Making “A Post-Pandemic World” — Jake Glanville

New episode on universal flu vaccines (and antivenoms).

I interviewed Jake Glanville, the co-founder and CEO of Centivax, a small company trying to create a vaccine that protects against all strains of influenza.

This is obviously a difficult thing to do. Seasonal flu vaccines are designed to protect against a virus that constantly mutates and recombines in animals. The efficacy of these seasonal vaccines are quite low; ranging from about 15 to 60 percent.

Instead of making vaccines that protect against only a few circulating strains of the virus, Centivax is trying to teach the immune system to recognize parts of the virus that many strains share and that resist mutation. The hope is that antibodies targeting these regions could protect even against strains we haven’t encountered yet, without scientists having to reformulate the vaccine every year. And things seem to be going well: the company has tested the vaccine in about 180 people so far and is preparing for a Phase 2 trial.

This is probably the most ambitious technical interview I’ve ever done. We cover some extremely deep immunology, but Jake patiently explained the ideas, and I left feeling like I finally understood how vaccines actually work and how scientists make them. I also came away much more convinced that a universal flu vaccine could work in theory. Enjoy.

Watch on YouTube. Listen on Apple Podcasts or Spotify.

Sponsors

Edison Scientific created Kosmos, the AI scientist I use to help prepare for interviews like this. Kosmos searches the literature, analyzes data, and investigates hypotheses in parallel, with licensed access to the entire Nature research portfolio. In one evaluation, Kosmos read an average of 1,500 papers and executed 42,000 lines of code per run, on average. It also links every claim or result to supporting papers or code, making it much easier to follow threads of evidence. Learn more at edisonscientific.com.

Plasmidsaurus helps Centivax verify that the DNA it builds matches its designs. They handle whole-plasmid, amplicon, genome, and RNA sequencing for more than 70,000 scientists every day. Place an order online, drop off your sample, and receive results with analysis the next morning. Get started at plasmidsaurus.com.

Timestamps

00:49 — Why flu vaccines need constant updating
03:07 — How influenza infects a cell
06:39 — Why our bodies don’t always make broadly-neutralizing antibodies
16:07 — Mutations and animals
23:42 — What is vaccine efficacy?
28:55 — Designing a universal flu vaccine
37:40 — The idea behind Centivax
44:16 — Clinical trials
57:33 — The business case for eradication
1:03:26 — How to eradicate the flu
1:07:26 — Could we make broad vaccines for the common cold?
1:09:07 — Building a universal snake antivenom
1:23:09 — Antivenom cocktails

Transcript

Glanville (00:00:00): We put up with a global pandemic that happens annually, two times a year, and we call it flu season. And we shouldn’t have to. We should attempt to create an eradication campaign. And one of two things ends up happening.

One is you try, you’re not successful. Or the second scenario is that you succeeded, in which case you have people a thousand years from now high-fiving us throughout history for the work we did to create a future where there is no longer that pathogen, which has been with us since the beginning of time, and we’ve created a future without it.

McCarty (00:00:33): Today’s guest is Jake Glanville. He’s the founder and CEO of Centivax, a clinical-stage biotech company that is making a universal flu vaccine, a universal snake antivenom, and other programs. Jake, welcome.

Glanville (00:00:48): Thanks for having me on.

Why flu vaccines need constant updating

McCarty (00:00:49): My first question is: the World Health Organization has been picking and selecting flu strains to make vaccines against since the 1970s. And the effectiveness of these vaccines historically has ranged from 15% on the low end to 60% on the high end. And if you look at the historical data, it doesn’t seem to really be getting better with time. I’m curious why that is.

Glanville (00:01:13): The problem with flu is really a common problem that exists across many, if not all, of the pathogens that are not currently well treated by the vaccine technology that was really founded by Edward Jenner 230 years ago. And the problem is that the pathogens mutate as an immune escape mechanism. We learned this pretty early with flu. In 1945, there was the first flu vaccine, and by 1947, they realized it didn’t work anymore. And ever since then, we’ve been in the Sisyphean challenge of having to perform constant updating to be able to adapt to the new strains.

And that grew more complicated in 1968 when a new subtype, H3N2, entered the human population and became endemic. And then they had to add more components into the vaccine. They do what they can. There’s a race that kicks off two times per year, once in the Northern Hemisphere and once in the Southern Hemisphere, where the World Health Organization, the CDC, some other bodies get together and they announce around February, “Here are the new strains.” And then six months later, they do it for the Southern Hemisphere.

And at that point, all the groups that are making vaccines need to do this unusual mad rush to go create a new medicine and be able to manufacture it within about a six-month period and get it out there. There’s been times where that wasn’t enough time. Their manufacturing failed. In 2004, we didn’t have enough vaccine because one of the strains they selected was hard to produce. And they are now a little cautious where they try not to update too much to pose new risk.

They’re resistant to just changing the vaccines entirely every year to the most recent thing they can find. They go, “Do we think it’s changed enough to justify the added risk and burden of having to update?” And that’s the world we live in for flu shots. And that’s why, on average, the last couple of years, about one out of three people who got a flu shot benefited, which gives rise to this big Pavlovian problem of people saying, “I took a flu shot and I still got sick.”

How influenza infects a cell

McCarty (00:03:07): I really want to understand what influenza is and what actually happens when an influenza virus enters a human. What are the cells inside the body that are binding to that? What elements of the flu virus are they actually binding to?

Glanville (00:03:21): All viruses at heart are basically a biological hacking instrument that contains a malicious payload, typically mRNA or DNA, and a little bubble of lipid typically, and they’re surrounded by spikes that are specific to a certain host cell class to enable entry. In the case of flu, it’s round. It has these spikes on its surface. One of them is HA, which is hemagglutinin, and the other one is NA, which is neuraminidase. And it also has one other minor proteins. The main spike protein that people focus on for vaccines is the HA protein.

And the purpose of this protein is basically an immunological grappling hook to tear into your membrane, tear it open, and inject the malicious payload. And the way it works is you’re wandering around and someone coughs in your face. And some virus gets inhaled. It ends up going in towards lung tissue and nasal tissue, which is its target tissue. The HA starts off like a spring-loaded grappling hook. It’s in what’s called the prefusion state. It looks like a mushroom; it’s a trimer.

The virus is floating along in the prefusion state and it gets brought into an endosome, which is a little bubble that cells pull in some of the stuff that’s just floating around in the extracellular media. And the endosome closes up and the pH starts dropping. And that’s part of it destined to be digested and stuff used. It’s really a sanitation procedure as well as a lunch prep procedure by the cell. And the viruses are ready for this. A common technique that flu uses that other viruses use is when the pH drops, it has some very carefully placed histidines inside of that spike protein that suddenly protonate at pH six.

And when they protonate, they cause something like those little explosions on a spaceship to release part of some surface, the little pop locks. It’s a pop lock that causes the grappling hook to change shape from prefusion to postfusion in a pH-sensitive manner. It just does that inside an endosome and suddenly reveals the business end of the grappling hook, or these hydrophobic spikes, and those stab into the membrane, tear it open, and the influenza mRNA is injected into the cell. Once it’s in the cell, into the cytoplasm, the mRNA starts making copies of itself, and it brings in its own polymerase and a series of instructions for making more copies, and that cell is now infected.

And pretty quickly, that cell’s hijacked to start making huge numbers of copies of additional influenza virions. And those leak out and they start infecting more and more neighbors. You’ve walked away from the person sneezing in your face. And within a couple of days, those things have been silently dividing and dividing under exponential growth. And if you don’t have antibodies to slow it down, and your T cells, if they even detect it, are taking about five days to spool up enough responses, you start getting a sore throat.

And that’s because a lot of those cells in your throat are infected. And then it starts getting into your lungs and it starts causing you to feel terrible for the next seven to 14 days because it’s undergone massive exponential growth, infecting a whole bunch of your cells. And as it does, it also causes you to sneeze. It causes you to have the kinds of phenotypes that are going to cause you to transmit that virus to the next person. The hack continues. That’s how these viruses work. Flu is a classic example of it.

Why our immune system doesn’t generate broadly-neutralizing antibodies

McCarty (00:06:39): How is our body mounting an immune response? Classically, one of the things people talk about with flu, if you read about flu vaccines, is, “We have to update them because they’re binding regions of the flu that are not conserved or they change a lot over time.” Why is our body eliciting an immune response towards highly mutating regions? Why are we not randomly finding antibodies in the human that are broadly neutralizing, such that we don’t need to get a vaccine every year?

Glanville (00:07:08): That’s the beating heart of the whole problem. Let’s say flu entered a population that had no immunity, right? It gets in there, you have no antibodies to stop it, so it rapidly divides You have no real T-cell responses. You’re building your adaptive immune system response for the first time. And that first time, it infects you very easily. But what happens anytime you’re infected with anything, your immune system does respond and it builds an adaptive immune response. Your body starts taking pieces of that virus, bringing it into your lymph nodes. Your B cells are grinding away and getting T-cell help to create antibodies against random surfaces that it discovers against that.

McCarty (00:07:48): And this usually happens when we’re a baby.

Glanville (00:07:50): It starts happening when you’re a baby.

McCarty (00:07:52): Do we get antibodies from the mother?

Glanville (00:07:54): You get your mom’s antibodies through the milk, but they mostly live in the intestinal system and the stomach. Some of them get into the rest of the body, but they also wear off. They don’t teach your B cells to make your own. You get adoptive transfer of your mom’s antibodies that are absolutely protective and helpful. But then you have to start developing your own. This is why children are notorious for getting sick all the time while they’re in preschool and kindergarten, and then the teachers all get sick for the first three years of working as a teacher, and then they stop getting sick so much.

