[Part I of II]
Growing up in Tźutujil village in Santiago Atitlán, Guatemala, to parents who ran a successful hotel and restaurant business, Jacob Glanville, PhD, was infected so frequently with amoebas, giardia, worms, and other common pathogens that he has lost count. Moving to the United States at age 16, Glanville was first struck by how most people were much taller and took for granted their comparative good health compared to the developing world.
Returning to Santiago Atitlán for four years of vaccine studies, Glanville saw how much medicine had improved since Guatemala’s 36-year Civil War ended in 1996. Tźutujil teenagers were a head taller than their parents and older siblings. Villagers could finally spend time and resources once spent on illnesses toward bettering themselves, their families, and their communities.
“These observations have left me with the conviction that pathogen burden, from the microcosm of a single child to the macrocosm of all humanity, is an avoidable waste of human potential,” Glanville is quoted as saying on the website of the vaccine developer he founded in 2021, Centivax.
Based in South San Francisco, CA, Centivax recently raised $10 million in seed financing co-led by investment firm NFX and the Global Health Investment Corp. (GHIC), a nonprofit that aims to accelerate the development of technologies that improve global public health and health equity, while generating sustainable financial returns.
The seed financing is intended to launch manufacturing of Centivax’s lead broad-spectrum vaccine program in influenza for first-in-human clinical trials, having completed preclinical studies in models of ferrets and pigs. Proceeds will also help continue the development of the broad-spectrum vaccine platform technology in COVID-19, HIV, and other critical areas of unmet global health need.
“A universal vaccine has the potential to eradicate these diseases forever,” Omri Amirav-Drory, PhD, general partner at NFX, predicted. “[COVID-19] continues to mutate to overcome our vaccine efforts, leading to a game of whack-a-mole where we’re constantly surveilling for new strains, and quickly developing new vaccine formulas to fight them. This same fight is playing out across many infectious diseases including the seasonal flu, HIV, and others.”
The potential broad applicability of Centivax’s platform and the experience of Glanville and his team are two other reasons cited by Amirav-Drory for NFX’s co-leading the seed financing.
Rounding out Centivax’s pathogens of high priority are malaria and Staphylococcus aureus—a total of five pathogens accounting for more than 1.76 billion cases/year and more than 6.1 million deaths/year.
The company has also disclosed a dozen other pathogens of medium priority: syphilis, hepatitis C, norovirus, rhinovirus, Chagas, gonorrhea, Ebola, trypanosomes, cytomegalovirus (CMV), lymes, West Nile, and herpes. Together the 12 account for about 2.335 billion cases/year and more than 800,000 deaths/year.
“These are all high-frequency pathogens that have high morbidity and mortality,” Glanville, Centivax’s CEO and president, told GEN Edge.
Glanville, a serial entrepreneur and computational immuno-engineer, founded his first company in 2012—Distributed Bio, a biologics discovery contract research organization that he sold to Charles River Laboratories for up-to-$104 million in 2020. That year, Distributed Bio and Glanville gained a measure of notoriety in the first season of Netflix’s “Pandemic: How to Prevent an Outbreak,” which focused on efforts by doctors, researchers, healthcare workers, and public health officials to fight influenza and future global pandemics.
As part of the deal with Charles River, Glanville spun out from Distributed various assets in COVID-19 therapeutics, broad-spectrum vaccines, anti-venom antibodies, anti-wound pathogen antibodies, anti-CXCR5 autoimmunity therapeutics, and blood-brain barrier translation technologies into Centivax. The broad-spectrum vaccine technology was awarded a Gates Foundation Grand Challenge “End the Pandemic Threat” grant in 2019.
In an exclusive interview with GEN Edge, Glanville discussed Centivax’s effort to develop broad-spectrum vaccines for mutating viruses, the promise of the technology, and the challenges the company has encountered developing it. (This interview has been lightly edited for length and clarity; Part II can be read here.).
GEN Edge: Centivax was launched nearly two years ago in January 2021, with the goal of developing broad-spectrum vaccines and therapeutics. How and why did you launch the company and what progress has it made since then?
Jacob Glanville: The genesis of the broad-spectrum vaccine technology dates back to 2012. I developed it initially with the resources of my previous company, Distributed Bio. We won a Gates Foundation Grand Challenge in the Pandemic Threat award, which enabled us to run live, challenge studies in pigs and in ferrets here in the United States. Prior to that, I built an animal facility in Guatemala to do the initial rounds of testing.
When we launched Centivax, the technology already had six years of animal studies behind it. We’ve been able to advance pretty quickly since then. We were working on antibody therapeutic programs focused on broadly neutralizing antibodies, both for vaccines and for antibodies. But data was coming in from these live challenge results that made it clear to us that this was the single, most valuable thing we’d created and that it would have the biggest impact and drive the most value.
