear, but sort of of log rhythmic changes. Again, not that they occurred very quickly in real time over a log scale they looked to have occurred more quickly. What was the biggest change in the evolution of the immune system as you studied it?

I think probably the advent of the adaptive immune response because many, many different animals have innate immune responses that are incredibly important, but the evolution of T and B cells that then allowed the immune system to have greater memory to respond to pathogens. And in the end, it's the basis for vaccination, which as you know, is the public health measure that has saved more human lives than any other public health measure. So, yeah, probably that too in response. And of course, that's what I'm interested in too, so there's a little bit of bias here. Well, when did that take place? How long ago did we acquire that out of just the innate system? We certainly know that amphibians have TNB cells

and make antibody responses and T cell responses. So this occurred well before that branch of the animal kingdom. That's amazing. I actually would not have guessed that. I would have guessed it was more recent than that, but that's pretty impressive. And it speaks to obviously the importance of it So let's build up what you just said and give people a really good primer on immunology I love this topic as well, David and I studied immunology, but in a different lens

I studied it through the cancer lens so mostly focused on the cellular branch of the adaptive system. Could you walk people through kind of a diagram that people might keep in their minds, I, which says you first would bifurcate the immune system as innate and adaptive, and then you would further bifurcate the adaptive system as cellular and humoral. So maybe talk about what those two branch points mean. Let's say people get infected with influenza virus or even coronavirus. What happens is that the virus enters a cell through a reset. And the virus can't replicate by itself and needs to get into that cell and replicate. And then the virus starts replicating, produces copies of itself which are sent out into the blood and in fact other cells.

That infection event triggers the innate immune response. There are sensors inside cells that will then trigger the turn on immune system, including the adaptive immune system. The adaptive immune system has really has two major arms, the T cells and the B cells. I'm going to talk a little bit about the B cell response for the moment because that is what has really fascinated me for the last two or three years. And we're getting influence, we influence on infection on lymph nodes, under our jaws, swell up.

And the question is what's going on? And what's happening there is that pieces of the virus are being presented to the B cells. And the B cells have receptors on their surface. And they recognize this piece of the virus. And they bind very weakly, but that stimulates the cell to divide. Every time the cell divides, it makes an error in copying this receptor on the cell surface. And some of those errors make that antibody less able to buy, and that

B cell will die, but some make it better able to buy the antigen. And this process goes on and on, and so the B cell starts growing and your lymph node starts swelling. And during this process, even though you're born with a set of B cell genes, by the time you're 60, you may end up with a different set of B cell genes through this beautiful evolution. In fact, this after HIV evolution, the face of the immune response is one of the most beautiful examples of evolution that I've ever seen. So what happens is this receptor on the B cell starts mutating and then is selected for and you arrive at a antibody that now binds to the antigen with very high affinity.

Can you tell people the difference between an antibody and an antigen and what some of the different antibodies are? Absolutely. Antigen simply means a piece of the virus. So when the virus comes in to the body, it starts replicating and be picked up by a macrophage which will engulf it and then put it back out on the surface of that cell or on dendritic cells. It's all very mechanical and I think it's important that people understand this, right?

These things you're talking about, like these are physical proteins. This is a virus that invades a cell. I think for people who don't understand immunology, it seems like a bit of a black box, but the way you're explaining it, if people understand that you're talking about a physical piece of the virus, a tangible piece of virus makes its way into these cells that present the antigens. I mean, it becomes actually a lot less intimidating, I think, to understand what you're saying. It's simply a piece of the virus.

Antigone, perhaps, is a piece of jogging that we should use. So, just a small piece of the virus. And that's out on the surface of this salad. But it's enough for us to know it's not us. That's the key point here is it's an antigen, not just because it's a piece of the virus. It's an antigen because our body has some capacity to realize, hey, that thing is foreign. Isn't that sort of the key piece of this? isn't that sort of the key piece of this? Yes, it's a recognition of something that's not self. That is what stimulates these biceps to start replicating. And then on the surface of the biceps is another protein,

which you can think of as a shape or a structure. And this interacts with the piece of the virus, on the other cell, which is presenting that to the B cell. And then the B cell replicates, and every time it does, it makes a mistake, and it gets either a better or a receptor that's not so good, but those better receptors then start binding to the piece of the virus with greater affinity and can basically, now bind very tightly to the piece of the virus. So then they circulate in the body in your blood and in a year's time, you have another infection from the same virus.

And this time, those antibodies are there already pre-made. They bind to that virus, and they stop it infecting cells. And you're protected. And again, that's the basis of vaccination. If I vaccinate somebody, I give them the virus. And that gets presented to the B cells. They make these antibodies and they make them better every time they see a piece of the virus. And so even though you haven't been infected with the virus, you've been vaccinated. The next time you see live virus, these antibodies will bind to the live virus and prevent it infecting cells. Let's talk about a virus that doesn't really

mutate much from season to season. I don't know, pick a rotavirus or something like that. In that first round of iterative replication of the B cell, where it's basically going through an evolutionary process on its own to, quote unquote, naturally select for the best antibodies, how many times, what's the speed with which it is able to replicate until it starts to converge on picking the optimal antibody. These cells are replicating at a matter of hours. But with a new virus, maybe after a week or two, you'll see antibodies that will be able

to neutralize the virus. Now, neutralizes a bit of a technical term, and I'm gonna try to explain it now. You'll get many antibodies that will bind to the virus, but they won't necessarily neutralize the virus because they won't stop it infecting cells. They'll bind to it, but they won't affect its ability to infect cells. And so the key antibody that most of us are most interested in are these neutralizing antibodies.

And that is that they were bind to a part of the virus and prevent that part of the virus getting into a cell. So let's take an example of the new coronavirus. That has a spike on its surface. Part of that spike is a region that binds to its receptor on a human cell. And if you have an antibody that covers up that area, that will stop infection of a human cell. That's a neutralizing antibody. If you have an antibody that binds to another region of the spike that's not involved in binding to the receptor on the human cell, it won't necessarily prevent infection. So, David, let me pause you for a sec sec because this is such an important point that I want to make sure everybody understands it and I want to throw in an orthogonal concept, which is most people when they start hearing about antibodies, they think about

these serology tests because they're all over the news and they start to say, wait, antibody, I've heard of that, that's IgG, IgM, or maybe they remember hearing about IgA. So I want to now have you explain a little bit what's the difference between IgG IgM. Let's just keep those two simple. And then talk about how knowing that you have those antibodies doesn't necessarily mean they're neutralizing advice versus. So how do we reconcile that nomenclature and explain, I guess, going back to the beginning, what does immunoglobulin G or IgG refer to versus IgA, etc. There are many different types of antibodies that can be used at different mucosal surfaces and can be used for various different tasks in the body. So when you get infected, let's say you get infected with dengue virus,