Because what they’re doing is they’re building up an arsenal of antibodies and T cells against the various classes of infections that routinely circulate among naive immune individuals. But here’s the issue, right? Then you have all these antibodies, and if it was chickenpox, you’d be in great shape. You’re actually heavily protected from ever getting infected again because you produced a beautiful class of antibodies and T cells, and the virus doesn’t really change much. The next time you’re exposed, the antibodies block it from infecting in the first place.

The T cells go in and prune the garden of infected cells, telling them to stop working and in some cases, killing the cells. And the infection can’t propagate a second time. The problem with flu is that if that had been successful, flu would have had one big flash in the pan globally and then gone away. And the reason we still have flu is that flu can mutate quickly enough that it changes enough so that it’s able to go back and reinfect someone it’s infected before while getting around their antibodies.

And for a while, really from 1947 until 1993, people thought that we’re just stuck. We’re always going to have to update because this thing is just mutating its surface all the time. And then in 1993, there was this beautiful paper where people said, “Hey, there’s actually some antibodies that are coming from someone infected with one strain, but those individual antibodies are neutralizing a bunch of different strains.”

McCarty (00:09:47): And this was in a human?

Glanville (00:09:48): In a human.

McCarty (00:09:49): I know about the study in Japan where they injected a mouse with a single flu strain and then they took the antibodies out of the mouse and they found an antibody that could neutralize that strain and another strain of flu. And then they were like, “Oh, wow, there are broadly protective antibodies.”

Glanville (00:10:06): Yeah.

McCarty (00:10:06): I didn’t know that there was a human study.

Glanville (00:10:08): I may be misspeaking. It was a 1993 study, and then I should say it was an H1 and an H2, so you might be right. Okay, so maybe a mouse was the first demonstration.

McCarty (00:10:15): But that was the first time people were like, “Wow, maybe we could find broadly neutralizing antibodies.”

Glanville (00:10:19): That’s exactly right.

McCarty (00:10:20): But the question then is, why don’t humans make them? Why are our antibodies not stochastically, randomly finding really highly conserved regions of flu?

Glanville (00:10:29): And that’s the fundamental question, because then you shift from despair to greed. And you’re like, “If these broad sites exist and we now have them very well characterized from a series of glossy papers showing crystal structures of antibodies targeting these sites that the virus cannot change, why the hell aren’t we all generating them every year?” And that was really the state of the field for about 20 years: these conserved sites, and yet these other regions that are mutating more easily seem to be much more susceptible to targeting.

They were immunodominant. Why were the conserved sites not immunodominant? And that was a critical question because if you can crack that question, you can create a universal vaccine. And just on the geography of the surface, the top of the mushroom of the hemagglutinin is the most variable. The hemagglutinin itself, by the way, is the most mutable protein in the entire virus proteome, which makes sense because it’s the surface that it’s trying to use for immune evasion.

McCarty (00:11:27): I guess my question is, when flu enters the human body, is it just the case that we have an antibody that binds to the exposed head and that antibody becomes activated first because that’s the easiest thing to bind? And then that population of antibodies proliferates at the expense of maybe an antibody that would have bound somewhere else?

Glanville (00:11:48): Yes, with a twist. When I got into this field, my timing was good. I got in and I was one of the people that contributed to pioneering the use of next-generation sequencing and some other tools to look very deeply at the adaptive immune system. Because up until then, the car wasn’t working, but you couldn’t open up the hood to look at the engine. And with these new tools, we could look deeply into the adaptive immune system and ask simple but fundamental questions like how many antibodies am I making after I’m vaccinated?

And from [next-generation] sequencing, as well as from mass spec work by George Georgiou and some single-cell work, we now know that there’s about 1,000 responding B-cell memory clones, and about 10 percent of those end up producing antibodies. You get about 100 antibodies after a vaccination. Then my question was, “Okay, you get 100 antibodies. What’s the probability of hitting these conserved sites? Why do we miss?” And I took all of that and I performed an analysis of what’s the probability, what proportion of all antibody sites are the conserved ones?

And what it showed is less than 1 percent of the sites are the very conserved sites. 99 percent were prone towards mutation in the next one to two years. It was almost like an optical illusion because you can see the conserved site right there. But mathematically, there are so many solutions that are binding to it, but also adjacent sites. It’s a combinatorial nightmare to just hit that correct site. There’s this probability that if you took 100 darts and you threw them at this dart board, the bullseye is very small.

By random chance, you will miss most of the time. And even if you hit, it’s what you said that you hit randomly, and then the ones which proliferate become imprinted onto the memory because you make lots of copies of those cells. They swirl around and sit in all your secondary lymphoid organs. And your body adds mutations to improve the binding affinity. It’s called affinity maturation of your B-cell memory. The next time you’re exposed, you have what’s called imprinted or original antigenic sin memory, where your body will prefer to use the memory antibodies and continue to work with those rather than discover new ones, even if they’re maladaptive.

It’ll keep tinkering over and over again. It’s like an old guy who’s just like, “No, no, no, I’ll go back to the car and bang on it,” rather than being like, “Okay, I need a new car for this.” And that actually interferes if you don’t get the good broad antibodies the first time. It interferes with getting the broad antibodies later.

McCarty (00:14:18): Our immune system is stuck in this local peak and we can’t jump to the next peak.

Glanville (00:14:24): Yeah.

McCarty (00:14:26): Statistically, though, right? If I’m infected with flu and my body creates 100 antibodies, if you scale that across a population and hundreds of millions of people are being infected, there are people out there who are eliciting very broadly neutralizing antibodies, just statistically, right?

Glanville (00:14:45): Yeah. At two levels. My estimates were about 20% of your antibodies should be semi-broad within subtype. And then about 1% are these super sexy ultra-bNAbs. Statistically, you and I have about 20 good-looking antibodies we produced. But the problem is that that means four-fifths of our titer degrades. And the problem is your titer drops: even if you have 20% as your baseline, the titer drops too much to be useful. You get a fivefold drop. It also suggests—

McCarty (00:15:15): You mean just over time because the cells producing those antibodies don’t keep getting stimulated? And they disappear from our blood?

Glanville (00:15:22): Well, let’s say you and I made 100 antibodies in response to 2024. And then 2025 rolls around and we go, “Do they still work?” By my estimates, four out of five of our antibodies are no longer good enough.

McCarty (00:15:33): It won’t even bind.

Glanville (00:15:34): Yeah, or bind too weakly. Antibodies can still bind and get picked up by an ELISA, but they’re too weak to provide neutralization. Four-fifths of our antibodies are defective. And then the remaining one-fifth, there’s not enough left. And then the super awesome antibody, it’s about 1%. That means about 50% of the time you and I have made one of those, but it’s only 1% of our total titer. Even though we have it, it’s not enough to really do enough to protect us.

And that said, if you look across a population, you will occasionally find someone in whom that rare antibody happened to be coaxed to dominance.

On mutations and animals

McCarty (00:16:07): Of course, there are many RNA viruses, and RNA viruses have a reputation for mutating quickly, right? But as you were alluding to, there are classes of viruses like measles and other things that don’t seem to mutate as quickly. I guess I’m curious, like, what is it about flu that makes it mutate so fast? Other RNA viruses also have animal hosts that they can recombine in, right? Or is it just flu is doing that a lot?

Glanville (00:16:38): It’s got a couple tricks. First, it’s an RNA virus. RNA viruses mutate a lot faster than DNA viruses. The major tectonic successes of early vaccine science were on DNA viruses.

McCarty (00:16:49): And is that because the enzymes that are used to replicate RNA strands are more error-prone than DNA viruses?

Glanville (00:16:57): Yeah. DNA lasts longer and it has proofreading mechanisms. The viruses, in fact, they often bring their own transcriptase with them, and their transcriptases are designed to be error-prone. Their polymerase is designed to be error-prone. And they can tune the degree of mutation that’s useful to them to be able to affect permanent escape. Respiratory viruses affect a lot of people very quickly. They have that beneficial property, and then they have the periodicity of seasonality often that causes them to have an incentive to mutate faster.

And they have the tuning ability by evolution to be able to do that. They’re not the fastest mutating ones. HIV is pretty high up on that list. It has an astonishingly high mutation rate and actually has some active mechanisms to enable some shuffling and some other stuff to happen. But they’re up there. The other one you mentioned was the zoonotic host. Yeah, if you have nonhuman or zoonotic reservoirs for your virus, then that affords another way to create diversity, especially when you jump from one host to another, there’s often rapid adaptation that’s necessary.

Now, on one hand, it poses a barrier. Flu doesn’t jump easily from birds to humans because birds, first off, have different biology in the cell, but they’re also warmer than we are, and the sialic acids are somewhat different. And the jump means that the viruses are initially maladaptive and they need to mutate to adapt. But the flip side is if they can adapt, they’re often quite lethal in humans. But with flu, we also have pigs, which are a massive reservoir. They’re these megafarms, and I think many of the five pandemics of the last century had what we think was recombination happening in the pig, which is a mammalian host that seems more permissive towards avian viruses.

And we see shuffling evidence that they’re mixing and matching the pieces of human and nonhuman influenza in a mammal, which then can propagate into humans. And that abundant reservoir that humans hang out next to, and often there’s migratory birds or even there’s chickens near the pigs that can serve as an engine of war to increase the probability of a shuffling event.

McCarty (00:19:11): If pigs are a major source of flu outbreaks, why are we not just installing surveillance stations on those farms where workers before they leave, they have to get swabbed to see if they’re carrying virus? Would we even be able to detect it?

