Broad Strokes

“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.