The unforeseen consequences of striving for covid-zero

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Things Discussed on Episode:

• Covid: Brazil hits 500,000 deaths amid 'critical' situation
• Expect the Unexpected From the Delta Variant
• The Countries Stuck in Coronavirus Purgatory
• So, you got AstraZeneca. Here’s what experts say about mixing doses, variants and more
• How mRNA technology is altering vaccine treatments

Transcript

Matt Boettger: 0:00

You're listening to the pandemic podcast. We equip you to live the most real life possible in the face of these crises. My name is Matt Boettger and I'm joined with Dr. Stephen Kissler. Once again, his brother is Mia. We have him here from the Harvard School of Public Health. How are you doing

Stephen Kissler: 0:13

one day? Yeah, I'm doing all right. How

Matt Boettger: 0:15

are you? It's good. Good doing well. So, you had a birthday to celebrate this weekend, not yours, but so you were outside doing some fun stuff and just relaxing a little bit, a nice heat and humid.

Stephen Kissler: 0:27

That's right. Yeah. It's emphasis on the heat. But it was, it was good. It was yeah, just really nice to spend some time outside. And there were a lot of people who I got to see for the first time in months and months and months. So it's funny. We're all just like, kind of emerging into the world. And everybody sort of has this like dazed look on their face. Like they're walking out of a cave trying to figure out how to socialize with people again. Yep. Yeah, it was really

Matt Boettger: 0:53

awesome. As I mentioned to you, my, my sister and brother-in-law in law and Sammy were out here in Denver. I go see them since the first time, since September, 2019, it was like a culture shock for them because they're coming from California where everyone is still masked, even though the mandate's been released just to kind of resist. And, and the caution and they came out here and they're like, what is going on? Like nobody wears masks here. It's just from state to state, radically different cultural realities of how you deal with the pandemic at this state, in the games. So. It was really good to see them and they got to see a Rockies game and it was a really quick turnaround but really just been made the best father's day ever. Just the CSUs and Brian and Sammy. So I'm sad to see him leave, but so thankful that we're able to start seeing family and friends again, it's been just awesome. Yeah. And I'm hoping all of our listeners are seen from family and friends. Re-engaging those kinds of things. However, it is in your neck of the woods. And before we get started, same stuff. If you can leave a review, please do apple podcasts. We'd greatly appreciate that. If you want to support us at any time way, patrion.com/pandemic podcast or one-time donation, Venmo, PayPal, all in the show notes. So, there's not a lot to cover, but there's some fun topics that we kind of mind up a little bit to kind of see what we can talk about first. Let's talk about cases rising a little bit, you know, we, I just saw here with Brazil, which for me, I guess was kind of unexpected. I mean, yeah, there was, it wasn't really unexpected. I kind of expected it. It was given their, their, their kind of historical record that they'd probably get hit again. But you were saying you saw even an article in Colorado, a little place starting to see. Cases are as well was I'm guessing. So you can talk a little about that and I'm guessing with the Delta area, and this is something that's going to probably be part of this kind of new reality of just random popcorn places seen, you know, slightly spikes in cases. Right,