Glanville (00:19:27): And the best thing to do would be vaccinate the pigs with a universal vaccine as well as humans, and then you push the zoonotic problem. Now, conveniently, that has been my plan for the last 10 years. It’s okay to know that there’s something there. You’d much rather have countermeasures to kick it out in the first place. I’ll give you an example. Here in California, as in many other states and other areas of the world, we have a problem with H5N1 infecting our cows.

That is a horror story, and very few people are paying attention to it, right? Throughout the history of H5N1 infections, half of the people over most of the period of H5N1 detection have died who’ve been infected. Now, this current strain, we’re actually very lucky. It seems like it mostly infects mucosal surfaces, so the cow udders and eyes, and so people mostly get what looks like pink eye.

McCarty (00:20:15): But why is this a horror story? Is it just new to cows?

Glanville (00:20:18): Oh, it’s a horror story because we have a big population of mammals adjacent to humans that harbor a virus that, over most of our observations, has killed half of the people who get infected with it. And we don’t know how many mutations—

McCarty (00:20:28): And it wasn’t in cows before?

Glanville (00:20:29): Yeah. No, it used to be an avian strain. It evolved to infect cows. It’s now in mammals. The fire is not smoke over the hill, it’s embers coming in through the windows in our backyard. And it’s being ignored.

McCarty (00:20:41): Well, where is this happening?

Glanville (00:20:42): This is here. This is California. This is across the United States.

McCarty (00:20:44): Never heard of this.

Glanville (00:20:45): Yeah. We have a major H5N1 mammalian infection, which is endemic in the cattle of the United States. And this has happened in the last two years. It’s now no longer an avian pandemic strain. Humans are being infected with it, by the way. It’s just that for some reason, very fortunately right now, it’s mild in humans. There’s only been one death. Otherwise, the major symptom has been mostly pink eye and some infection symptoms. The problem is, that’s great if it stays like that, but the problem is these viruses change and that can change. If it changes back to becoming super lethal, we have a big problem.

McCarty (00:21:21): Yeah. But is the idea that they just sequence these cows and then kill any cows where they detect H5N1 or are they not even doing that?

Glanville (00:21:28): I think it’s no. There’s significant resistance by the cattle and dairy industry to test. In fact, I think in Europe, we had looked into, we’d done a cow study with H5N1 immunity. There’s resistance to vaccinating cows with vaccines for H5N1 because of, I think, cattle meat trade with Europe or something. The whole system is set up for a horror show here. It’s a problem. And then you can’t do cow slaughter because I think a lot of farms have over 30% of the cows infected.

It’s a high rate of infection. And it’s particularly because of the new way that this virus has adapted. I think it’s transmitting by the udders through the milking machinery. And in the milk, by the way, there’s a bunch of virus in the milk. There’s an H5N1 problem that is—basically, we’ve put our head in the sand because it looks mild right now. And I hope it stays like that. That’s actually very fortunate.

What is vaccine efficacy?

McCarty (00:23:42): Let’s talk about Centivax.

Glanville (00:23:43): Cool. I’m happy to do it.

McCarty (00:23:44): You have a vaccine called Centi-Flu 01.

Glanville (00:23:49): Yep.

McCarty (00:23:49): That is in phase one trials. The first thing I want to understand, and this goes back to the first question about the WHO, right? They say things like, “Oh, this year the effectiveness was 20%.” My question is, what does that actually mean? And when you’re making a universal flu vaccine, people could still get sick. What are you actually measuring? How do you say, “This is the effectiveness of our vaccine”?

Glanville (00:24:15): When people talk about efficacy or their effectiveness, similar but slightly different concepts, what they’re saying is, people who got the vaccine versus people who didn’t, what were the rates of influenza-like illness that they got after? And they typically test to make sure it was actually flu and not other viruses that also give rise to influenza-like illness symptoms, ILI. And what they’re saying, if it’s 20% efficacy, they’re saying that there was a 20% less rate of flu in the people who got the vaccine than those who didn’t.

If you hear those numbers, you’re like, “That sucks.” A good vaccine should be 85, 90, 95%. People, I think not unreasonably, expect vaccines to be like the tetanus vaccine or chickenpox vaccine. I want to take it and then not have to worry about that thing anymore. And unfortunately, that’s not always the case, particularly for rapidly mutating pathogens. And that’s what that means. For Centi-Flu, as with other vaccines, you run through a series of tests. It’s kind of like Indiana Jones and the Holy Grail.

You have the three challenges, right? You have to do a phase one study, then a phase two, and then typically a phase three study. Normally in phase one, you’re mostly looking for safety. You’re basically saying, “Is the medicine I’ve created not causing harm to healthy people?” And in most cases, if it does, that’s a showstopper. Normally, people test them against the three guidance strains, but that’s not our objective. We’re not trying to make a vaccine against the three guidance strains. We’re trying to make a vaccine that is ultra-broad-spectrum against all flu.

And we chose a panel of 24 viruses that included deep viruses from the past, like 1975 onwards, but also the guidances and then also circulating strains that occurred after the guidances. Most notoriously, the K strain that was in the news that was a mismatch to the flu seasons. And then the clinical sites draw the blood, and then it’s actually not in our lab. It’s a group called IQVIA. There’s a group that’s a standard group that everybody uses. We wanted to use a third-party group that has standard assays because then it’s directly comparable to everyone else.

And we send the serum from the 180 subjects from our study to this group, and then they test it against this panel of 24 viruses. And we looked at—

McCarty (00:26:29): Are they synthesizing those viruses? They have the historical sequence of a virus, and then they use that to build viruses in cell culture.

Glanville (00:26:38): We build them. We use cold-adapted. The other challenge of this work is that if we made viruses back to 1975, what if something leaked out?

McCarty (00:26:45): Exactly.

Glanville (00:26:46): There’s some evidence that that’s happened in the 1977 pandemic, that it was an accidental leak of a 1949 strain. And you don’t want that as an optics problem or a global societal problem. And what we do is we make these viruses here, we do them cold-adapted, which means the viruses can only grow well five degrees below human body temperature, which means that this is a standard technology that’s been used for decades in influenza research to make sure that you have a virus that cannot leak out of your lab because it cannot survive in mammals.

McCarty (00:27:17): How do you do that?

Glanville (00:27:19): People before us had serially passaged over and over again virus at colder and colder temperatures until they made a new version of the virus that would only survive at these cold temperatures and it would stop working at the higher temperatures.

McCarty (00:27:32): But how do you know that that’s not changing the parts of the virus that you care about?

Glanville (00:27:36): You got it. That becomes the chassis. And you go, “I have a cold-adapted generic virus.” Then what we do and what everybody else does is now you go, “Okay, now I’m going to impose the strain 1975 HA and NA into that virus.”

McCarty (00:27:49): I see. You’re adding these recombinantly.

Glanville (00:27:51): And you have a virus that only grows cold, but it’s safe because it’s essentially noninfectable to mammalian populations, or really any population at that point. It only survives in a petri dish in these cold settings. And we run HAIs, we run neutralization. Our vaccine is designed to produce this universal immunity, these broad-spectrum antibodies, but it’s also designed to produce broad-spectrum T-cell immunity. And we also run what’s called an ELISpot, which is a way to check to see do the subjects produce T cells that are targeting these ultra-conserved sites that are found across all flu A and flu B.

We also looked at the serum of the subjects to see if they could respond just by antibody responses to the recombinant HAs of H2N2s and H4s, H6s, H7N9s, a whole panoply of these exotic subtypes to say if a pandemic were to break out, could this vaccine provide protection on day one? Basically, can you make a technology that if people started taking it, you end the influenza pandemic era of humanity? And that was part of the question.

Designing a universal flu vaccine

McCarty (00:28:55): I don’t know how much of this you’re going to be able to talk about, but I want to really understand step by step how you design a universal flu vaccine.

Glanville (00:29:03): Sure.

McCarty (00:29:04): My understanding is that the first thing you do is you have some kind of historical data of antibodies elicited in humans, and you have all these flu structures, and you say, okay, well, these are antibodies that people have found in human populations, before us, before our clinical trial. And these are the flu, HA and NA and stuff. And we’re going to run a bunch of computational docking. And we’re going to see where these human antibodies bind. Yeah, tell me about that experiment. What is the point of that? Why are you running these huge computational docking things?

Glanville (00:29:40): I’ll describe what I can. There’s going to be some parts I’m going to have to remain vague. But to start off, you want to be able to target the conserved sites of the virus that it’s not able to mutate. Because you don’t know how the virus is going to mutate in the future. Except you do know it’s not going to mutate these two key sites on hemagglutinin. There’s the stem that’s been well studied. And there’s a second site called the lateral patch up in the head, which has been far less studied, but there’s a second conserved site.

McCarty (00:30:06): I don’t want to derail you, but one idea I had was, if we did have such a great vaccine and it was targeting these conserved sites and the flu is mutating randomly, how can we be sure that a new flu strain will not emerge that does evade immunity?

Glanville (00:30:24): It’s a great question, and that’s always the question. Let’s say everyone started taking this vaccine, would it accelerate pressure on those two sites? I can’t predict with perfect certainty the future, but what we can say is we know those two—the stem site has not changed in at least two and a half thousand, maybe eight thousand years. We know because of the history. And then remember, it’s mutating every year all the time. Those sites, every time it tries to mutate, that flu is no longer infectious.