We’ve gone all in on the broad-spectrum vaccine technology. Since the founding, we’ve gotten live challenge data back from two different animal models, ferrets and pigs. We’ve also studied mice, where we can give our vaccine, which is formulated with components only up to [the year] 2007, and then the animals are producing live challenge protection—sprayed in the face with virus and protected from infection 10 years into the future, including the past pandemic H1N1 2009 pandemic shift, swine flu strain. Then, we also can test their serum for microneutralization and hemagglutination inhibition assays, and that goes out 13 years into the future.
The breakthrough is that we’ve overcome a central problem of vaccine science. Vaccines are one of the greatest medical advances since sanitation and fire. In 1980, vaccines successfully eradicated smallpox, the pathogen that killed Pharaoh Ramesses V, but they struggle against mutating pathogens. That’s what we focus on—vaccines that selectively elicit broadly neutralizing antibodies against conserved sites.
GEN Edge: What do you consider the challenges of developing vaccines against mutating viruses? Is it primarily the speed of mutation or are there other considerations?
Glanville: There are a couple of layers to this. The core problem is that the pathogens are constantly mutating. Some mutate slower than others, and vaccines have done a remarkable job against the slow mutating viruses. The problem has been the ones that mutate faster, like flu. It mutates fast enough that we have to make a new vaccine every year in the Northern Hemisphere, and one in the Southern Hemisphere. We have to keep changing the formulation to update it, and it’s still not very effective. We’re talking 40% to 60% efficacy. In some years, we’ve missed, and it was 10% efficacy, because we have to forecast what the virus might be like more than six months in the future.
That’s half of the problem. The rest is what you’re injected with—we see that same problem with the coronavirus. We’ve seen deteriorating efficacy of the vaccines over the course of the pandemic, until now when they’re updated with a bivalent shot. We’re probably in that same Sisyphean regimen with coronavirus as well. For a long time, people thought, “Oh well, there’s nothing we can do about it.”
Then came really exciting studies in 2000, 2004, and 2006, where people began reporting on crystals of antibodies binding broadly neutralizing epitopes. These were antibodies that bound conserved sites on the surface of influenza and HIV. It turned out that the virus couldn’t mutate anywhere. There were certain conserved sites that if they mutated, that site was no longer able to infect and propagate. If you could get an antibody against that site, you would enjoy this ultra-broad protection. That was incredibly exciting because it opened up the prospect of broad-spectrum or even universal vaccines.
GEN Edge: How hard is it for the immune system to target those conserved sites?
Glanville: It’s very difficult. People have tried doing this since the early 2000s. For the first decade, they were operating in a black box, because we did not yet have the modern high throughput immune interrogation tools that started emerging in 2008 and 2009. I was one of the early pioneers in using deep sequencing to analyze antibodies, repertoire and single-cell sequencing, and high throughput phenotypic screening.
In addition to how do you get the immune system to focus on those sites and not hit other sites, is that fundamentally there’s an immunodominance of non-conserved epitopes. Most of your antibodies are against sites that easily mutate, and the virus exploits that to escape. How do you get the immune system to focus on the conserved sites?
The second problem is that the immune system is lazy. Once you develop immunity against a given antigen, it tends to re-evoke the immune memory, even if it’s not well suited. It will tinker with existing memory rather than provoke new naive antibodies. This is called immune imprinting or original antigenic sin. You’re kind of trapped on early immune exposures, which is very annoying because if you’ve already overfit in the past, you’re stuck constantly re-tinkering. If you’ve missed the conserved sites, it creates an additional barrier to get your body to discover new antibodies against those conserved sites, because your immune system has lots of immune memory cells. They’ve proliferated, they’ve colonized all over your secondary lymphoid organs, and they activate more easily. So, they bully the new, better antibody—like, get out of the way we got this! You have to overcome that challenge as well.
There is also a third challenge: As people get older, they undergo immune aging or immunosenescence. The cells are a little harder. You’ve got to give them an extra kick to get them to activate and do useful things. And that person’s got more imprinting because they’ve been exposed to viruses for a longer period of time. All of these things work against people.
I think the biggest thing, though, is that there was a theoretical problem in understanding: why do we miss? Why is it that the conserved site is not immunodominant? Our breakthrough was using computational immunology to better understand the underlying mechanisms, and that enabled us to build our technology to address the problem.
GEN Edge: How is that overcome? The immune system needs some sort of new learning to overcome the imprinting that you mentioned.
Glanville: I built this technology right in the emerging golden age of computational and systems immunology. I had the tools to begin deep sequencing the immune system, to ask questions like how many antibodies are actually elicited after a vaccination? I published about 35 papers in this area, and the answer is, it’s less than we think.
From the work I did, and work by others, we know that after you’re vaccinated, you produce about 1,000 unique B cell lineages that wake up and respond, from naive or from your memory compartment. Of those, only about 10% are provoked to produce a serologically protective antibody. They convert to plasma cells. The punchline is, you get a shot. About 100 unique antibodies are emerging with subtle mutations…You have 100 shots on goal.