Stephen Kissler: 2:42

right. Yeah, totally. It's I think we're going to see more and more of this kind of thing. Because we have this really heterogeneous landscape for vaccination, right. So, so like you say with Brazil, Terribly surprising. Because frankly that epidemic has really been you know, despite the. The great efforts of so many public health officials in Brazil. So many doctors a lot of the efforts at the very highest levels of really frankly, than very mismanaged. And so it's really hard to work against that momentum. And I think that that part of part of what we're seeing now is just sort of the continued impact of that. So, so that's really difficult. And you're right. We're starting to see spikes in cases there, but yeah, again, I mean, as, as we move forward, we're going to have very heterogeneous vaccination rates. The different places are gonna have very different vaccination rates. And, and we've seen what this does in the past. I think the one that I always go to is measles, where before the pandemic, we We're starting to see outbreaks of measles in particular communities. And, and there were still plenty of vaccination in the United States as a whole, but there were specific communities where vaccination rates were somewhat lower and that allowed for measles outbreaks to really flare up. And so it's, you know, to, to really achieve control of any infectious disease, we really need high vaccination rates. Everywhere in all communities and all sort of places where people mix with one another. And so, you know, absolutely, you know, it, but depending on the community, you're in, we have upwards of 90% vaccination rates among adults. And then in others we have. 30 to 40%. And that, that causes a huge difference, especially when we have, I have a more infectious variants starting to spread. So, I think there was this write-up of it was, I think in Mesa county, Colorado, where we were starting to see a rise in cases. And again, I mean, it's. That particular area of the state, I think has relatively low vaccination rates relative to the national average. And so that could be part of the reason why they're starting to see a spike in cases. I do want to put in the caveat that I always put in here that I think never is stated enough, which is that there is a lot of rain. This too, you know, so certainly the best way to hedge against new spikes in cases is to have high vaccination rates. Like please, you know, like people getting vaccinated as the best way to prevent this from happening or the vaccines are especially the vaccines that have been approved in the United States are still very effective against preventing infection and severe disease from the Delta variant from all other sorts could be two variants of vaccination is the way to go. But again, you know, certainly low vaccination rates allow for spikes in cases to occur. But of course there are a lot of other things that could be happening as well. There's some randomness, there's some, you know, we may well see spikes in places in certain places that have high vaccination rates and, and there's some randomness to that as well. So, so the, in, when we're working with infectious diseases like this, there are no guarantees. But you definitely improve your odds substantially, substantially if you're vaccinated and if your community is highly vaccinated. So I think we're going to start to see spikes and cities in places where vaccination rates are still low. And I think that's just a reality we're going to have to live with and just do our best to make sure that we're able to get vaccines to the people who need it.

Matt Boettger: 5:42

Yeah, absolutely. You know, I was thinking about how, oh yeah. Some people thinking, okay, well, you know, you're gonna see cases spike anyways, so it doesn't matter. But you know, the biggest thing is there was some things outside of our control and there's some things that are inside our control and doing the vaccination is the one little piece of information that's inside of our control to help the communities and societies and states to be able to best manage Cubs cases and the rest that are outside of our control. We just have to allow it just to fall where they made those cards to fall, but just encouraging people to continue to be vaccinated. Jump forward for a second, because I think this is related. So you're seeing like Mesa county and Colorado, we're having a spike. This is kind of expected because there's low vaccination or relatively speaking compared to the national average. So I read this article about the place is still targeting zero COVID. So there are places around the world that are still focusing on zero COVID. And I think this was really related. Because it's the same kind of problem they're encountering of low vaccination records or rates because of a different reason, you know, where the U S got slammed. So we're dealing with ideological differences. I'm just caution is there's a hodgepodge of different reasons why we have different vaccination rates. China being an exception because, you know, from what I hear China, zero COVID, they rolled out a quick vaccine, not very effective. So that could have really chipped away at the trust at the vaccine vaccine. But other places like Australia, Japan who have better vaccination resources are suffering tremendously because obviously, as you know, and you've talked about this idea of pushing for zero COVID is unsustainable. And so they're doing this, but then the result has been very few people are being vaccinated because it's not that big of a concern. So this is this weird Twilight zone reality, by which in some sense, the government did a great thing, but almost build like a gosh. What's the name of that Jim Carrey movie, where he's on that screen set. The Truman show. Yeah. It's Truman show, right. We almost create this facade. So nobody really wants to take the vaccine. And now they're done with this hard part of like low vaccination rates. Not necessarily a suspicion because there's nothing really going on. And have you been talking about this or seen this in the news about epidemiology and how, gosh, it's a whole other, you know, the psychology and sociology of the human condition. And how do you get people to like, keep them safe, but then maybe not safe enough so that you can actually get them to get the solution when it becomes available?

