“A post-pathogen humanity.” This is what biotech company Centivax is working towards by developing broad-spectrum vaccines for a variety of infectious diseases – including influenza.
The genesis of Centivax dates back to around 2012, when Jacob Glanville was building a previous company called Distributed Bio, which was using computational immunology to identify new therapeutic antibodies to target specific protein sites. However, the tools the company was developing also provided better insights into immune systems – such as the induction of autoimmunity and the failure of vaccines for quickly mutating viruses.
“At that point, I realized that I had invented a vaccine technology and I worked to develop it further,” says Glanville. “It was the beginning of a golden age of biotechnology. We had access to high-throughput genomic sequencers that we could point at the immune system to look at tens of millions of antibodies and T cell receptors. High-throughput synthesis technologies also allowed us to use DNA synthesis to build antibody libraries of thousands of human immune systems, which could be interrogated in vitro. This work gave rise to some new ideas around the conserved sites that exist in otherwise mutating viruses, and why our immune systems so often miss these sites. If we can get the immune system to focus exactly on these conserved sites, we can create universal vaccines.”
Glanville spent years developing the technology in Guatemala – where he grew up and where he is also an affiliate professor at the University of San Carlos. Distributed Bio was performing well as a business and profits allowed the technology to develop, until it was eventually noticed by the Bill & Melinda Gates Foundation.
“We were selected for a Millennium Grand Challenge: End the Pandemic Threat award,” says Glanville. “A lot of science that gets funded is iterative rather than disruptive, and there will always be reviewers who don’t agree with a new idea. The funding from the Bill & Melinda Gates Foundation was a huge breakthrough and allowed us to conduct studies in the US with key collaborators. But let’s not fool ourselves – this is only the beginning and we have a lot of work to do!”
On December 31, 2020, the Distributed Bio services business was sold to Charles River laboratories – on the condition that Glanville could spin out the universal vaccine technology. “Many of the Centivax co-founders have known each other since 2008, so we’ve pulled a dream team together to execute this,” says Glanville.
The company’s portfolio includes “universal” vaccines and antibodies against rapidly mutating viruses – as well as bacteria. However, Glanville explains that “universal” is not quite the correct term. “The term ‘universal’ when applied to vaccines is a buzzword; a more accurate description is ‘broad-spectrum.’ Unlike current flu vaccines and current COVID-19 vaccines, our vaccine should produce antibody responses against non-mutating sites and therefore will have a broad spectrum effect against the majority of viruses that could occur in the future. But biology is complex and eventually it will defeat you. Universal implies that the vaccine won’t ever require modification, but I don’t have the data right now to say if that will be the case or not. It may be that the vaccines still need modifying, but it should be far less frequent than current approaches – vaccines updated perhaps a few times per century, instead of the current practice of updating the vaccines every single year.”
Hitting the right target
The idea of a universal – or broad-spectrum – flu vaccine has been discussed amongst researchers for years. Despite numerous early-stage projects, there has been no true breakthrough. According to Nick Bayless, Chief Technology Officer of Centivax, influenza belongs to a club of viruses that have the same challenging hallmark: rapid mutation. “This isn’t true of all viruses, but HIV, influenza, and the coronavirus mutate very rapidly as a survival strategy to avoid the immune response,” says Bayless. “There are many different mechanisms involved in how each virus does this, but essentially they change the parts on the virus that are recognized by antibodies, which means that the immune system is unable to prevent the next infection after the virus has mutated.”
But even viruses that mutate rapidly are bound by certain goal-based constraints; for example, the influenza virus has to enter human lung cells and the HIV virus must enter human T cells at a certain efficiency. The viruses attack their target cell by precisely docking onto a receptor on that cell, much like a rocket must precisely dock with the airlock on the ISS to deliver astronauts. Ultimately, this creates bottlenecks in viral evolution; the virus cannot mutate the “airlock” or it is unable to dock and is therefore no longer infectious. This conserved docking site creates a conserved and vulnerable patch that antibodies can attack and prevent all viruses from docking.
“However, these rare, conserved epitopes are outnumbered by all the epitopes on the rest of the viral surface that can mutate – and a typical antibody response will go after the parts of the virus that is changing year to year,” says Bayless. “Our technology targets these areas because we know these viruses cannot infect cells without them.”
Glanville adds, “The first time that someone described a broadly neutralizing antibody hitting a conserved site on flu was back in 1993. More papers were published in the 2000s and this started a race for a ‘universal’ vaccine, but everyone was flying blind because the tools for interrogating the immune system weren’t good enough; it’s only in the past ten years or so that we’ve really seen a revolution in high-throughput sequencing and DNA synthesis technologies.”