the first antibody that comes up is the IgM antibody. So if you have a task that says your IgM positive for dengue, that means it's a very recent infection. Those IgM antibodies tail off over time, maybe two months, three months, not everybody is the same. Then come up your IgG antibodies. Now, these are the antibodies that will contain your neutralizing antibodies eventually. Although IGM antibodies can also carry out neutralization, that is they combine to regions of the virus and prevent infection. IGA antibodies are generally found at Mucosal surface, so obviously, are very good for Mucosal infections. So let's focus mostly on the IgG and the IgM. So you said the IgM is the first

antibody that typically shows up, and then the IgG comes up as the IgM is trailing off. What determines when a person makes those in that first exposure, if they are neutralizing or not neutralizing? In other words, could you take two people who are exposed to the same virus who both managed to successfully fight off the virus but do so with a different proportion

of neutralizing antibodies and therefore maintain a memory of different neutralizing antibodies and therefore maintain a memory of different neutralizing antibodies that would render one more versus less successful years later. There is actually an enormous variability in the way that people make neutralizing antibodies. There's a paper under consideration, a coronavirus at the moment from a very, very good lab in Rockefeller. They looked at, I think it was 70 individuals, and

they looked for the presence of neutralizing antibodies. They found that almost 20% of them did not make neutralizing antibodies. So, they could be enormous differences in the way that we make neutralizing antibodies? I'm sorry, I just want to make sure I understand that. Does that imply you're saying 20% of individuals who were zero-positive for exposure to coronavirus? So meaning on an Eliza test or some other point of care test, they showed the presence of IgG or IgM in the blood. But when you did a special assay to see if those antibodies

would actually neutralize the virus, they did not neutralize the virus. That's exactly correct. Furthermore, there was a great degradation in theality of these individuals to make neutralizing antibodies. One or two of them made neutralizing antibodies at very high tiches. And what that means is that you can dilute their sera, and it will still neutralize the virus at a 1 to 5,000 dilution. Whereas most people, it's 1 to 100 dilution, can still neutralize the virus. So there was an enormous variation in the levels of neutralizing antibodies made.

Now, I know the sample isn't large, but did they speculate on whether that directly factored into the clinical response of those patients? Not sure. Not sure. Because the next question it begs is those 20 patients that did not have neutralizing antibodies, how did they thwart the virus? Or did they not? Is that the point? Not necessarily. They could have had a lower inoculum of infection. They could have been asymptomatic. I would have to go back to the data to make a correlation between those two

things. But I think what it says is that there is enormous variability in the B cell response to this virus. And that means for me at least those individuals that didn't make a good neutralizing antibody response. Can they be reinfected? And can they be reinfected? How soon after their initial infection? We know that people infected with other coronaviruses, like the cold virus, for example, can be repeatedly infected with the same virus. So one of the big issues for me at least is if you've been infected, can you be infected again?

That ability to be infected does it correlate with neutralizing antibodies in the serum, which is I likely thought but maybe completely wrong. Remember you also have T cells that I haven't talked about. I'm saving those guys in the back for a moment. We're not stopping the V cell discussion yet. I should say that I spent 15 years of my life working on T cells and only more recently, I have been working on V cells. And I'm sure there's some V cell experts

that will be listening to this and laughing at me, but this is my understanding of V cell responses. So another question I think digging deeper into this is, and not to this and laughing at me, but this is my understanding of B-SUN response. So another question I think digging deeper into this is, and not to put you on the spot, but do you know if there has been a study done where they've taken a look at many, many subjects who were vaccine naive, given them a vaccine, so human challenge vaccine for a virus that does not have huge genetic drift, So that would exclude influenza vaccine. And then done what you've proposed, which is followed those people post-vaccination

for measurement of neutralizing antibodies, because at least in that situation, you would have a standardized anoculum presumably. And then you could sort of try to adjust for other host factors such as age, but you could maybe say, look, you have four different cohorts of neutralizing response, but they generally correlate to factors x, y, or z. Do you know if that's been done? It may well have been done, but I'm not aware of the results, but I can tell you a study that we've done in collaboration with Asma Calas in Sao Paulo and Lena

Pumaldum in Fiercruz in Rio. We looked at the immune response to one of the most successful vaccines. And that is the 17D yellow fever vaccine. So this is an attenuated vaccine that was derived from somebody in Africa who had the aloe fever, then put into monkeys, and then culture in the laboratory for many, many rounds of tissue culture. What emanated from this was a virus that was weakened, and we call that an attenuated virus. This has many differences genetically from the original virus in Africa. But if I inject this into a human, the virus will replicate, and it will do all of those things that I

talked about initially. It's an immune response, then the adaptive, your have T and B cells generated, and you will have antibodies generated against the vaccine virus. And in fact, the best way to make a vaccine is often attenuating or weakening the original virus. Now, there's a few problems with the other people virus, vaccine. And that is that there are some people whose immune responses cannot handle the attenuated virus. And some of these people will actually, one in 300,000, will get sick from the virus. And some of those people will die from the virus, especially if you're older.

There is some risk associated with it. And for perspective, I think measles, mumps, chickenpox would be other examples of live attenuated viruses. But this one is something about this one the 17D is its efficacy is great. What is the approximate efficacy? The one thing about humans is they're all different. They're all different ages. And as you get get older your immune responses are not as good. But the study that we did with MENA and ESPA shows that all of those vaccinated individuals will make beautiful neutralizing antibody responses against 17D, one in five times. So I can dilute this here one in five thousand so I can dilute this here one in five thousand it'll still stop the virus from infecting cells beautiful immune response

but if we take a virus out of a dead monkey that's died of yellow fever recently in Brazil not the sake so one or two individuals didn't make any responses against the wild type, primary icing, because these viruses that come right out of a monkey, for example, are incredibly well adapted to replicating in the monkey and have not been adapted to replicate in tissue culture. But was there anything special about the gentleman in Africa who was the person who, from whom the yellow fever virus was first pulled or was it just that happened to be a person there? Like was there some characteristic about this person that ceded? No, I don't think there was anything special about this individual, but the virus has so changed the vaccine virus from that original virus, that it engenders immune responses that

may not be able to recognize a pathogenic primary isolate. And this primary isolate is incredibly important to test any vaccine against. But what we found is that there was a large range in ability of these people that were vaccinated to respond to the wild-time virus. So I wanna come back to a really deep discussion actually on viruses and take what you've just talked about, which is these attenuated viruses and put them in the context of RNA

and mRNA viruses, the inactivated viruses, and also some viruses for which we have not yet come up with vaccines. RSV, at least not safely, HIV and hepatitis C. I want to come back and talk about that, but I think to do so, we have to go back to these B cells and these pesky T cells. So I think you've done an amazing job, at least to me, clarifying some of the nuances around B cells. And I just want to make sure I'm playing it back correctly, which is the B cells arrive pretty soon after that innate response takes place.