Stephen Kissler: 8:02

Yeah. I mean, it's, you're right. It's like, so, so hard to know what to do with this it's I think it's really. Hard to, it's hard for me to wrap my mind around just the huge diversity of experiences that different countries have had with this pandemic. I have a good friend who lives in New Zealand and they've been living their lives pretty much as normal since July of 2020, right? Like, like basically basically, you know, almost no change. And so there's, you know, you're right. That, that I think that, that Was a great strategy for them to to pursue as this acute phase of the pandemic was spreading, especially in the absence of more information, you know, they prevented so many hospitalizations and deaths in their own countries by, by doing that. You're right. I mean, we, we both have to pay attention to the short game and the middle term game and the long game. And I think that that's, you know, that's one of the issues that some of these places are going to be one of the, one of the issues that some of these places will start running into is that, you know, it's, it's true that these really strong suppression measures are. W were and have been probably the right approach up to this point. But they're not sustainable, you know, there, we, we can't probably keep them up forever. It, maybe they can, but it doesn't, it doesn't seem that way. It, it demands a lot of resources. It meant, you know, a lot of countries, I mean, ourselves as well, but you know, required quarantine for travelers. Will we keep that. Forever. Like how, w how do we start to make these decisions as we transitioned back into a world that is living with the reality of COVID-19 recognizing that it's probably not going to totally go away. I think it's really difficult. So I think, you know, it's easy to sort of say like, oh, well, you know, they, they chose the wrong approach because now look it, you know, who's, who's going to have the last laugh and it's like, well, I mean, it's hard to say that we're going to have the last laugh. You know, 600,000 people dead from COVID-19 at this point. Right? Like that's, I, I can't say that, like, we, we picked the right course, you know, we, we need to bear all of that in mind, but that said, you know, we, we may weather this next transition, right? More gracefully potentially because of some of our past experience, I don't think that that necessarily justifies our past experience. And the horror of what we've been through here. And in many other countries, we were just talking about Brazil, for example. But it, it, you know, as we're looking, you know, trying to scrape together, whatever silver linings we have it, we can in this crazy situation, that may be one of them. Yeah. I do think that realistically speaking that that total elimination of COVID is, is unlikely to be a sustainable strategy for any given country and certainly as the global community. And so we're going to have to figure out ways to live with it, and that will include figuring out ways to get countries vaccinated that have not had much transmission up to this point. And that's, that's a really difficult problem. And so that's, that's, you know, that's, that's sort of the next thing we're, we're going to be working on.

Matt Boettger: 10:54

Yup. You know, I, one of the big reasons why I wanted to bring this forward is because again, it goes back to the episodes of like it's complicated and it shows another level that man, it really is a complicated, really good. Powerful strategy, whether you can criticize it or not. And then there is collateral damage to everything. There's no utopian, you know, like silver bullet, there's just going to fix everything because we're dealing with human beings and the way we build our habits and our social infrastructure. So I think at this one and another article that I read probably a month ago, Stephen, that we kept, I kept kind of toying with the idea. We're going to bring it up in the podcast. I'll bring it up now just to highlight it. I don't know if it was NPR or, and if it was NPR or if it was the Atlantic, but talking about how looking at Texas, particularly in just showing how in other places as well, and around the country. People who would do lockdowns for X amount of time, you know, four weeks, six weeks early on the pandemic, right? Some did longer, some did hardly any. And just looking at the economic fallout from different types of lockdowns, pretty much zero two, rather lengthy ones and show them there was really almost no a marginal difference in economic. Downturn, whether you had a locked in or not in the U S particularly any, of course, you're just going to think, oh, if you're do a lockdown automatically, the economy is going to collapse. And that is definitely an option on the table for discussion. But again, it's the human factors that come into play that we're not, we're just looking at it, an algorithm and realizing that human beings just don't fit that bill. It did they just don't. And so then when you actually see the differences, there was like, no, there really wasn't that much of a difference in the economic of these towns that had lockdowns or not. I think that kind of fits this framework of like, it's not like, oh, I won that argument because lockdowns don't affect economic, you know, the economy. I'm not saying that. I'm just saying it's just complicated because you're dealing with messy people that have different perceptions and that's just how we deal with it. I mean, for an epidemiologist, it's got to make your mind just want to like explode of how do you deal with infectious diseases. When you think about public health, how do we do something that we know this to be true, but how do we convey this message in such a way that actually doesn't cause more problems for a community or society?