And we know when we try to change it in the laboratory, it breaks the virus and we have a handle on why because it can no longer do its grappling hook trick. And it’s trapped in an evolutionary minimum. And we think that if you can target those sites, if it hasn’t been able to change in thousands of years, it probably is not going to be able to change in the next 50 years. And that even under selection pressure, it’s trapped. The other argument for why that should work is that when we created the smallpox vaccine and lots of people started taking it, the result was not added pressure to create escape.

The result was eradication. And smallpox mutated slower, but if you target this site, you’re actually targeting a site that effectively, from your view of your antibodies, you’ve made influenza evolve slower. What you have is a race condition between the growth rate of immune response and the mutation rate of the virus. And if you focus on the slower sites of the virus, you effectively made that virus mutate slower from the perspective of your immune response. Is it global suppression and tools eventually for eradication rather than immune escape?

Both could happen, but I think that there are these evolutionary traps, and we’ve done it before: guys with pocket protectors in the 70s, with none of our shiny technologies, managed to eradicate one of our most ancient enemies from the earth. And I think that these tools could enable us to do that with future viruses.

McCarty (00:32:07): One thing I’m confused about, though, is, in the context of this computational docking experiment, you said, well, we’re going after these two conserved sites, but finding those conserved sites, I mean, we could get that just from the phylogenies and crystal structures, right?

Glanville (00:32:24): That’s right. Yeah.

McCarty (00:32:25): What is the docking providing?

Glanville (00:32:27): The docking was for me to understand what the proportion was, what was the probability of hitting those sites. It was for me to answer the question, why do we miss? And the docking, where I took every solved crystal structure of a human antibody and docked it hundreds of millions of times against the surface, was to basically enumerate what are all the possible orientations that an antibody could bind every possible epitope or binding patch on the surface of hemagglutinin. And once I had that, I cross-indexed it against the last hundred years of evolution of the flu, that we have data all the way back to the 1918 strain that killed 50 million people.

And then I say, what proportion of the antibodies of all possible ways an antibody could bind are targeting the universal sites? And that’s how I came up with those numbers of 1% and 20%. And what it did is it told me those sites are just rare, and therefore these other technologies people are using were never going to work. What I said has to work here is, you have to shift the distribution to create an in vivo selection system that favors targeting these conserved sites, because otherwise you’re constantly going to be overwhelmed with the strain-specific sites.

That was the purpose of the docking, to understand the underlying selection forces and therefore the engineering solution. Once I had that, then you get into okay, I want to design a technology to respond. At heart, the engineering principle was what if I were to get a bunch of different hemagglutinins that have been mutated all to hell from the last hundred years by nature, except those two sites are in common? And then what if I were to mix them? And if you just mix them together and inject, that doesn’t really help you because you’ll produce some antibody, you’re basically diluting your limited antibody response budget, where you’re going to produce some strain-specific against the first strain and some strain-specific against the second strain and so forth.

But you’ll just get a limited response against each strain and that won’t select for breadth. The key thing I thought was: what if I were to dilute that mixture? I start lowering the dose so that there’s actually not enough dose of any one of the strains in the vaccine to produce a strain-specific response. And that’s true for any vaccine. If you lower the dose at a certain point, you’re just not putting enough in to produce an immune response, which seems obvious, and that’s true.

But if I put 20 of them in all at the same time, then any of the B cells that recognize a single strain won’t have enough vaccine to respond. But pumping through your veins and mine and yours are these B cells that recognize this conserved site. Those recognize all 20, so they get 20 times the dose.

McCarty (00:35:02): I was actually going to ask you about this because I did not understand this at all until what you just said. Yeah, so that’s brilliant.

Glanville (00:35:09): What happens is your minority population of B cells, that 1% that you really like—all B cells have 100,000 copies or so of the receptor on their surface of the single antibody they can make. A strain-specific B cell, let’s say it recognizes 1918, it grabs just a tiny little mouse fart amount of antigen and it doesn’t have enough to activate and proliferate. And the majority of those strain-specific B cells are basically starved of attention. But the minority B cells, those really good ones that normally get neglected, they get 20 times the dose.

They’re like, “I don’t know what you’re talking about. There’s plenty of antigen around here.” And they’re able to proliferate and respond without being outcompeted. And that’s the fundamental concept.

McCarty (00:35:47): Just to clarify, this is what you call conservation–concentration coupling.

Glanville (00:35:52): Yeah, that’s right.

McCarty (00:35:53): And I did not understand this until—to provide some context to the viewer or the listener, the flu that you’ve made, it’s not just that you’re putting in one antibody. You’re mixing 20 different hemagglutinins into the body. And I’ve read your patents on this and stuff, and it’s like, “We’re providing these at very, very low doses.” And I didn’t really understand why that is, but it’s brilliant. The dose will only be high enough for a B cell that can bind many of them.

Glanville (00:36:30): That’s right. That’s exactly what it is.

McCarty (00:36:31): Which is amazing. Are there other vaccine makers that have followed this approach?

Glanville (00:36:37): When we filed the IP, this was a completely empty space. We have ultra-broad genus patents because everyone just assumed, as an axiom, well, the first thing you need to do in a vaccine is put enough of the thing in. And I violated a rule that existed for 230 years by saying, “I’m deliberately putting too little.” And we have very broad patents covering this whole concept, and it’s a very generalizable concept. You just go, “I’m going to put too little of a bunch of variants that share one common site,” and therefore the only surface that can be targeted— You’re actually creating, on a three-dimensional surface, a concentration gradient, depending on where you recognize.

And that’s the emergent property of this methodology: one surface will be at a higher concentration than another surface. And you’re coupling that by this conservation–concentration coupling, where you have a whole bunch of components at low concentration. And if you scan across that surface, suddenly there’s a surface in common that suddenly is effectively 20 times the dose of other surfaces while retaining three-dimensional or quaternary structure, which is the whole thing. You can’t just chop these sites out or they fall apart. That’s the organizing principle. And we’ve demonstrated it in flu and a number of other pathogens as well.

The idea behind Centivax

McCarty (00:37:40): Where did this idea come from, though?

Glanville (00:37:41): I was on a motorcycle ride driving home one day. I was working at Pfizer. And to clarify, I never worked on vaccines at Pfizer. I was trying to figure out why we were having such a hard time making antibodies against this site on a protein called PCSK9. And I think it’s public that they’ve worked on that at this point. I was working at a site that made monoclonal antibodies as drugs, and I was an antibody engineer at the time, a computational antibody engineer.

And the protein looks kind of like Mickey Mouse’s head. It’s got these two small globular domains and then a much bigger central domain. And if you use phage display or you immunize mice, you’d get a whole bunch of antibodies against the ears. Those were immunodominant, immunogenic. But the antibodies you want are sort of like where the neck goes. And if you get an antibody there, you’ll cause PCSK9 to block an interaction with LDLR, which will result in lowering your cholesterol. And I was fascinated by why this site was not being targeted.

And there’s no immune evasion on purpose. It just happened to be less immunogenic. Which got me to the idea that these things are probably governed by other forces that are mathematical. And then I thought, well, what if I were to grab a bunch of different versions of PCSK9 from different species, as far as I could go, chickens and alligators and capybaras? It doesn’t really matter as long as they were all mutant, except that they shared that common site that I wanted.

I diversify everything else, but I share the common site. And if I mix those together at too low of a dose to produce an immune response against each one individually, then they would no longer be distracting. And the only thing that could be focused on was the shared site. And I thought of this concept. I got home, I did some computational analysis and confirmed that that site would work. And then I realized, I was like, “Jake, you’re being a moron. The application is not to save us six months on a discovery campaign. This is the basis of a universal vaccine technology.” And I began looking at influenza and HIV and not coronaviruses at the time, but other viruses.

And I looked at it and I just felt that it probably could work. I got obsessed with it. I eventually resigned from Pfizer. Again, I was never working on vaccines there. I never did any work on this. It was a motorcycle ride home, but I was like, “I think I have to try this.” I applied to the PhD program for immunology at Stanford that was creating this computational systems immunology program because, A, I felt like maybe I’m being myopic and I want to surround myself with immunologists.

If there’s something stupid about what I’m thinking, I needed to hear that so I could stop obsessing over it. But also, I felt that if I was right, I needed to be a card-carrying PhD immunologist so the world would hear me.

McCarty (00:40:21): Big question, of course, is you have this concept, you’re putting in 20 low doses, but the secret sauce is how do you know which ones to put in? I don’t know how much you can say about that, but—

Glanville (00:40:35): I’ll be somewhat limited on what I can say, but I can describe the organizing principles. First off, there are these two sites, although I will say that this technology does not actually require that you know in advance what the sites are. As long as you do the analysis to convince yourself that you’re not going to be wasting your time, there should be some conserved sites. But the technology can actually discover sites without your knowledge. You don’t even need a crystal structure to know the answer.

You could just deploy them and see, am I generating broad immunity that extends beyond the components? And the experimental designs, where you immunize pigs with a bunch of different components, and I chose a limit of 2007 where I said, I’m not going to use any components from 1918 to 2007. And then what I’m going to do is check their serum against 2009, 2017. And we’ve kept those serums. We’ve tested them out to 2026. And if the technology is doing what it’s supposed to, it should be able to create broad immunity that continues to be protective out in the future.

I did some early experiments demonstrating it, and the Gates Foundation supported us to test challenging animals against pandemic shift 2009. And the same serum from those pigs is still neutralizing H5N1 from 2024. The choice of the strains—there’s some beautiful math that allows you to optimize for the choice of the strains. And I’m going to be a little bit vague about the process, other than saying that one of our criteria is that there is some favored space, and that’s what our IP covers, which is I’d like to choose strains that are of historical relevance and have a history of infecting humans abundantly.