And if anything, they're probably sped up by the cytokine storm that follows the innate response. They go through this sort of evolutionary replicate of cycle until they converge on the perfect antigen. And if we're lucky, they preserve that memory. So the B cells that reside in our bone marrow for years and years later will always hold on to the dear memory of what the final best antigen was. And if we get reinfected, it's a neutralizing antibody if we're lucky that goes back and gets it, but the risk that we don't yet understand is why do some people not make neutralizing antibodies?

And of course, what's the implication of that clinically? Is that a fair synthesis? Yeah, I mean, the only addition I would make to that is that once the antibodies, the B cells, we call it affinity matured, that is they get better and better at binding to the piece of virus that they attach to. And this occurs in the lymph nodes, where the architecture is very important, because you've got T cells that are absolutely necessary to help them develop in those lymph nodes. But then they exit the lymph nodes about 7 to 14 days later. And then they become either memory B cells, which are very small B cells that circulate or they go into the bone marrow where they become these big plasma cells, which essentially become the factories of antibodies.

So if you have laid down in your bone marrow, a plasma cell, we call them plasma cells, they have large cells that are spewing out antibodies. And if one of those cells is making considerable amounts of neutralizing antibody, you will be protected likely from an infection with that virus that you've just seen for a long, long time. Now, that will vary from virus to virus, but that's essentially the ontogeny and evolution of the B cell

risk form. David, you've consistently referred to the delusions that you do when you're actually looking for basically a way to quantify neutralizing antibodies. I'm going to take it to mean then that when I either poke a person's finger or draw blood and look at the quantification of IgG or IgM that we are typically now seeing as common tests that people are doing for coronavirus, we are not distinguishing whether or not neutralizing antibodies are present. That is not an assay that is capable of determining, is that correct? Absolutely. You're not looking at neutralizing antibodies at all. You're looking at the quantity of antibody that is bound to the piece of virus that you're using

in that assay. And that doesn't tell you if those antibodies, combined to the region of the spike protein on the surface of the virus, that is critical in binding to the receptor on the human cells for entry and the value of those antibodies that are not neutralizing not clear at all But we do know that antibodies that neutralize are really really very important That's really the goal of any of the vaccine efforts that are underway at the moment. It's to generate neutralizing antibodies. I admit something kind of embarrassing. I did not know that until I met you and Stanley Perlman. So just to put that in perspective, up until two months ago, I did not know that the antibodies

we measured in a person's serum, whether it be to coronavirus, which we're doing now, or those that I've looked at my entire medical career when I check a patient's antibody levels, whether it be to see if they had varicela'soster and they're at risk for shingles, or whether they had Epstein bar, or you pick any virus. I had no clue that every time I ordered that lab test

on a patient and I was looking at their IgG's and IgM levels, that I was not necessarily being a short of immunity because I had no insight into whether those were neutralizing or not. And that must be the analogy would be, you know, making this up as I go, but like a cardiologist looking at a patient's lipid numbers, but realizing that no matter what these numbers say, 20% of the time potentially, this has no bearing on anything because it's not actually the lipid that matters.

You're measuring the lipid level in a cell as opposed to the lipid level in a lipoprotein, which is the one responsible for disease. It's such a stark wake up call to me. I'm guessing I'm not the first person to be shocked by this. And the fact that we still don't have clinical assays to do this, only laboratory assays suggests it's very difficult to do this or at least not cost effective to just routinely screen patients for neutralizing antibodies. It's quite a difficult to assay

there requires a you incubating the patient's plasma or serum with the actual virus, then plating it out over cells and then watching the virus infect the cells over the next two, three, four, five, six days depending on the virus. So what you're looking for is a serum that will block the virus of interest from infecting the cells. So it's not trivial, but we standardly do it for HIV, for Zika, for Tangi in a laboratory. And we'll soon be doing it for the new coronavirus.

So let's now pivot to that second arm of the adaptive immune system, this highly, highly advanced immune system, where you actually spent the majority of your career, which is talking about these T cells. First of all, how does a T cell differ from a B cell? How do we define it as a different cell? They're clearly both very advanced types of immune cells. Well, I lost something that I know, something about. I used to think that the most important cell in the body

was the cytotoxic T cell. And worse than that, I used to think that the heart had one function, and that is to pump T cells around it. and that is to pump T cells around. I could see the immunology meetings now with pictures of hearts and just, you know, one function, pump T cells around the lungs only function, provide cellular respiration for T cells. The kidneys only function, filter T cells. There's a whole T-shirt industry for you.

Yeah, but I have to admit that I love the cytotoxic T cell. It's called the CD8 T cell. It is a cell of immense power, probably one of the most and powerful immune cells you have. We can see it's awesome power in HIV. By the way, just for the record, I'm kind of partial to CD4. We'll come back to it, especially CD4, CD25, but we'll get to that later. I'm less interested in CD4 cells as an admission.

The CD8 cells are really really action. So we made a discovery in the early days of HIV in the animal model of HIV infection, which is an SIV-symium immunodeficiency virus. I remember this very clearly. We infected monkeys with a symium immunodeficiency virus, and then we looked at the virus two weeks later. And two weeks later, we couldn't find the virus we infected those monkeys with. There was virus replicating in the blood, but it was a new virus.

And it had changed at one site. And I remember when the student brought in the sequence of the new virus virus and it had one change and I said you've made an error we need to get this checked by other labs because I couldn't believe it but what had happened is that how many base pairs by the way just to put in it had two or three changes it depends this is an RNA or DNA virus this is an RNA virus so this is HIV which is an RNA or DNA virus. This is an RNA virus. So this is HIV, which is an RNA virus. So and it's notoriously error prone when it copies itself.

But what we discovered it happened is that the monkey had made a massive T-cell response directed against eight amino acids. And an amino acid is a, you think of it like a string of pearls. And this was eight pearls. This T-cell response had wiped out the initial infecting virus. So that all that was present, replicating in that animal now,

was a virus that had mutations in that area. So when you see dramatic effects like this, you understand the power of the cytotoxic T cell. So basically these CTLs have been generated and IACTL, cytotoxic T lymphocytes is the abbreviation. They had wiped out the virus that I put into these markets. And more recently, you've seen this in cancer. There was a paper published in the New England Journal where, if I remember the paper correctly, this patient had a melanoma and then she had a massive, she tried every treatment and she had a massive tumor under her left breast, I think it was. She was treated with an antibody that turns the T cells back on.

And in a matter of weeks, she now had a hole in her chest because the T cells had just gone and wiped out the tumor. So to me, this is the awesome power of these CD8 T cells. And that's what I initially fell in love with, was CD8 T cells in the immune system. But after spending 20 years trying to make a vaccine against HIV based on inducing T cell responses and failed spectacularly at that.

And then recently discovered the power and the beauty of B cell responses and antibody evolution, which is the same way that the virus had evolved in the face of this CDAT cell onslaught is the same way that a antibody evolves when it affinity matures to become the perfect fit binding antibody. There's two sides of the same coin. Let's explain a little bit to how that CTL works. The cancer example, of course, is near and dear to my heart, but let's use another viral example to explain how the CTL or the CD8 T cell is basically instructed to destroy in the same way that the B cell makes neutralizing antibodies that ultimately destroy the virus.