In other words, scientists were trying to fix an engine when they couldn’t lift the hood. Glanville also points out that there has been a lot of attention directed at why our immune system don’t target the conserved sites of viruses over the last decade. “Computational biology allowed me to understand more about what is going wrong – and how we can fix it.”
Diluting for strength
Centivax’s technology is state of the art, but Glanville has a simple way to describe it. The company takes 10 representative versions of influenza vaccine, dating all the way back to 1918. “These strains are all very different to one another, but there are some conserved sites – as Nick explained – that have not changed. We take these strains, mix them together, and dilute the mixture. There is not enough of any of the ten individual strains to produce an immune response – but there is a large enough dose of the shared site, because all ten components share that exact site.”
So far, Centivax has tested its approach in animals – and they, as well as laboratories at the University of Georgia and Auburn University, have observed it providing protection for up to twelve years of future evolution of the viruses. And critically, the approach was able to neutralize future variants of the virus that didn’t exist when the study began. “Now, we’re preparing to run in vivo studies for validation of our delivery of our vaccine using LNP mRNAs, and then we can enter manufacturing,” says Davis Tsao, Chief Operating Officer and co-founder. “Initially, we were planning to commence manufacturing earlier this year, but we’ve decided to hold our fire because there is the possibility that our approach will be compatible with the mRNA lipid nanoparticle systems that have been used in COVID-19 vaccines.”
“The advantage for us is that those systems are much faster to manufacture, are less expensive, and have a built-in ability to stimulate the immune system,” explains Glanville. “And they have been de-risked significantly over the last two years. There are advantages and disadvantages to every delivery platform, but we’re excited by the mRNA studies we have ongoing. If we go the mRNA route, it could speed things up getting our vaccine into clinical studies.”
Centivax’s most advanced program is its flu vaccine, but the company is also working on a broad-spectrum coronavirus vaccine and is starting to apply its technology to HIV (both vaccines are currently in animal testing). Another area the company is interested in is a side effect of some mRNA COVID-19 vaccines: myocarditis – and whether it is possible to engineer delivery systems to avoid the side effect. “We should always make the delivered medicine as safe as possible,” says Glanville.
Movie Stars and Spreading Positive Vaccine Messaging
In January 2020, Netflix aired the documentary series Pandemic: How to Prevent an Outbreak. The series focused on a number of different public health topics, including influenza, Ebola, and vaccine research. And the timing was eerie – just as COVID-19 was just beginning to ramp up in certain parts of the world.
“We allowed the film crew to follow us around in 2019,” says Glanville. “But I didn't know where it was going to end up to and I didn’t know whether we would get the Gates funding at the time.”
One of the reasons that Glanville agreed to the filming was because of the misinformation and unnecessary scepticism that exists around vaccines globally. “I felt that if people watched us working our asses off to make better vaccines, they might recognize that people are investing their lives into this – all for the purpose of making lives better for others. And this realization might make people feel more comfortable about vaccines. It’s a small world. And it’s a very populated one. We are going to see more pandemics and outbreaks. Vaccine technologies are necessary more than ever. People need to see how hard we are working on this. We won’t reach everybody, but I think we can change some hearts and minds if we are more transparent in biotechnology and learn to communicate more effectively with the public.”
Here’s what other experts at Centivax have to say on the topic of vaccines and the public:
Stephanie Wisner, Chief Business Officer: “Jake was a thought leader on vaccines during the pandemic and appeared on multiple news channels. It is so important to communicate science in a way that is accessible to people and to give them the facts that they can engage with. I think scientists sometimes find it very difficult to communicate in language that makes sense to a layman who is not familiar with the terminology. Our industry as a whole needs to get better at this.”
David Tsao, Chief Operating Officer: “In pandemic situations, epidemiologists often try to oversimplify – sometimes because they just want people to do something, like take a vaccine shot, but this ultimately leads to distrust. There will always be people out there saying crazy things and we can’t win them all, but if we stick to the facts and make information as accessible as possible – jargon-free, and so on – then people can make informed decisions. We also can’t pretend that everything is completely safe. There are side effects, but they are rare – and we shouldn’t hide that.”
Nick Bayless, Chief Technology officer: “The current flu shot is only around 30-60 percent effective. It’s better than nothing, but you can see how this can lead people to be sceptical about the efficacy of vaccines. I think one of the best things that immunologists can do is to produce better vaccines that are more effective at preventing disease. But there are a lot of people out there who don’t think the current flu shot is worth it.”
Sawsan Youssef, Chief Science Officer: “During the pandemic, everyone was very exposed to social media and there were a lot of anti-vax messages. A lot of friends and family were asking us many questions – and we were then able to spread positive information. Before the pandemic, these people would never normally ask questions like this! I think the general public is now far more aware of vaccines and viruses – and it has helped information be transmitted in a far more positive way.”
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