And we’ve covered that space, but our IP more generally covers the principle. There are details on choosing the strains correctly. The other consideration we found was that—I mentioned that HA undergoes a prefusion to postfusion switch. And it turns out the spike proteins from HA, like many other viruses, they actually flip over pretty easily. And you don’t really want to make antibodies against the postfusion version that falls apart or monomers that fall apart. And flu shots are actually mostly monomers. They’ve mostly fallen apart, which means a lot of your antibodies are wasted against single pieces of a trimer against the interior surface instead of against it stuck together the way it should be, which means you have a lot of antibodies that are not productive.

In coronaviruses and in RSV, people who added mutations to trap the viral spikes in the prefusion conformation, that technology was necessary for successful vaccine creation. The people who did it properly made working vaccines, and the people who didn’t made failed vaccines. Adding mutations to prefusion trap these things so that your antibodies are targeting the thing you want to stop, the prefusion form, turns out to be an important breakthrough in those two viruses. And Jerry Sadoff, my chief medical officer, he had gotten more vaccines approved than anyone alive, and he was advocating very strongly for this.

And we engaged a program to identify a generalizable solution for prefusion stabilization with as few mutants as possible so that it resembles the character of the native protein but not able to flip. And that turned out to be important. And we include that as well. And that’s the choice. We think we have an effective strategy to create this and generalize it. And we’ve demonstrated it now on coronaviruses, we’ve demonstrated it on malaria to focus on a certain site. We’ve actually done a demonstration on antivenom because we work with antivenom for other reasons.

Clinical trials

McCarty (00:44:16): I’ve read through some of the patents and the sort of evolution of what you’re designing, right? It’s been a different number of components through time. At one point it was 18 components, 22 components. There has clearly been shuffling. One thing that I think is interesting is if you were to choose 20 components to put in your vaccine, you can do cell culture assays to see how well it neutralizes strains. I’m curious how well that actually translates to human clinical practice. How confident are you in the data before you go to the clinical trial?

Glanville (00:44:52): I’ll tell you before, but we’ve also completed a clinical trial, so I can.

McCarty (00:44:55): But the data hasn’t come out yet, right? Can you share anything about the data?

Glanville (00:44:57): I’ll tell you what I can share at this point. Going into the trial, from an algorithmic perspective, I’m always concerned about overfitting in clinical drug development. There’s a tendency for people to just go, I’m going to run a bunch of studies on mice and then let’s just be legends. And then they go straight to humans and they act all surprised when humans are not mice. And especially for the immune system, on one hand, the immune system and pathogen interaction, animals can be pretty good models for it.

But on the other hand, every specific species has been in an arms race against its pathogens. And it evolves quickly and it might be overfit and have a different configuration point. And to defend myself against that, I started with pigs that get infected with human viruses, but I also tested in ferrets and mice and rats and cows. And I also did these human immune organoids that are built from the lymph nodes of adult donors. And we tested in all of these systems prior to going into humans.

And during that period, we were refining, we were testing different configurations, and we got to a point where we had a pretty consistent universal immunity response, including against very different viruses than were in the composition. That was a requirement. And that got us to a place where we felt we were confident going into humans. As of right now, we’ve recently completed a majority readout of a 180-person trial that had 90 people 18 to 64, 90 people 65 plus. We were trying different dosage levels.

We were comparing to randomized double-blinded placebos. And then also at the conclusion of the immunization and the unblinding, the placebos all got standard commercial vaccines, so we can compare to that response. What I can say at this point is that the clinical committee met and universally voted to advance the trial. We’re now gearing up towards phase two trials.

McCarty (00:46:51): And how can you be sure when you’re planning these clinical trials that your data is suggestive of long-term protection? Is there any way to evaluate that these patients will be able to elicit an immune response after three, five years?

Glanville (00:47:06): Yeah, you follow the subjects.

McCarty (00:47:08): You’re doing that for the phase one?

Glanville (00:47:10): The phase one, yeah. There’s things you can do in animals, but again, animals are not humans. There’s some interesting things we saw in the human organoids that are suggestive to us of interesting things. We’re monitoring them. What we have is the subjects that got vaccinated starting in February of this year, we continue to monitor them and we’ll be doing so for multiple years. And that gives you an ability to assess the durability of the immune response and therefore the periodicity of they get their universal flu shot.

Do they need to update every year or can they go every two years or every three years? Or what’s the rate that you need a booster shot? And that’s something we’re monitoring for. And ultimately, human data in adults and elderly is what’s going to tell us the answer.

McCarty (00:47:49): And when you were funded by Gates, there was this announcement that you were planning to start human trials in 2022.

Glanville (00:47:56): Yeah.

McCarty (00:47:57): But obviously, it took four years longer than the anticipated timeline…

Glanville (00:48:01): Yeah. The Gates Foundation had two parts to the Grand Challenge. They had an initial $2 million, which we were awarded. And we delivered our data quite early. We actually delivered our results to the Gates Foundation in the middle of the pandemic, and I believe in February of 2021. And we were so much ahead of the other groups that the response that we got back was, “Hold on, we’re going to actually wait till September because we want to get a chance for the other groups to catch up.” And my response was like, “Come on, come on. What are you talking about? We won handily.” And then it went to September.

And then we had some meetings and it was unclear. We did not get the $10 million follow-on. And it was unclear if anyone else got it. Had I got that money back then, then yes, we would have obviously been in the clinic much faster. Without that money, it took more time for us to build up and be able to advance.

McCarty (00:48:49): It was a funding thing.

Glanville (00:48:51): Yeah. As always is the case, funding. I will say it’s gotten easier over time. When I first started doing this work, in 2012, I said, hey, look, I think I’ve got a technology for a universal vaccine. And the idea was too new. And it was sort of unfundable. And I solved that by creating a company that was self-funded and incubating it. Then I got some money from the Gates Foundation. Then I sold Distributed Bio to Charles River and I negotiated, “Look, okay, you guys can have the rest of it, but I’m taking this universal immunity stuff with me.” And they agreed to that.

And then I built it up. I can be very stubborn when I think the math supports—the math was too beautiful not to keep working on. If it wasn’t, I would have sold the company and probably made my wife happier hanging out somewhere with coconuts. But it worked. And I was like, “Look, I think this is the single biggest thing I could do in my lifetime to touch the long arc of history,” and so I couldn’t walk away from it.

McCarty (00:49:48): And besides the number of patients, what other things do you have to measure in the phase two to have supreme confidence in a huge-scale, 20,000-patient phase three?

Glanville (00:49:58): Phase two, and I’ll talk about the phase three in a second. Phase two, we’re planning to do over 500 subjects. We’re currently looking at 650. And again, we’re going to focus on the elderly first because it’s two-thirds of the market, the greatest medical need, and it’s the harder problem. And we have reasons to believe we have a unique advantage there. The goals are—in the phase one, like I said, safety, tolerability, and then you get a look, but your group sizes aren’t that big.

You’re talking about 12 subjects per group in the phase one. What you’re doing in phase two is now you’re saying, okay, now we’re going to put a shitload of subjects into each of these groups. That gives us statistical ability to assert, and our objectives are to assert superiority against mismatch strains relative to the guidance and equivalence, so noninferiority and potentially superiority against the guidance strain. We want to at least meet them at the things the dedicated vaccines were designed to treat, and we want to exceed them everywhere else: historical strains, but also the circulating strains that actually cause people to get sick that those vaccines struggle against.

McCarty (00:51:01): How well does it have to perform in the phase two for you to be like, this is so statistically obvious that it’s probably going to work in a phase three? Is there any efficacy that would say that?

Glanville (00:51:12): Yeah, really, the phase two actually is going to tell you if it’s going to work. The phase three, you run 3,000 subjects minimum, and it’s really for safety reasons to get approval. You actually don’t run—

McCarty (00:51:21): To find rare side effects or something?

Glanville (00:51:24): That’s exactly it. For phase three, there’s two paths. There’s accelerated approval, which is there are mechanisms by which you can get approved just by the correlates. You don’t actually need to run a 20,000-person efficacy trial. The question is right now, it’s not clear whether we would get approved that way with the current FDA. They may expect an efficacy trial. It’s great if you can use accelerated approval because then you’re talking about it ends up being about a 4,000-patient trial. Your minimum is they want to see safety in 3,000 subjects.

In a phase three, they actually don’t expect you to run the serum on all 3,000 people because your statistical numbers are actually satisfied by about 500 or 600 people typically. If you’re having to go deeper, if you see companies doing a lot more testing, that means that they’re right at the wire of whether they can show noninferiority, which means you’ve screwed up. You shouldn’t actually need to test a huge number of subjects if your vaccine is superior. For efficacy, you need to go much higher because there, what you’re doing is you’re casting a net, like you said, 18,000.

I’ve seen numbers in the 30,000s, where what you’re doing is vaccinating a large number of people right before flu season starts. And then you’re just hanging out to go monitor of the treatment group versus your control group where the influenza illness is popping up. And you’re waiting to see a noninferiority at minimum, otherwise, you have no chance. But what you’re looking for is superiority. You’re looking for more infections happening in the standard vaccine than the people who got your vaccine. And to do that, even though flu is this global endemic thing that happens all the time, it turns out you need to have a lot of people in your studies to be able to pick up enough infection cases in vaccinated subjects in order to be able to see the result.

McCarty (00:53:02): Isn’t it kind of interesting that the FDA has this thing, the better-than-the-Beatles problem, where your new thing has to be better than the current standard. But in this context, it’s a little bit different because it’s not only do you have to be better, but you’re also trying to offer broad protection. But the FDA doesn’t really care about broad protection. They just care, are you better than in this season against the current vaccine? Isn’t that a little odd?