So this is a different method of killing. So let's walk the listener through that. Let's walk the listener through that. It's completely different method of getting. So again, a virus, let's use HIV as the example. A virus will enter a cell and within 24 hours will make thousands of copies of itself and will burst the infected cell. And in the case of HIV, these are CD4 cells. The virus enters the cell 24 hours later, hundreds and thousands of copies of this virus and

now released into the blood. Now an antibody can interact to stop the virus from getting into the cell, although that's proven to be very difficult to an HIV and we can talk about that later But once that viruses in the cell it Cannot do anything the antibody cannot get inside the cell So the game's over as far as an antibody is concerned This is where CDAT cells come in Sorry, and is that just because HIV has so much replicative power or is it because

just by some stroke of horrible, horrible luck, the cell that HIV uses to replicate happens to be the general of the cellular immune system, the CD4 cell. What is it about that that is so ironically bad? Well, I mean, most viruses will get into any cell that has their receptor on their surface on it. But in the case of HIV, this receptor, the CD4, receptors on the surface of CD4 cells, these helper cells. But in any event, an antibody, whether it's a nepothealial cell that's been infected or a CD4 cell, once that infection

event is over, an antibody can do nothing because the antibody can't get into that cell. So what we need is a cell that can recognize an infected cell and kill it. Before it releases all the progeny virus. So, I like to think of an infected cell as a virus factory. You need to shut that virus factory down. So how do you get another cell to recognize an infected cell? Because that cell can't go around killing cells indiscriminately in your body, it has

to be able to recognize and infect it from an uninfected cell. And that is what a CDAT cell does in a very elegant way. When the virus binds the receptor and gets into the cell, it starts to make its own proteins in that cell. Then we have these buckets called MHC molecules, major histocombatability, complex molecules. These buckets, some pull what's on the inside of the cell and they put it up on the surface of the cell. And in the buckets on the cell's surface are pieces of the virus in an infected cell. In a normal cell, they're normal proteins of normal cellular machinery that goes on inside the cell. So a killer T cell

will come along and it will see, let's say it has 10 cells in front of it, five of them have been infected with HIV and five of them have not. So it'll move over them. It has on its surface a T cell receptor that looks like an antibody. It'll move over and look at the buckets and say, okay, I've got five uninfected cells here, I'm not going to kill these guys. But then it comes to an HIV infected cell and it sees a piece of the virus in one of these buckets and it goes crazy. It binds to that and then it blows holes in that infected cell and it closes the factory down. So these buckets full of pieces of HIV are like flags on the surface of an infected cell that say, kill me, because if you don't, I'm going to release a thousand or two virus

particles into the infected person's blood. So that is what a CD8 T cell does and it plays a critically important role in almost any viral infection. And in fact, you need both arms of the immune system, although I've waxed lyrically about the B cell response and the beauty of antibodies and their ability to neutralize. Sometimes they don't neutralize every virus that comes in. You need your CDAP cells, which are such efficient killings, to come in and kill those virus factories. And so, as with anything, you need multiple approaches to control and infection. And it also depends on the quantity of virus that's in the system as

well. But the CDAT cells are really exquisitely good at closing down virus factories. And that's really their main job. Now we can't generate beautiful neutralizing antibodies or these incredibly powerful CDA cells without helper cells that are critically important in providing a milieu for the development of the CD8 killer cells and for the B cells. And of course, the most dramatic example of the importance of CD4 cells is HIV. When a person gets infected, what happens is we get massive virus replication initially, because there's no immune response. And what's happening during that first two or three weeks is the

innate immune response is being turned on and that's generating the adaptive immune response about day seven to day 40 income the CDAT cells and they destroy everything they can but unfortunately they destroy the first virus they saw but the virus has been making errors. And so now by the time you're two weeks out, you have so many copies of different viruses in that infected individual. And it's simple Darwinian evolution. The CDHT cells were searching to destroy every infected cell that they can. But there'll be one that has a mutation in that string of eight poles that the CD8 T cells are seeing in that bucket on the surface of the infected cell.

Those CD8 T cells cannot recognize that. That cell will start spewing out thousands and thousands of copies of virus. And that will become the new virus in the individual and So does that mean that every patient who's infected with HIV will ultimately converge to a mutation that at least can that contains that section? it would if Everybody had the same buckets Ah, so it's different for different patients. Right, so the MHC is incredibly interesting

because it has so much diversity. So your MHC didn't a different than mine. And if you needed a skin graft, you couldn't have a skin graft for me for IQ reasons reasons including the fact That your T cells would recognize my skin as foreign because of the MHC molecules on the service and just Slough it off. Yeah, I mean the T cells are really I mean not just as you've described it their role in treating viruses or combating viruses

But it their role in treating cancer in Transplantation human transplantation so organ rejection their role in treating cancer in transplantation, human transplantation, so organ rejection, their role can't be overstated. The example you gave of the woman with melanoma is a very extreme one, but there's reasonable evidence that most people walking around have cancerous cells in them, i.e., cells that do not respond to normal cell cycle growth, and yet they will not go on to develop cancer anytime soon. And that's a great testament to the CD8 cell, which is able to recognize those cancer cells as non-self,

which is the key determinant and to eradicate them. And of course, this is exactly the reason we have to give patients who have been given a transplanted organ, immune suppressing drugs. It's really suppressing this arm of the immune system to prevent them from doing their job, which is saying, hey, that kidney or that skin graft or whatever is not me and therefore it needs to be eradicated. I share your enthusiasm for this, David. I find this to be some of the most interesting biology in the human system. And so it's kind of remarkable. It's funny. I still don't think I really understand

why certain viruses, in particular HIV and Hep C, are not vaccinated against. And I think maybe not. Eveli, I assumed that the problem with HIV was the rate of mutation and the fact that it was primarily targeting the CD4 cell. Is that, are those effectively the two reasons that we don't have a vaccine against HIV? Most of our vaccines are based on immunizing an individual so that they develop neutralizing antibodies. There are very few T cell-based vaccines, although it's likely that T cells play a very,

very important role in the vaccination process, but it's those neutralizing antibodies that when you first get infected, they come in and they stop infection. Your T cells can come in and clean up afterwards, but they are really the basis of almost all licensed vaccines. So the first attempt was to make neutralizing antibodies by vaccination. And the problem is it's very difficult to make a neutralizing antibody against HIV and SIV. Just for structural reasons, meaning, I'll explain that. That's not to say that neutralizing antibodies are generated. So let's go back to this infected

person or a monkey. Massive virus replication, you can have 10 to 100 million copies of virus per ml in those first two or three weeks. It's a massive population size, and they're almost all of them are different. So you've got enormous variability, and that's the basis for selection. So it comes to your CDAT cell response, it kills everything it can.