Stephen Kissler: 13:05

Totally. Yeah. It's I mean, it's a big part of what drew me to this field in the first place was it was precisely that, I mean, I love thinking about problems like that because it's they're so, they're so slippery in a way, right? Like it's, you're, you're dealing. What's really complex things. But boy, it's hard. So yeah,

Matt Boettger: 13:22

absolutely. Well, let's hit the, the variant update on the Delta. Cause this is related because you know, we, we talked about it last week. We've kind of hit, we talked about how last week, you know, the one shot deal doesn't work so well with, with the Delta variant. We know that I think what it was the alpha variant, which is the UK kind of the one where it started out of, there was a, roughly 50% more infectious than the original. Now the Delta's like 40% more infectious than the alpha. So really getting these more infectious or, you know, fast spreading coronavirus is being put all over the place. That's why Mason may be experiencing some of this. One of the things I wanted to talk about with this is word, this word in this article came up called over dispersed. I want you to talk about this, cause I know you've talked about it a time and a time ago. In this podcast, but I don't know if you've used a word. Maybe I just didn't hear it. But talk about what over dispersed really is what it was referring to and how it fits into COVID particularly. And of course the Delta, which seems to be the same as the other, via the other normal novel virus.

Stephen Kissler: 14:22

Yeah. So, This is great. I might I might give you a answer that goes much further afield than you were anticipating, but here we go. Right. So, right. So when we're thinking about over dispersed, what we're thinking about is a statistical distribution. And so generally when, when we see that word pop-up, and I imagine what, where this word popped up with respect to the Delta variant with SARS cov two in general is, is the number of infections that a person is going to cause. So we hear all about the reproduction, right? That on average, a person might be likely to infect two other people. If they become infected with SARS cov two or four or maybe six best estimates for the Delta variant is that maybe that number has increased up to the range of, you know, five or six, which is, which is really quite high in terms of the ranking of infectious diseases. But that's just the average of that destruction. And so we're used to thinking about things in terms of bell curves, normal distributions, where basically, you know, the average is six maybe. And that means that both the average of that distribution is six, but also the most likely number for any given person is six. And, you know, a few people might in fact, four and a few people might infect eight, but you know, six, six is sort of a representative number from this distribution. What over dispersion means is that basically the, that, that intuition no longer holds that you can have the average still be six, but that a lot of people might infect no one. And a few people might infect many, many, many, many people, 20, 30 people. Right. And so you still take the average of these numbers that are very, very different and you still get a number that's roughly six, but actually, maybe nobody is infecting six people. Basically everybody's infecting zero and then a few people are infecting 20 or 30, and that's a very different thing, right? Because now you're not trying to track down every single infection and reduce, you know, the average infectiousness of a given person. Really, what you need to do is focus hugely on the people who are infecting 20 or 30, and most people are actually irrelevant to the spread. And of course, that hugely changes. The intervention measures that we need to put in place. So that's why over dispersion is so important. Over dispersion as a feature of not just the Delta variant, but of sorry, Coby too in general. And and, and of many other things, infectious diseases as well. And so this is a really important thing that, that we're thinking about because it it sort of turns our intuition of averages on its head. And we have to deal with that. Like, it has very, very practical implications now. The tangent here is that. So I think that you know, we can think about over dispersion in terms of, of of you know, the number of secondary infections, but, but over dispersion actually applies in on a lot of different levels in infectious diseases and in life as a whole where, you know, bell curves and thinking of average values as representative values can sort of lead us astray in a lot of different ways. I think in a way, this kind of applies to the national level for SARS Coby too, as well. Right? Like we have many countries that have seen very few infections at all, and we also have other countries that have seen thousands and thousands and thousands of deaths. Right. And that's, that's another type of over dispersion where if you sort of think about the average way that a country has fared. That's not actually going to be representative of the experience of either Brazil or Australia. And in fact, it's not really going to be representative of any country because generally really they've sort of separated into different camps in a way. And it's much better to think about that entire distribution than it is to think about averages. And so that's something that we really try to pay attention to a lot is that, you know, the, the average value is not necessarily the most informative. About how something behaves really have to look at sort of all the diversity of what's going on here. And that pops up again and again, in infectious diseases, in sociology, in basically anything that deals with, with humans, because because, because we don't necessarily have the same sorts of constraints, you know, we have, we've talked a lot about exponential growth, for example, and that's a very different thing than like, thinking about the Heights of people in a population, right? Like your height. Is is very biologically constraint. You have some people that are four feet tall and some people that are eight feet tall, but you're not gonna have somebody that's 20 feet tall. You know, because they're just biological constraints there, but, but those biological concerns. Just behave differently when we have things that spread exponentially and when we have people that behave unexpectedly. And so we have to think about that in an entirely different framework and over dispersion. That's one of the things that helps us do that. Okay.