Glanville (00:53:26): It’s odd because it would be easier for me if I just had to demonstrate that I do better against the circulating stuff that actually gets people sick, which is what an efficacy trial demonstrates. They’re just expensive.

McCarty (00:53:36): But even if you were just as good, but it lasted longer, that would still be superior. But most clinical trials are not really equipped to test that stuff.

Glanville (00:53:43): To test that. You could frame that. But yeah, for the serology, I need to have that basically superior with breadth, but I also need to show I’m noninferior against the guidance, even though they’re outdated. And we’re obviously advancing to phase two, so we feel comfortable with that. I’ll tell you what it does: it creates a little bit of an arms race for higher and higher doses for subjects. Because I might choose to go with a lower dose if I wasn’t also needing to make sure I also hit that bar.

And that ends up meaning that humans are receiving a dose that might be different than they could have otherwise. And that’s true across the different groups. And there is a better-than-the-Beatles arms race here. The FDA does want something extra. They say you need to be noninferior to the current stuff and you need to have something extra. But our real extra thing we do is we solve the open problem of people being like, “I got the flu shot and I still got sick,” which is uniformly high titers against the entirety of the panel, including circulating strains.

That’s what a breakthrough looks like where people take flu shots. And first off, I think that some of the vaccine hesitancy around flu shots is based around that. People are like, “Why the hell would I take it? I took it and I still got sick.” Whereas if you took it and you know it was going to work, I think there’s some people who would be more likely. I think there’s also—our lives are busy and flu shots are kind of awkward where it suddenly pops up and you have to rush to go take them.

Otherwise, it’s too late. Whereas if you have a universal vaccine, you could take it at any point throughout the year. And you don’t have the time pressure. Elderly people can go in during their doctor’s visits and take it. And then the second benefit is that if you have a population of people taking that, then they have preemptive immunity, which basically creates a herd immunity layer against future pandemics. In fact, future pandemics would not be able to become pandemic if you have enough people that already have immunity.

They’ll just fizzle out before they start. That’s a societal benefit, which is outside the attention span of the average end user, but creates a post-pandemic world, which is immensely attractive from a societal perspective.

The business case for eradication

McCarty (00:57:33): The annual flu market is something like $7 billion a year.

Glanville (00:57:37): That’s right.

McCarty (00:57:38): There are hundreds of flu vaccine candidates in clinical trials, is my understanding.

Glanville (00:57:44): Probably.

McCarty (00:57:44): There’s a universal flu vaccine tracker that has dozens and dozens of assets that people are exploring. Under the assumption that your vaccine is extremely good and elicits broad coverage and it lasts a long time, and other people are getting approval for other types of flu vaccines, what is the business case for Centivax? What are the long-term economics for eradicating an illness?

Glanville (00:58:09): This is a fun one. There’s two parts to that question. One is the business case. It’s a $7 billion market, one of our biggest vaccine markets with one of our least successful classes of vaccines, right? 10 to 60% efficacy with about 30% [average]. That’s sloppy. We can do better. And again, I take the flu shots. I’m really appreciative of companies that produce these flu shots, but we should be having a flu shot that’s 85 to 95%. With respect to all of the other things in the pipeline, I honestly don’t pay that much attention to them.

Some of them I’ve looked at and I don’t think they have a credible chance of success. I’m sure there’s groups out there doing good work. I just look to what the market is right now and our ability to go establish superiority over the existing vaccine classes. And we have a strong case to do so. Tracking to a $7 billion market where if you can have a vaccine that can be offered all year round, that can provide more durable and broad protection against flu and new emerging flus, and as a side benefit, can avoid pandemics when they start.

That’s a product that should exist, and we should make that. And there’s a huge amount of economic incentive and personal incentive. I also think that this vaccine could help address some of the vaccine hesitancy out there because I think it’s not unreasonable for people to be like, “What the hell? I took the shot and I still got sick.” Whereas if people get that Pavlovian satisfaction that, “I take it and I don’t get sick,” I think that they’re more likely to say, “Yeah, Centivax is making them right. What else are they making?” And that’s my thinking for why there’s a market incentive.

You asked a separate question, which is we’ve talked a couple times about eradication. And I’ve mentioned that I want to build tools that go out and solve these problems, but I also want to arm future decades with the capacity for eradication. And every time I brought this up, I definitely have people be like, “Jake, I don’t want to be a jerk, but isn’t eradication bad for your business model?” And it’s actually not. And here’s the interesting reason why. I was at Pfizer in 2008 to 2012 when they hit their patent cliff.

And up until then, Pfizer had been living in this 15-year frat pirate party of endless abundance from Lipitor and Viagra, which had entirely decoupled research success from economic success. But suddenly they were hitting that wall, the hangover was hitting, and they had to go restructure things to be able to handle what comes next. And it left an impression on me. And what I do is when I look at Universal Flu or really any one of our other programs, I imagine the following trajectory where you get it out and get it approved, which we’re still working on, right?

These things are challenging. But in the first few years, your major goal is to gain market share, to go out and have increasingly more and more people say, “I’m going to switch over to use this because this is more effective.” And that’s the individual choice of the people choosing which vaccine to take, word of mouth, which is how I’ve always built my businesses. I want people to be like, “You should go take that. That thing was way better.” And then, increasingly, with postmarket surveillance and test-negative design studies, we should see a superior protection from hospitalization and death, which means the insurers are going to be like, “We should shift over to this because it saves us a huge amount of money because we’re not paying hospital bills.” That period is where you’re gaining market share, which doesn’t happen overnight and takes a couple of years.

That’s a useful period anyway, because then you’re talking, you’re five, eight years into the market. And that’s where people are no longer being like—some people are like, “I don’t want to take a new thing. I want to wait for some other people to try it.” And you’re no longer a new vaccine, you’re well established, then your market share can become incredibly dominant. Now you’re out 15 years, your patent cliff is coming up in five years, right? There’s various ways to extend it, but it’s not forever.

At a certain point, people can come and create generics to compete against you at your own vaccine. And that’s a point where I think there’s actually an alignment between the bean counters and the futurists to say, you know what? We should attempt to create an eradication campaign because A, it’s no longer a new vaccine. Everyone knows it. It’s well established, well characterized. B, we’re about to go off patent in five years anyway. And we should get the world to say, “Go try to do this.” Get the equivalent of 15, 20 years worth of economics in a five-year compressed period.

And one of two things ends up happening. One is you try, you’re not successful. You’ve got a bunch of extra money up front right before you’re about to hit competition anyway. The bean counters are happy. Or the second scenario is that you succeeded, in which case you have people a thousand years from now high-fiving us throughout history for the work we did to create a future where there is no longer that pathogen, which has been with us since the beginning of time.

And we’ve recreated a future without it. And I’ll say, in addition, for the economics, the thing is, with smallpox, it wasn’t the case that in 1980 they eradicated it and announced it and then everyone stopped getting vaccinated. The vaccinations continued for the next 20 years. And there’s a very long period where you actually can gain extra economic benefit by producing a shitload more doses than you would otherwise to attempt to do a permanent advance of the human condition for every generation that comes after and help the company along the way.

And I don’t think there’s a misalignment. I think there’s a lack of vision sometimes, but I don’t think there’s a misalignment of economic incentives and eradication campaigns. And that’s the timing that you’d accomplish that.

How to eradicate the flu

McCarty (01:03:26): What is the plan to eradicate flu? Let’s say we’re 10 years out, you have approval. Is it immunize everybody or at least enough to get some really good herd immunity and immunize livestock and birds? What do we have to immunize?

Glanville (01:03:42): What do you have to immunize? First off, people talk about how we’ve eradicated two things, which has been smallpox and rinderpest. That’s actually not true. There’s a third that people forget about. And that is during the pandemic, by accident, we eradicated the Yamagata strain of flu. Everyone was wearing masks and there was social distancing. There used to be two strains of flu B: the Yamagata strain and the Victoria strain. And because of the distancing and social distancing, the masks, and all the other countermeasures against coronavirus, flu comparatively is actually easier to eradicate than coronavirus.

And we, by accident, ended up extinguishing from the earth the Yamagata lineage of flu B. It’s no longer in human populations, it’s declared eliminated. I smell blood in the water with the influenzas. What you would do to effect an eradication is you would treat those pig farms I was talking about, and then you would treat human populations. You don’t need to get everybody, you just need to get enough for herd immunity to do its job. The thing has what’s called a negative, too low of an R₀, a sub-one R₀, so that it basically just peters out and goes away.

You’re not going to get all the birds, and you don’t have to, because avian flu actually propagates very poorly into mammals. I guess you’d also have to get the cows these days because they’re chock full of H5N1. But the point is, there’s a couple different major herd species of mammals that live adjacent to humans, and you’d vaccinate them as well. And then you’d vaccinate enough people that you no longer have influenza propagating. And once you’ve extinguished human influenzas and the neighboring mammalian influenzas of our major herd species, then you’re stuck with avian influenzas, which are optimized to operate at a much higher temperature because birds are hotter than humans, and they’re actually maladaptive to go into mammals, particularly when they no longer have the ability to recombine with pig or human influenza.

And that puts you in a position where maybe every decade you have a couple outbreaks of three or four people who get infected. And that’s really 20 years later after people maybe stop routinely immunizing with influenza, but you no longer have a genetic reservoir which is adaptive to human infection. And I think there is a path. I’ll be blunt. The problems here are probably political more than technological. First off, my technology needs to survive the next clinical trials. It needs to get out there.