And now what you're left with growing out are these new viruses that have CTL escape mutants. Your antibody response then kicks in along the lines that we discuss, and patients will make a neutralizing antibody response, but guess what happens? The virus escapes. So you go through these cycles of escape generation of new antibody responses, but there are rare individuals. Well, the point also is that there is enormous variability in HIV. The reason for the enormous variability of already gas. And that is this aeropron mechanism of generating new variants, coupled with the fact that HIV, unlike most viruses, are chronic virus. So the virus constantly

gets selected upon by the immune response. And we've done these experiments. We can infect a monkey with a clone virus. So we know entire sequence. We can then get that virus a year later and look at the variation in the virus. An outside envelope, which is the piece of the virus on the surface of the virus for entry, all of the variation is selected for by CTLs, by killer cells. On, in envelope, it's all selected for my antibodies.

So this virus, because its chronic is so variable, so when you talk about HIV, you're basically talking about lots of different HIV. So here's the question for a vaccinologist. How am I going to make a vaccine that I'm getting a gift to 100 people in Boston, but those 100 people are all going to be exposed to different viruses. If I vaccinate them in yellow fever,

I know pretty much what the sequence will be. But here, I've got a hugely diverse set of viruses that I'll be challenged with. The second problem is that today, nobody has been able to generate by vaccination a neutralizing antibody against HIV. Meaning, every vaccine that has been given to patients, even if it generates antibodies, they fail to actually neutralize the virus. Exactly. That's the big problem. I can vaccinate

monkeys and generate huge levels of antibodies, the bind, none of them neutralized the virus that I'm going to challenge the monkeys with. That's another huge problem. The reason for that is that this virus, this envelope, first of all, there are very few copies of envelope on the surface of a HIV barrier. That envelope is a protein, but it's covered in a shield of sugars. So it's hard to get in to bind to the regions of the envelope that are important for binding the CD4 and getting into the cell. So this virus is unlike anything I've ever seen.

It is so, so difficult to generate neutralizing antibody responses because of the biology of the virus. And the biology by that, I mean both the fact that it's covered in this sugar shield. And if I vaccinate with one envelope, humans, they're going to be challenged with a bunch of different viruses that have all gone through selection and mutation and a different one from the other. And this can be as different as different as 30% of their structure. one from the other, and this can be a different, it's different as 30% of their structure. It's a very, very difficult issue. And the fortunate news here is that on a drug development standpoint, the progress has

been remarkable. I mean, the advent of highly active anti-retroviral therapy in the mid-90s is a game-changer. I mean, it is unbelievable if you just take a retrospective look for 40 years at HIV mortality matched against exposure to or capacity to receive heart highly active and preventive therapy. It's, I don't want to say overnight, but it's like within a span of two years, you took something that was uniformly fatal and you've rendered it a chronic disease that is to no way diminish the struggle of it, but having friends with HIV and watching how long they can live with T cell counts that would have in the past rendered them dead within

months. It's on the bad news, I think you came up against a virus with the most superpowers of any virus. The good news is it's a very chronic killer on the medicine side. There were opportunities to keep it at bay. Am I being overly optimistic there? No, no, no, and I think the big point you raise is that as we stand here with the coronavirus epidemic three months old, I think we should have

faith that science will find a solution to this. And I'll go back 30 years, and I'm going to laugh at Harvard at the primates center there, and I'm hearing about these people in San Francisco with these lesions and they're dying. And I remember, we don't know what's causing us. Bacterium is it drugs, is it a virus? Nobody could isolate virus from these individuals. And I'm at the primate center, and monkeys are dying as well. And Ronda Rosia is at the primate center,

the new interprimate center, isolated a virus that looked very similar to HIV. And that was the birth of the animal model that we were able to pass therapies on. So we discovered it was a virus, we thought, well, okay, then we can use condoms to protect from it. Okay, that's good. That's a behavioral measure. Then came AZT. And that was not until the late 80s that that insight. I remember the exact time long. Maybe a bit earlier, right? Potentially mid 80s, but okay.

But so now we have the first measure against the virus. We have social distancing. That's right. And then AZT was a repurpose drug. And I remember where you could see the virus loads coming down and then they came back up, of course, because the virus escaped. Then Ray Shanazi at Emory discovered a couple of drugs

that if you put these together or in combination with other drugs, you now had a treatment. And this was the game changer. The rest of us are working on vaccines and immune responses and what we're learning is that it's so difficult this virus can escape from just about any immune response we throw in it. And then you have the ground breaking print studies pre-exposure, profile access where people take a drug, truvada in this case, every day, and they simply don't get infected.

And if everybody who's sexually active takes truvada, the epidemic of new infections is over. We still have a large number of people already infected and they need to get on treatment. But in that example, science found a solution to the epidemic. Although it wasn't a vaccine because of the unique nature of the virus and I think it's important to understand that every virus presents its own particular set of challenges, and HIV presented us as vaccinologists, with a set of challenges, which I think, frankly, are going to be insurmountable, and thankfully we have these drugs that are highly effective.

That's not to say that we don't need an HIV vaccine. We need an HIV vaccine. And this virus is in fact a 75 million people to give you some perspective on the new coronavirus virus infection. It's killed 32 million people. Again, we're not even close to that with coronavirus. But I think the general lessons that we learned from the HIV epidemic and many of us that worked in the HIV epidemic are now better able to deal with the coronavirus because we've learned a lot of valuable lessons from HIV. Now how much do you know about hepatitis C? It has a similar story in that I remember 20 years ago or a little longer than that maybe

22, 23 years ago. I'm in medical school. I'm sitting in Miami, Nology 101 class and they're saying just so you understand there will never be a vaccine for this virus. Don't think about that anymore and not going into that field. I never did think about it anymore but I did notice that by the way a couple of years ago we got a drug that now eradicates Hep C, and it's a lot like the HIV story, which is we still don't have a vaccine. I don't understand why I'm hoping you might be able to offer an insight there, but there is a pretty successful work around because prior to that, David, it was predicted that Hep C was going to be accounting for something to the tune of 70% of liver transplants. Absolutely.

Hep C is a virus that replicates to enormous levels, even higher than HIV, generates lots and lots of variants. And it's going to be very, very, has enormous variability, even though it's a different family of viruses, but it's a virus that's going to be very, very difficult to find a vaccine for, but luckily, the same man Rationazi, PhD biochemist, who discovered the first two drugs, he was involved in the discovery of these first drugs that not only treat hepsi, but the cure hepsi, which is the key, the virus is gone. Now, even with our best anti-retroviral drug therapies, we're still not curing the infected individuals. And of course, that's a huge and important area of research.

My view on this is, I want to be careful. I don't say something that I'm going to think sounds really stupid after the fact, but I'm going to go ahead and say it anyway. It's quite possible. There has been no greater advancement in medicine in the past 10 years than the drugs that cure Hep C. When you think about the scale of what that has done, it is enormous. And to put this in perspective, when I was in residency, and I did my training in surgery, so we were always exposed to sharps and things like that, I was far, far more afraid of hepatitis C than HIV for the following reason.