Matt Boettger: 18:31

Now you were saying that like over dispersion versus like just taking the average, have practical differences or consequences as an epidemiologist. How do you look at things differently? Practically, when you say this particular virus has shows signs of over dispersion where I'm maybe I'm off track. And other viruses just seemed to hold kind of more of the average. Right? So practically speaking, are there, what are different ways by which you look at and then different health initiatives for either one? Are they usually the same or do they actually have practical public service announcements to,

Stephen Kissler: 19:01

to, to, to people? Yeah. So, there's this incredibly nerdy, but one of, one of my favorite scientific articles. In an epidemiology has to do with exactly this question where basically it this came out in, I think it was like 2006. And so this was post SARS, cov one, but pre SARS, cov two. I think also pre 2009. Page one. Yeah. Flu pandemic, but I don't recall, but basically what it was doing was it was taking this whole, it was taking a bunch of different infectious diseases that we know about and basically putting them on this graph in terms of how over dispersed their secondary infection distribution was. And so you have some infectious disease, it was actually fluid. Particularly over dispersed. If you're infected with the flu, the reproduction number is actually a pretty good estimate of how many people you're likely to infect. It turns out that SARS SARS Coby one was actually one of the most over dispersed infectious diseases that we knew of part of that comes from the biological mechanism through which they, they spread. So we talked a little bit about flu, how We've talked a lot about droplets and aerosols and surfaces. Yeah. Flu flu is you know, both fluid and stars, both Kobe one, and COBie two can spread through all of those routes to some extent, but flu is really dominated by droplets and surfaces. SARS. Cov two is really dominated by aerosols and that's part of what's behind this, where if you actually have. Spread flu by coughing in somebody's face. That kind of limits how many people you can spread it to. But if you can, in fact, it's an entire room by just breathing in it, then that really creates this over dispersion, right? Because me living in my little apartment here. Yeah. Even if I was infected with SARS, cov two, I might expose one or two other people. But if you're a lecturer, for example, in a large hall, you know, then you might expose, you know, 200 people. By being infectious. And so that's one of the things that creates this over dispersion. And then that I think implies sort of what the different messaging might be around this. So one of the things that actually came out very early on in the pandemic were some observations from some of the epidemics, from some of the outbreaks in China that showed that really super spreading seemed to be super spreading as another sort of way of thinking about over dispersion. W was really dominating the spread of SARS cov two. And so what that implies is that if we can limit the possibilities for super spreading events, that we might do a really good job of. Sorry, scruffy too. So if this was behind a lot of the rationale behind limiting gathering sizes, for example, because you can't have a super spreading event that infects 200 people. If there are never any situations in which 200 people see each other. And so while limiting gathering sizes might not be as effective for something like flu, where everybody's going to be. Mid-level infectiousness. If you do that for SARS, cov two, you actually chop off that long tail and that can go a really long way towards preventing the spread. And so it, it varies from, from pathogen to pathogen. And that's why it's so important to know sort of where this disease sits on that spectrum of overdose. Because that, you know, do you again, do you contact, trace every case? Do you limit gathering sizes? What type of masking is most effective? Do what sorts of infrastructure do we need to control these things? What sorts of public health messaging? All of that changes, depending on what this over dispersion is, even for infectious diseases that have the same average reproduction.