It needs to be successful. There’s a lot of ifs before the scenario plays out. But all those things line up, and the challenge we would have still would be the problem of the common goods problem globally of political alignment. And I’m hoping in the next 20 years we have some improvements there so that there’s a resurgence of common interests recognition, similar to what was observed in the 60s and 70s, that gave rise to the eradication of smallpox. Smallpox used to kill a quarter of all children in the first two years of life.

And it shortened the rest of our lives. And we had that since the beginning of time. We have scars on the face of the Pharaoh from smallpox. And yet, people rose up and they eradicated one of our most ancient enemies and did something that I think is on par with the moon landing in creating a permanently better future. That was the first virus, the first vaccine. Edward Jenner created a smallpox vaccine. And you fast forward in this tiny little blink of an eye and we eradicate it forever from the earth.

And that’s one step closer to utopia. And they’ve already shown it can be done, which means our problem is easier than the first people who put men on the moon because we already have a template and we have better technology across the board than what those guys have. We have wastewater surveillance systems that allow us to detect if there’s a pop-up in different cities. Technologies exist, it’s really a political challenge to be able to say 20 years in the future when this hits, could we align and say, let’s just get rid of some extra pathogens so that we can spend less of our time fixing our broken selves and more time and resources towards advancing creative enterprises of humanity?

Could we make broad vaccines for the common cold?

McCarty (01:07:26): What would make it harder to do this for, let’s say, the common cold?

Glanville (01:07:30): Sure.

McCarty (01:07:31): For rhinovirus?

Glanville (01:07:32): Yeah, with respect to the common cold, I’ve looked at a whole bunch of pathogens because if you think about what I just described to you, this method is very generalizable. Anytime there’s a common site that the pathogen can’t change, which it almost always has, by the way. Because the pathogen can’t change the site that it needs to interact with your receptor, because it can evolve, but you’re not really evolving. And it can’t change—if there’s two spaceships that need to dock, they can’t change the docking port.

Otherwise, they’re no longer compatible. And that creates a selection pressure to preserve conservation at the exact site that’s the most useful for you to block. Many pathogens have this property, and many pathogens you could do the dilution trick I just described. When I look at the rhinoviruses in particular, I think there is a path here. Initially, I shied away from them because they have a complicated surface geometry of the proteins they pack in this complicated lattice. But more recently, I’ve looked at them and I think there actually is a path to be able to go tackle them effectively.

And we have some designs. I just have not executed on them because I think we have enough active programs. And for various priorities, I felt that those programs made the most sense for us. And similar, each pathogen has its own story and various challenges. At the extreme end, there’s things like tuberculosis that I don’t think antibodies matter that much for. The T-cell immunity could be effective, but I think the antibodies are somewhat useless. And we look at each pathogen and we don’t try a one-size-fits-all.

What I’ve done is I’ve tried to build a series of generalizable, empowering technologies that we can combine to effectively attack the pathogens in whatever order we think makes most sense for the company and for society.

Building a universal snake antivenom

McCarty (01:09:07): Do you want to talk about antivenom?

Glanville (01:09:08): I would love to talk about antivenom.

McCarty (01:09:10): Sure. I’ve spent a lot of time researching antivenom, mostly through Renaissance Philanthropy, and there’s donors who are growing increasingly interested in funding antivenom work, especially because the Wellcome Trust is now backing out. And it’s clear to me that the problem is so multifactorial that it’s not only that the snakes present in different regions on earth are different and their venoms are different, it’s that you have to give them quickly. The really good antivenoms are expensive. There’s a distribution problem. When a person in Nigeria is bitten by a snake, they don’t always know what the snake is.

Sometimes people actually beat the snake and kill the snake and then carry it to the clinic on the back of a motorbike. And there’s this class of interventions like, well, maybe we should just give people boots, but then there’s cultural reasons that people don’t wear boots, or we should just do bed nets because a lot of snakes bite during the night. Centivax has many extremely interesting programs. I mean, I could sit here for 10 hours and talk to you just about all the super interesting programs you have.

But I think the antivenom work is also almost uniquely interesting in that it’s not a vaccine, but it is a case where there’s this huge molecular diversity and you’re trying to design something that can neutralize that diversity. But of course, there is this debate where some people say we will never be able to neutralize globally snakes with a single antivenom. It will only ever be regional, cobras in a region. I’m curious what you think of that. Are you actually optimistic that we could have a single universal antivenom? And what sort of evidence do you have to suggest that this could be true if so?

Glanville (01:10:57): I’ll tell the story. I would refer you to the Cell paper we published last year, which represented the culmination of the first set of work that was started from 2017. And we’d heard those kinds of conversations. In fact, when I’d spoken to some of the experts in the field at the time, they said epitopes don’t matter, there’s never going to be a broad immunity. In that paper, we’ve demonstrated a set of broadly neutralizing antibodies, a cocktail of two bNAbs and a broad small molecule was able to provide broad protection against a diversity set of World Health Organization category one and category two.

The hardest snakes. I didn’t want to pick a straw man across every continent that has that class of snakes. The neurotoxic snakes. And what it was was one bNAb that hits all the long neurotoxins, one bNAb that hits all the short neurotoxins, and then PLA2, which are the three dominant toxins found in the Elapidae. And we saw complete protection of 13 of 19 snakes and then partial protection, which is a delay to death and less death for the remaining six. That’s a proof of concept.

We know there’s two extra toxins that should be targeted to create complete universal immunity on the Elapidae, but we demonstrated already that it’s not geographically confined. It is very broad, and in fact, it’s very potent. And I’ll just point to that paper that I’m not just speaking here from an armchair. We have direct demonstration of the result that I think refutes many of those arguments that existed prior to that data. The story here started in 2017. I was already deep in universal immunity for flu, I was doing the pig work in Guatemala and that stuff.

And the World Health Organization had just announced that snakebite envenomation was a neglected tropical disease. And the reason they did that was that Sanofi had just pulled out one of their key antivenoms for Africa, where they had chosen to discontinue it in 2014. They had not really updated the world until 2016, but they’d stopped producing it. And because there was no communication, they were stuck with a gap where suddenly a lot of areas had no antivenom, no medical recourse. And the nature of the field, as you’d mentioned, was tough.

There are 650 species of snake around the world that are of medical concern. There are about 35 different products that either treat a single snake or a couple snakes in a certain region. And those products are made from horse serum or sheep serum. They’re basically antiserum where they inject a horse over and over again with the venom from a particular cobra or whatnot. Then they take the serum from that horse that has some antibodies. And then, really, this is 130-year-old technology that really hasn’t changed that much.

Their big innovation was to chop the antibodies in half and create F(ab′)2. And the purpose of that was that the horse serum might neutralize the venom, but it’s also horribly immunoreactive, where you get risk of anaphylaxis and serum sickness and some other problems. And they ameliorate that by chopping off the Fc so it doesn’t decorate all your Fc receptors. But it also shortens the half-life to a couple hours. They have to keep administering vials every few hours. Partially because of the short half-life, and partially because most of the serum from a horse is not against the venom, even though you’ve immunized it.

It’s mostly against other stuff, like some bacteria in the grass or whatnot. And it’s not particularly potent. And when you add in multiple species from a region, you’re basically dividing that vial across those different species, which also reduces the potency.

McCarty (01:14:24): I’ve heard that some patients get 10, 20 vials. It might be like 80 bucks a vial, and they need 10, 20 of them.

Glanville (01:14:31): In the United States, it could be $2,500 to $5,000 a vial, and people could spend half a million dollars on a snake bite or the insurers. But yeah, 10, 20 vials is not unusual because they administer them every two hours because of the short half-life. Also, because they’re titrating in how much to give because they’re not certain. That’s the state of the art.

McCarty (01:14:52): For context, this kills hundreds of thousands of people a year.

Glanville (01:14:55): Yeah, there’s 140,000 people roughly that die every year, but there’s an additional 300,000 to 400,000 that have a permanent disability. And most of those are subsistence agriculturalists and rural people in low- and middle-income countries. And it sucks if your whole family is working to make ends meet and suddenly dad doesn’t have a leg, right? And it’s a level of impact that is, first off, much higher than most people think, because we don’t have that many snake bites in the United States.

And they’re really largely restricted to a couple types of vipers, the rattlesnakes, essentially. There’s about 5 million bites a year. It’s a lot more than most people think. Epicenters in India, Asia, Africa, after that, South America. And it’s disproportionately under-affecting the high-income countries. There’s not that many bites in the US or Australia or Europe. And it becomes neglected. It’s also neglected because if you unified it, it’s about a $500 million a year market, but it’s split, fractured across 35 products. And that makes it very economically undesirable, which is why Sanofi pulled out.

They’re like, why the hell are we making this? We’re not making any money on it, right? That’s the field. The World Health Organization tries to shine some light on it. I was reading about it and I’m just interested in the developing world because I grew up in a Tz’utujil village and we were about four hours away from the proper hospital. I had very bad asthma when I was a kid. I was familiar with the unique needs and deficits of not having hospitals nearby and how you kind of make ends meet and how, for a lot of the world—for a large proportion of the human experience—what you have nearby is not a hospital.

You have a pharmacy, which is really just a store in the front of someone’s shop that has some shelves of some medicines that don’t require cold chain. And you need to have a product that fits that. And what I really got interested in was I was looking at it and I’m like, “Hold on a second. Nature’s lazy.” Yeah, there’s 650 species of snake, but I’m willing to bet dollars to donuts that they all probably use the same limited set of classes of toxin protein folds.