HEPB. So the big three are HEPB, HEPC, and HIV. Those are the things that are bloodborne transmission. You're going to be worried about them. All of them have devastating consequences. HEPC, probably having the quickest consequences if you are untreated. HEPB, we could vaccinate against. HIV was a lousy virus in terms of transmission.

A solid needle going through a double glove is pretty low transmission. But hep C was a very transmissible virus. If my memory serves me correctly, it's at least an order of magnitude more transmissible than HIV. And no treatment, no vaccine. So I mean, I remember being scared senseless of hepsi and to think that as you said today, I think it's about

a 30 to 60 day course of a medication, albeit a very expensive one. And you take somebody who's got a 40 to 50% chance of dying of liver failure in a decade and you cure them. I mean, this is unbelievable. Science is truly wonderful. I want to bring it back to your point, which is we are still early in this coronavirus situation. And there's probably a greater effort on this than there is on anything else that we've talked about, at least relative to the moment in time when it was perceived to be an issue. I completely agree and I think we have to put it into context of other pandemics, like HIV, like the 1918 flu, for example, where 50 to 100 million people, like they died from

influenza. I think we're much better able to mount a rapid response. I think when much better able to mount a rapid response, I think that this virus will be easier to develop a vaccine against, but I should put in a disclaimer here, and that is that I have been wrong about every prediction I've made about this new coronavirus since January, where I thought that maybe this would be like a very, very bad flu. And I was completely wrong about that. But do you think you are wrong about that, David? I mean, it's still not entirely clear to me that this isn't just three to five times worse than a flu. How much worse do you think it is?

I don't think that a really bad flu has closed down the world economy like this. I'm sorry, yes, no, no. I'm speaking from a purely biologic standpoint, not from a sort of policy standpoint, but from a biology standpoint, my reading of the data is that when you really look at the IFR and not focus on

the CFR and you age stratify, this is a disease that depending on your age is maybe twice as bad as the flu, is maybe five times, maybe eight times as bad as the flu, but it's not 25 times as bad as the flu. How do you read the literature? Again, remember the caveat. When I first started looking at this and I looked at some of the crucial data, I thought, yeah, this is going to be five to ten times worse than seasonal flu. I think it's more likely ten times worse, but I think it also depends on what sort of pre-existing conditions that you have diabetes or B-City. And I think there are lots of things

that we don't understand that can predispose you to us. I mean, what about the amount of virus that you see initially? So I think there's a lot of things that we need to have a lot of humility about understanding in this new virus. But I am buoyed by the fact that the evidence for escape, there is some, but it's logs less than we see with HIV. This is not a chronic virus. So that means that it is possible to generate a antibody response. It's been difficult in the monkey studies to understand the exact type of the neutralizing

antibody response, but the key experiments are putting these vaccine concepts into humans and looking at their neutralizing antibody response. But we don't know what levels of neutralizing antibody responses will be sufficient to prevent infection. And I think that's a very important issue. We don't know that, so we don't know what percentage we don't know the frequency of people who would develop them and we don't know the duration that they will last.

Duration I think is a key issue with respect to infected people and with respect to vaccines. Because you've got to make a neutralizing response. And then you've got to keep that neutralizing response up to a level where we'll prevent infection. But for me, the most exciting hope that we have for treating this virus is neutralizing antibodies delivered as monoclonal antibodies. And maybe I should explain that concept because it really is a beautiful concept. So let's go back to

So let's go back to the example I gave of yellow fever. 5xnate 100 people with this yellow fever virus. That's a 10-rated. It's say 90% of them will make a response against the vaccine virus. 20% of them won't make a response against the wild-type virus, the virus that circulated. So they're going to be susceptible to infection. But at the other end, you're going to have three or four individuals are going to make wonderful antibody responses against the vaccine virus and the wild type virus.

So those individuals, what if I could take their blood and give it to everybody else? Well, there's lots of problems with that. And that was proposed very early via the lingo of convalescent serum, which is we give concentrated amounts of convalescent serum to people who are sick. Maybe we give diluted amounts of convalescent serum to people who are not sick, but at high risk because they presumably wouldn't need as many antibodies to fight off the initial response, if exposed. Right. So I've got these three people that are super responders that are making beautiful antibody

responses that neutralize the virus. Or what I'm going to go in and do is I'm going to get their memory B cells, and I'm going to clone the genes of those antibodies that remember have been through this beautiful process of affinity maturation and changed and now buying very well to the piece of virus that prevents the virus from getting inside the cell. So they neutralize. So I'm going to get these neutralizing antibodies and I'm going to clone them. And then I'm going to test them against the virus. And then I'm going to test them in animal models.

And then I'm going to grow them up in large vats. And I'm going to go into a nursing home, let's say, is 100 people. And I'm going to give them each an injection of this monoclonal antibody. And that is going to prevent infection. How long will that last? It depends.

It depends on the dose you give. And it depends on how you genetically engineer that antibody. So you can put mutations into that antibody without antibody will last for three to six months at levels that should prevent infection. To me, this is the most exciting aspect and the most hopeful treatment for coronavirus. And it's a new type of vaccinology, if you will. And it's, I think, the way forward for the vaccine field is to get those individuals that make the best antibody responses, clone their best antibodies, grow them up in vats, and

then distribute that to the people that need it. And this can be used for prevention, and it can be used for treatment. And one of the things that we're doing at the moment is in the setting of yellow fever, there have been yellow fever outbreaks in Brazil, and my colleague Espa Callas has been managing patients in Sao Paulo, and they come in, and you don't know if they're going to die or they're going to live. And 40% of these people are dying. And there's nothing we can do about it. So the exciting idea is to inject them with an antibody that neutralizes the virus and

stops it replicating. Can we save their lives? And as you saw from what happened with Ebola last fall, simple injection of a monoclonal antibody that neutralizes the virus after infection saved many, many people's lives. Drop the death rate from, I think, 50% to about 50%. And that's the part I want to actually double-click on here a little bit. So let's go back and review. We spent a lot of time talking about vaccines and the goal of a vaccine for the most part is a B cell strategy, which is put in some form of attenuated inactivated virus, or maybe just its RNA, we'll come back

to all the full means. But you do something that elicits an immune response that is appropriate. If we're lucky, we not only get the appropriate immune response, but it generates these specific antibodies called neutralizing antibodies, though the ones that matter. We go off, and if we're lucky, we get beautiful big fat effector B cells that turn into plasma cells that hang out in bone marrow. They are just sitting there primed and ready. If you see this infection again, it's not even going to be a blip on the radar because the antibodies are right there right away to neutralize.