Matt Boettger: 22:08

Yeah. Okay. That helps a lot. Okay. I'm just imagine in your epidemiology work, there's like, it's like a little toolbox set where like K over dispersion, you open that toolbox and there's all these little resources for that. And if it's not, you have a different toolbox of different resources and all these different ones, how you handle different levels of, of, of viral spread. That's fascinating. Thanks for sharing. That's good. So let's, let's get into AstraZeneca, because this was weird. I know I don't have it in the show notes. I will. I mean, if I find it again, I know I read this Stephen. I shared with you before we got on, but it was this article. I don't know if was Bruce Springsteen or somebody famous there. They were going on Broadway in New York doing a special kind of, I don't know, show. And it actually specifically said that AstraZeneca vaccinated people were not allowed into the show, which has opened my eyes to like, wait a minute. Is it. Is this going to be a new game of like, not, it's not just the, if you're vaccinated, it's what type of vaccine do you have? We'll let you in certain doors. I don't know if this is just an outlier, but I want to throw this back your way to first. And he's like, have you heard about this yet or seen this or talked about this idea of it's not just vaccinated it's type of vaccination. And on top of that, I read this article about, particularly with, with AstraZeneca, about mixing dosages. So, you know, having your first dose AstraZeneca, your second one being like a COVID or Pfizer, which obviously it, additionally added alarms to people saying, wait a minute, are you secretly telling us AstraZeneca doesn't work? And you're trying to get us a second dose. That actually is more effective. It seems like it's not the case. There are some German study, just randomly trying to show mixing dosages, which we've talked about in the past. This is probably going to be a future probably is right now going on. Like how can we even raise the infectivity by mixing dosages? Have you heard much about this and about the safety dashes, Seneca now mixing dosages and its effectiveness.

Stephen Kissler: 23:55

Yeah, so, I mean, I think that the, you know, separating entry requirements for a show or for travel or whatever that by vaccine type, I can't say I'm surprised. I can say that I'm discouraged. I think that that's not I, frankly, I don't think so. Sense. I mean, because again, I mean, I'm, I'm constantly thinking from the population scale, right? Like if everybody in a room has been vaccinated with one of the vaccines, like it's probably gonna be okay. Right. Like, and so, I think that it's, it really is sort of zooming a little bit too far into the individual level and that, you know, it's true. These vaccines vary in terms of their effectiveness. But they are all good. Especially these ones that we've, that we've brought up here, you know, the AstraZeneca Pfizer and Madrona, like, Johnson and Johnson, like they're all good vaccines and absolutely. I mean, yeah. There were naturally going to sort of make this hierarchy of vaccines, you know, where, you know, what, where we feel like one is better or superior than the others. And to some extent, you know, that is, that is true. I one of the things that I've been really frustrated amongst some scientists is that they've sort of been shouting that like, you know, all the vaccines are the same and equally good. And it's like, well, you know, like we need to be real about the fact that they have different results, right? Like they behave in different ways and they. They have different levels of infectivity. Now of course, the bottom line is that almost all of them are going to prevent you from going to the hospital or dying from COVID. Right? Like that's, that's, that's amazing that they do have different, different levels of effectiveness and their effectiveness is going to change as our immune system declines. And as our, as the variants emerge, you know, all of this is going to affect things. So, but I think that that. Oh, gosh, you know, I think that just the difference between having vaccine and not having a vaccine is so much greater than the difference between the vaccines. That's the main thing is that absolutely there are differences between the vaccines, but the Delta between no vaccine and vaccine is so, so much greater than the Delta between the vaccines. That it's just not really the right message to be sending. And certainly doesn't help. People vaccinated, certainly doesn't help to reassure people who have been vaccinated with the AstraZeneca vaccine who are very well protected against severe disease from COVID-19. And so, I don't know, like I said, I'm not surprised, but I am kind of discouraged by it. And so there's that yeah, you mentioned, you know, the mixing and matching of vaccines as well. So this is the reason why we're not doing it on a large scale right now is because again, it's. We don't have the data on it yet. And that's, that's being collected. As you mentioned, there was this German study and there are others that are sort of in the pipeline trying to understand what happens when we mix different types of vaccines now from a biological perspective. There's very good reason to believe that mixing vaccines could be a very good thing. Because again, each vaccine is right. Exposes your immune system to a slightly different biological shape that each of them targets sort of a different part of the virus. They're all targeting the spike protein. The thing that is sort of generates the immune response from a natural SARS cov two infection, but they expose your body to sort of different, different parts of that spike. And they do it in different ways. And so, one of the benefits of this is that potentially if you. Different types of vaccine than your body sort of, has two shots on goal in a way it has two different ways of identifying different parts of the virus. And so, so for example, if the virus doesn't mutate, so that one of those regions of the virus is disguised from your immune system, maybe it has a better chance of picking up the other part. And so it gives you sort of this more broadly effective immune response potential. And that's one of the reasons why this is an interesting thing to study. As always, we need the evidence because science is full of surprises and it could be that it is less effective when you mix and match vaccines. But a lot of the early evidence suggests that maybe, maybe it is at least if not More beneficial that it probably isn't less beneficial either if the vaccines are mixed. So this is not to say, to go out and, you know, mix vaccines, haphazardly, you know, this is, I, we really, we really need the evidence around this. Both for the immune response, but then also for the, the biological tolerance, like, does your body respond well to it? Are there differences in the levels of sites? All of these things really need to be studied very rigorously, but there's based on biological principles. There's reason to think that this is actually a good idea. So I'm glad, I'm glad we're continuing to look into it. Yeah.