And that, much like flu that I’ve been studying obsessively, I bet that they have a core active site, if it’s an enzyme or a core binding site, if it’s not, that has remained conserved because the hosts are not mutating. And furthermore, there’s not really enough selection pressure from predation to affect mutation in most cases, unless you’re predating to extinction. And the snakes have diverse food sources. Many snakes eat frogs and birds and mammals, mice. It’s probably hitting conserved sites on the hosts also because the venom needs to be generalizable.

And I think these selection forces mean there’s going to be conserved sites and broadly neutralizing antibodies should target them. And I looked around and I pulled down these big databases. And sure enough, when I just clustered all the toxins, UniProt has a toxin database for snakes. They clustered into a limited set of clusters. And when I looked at them, they recapitulated some very nice studies of people who’d already gone into categorizing the classes of toxins. And sure enough, there are about 10 major protein folds of toxins, and not all of them were equal.

Some of them are critical for morbidity and mortality, they’re going to kill you or mess you up. And some of them probably only matter if you’re a mouse. And I looked at this and I was like, you know what? I bet you could probably make something with less than nine antibodies that would create a universal antivenom if you could have a bNAb against each one of these things. My challenge was I felt that it also had to be human antibodies. Because if it was sheep or horse antibodies, then that’s the other half of this problem: you’re giving something that has so many side effects that you have to bring that person and give them an IV rather than a subcutaneous injection.

Because you also need to administer norepinephrine or steroids or something to limit the side effects. Where human antibodies, my little boy takes Dupixent. It’s a monoclonal antibody that’s fully human. It’s just injected and there’s no side effects. Your body just thinks it’s one of its own antibodies. If you can make a product like that, it could be out in the field. It could be lyophilized. It doesn’t need cold chain anymore. It could be a treatment that could be much closer to what actually matters, which is a farmer gets bit and they can go in and give them something without taking them for four or five hours where they’re being damaged the entire time.

I wanted human antibodies. And I started initially calling up vivariums, like in Costa Rica and the United States and Australia. And I was trying to find a clumsy snake bite researcher that had been bit a couple times, although recognizing that was going to have a problem that that person would likely have antibodies mostly against just the species that bit them, just like the horses do, right? Just like flu. And then while I was Googling around and kind of coming up empty, I started finding these stories about this guy named Tim Friede, who for a period of 17 years and nine months had been self-immunizing with escalating doses of cobras and taipans and black mambas and kraits and Western diamondbacks and Mojaves, and this set of 19 species of ultra-lethal snakes from around the world.

And because he had been rotating between the species and been doing it for hundreds of times for years, I felt that his unique immune history would have broken through the thing that normally causes you to go strain-specific. And I reached out and I managed to contact him. And I said, “Look, I know this is awkward, but I would love to get my hands on some of your blood.” And his response was not surprised at all. He’s like, “I’ve been waiting for this call for a long time.” And we spent four months setting up: how do you do this ethically, right?

What’s an ethical way to be able to do a study with this guy’s blood that doesn’t expose him to any extra risk? Because it can’t be like, “Oh, here, I want you to go take these venoms and then we’ll take your blood.” And what we settled on was called a noninterventional study design, which is the same study design that people do when they’re looking at HIV resistance among sex workers, where you don’t give them any instruction for any activity that could give them increased risk, which is to say, not instruct on venom.

We just send them a package telling you, “Hey, venom is very dangerous for humans. You should consider stopping doing this.” And we just say, “We’re going to take blood from you 28 days apart and don’t change anything about your schedule. We’re not asking you to change anything about your schedule. We’re just taking two blood draws,” which is all I needed. And we set that up. We took the blood draws. And then I was using technologies that I had developed for antibody discovery.

And we used them on his hyperimmune B cells. And it was just phage display at the time. We now use some additional technologies. And we started identifying these broadly neutralizing antibodies, right? We started identifying one that hit all the neurotoxins from all snakes that have neurotoxin and long neurotoxin and neutralized it. That was the proof that you could make a universal antivenom. And since then, we’ve been building more and more of those in. And we published a paper that showed the first two.

Since then, we’ve recovered antibodies against all the major remaining toxins, although there’s a couple we still like to have more broad than the one that we currently have. And we’re continuing to do screening.

McCarty (01:21:48): But is this the same as flu, where the antibodies that his body was eliciting were mainly binding regions you don’t want? Were these mostly underrepresented B cells that were making the broad-spectrum antibodies?

Glanville (01:22:01): I think initially, he probably did, right? The first time he got a shot, he was making random antibodies that just by the math I described for flu were mostly hitting whatever, king cobra–specific or whatever he was immunized with for the specific time. But then what his method was, he kept rotating species. And if you imagine his initial immune response, 99% of the B cells were against strain-specific sites, but 1% was broad. But then he changes species. The first couple times he does this, it’s just going to be like the thing I described with flu, where you’re going to overfit.

You’re going to find new antibodies and overfit, and new antibodies and overfit. But in those studies, they tried three immunizations. This guy had done 654 immunizations rotating over and over and over again. And I felt like that pattern of consistent repeat cycling—eventually, what’s going to happen is you’re going to find broad cells that recognize a broad site. And whereas your individual cells maybe get boosted once every 16 times or 19 times, the broad ones are going to get boosted 19 times.

You’re going to get more boosting for the cells that have more breadth if you do this over and over again for long enough. And that was why I hypothesized that he probably had broadly neutralizing antibodies, and that turned out to be correct.

Antivenom cocktails

McCarty (01:23:09): And the antivenom that you made, it’s like you said, it has these two human antibodies, against long and short toxins. Then it has a small molecule called varespladib. Why do you need this small molecule in your antivenom? Why can’t we just recapitulate all the functions and behaviors that you want in terms of eliciting the immune response purely using antibodies?

Glanville (01:23:32): I completely agree, and that’s what we’re doing. For the first paper, we had two bNAbs, and our PLA2 antibody wasn’t really as good as we’d like. We chose to put in varespladib as a surrogate because the top three toxins in the neurotoxic snakes are long neurotoxin, short neurotoxin, and PLA2. And we demonstrated that a three-member cocktail addressed what you brought up in the beginning: people saying you’ll never get out of region specific, and we disproved that with that demonstration. We have since replaced that.

We have an ultra-broad antibody against cytotoxins. We have SVSP antibody and SVMP antibody. PLA2 antibodies—there’s a couple of them that are broad. We’d still like to find a broader one. We’re continuing to look. And we’ve shifted from phage display, which we’ve used quite a bit. We took additional blood samples from Tim. He retired from self-envenoming in 2018, but his titers remain crazy high. And we took blood samples from him and we used single-cell sequencing. We had a way of isolating out his single cells that were reactive to toxins, with which 25% of his IgG B cells were venom-specific, which is crazy.

A quarter of his entire immunity is snake-dedicated after his adventures in antivenom self-immunization. And we’ve taken those single cells and we found some really exciting new antibodies from that set. We’re finalizing our cocktail. We’re also combining them into multispecifics. Rather than having, let’s say it’s seven different unique antibodies, instead we combine three antibodies into a single scaffold. And that simplifies manufacture and increases the potency. And we’re doing that work. We’re actively talking to a major pharmaceutical partner that’s potentially going to partner with us to go bring this out to the world. And those discussions are ongoing now.

McCarty (01:25:23): Well, Jake, I’m extremely grateful for the conversation. And I hope people watching this like it, and it motivates them to think about, “What are the biggest possible things I could do in my field?”

Glanville (01:25:34): Part of the reason I got into this whole thing was I grew up in Santiago Atitlán, which is a Tz’utujil Mayan village where my parents had a hotel and restaurant in Guatemala. And ever since I was a kid, since I was 11 years old, I could stare all the way across the outdoor market and see my family. And in my ignorance, I just felt that Tz’utujil were short. That was what I thought. That’s what everyone thought. And when the Civil War ended in 1996, I had gone to the States in 1997 to do my last year of high school and go to college.

And I didn’t come back for almost two years. And I came back and I remember walking through the village with my brother. And I remember there’s this old 500-year-old church. And down below it, down some steps, there’s a basketball court. And we saw these kids playing basketball. And I remember looking over and being like, “Who are those kids?” And then they turned around and unmistakably, they were Tz’utujil. And I remember being like, “What? Those guys are so tall.” And we started noticing the other young kids or young teenagers in the village were much taller than we’d seen before.

And I was wondering what was going on. And it turned out at the end of the Civil War, NAFTA and some other things had changed, and they started having better medical support in the village. They started handing out deworming medicine in the schools and giving vaccines. And there was a Hospitalito Atitlán that was established that handed out antibiotics and other treatments. And it turned out, on one hand, it was humiliating because what I had interpreted as genetics was actually this hidden force of suppressing the human condition, and that simple medicines could repair that.

And it wasn’t like these kids were just getting taller. They were paying more attention in school, they were getting better educated. And it made me wonder what else am I taking for granted that is actually this hidden force of oppression of pathogens? And I looked around and I realized there’s so much. We put up with a global pandemic that happens annually, two times a year, and we call it flu season. And we shouldn’t have to. I think we can build tools to create a world that maybe takes that microcosm of my village and manifests it globally.

And imagine a future of the 21st century for us and for our children and for the rest of humanity where there’s less of this constant burden that’s holding us back. And that’s what got me into the problem in the first place.

McCarty (01:27:47): I think even if Centivax fails for whatever reason, at least you’re working on the biggest possible problems that you could work on. And yeah, thank you so much for the conversation.

Glanville (01:28:00): I appreciate that. I will say that we’re currently not anticipating failing.

McCarty (01:28:05): Okay, good.

Glanville (01:28:07): But yeah, thank you for having a conversation with us. This is great.