You're saying great. In parallel, here's another strategy. We figure out who the Olympic champions of making neutralizing antibodies are. And using recombinant engineering, recombinant DNA technology, we basically make copies of these things, effectively synthetic copies of these things, effectively synthetic copies of these things, and inject them into people. So that even if their B cells are out to lunch, it doesn't matter because it's the substrate or it's really the product of the B cell that is sitting there waiting. Now, the issues with this are as follows. One,

they don't last forever. So you said, get three to six months out of this. So if we said, look, this will be something that we would use to target the most high-risk people, presumably the elderly, those with the greatest number of comorbidities and healthcare workers. And I think then that there's also tears of other people who are working in close proximity to others, et cetera, et cetera. You would come up with a list of people who probably need to receive these monoclonal antibodies on some regular frequencies, say two to four times per year. How feasible is that in the context of what it takes to basically scale and deliver vaccines? Is it on par with that in terms of challenge?

Is it more difficult? Where does it rank? No, I mean, let's not forget that a cheap vaccine is really the best way 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 HIV. And if we can get that for coronavirus, that will be great. And I think one of these vaccine approaches will result in durable neutralizing antibodies. And then you can be a prime boost with a different vaccine to boost your immune responses. But there are certain people who don't do so well with vaccines, and that's the elderly.

They don't make such robust immune responses. And in fact, it's this population that you might vaccinate with these new vaccines against coronavirus, but they may not make such robust responses. So using a monoclonal antibody, I think, or a combination of monoclonal antibodies would be the way to go in this population. If we can increase the herd immunity in the younger people by vaccination, therefore reducing the number of transmission events, then that would decrease transmission to the elderly. But as we've learned with HIV, we need to use lots of different approaches to treat this virus. So initially we use condoms, we have drugs, and we can use drugs to prevent infection. So the same thing will be with coronavirus.

We need drugs, we need social distancing, we need vaccines. But the point with regard to, is this feasible, is the follows, is as follows. Humira is one of the most prescribed drugs that we have today. That's a monoclonal antibody that's repeatedly given to people. So I think that the advent of monoclonal antibodies is going to be very, very important to treat infectious diseases. In fact, it may be the way of the future. There's a trial going on now using monoclonal antibodies that neutralize HIV to see if it can prevent infection in Africa.

And it's going to be very, very interesting. Where did they get the neutralizing antibodies in the first place given that so few people, if any, would generate them? Absolutely right, that's an excellent question. So one of my colleagues, Dennis Burton, at Scripps, was instrumental and a pioneer in this area. So they developed these huge cohorts. So after about five to 10 years, a small number of individuals make antibodies

that can neutralize not only their own virus, but they neutralize many other different viruses. And what this is is that they're buying to conserved regions on the envelope. And by binding to those conserved regions on the envelope, they'll prevent infection. So that's how these very rare antibodies were isolated. And Dennis was amongst the first to clone and express these and test them in monkey animal models. And then subsequently, many different antibodies

that what we call broadly neutralizing. So it's important to understand we have neutralizing antibodies and people infected with HIV will make neutralizing antibodies but the virus it escapes and that neutralizing antibody will be peculiar to their own virus. But then later on as the virus evolves and the antibody evolves along with it, they will generate what we call broadly neutralizing antibodies and those are the key antibodies.

Those cannot only neutralize their own virus, but everybody else's. And so that's how they isolated those. And that was a massive breakthrough for the HIV vaccine treatment field. So David, coming back to this vaccine issue, you've touched on kind of one of the pillars of vaccine development, which is using the attenuated virus. It's weakened. And again, the example that you used there of yellow fever

being a very successful one. And again, other very successful ones would be measles, mumps, and varicela's oster. On the inactivated virus side, so these are viruses that can't do anything, but you still have the entire coat of the virus that's given. Polio, hepatitis A, and rabies would be the sort of flagship stories there. Those two categories of either inactivated or attenuated are the lion's share of our vaccines. I mean, I know that spike proteins did have B and I think maybe HPV, I think so. But most of the current approaches to coronavirus

vaccines are not looking at the inactivated or attenuated strategies, are they? Or am I just misreading it? Because all of the stories that we're reading about the companies, whether it be Pfizer, the Oxford example, Moderna example, which I think is getting far more attention than it deserves, I mean, they're all looking at other sort of newer approaches of taking DNA or mRNA from these viruses, or spike proteins directly. So is it just that that's the way technology is going? And this is the first time we're seeing an all hands-on deck fire drill for a vaccine development? Or is it that there's something about

inactivated versions of coronaviruses or attenuated versions that scares us? So I'm going to give you an example. Very early on, Ronda Roses, at Harvard Medical School, the man who isolated the first simian immunodeficiency virus, the subsequent clones of that virus, and really is a pioneer in this field and it's done some tremendous work. He discovered that if you attenuate that virus, SIV by knocking out a piece of NET,

and you vaccinate, you infect animals, the virus replicates, but it's weak. It then goes away to a very low level of replication. But if you come back with a wild-type virus, 20 weeks later, those animals are protected. I mean, this is the best vaccine that we have. And so the argument would be, well, let's go into Africa and vaccinate everybody with us. Well, there's a couple of problems. It was noticed that monkeys that

were given this naphytenuated virus many years, late to start developing some clinical signs from SIV infection. It had repaired itself and was now pathogenic. In fact, we did an experiment where we took attenuated virus infected monkeys, and then we challenged them with a different virus and we got some level of protection but What we saw was a few animals that had very very high virus so to and I protected at all

The incoming virus had recombined with a vaccine virus to form an entirely new virus that was highly pathogenic, a remarkable story. We couldn't understand why a couple of these animals had these huge virus ones, and when we sequenced the virus, it was a chimer between the incoming challenge virus. And I think this also bears on the issue that development of vaccines is very, very difficult and you have to be very, very careful before going on to thousands and millions of people with whatever vaccine construct you might have and that is part of the problem in developing vaccines But every way to make a vaccine is being tried at the moment

every way to make a vaccine is being tried at the moment. The Oxford approach is to use a chimp adenovirus to express the spike protein of the coronavirus. And it's going to be very interesting to see what sort of neutralizing antibodies that vaccine generates in humans. Do they test that, David, in sort of an attitude? Do they test for that in phase one, even though the purpose of phase one in humans is safety, given what's at stake, do they at least use the phase one to confirm that when I stick a piece of spike protein

into this defective adenovirus and give it to even 100 humans just to make sure it doesn't cause any acute toxicity. Oh, by the way, I can at least find a couple of neutralizing antibodies. And if I can't, I better question whether we're going to move ahead. I guess what I would say is I would hope that they would be doing that. But again, it depends on what sort of tighter is being induced by these antibodies, by these vaccines? What's the neutralizing tighter? And not necessarily just in monkeys, in humans, because in the end, that's the only experiment that we truly care about.