Matt Boettger: 28:18

Yeah. You know, I know I mentioned this before in months past and maybe a different The subject, but this idea of fuzzy search, I don't know if you don't know the answer to this, but like, is it possible by the, the immune response? If you have one vaccine that say Pfizer or say once AstraZeneca and they're close, right? They're like a and B they're not like worlds apart. They're both tailoring the spike protein. Could the immune system almost have like a little fuzzy search in between saying, Hey, well, a and B are very close and that connect in that connects enough to where anything in the middle that resembles that we're going to go ahead and take care of it as it being, if it's am curious, if that, do you know anything about, like, what does he mean? Is, is it an intelligent enough to be able to do those kinds of smart? Processes when you have two things

Stephen Kissler: 29:00

close together, right? Yeah, because it's, I mean, basically what the immune system is doing is when you get exposed either to a virus or you get the vaccine there's sort of this, this foreign protein in your body, which is basically just like either you of these, this cluster of, of stuff that your body is trying to mimic. And so the way that it basically tries to attack that and to train itself, to fight off things that are similar, is it generates In your lymph nodes and it generates basically a bunch of different antibodies, these different molecules that have sort of this whole range of random shapes, and it just sends them all off and sees which one is effective. You know, it just sort of like generates this like huge diversity of, of of proposed shapes and sort of sees which key matches the whole And because of that, it you know, you're not going to get, you're not going to get a hundred percent match ever. There's going to be a little bit of variation. And so, and so when you expose your body to two different ones, then basically you're allowing that random variation that your body has naturally produced to sort of do that fuzzy search for you, right? Because yeah. It will be sort of biologically constrained to, it says, well, I've matched this one this way. And I matched this one this way. Then you're likely to have sort of strategies in between that were maybe not the most effective, but that were decently effective. And both of which sort of got reinforced by exposure to these two different vaccines. So I think biologically speaking, there's, there's every reason to believe that that, that your, your immune system is also able to sort of traverse these boundaries between. Connect the dots from a to B, like you said, it's not always, but, but I think in a lot of cases it probably does work though.

Matt Boettger: 30:37

That's fascinating. And for those of you guys who maybe don't know if Plessy has searched me, it's just basically like, you know, search something like theater at a T H E a T R E or E R. You do one of those and ultimately know that you're, you know, searching for both like in Google or some kind of other searching software, that kind of stuff. That's awesome. Okay. Last question. Before we get going for the day, this, this requires Mr. This is talking about MRN, a technology. But I wanted to check in with you in general, any updates on, I know we've had MRI, M RNA technology in the past, but he updates on how it's all trained vaccine treatments or future pipelines of cool innovations that are coming that could help public health.