My second question was, how many epitopes are there on a hemagglutinin? I felt that people had radically underestimated the number of epitopes, so we ran large-scale, saturated protein-protein docketing experiments on the Amazon cloud to learn what’s the total, unique number of all possible ways antibodies could bind hemagglutinin? And we came up with a number that’s a little above 200 million—so there’s a huge number of epitopes.
Then, I looked at them and said, Okay, what’s the percentage that is conserved? If it’s one in 10, you should be hitting them every time. It turned out the conserved epitopes were less than 1%. The good ones are less than one in 100,000. That explained why most people miss—if you just randomly pick epitopes, you’re mostly going to pick things that shed. The right answer is there, but it’s hidden in this ocean of nonsense. With these studies, we’re able to find subjects that have those useful antibodies. But most of us aren’t making them.
That also provided guidance where there are a number of technologies that would never work because they weren’t sufficiently narrowing the scope to the conserved sites.
GEN Edge: How did you address that?
Glanville: We basically said, look, there’s no such thing as a perfect antigen. There are too many wrong answers. Instead, we exploited a pretty obvious phenomenon. There’s a minimum dose where a vaccine is no longer useful, right? If I take a vaccine, and I give you half of it, then a fourth, and an eighth or tenth, or a hundredth, at a certain point there’s not enough vaccine for your immune system to respond to.
We picked eight components from 1918 up to modern times. We mixed them so each one was below the threshold of activation. There’s not enough protein of a particular strain, like 1918, for the immune system to respond to, except that all eight of those spanning 100 years all share a certain site. So, a B cell that recognizes that site gets eight times the dose. Through that mechanism, we’re only dosing B cells that recognize the conserved site.
We’re able to weave past the bullies, we’re able to weave past imprinting, and we’re able to selectively list 100 antibodies that are all hitting conserved sites. That’s our technology platform.
GEN Edge: How does Centivax distinguish between broad-spectrum and universal vaccines?
Glanville: I think broad-spectrum is more medically and scientifically accurate. I think that’s what we’re accomplishing. I think universal is a buzzword, and it does imply that you have a single drug that would solve all binders. I think that you’re always going to have someone who’s either immunocompromised so they don’t respond, or there’s going to be some weird new virus that pops out of a guinea pig or something.
I think there’s not actually a human need to create universal. Humans get infected by H1s, H3s, and HABs, and really only H1s and H3s cause pandemics, and most of the morbidity and mortality that kill people and get them really sick. We occasionally get infected with these exotic subtypes like H5N1s. But they typically don’t propagate very well in humans at all.
Our objective with our vaccine is to address the human problem of the five pandemics of the last century—pandemic influenza as well as seasonal influenza—by targeting H1, H3, HAB. We know we also have some crossing out to the exotic subtypes, but that’s not a focus of our technology. For that reason, we call it broad-spectrum.
GEN Edge: Is the broad-spectrum vaccine program one program or three separate ones that target flu, COVID-19, and HIV?
Glanville: There’s no single antibody that could address all of those viruses. It’s possible you could choose to combine them into a cocktail. But your antibodies would separately be targeting influenza or targeting coronavirus, but not both. That’s another reason I don’t like the word universal—sometimes people think, “Oh, maybe one vaccine for all viruses.” I just consider that radically impossible.
So, that’s the way we approach the problem. The targets are different in each vaccine. It’s basically a broad-spectrum vaccine for influenza, a broad-spectrum vaccine for coronavirus, and a broad-spectrum vaccine for HIV in the future. We’re interested in malaria, and there are several other pathogens that our platform would be efficient at targeting.
For coronavirus, we can target SARS-CoV-2 and SARS-CoV-1 in the same cocktail and any new coronaviruses, provided that they use ACE2 as their entry to the cell.
GEN Edge: What effect have the variants of recent years had on Centivax’s COVID-19 program?
Glanville: For influenza and HIV, it was kind of easy for our technology because there are these massive databases. We have data back to 1918 for flu. They dug up infected people out of ice, and they found the sequences of the 1918 Spanish flu pandemic. For HIV, it just mutates so quickly that we have these massive databases of variants. That’s perfect for our technology because we can mine those databases to find a constellation of diverse components that we know fold up because they were pulled up from infections.
Coronavirus was tougher because at the outset of the pandemic we didn’t have that much information. We just had CoV-1 and CoV-2, and they’re pretty different from each other. What my technology needs are lots of diverse and evenly spaced diverse members. We kind of had to wait for the first year and a half in order to be able to apply our technology to the coronavirus. That said, we have a method of displaying libraries of millions of synthetic variants of a coronavirus on mammalian cells. So, we can select for future mutants, using this method.
My strategy was to wait a bit until we had some more data. The whole world has been prospecting on variants that emerge in people. But also, they were trying to look for an animal origin, and so they’d be pulled-up variant coronaviruses that still bind to the ACE2 [receptors] that were found in other nonhuman species, and those ones serve my purpose of being diversified by nature. So now we have enough diversity to execute the technology.