And then how long does that antibody tighter stay there? But in this case, remember what we're trying to do is not necessarily provide sterilizing immunity, which is what we really needed to do in the case of HIV. We're trying to knock down initial virus in opulom too, a level where it doesn't cause symptoms and also reduces the amount of transmission. And so the goal for this vaccine is not the same as an HIV vaccine, if you will, where we were trying to provide sterilizing immunity because once HIV starts replicating it spawns the necessary mutations to escape from any sort of immune response. But if

we can knock down the amount of virus in people that challenged with the virus die die Anfektion von einem so einem Immunersport. Aber wenn wir die Immunersport nicht in die Menschen, die mit der Virus verletzt werden, dann wird die Menschen von dem ICU verletzt werden. Die Menschen verletzt die Menschen, die sie bemerkst. Das für mich ist es wieder. Und so die Einzelbewerb der Coronavirus-Versen sind sehr anders. is again. And so the goal of an HIV vaccine and the coronavirus vaccine are quite different. You've also studied Zika extensively, and I know that that ties into your love of Brazil. Is there anything that you've learned through your years of studying Zika, both in its epidemiology and its immunology,

that factors into how you think about coronavirus either optimistically or pessimistically? The Zika virus had its own special set of issues, and that is that Zika virus infecting you and me is not really going to cause much of an issue. The problem is, is if it infects pregnant women, the legacy of Zika virus in South America is far greater than we could have ever envisioned. There are many children walking around today that don't look as if they're unusual, but because this virus infects brain tissue, they will have many, many deficits, neurological deficits. So that had its own set of issues. I think a vaccine against zikabar is again faces the same problems that you need to induce

neutralizing antibodies that can be durable. But in the end, we decided to take the approach to make antibodies, and this is a collaboration that we had with Dennis Burton, to make antibodies that we could inject into monkeys and prevent infection. So if you're a pregnant woman and you wanted to have a baby when there's a Zika outbreak, if we gave you these neutralizing antibodies, would that prevent infection? And, in fact, we were able to show in monkeys that a combination of antibodies completely gave sterilizing immunity to those monkeys. They couldn't be infected with Zika virus. Now we did the same experiment on pregnant monkeys that were already

infected. So we treated them at day three with them on a clonal antibody and it was a very small number of monkeys, but we did not prevent transmission to the fetus. So in that case, we fail. So again, it depends on the biology of virus, what you need to do to ameliorate suffering from that virus as to the approach that you might take. Yeah, I think that's actually a very helpful explanation, David, because it really frames for me and the listener

why you don't need a vaccine here that is perfect. It has to be good enough. It has to have neutralizing antibodies. That's non-negotiable. If you don't have that, it's all for show and so what? Who cares how many IgGs you have if they can't neutralize? But what you have to do is reduce the viral load because one, it reduces the transmission. And two, the viral load is proportional to the damage. So more virus is more entry through cells that bear the ACE2 receptor. Presumably is also more of a cytokine storm

so you get more of the immune modulation. And let's assume either through some combination of monoclonal antibodies or effective vaccines, you can reduce the viral load upon first contact by 70, 80%. That could have a commensurate reduction in mortality and spread. And all of a sudden, you know, I want to come back to something that you brought up earlier, which is, I think it's unfair to compare SARS-CoV-2 to influenza because influenza, meaning

the resistance to influenza has many advantages. And that is that healthcare workers are all vaccinated against it. And so are the elderly each year. Now, that doesn't mean it's necessarily always an effective vaccine, but you know your enemy, you know where they are, and you're ready for them. And I think a lot of the damage we saw out of the gate with coronavirus was nozocomial. It was transmission within hospitals, which also probably means higher viral loads.

And so that becomes yet another advantage to a coronavirus vaccine, even if it is not perfect, because the flu vaccine is never perfect, but it's good enough to do all those things you said. And I like this idea of you've got a few patients that are extra high risk and you bolster on to the vaccine with the monoclonal antibodies, especially if this ends up having a seasonal component to it, which I guess we're not going to know for a while, then even be more targeted

in your therapy. I'm a huge fan of monoclonal antibodies. In fact, that's what we're doing in our lab, is trying to develop monoclonal antibodies. In fact, that's what we're doing in our lab is trying to develop monoclonal antibodies against both this virus. And you know that they're going to be new viruses down the road. So I think that we have to be a bit smarter. Now, this is not the first SARS virus we've seen in the last 20 years. So need to try to anticipate the next one. And I think that monoclonal antibodies for me are the way forward to treat almost all infectious disease, to prevent and treat.

And there are logical extension of a vaccine. We're simply taking from the best responders, the best antibodies, and we're now distributing that to everybody because everybody genetically, we're not able to make those robust and highly specific and high binding neutralizing antibodies. So there's an internal beauty to the idea as well. It's just the new vaccinology, if you will. Well, I'm glad to hear that these approaches are going on in parallel.

Again, I'm not privy to all of it. I certainly see sort of the five to ten large vaccine efforts, but again, they're generally on the DNA or mRNA side. And, but hopefully there is at least some effort on the inactivated side. As you point out, the attenuated is the diciest of them all, though it has probably the potential to do the best. And I agree with you completely, David, that my greatest hope in all of this is that people don't forget about it. I think it's left a big enough shock that people aren't gonna forget about it,

but lots of smart people were sounding alarms on this after some of the recent pandemics where they were near misses. This one obviously was not a near miss in some ways it is in terms of, this could have been a lot worse, right? You pointed it out. If SARS-CoV-2 was 10 times more deadly, if it was on par with

the H1N1 of 1918, I mean, it's hard to imagine what that would do in a world that is this connected. It's not something I give a lot of thought to because it's so devastating. No, I completely agree with you. If this virus had the W-shaped curve of the 1918 flu, that is a killed the young and then went down and then came up between the ages of 20 and 40, came down and then went up again with all the people. This would, for me, have been a horrendous, horrendous pandemic. So we're very lucky in that sense. The other message that I think I'd like to give, when I was a young scientist, I always

thought, oh, this is the approach, this is the single approach. And as I age, I think the message is, guys, try everything that you can. We need everybody's approaches. And one of them is going to work better than another, but we need a combination of all of these approaches. So for example, I was like, oh yes, a T cell-based vaccine is the way forward because a neutralizing antibody vaccine is not going to work against HIV. Well, I was completely wrong, it's usual. But in this sense, let's try all the different vaccine approaches.

And in the end, the ultimate purvea is putting them into humans and then seeing if they're effective. Very famous vaccinologist once stood up at a meeting, we were talking about monkey data, and of course I was working in monkeys, and I thought it was an important, and it's not really. And he said, look, David, human data trumps everything. And he was correct, right? I couldn't agree more, and I think that extends beyond immunology and vaccinology and to every aspect of human health. With that, David, I want to thank you for your generosity, not just, of course, with this interview, which has been great, but also the work that you've been doing on the project that we're working on collectively with that huge team.

And obviously, in the midst of such a, what can only be described is very disappointing and upsetting loss of your life's work as you transferred your lab from Miami to Washington, D.C. One, to maintain your sense of humor about it, and two, to just keep sort of working on the problem. It's really a remarkable example for someone like me who can easily get frustrated, frankly, when existential crises hit. It's a real pleasure to talk to you, and I'm hopefully that we can embark upon this study and see whether a person that has had a coronavirus can be re-infected. And that to me is a very, very important issue. Thanks so much, David.

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