Stephen Kissler: 31:14

Yeah. So. The clear place is in developing more vaccines. And so, you know, we have a lot of infectious diseases that we don't have vaccines for yet. MRNs could help us develop vaccines to them. We have a lot of infectious diseases where we do have vaccines, but the vaccines could be better. I think thinking about MRNs vaccines for flu is a really interesting idea. I think that yeah, it's thinking about things like personalized vaccines. It's really interesting. So one of the things, I mean, this is, this is really speculative. I don't know. I mean, I imagine there are people working on this. One of the problems with HIV, for example, is that the virus evolves within your body very quickly. And one of the reasons why developing a vaccine against HIV is so difficult is because everybody's particular infection looks different from one another to some extent. And so developing a single vaccine that works again, you know, for a lot of different people is just really, really difficult because you're essentially producing new variants all the time. But with something as flexible as an MRI and a vaccine, you might even be able to start thinking about personalized vaccines, something like that, where you can actually have a vaccine that is targeted to a specific. Either a specific person's infection or to a lot of different types of infections that something could become in the future. I'm not entirely sure how that would work, but it's, it's interesting to think about not just a flu vaccine, but like an entire panel of HIV, vaccines of flu vaccines, that sort of hedge against all of the different places where a virus could potentially evolve. Very cool stuff. And we can also think about vaccines against sort of, you know, pathogens that we don't normally think about as big issues, but that protect against sort of longer-term complications. You know, there are some viruses that increase your rates of cancer, for example. And so, so maybe we could vaccinate against those The other thing is that, you know, M RNA technology is not limited to vaccines either. Now, one of the reasons why vaccines is one of the first places where we're really seeing widespread use of MRN technology is because you don't actually need to edit the. Human genome for an MRN vaccine to be effective, right? Like actually you don't want to edit the human genome. You want to expose it to something foreign because you're trying to train your body to fight off a foreign foreign body, you know? And so, and so that's an, that's an easier problem to solve, but something that people are looking at is, is using MRN to sort of, adjust parts of parts of the genome as well, which of course comes along with all sorts. Ethical issues and safety issues and things that are, that are not really relevant to the vaccines. So just earlier this year some scientists were successful in basically using to Make a slight edit to genomic sequences in the livers of a mice. And I think to some nonhuman primates and in doing so we're able to essentially essentially cure these animals from high cholesterol that could lead to hypertension and Strokes and those kinds of things. And so essentially, you know, that's, that's one thing where the, there are therapeutics that we can imagine for other sorts of diseases, even chronic diseases that MRN technology might be able to help us out with. We've already used MRMA technology. As cancer therapeutics in certain cases. And so, you know, that's, that's another area where I think there's going to be a lot of research as to, you know, how do we use these things to help train our body, to fight off cancer, to help train our body, to figure out how to you know, live live with it, to to reduce the sizes of tumors, things like that. All of which I think are super, super interesting and are sort of right on the cutting edge of this MRN technology. So I'm hopeful in the coming years, we're going to see a lot more research into this. And some of it might well be spurred by the fact that, you know, these vaccines were so effective. I think that Prior to this, there was a lot of skepticism about whether MRN technology was really going to go anywhere. In theory it seemed really interesting, but there was a real question as to whether it would translate into real real results for medicine. And I think, you know, at least in terms of vaccines, the answer is a resounding. Yes. And so I think that that then opens the door. It's like, well, maybe, maybe we can use these things for for other things as well. So I think it's really exciting as I said, there a lot of really. Scientific ethical questions. Safety questions to be answered with these things, but but I think they're worth, they're worth working on. Cause I think there's a lot of potential here too.

Matt Boettger: 35:20

That's great. Well, great. Thank you, Stephen. We'll end it here. For those of you guys wanna reach out to Stephen S D P H N K S S L E R on Twitter, going to give us an email, see how you're doing Matt. Calm. And if, when leave a review review apple podcast or support us patrion.com/pandemic podcast, or Venmo PayPal on the show notes. I hope you guys have a wonderful week happy father's day to all you dads out there, or even furry

Stephen Kissler: 35:45

creatures. And sometimes

Matt Boettger: 35:46

they're one of the same, have a wonderful week. I totally wanted to say you're Stephen you're so right. Have a wonderful weekend guys. Take care and we'll see you guys next Monday. All right. Bye. Bye.