Originally published in MedNous
This success has also galvanised the biopharmaceutical industry to increase research into more, and possibly even better types of RNA as a basis for new vaccines and therapies. This is the hope of researchers at Imperial College London, UK, who founded two companies in 2020 to investigate the development of a technology called self-amplifying RNA. At the time of the founding, there was no clear leader in the global race to produce a Covid-19 vaccine. VacEquity Global Health was created to develop a new vaccine, while VaxEquity, the second company, was to oversee the long-term development of self-amplifying RNA. The scientists conducted a Phase 1 study of a candidate self-amplifying RNA vaccine, delivered in a lipid nanoparticle, which showed the product was safe but didn’t meet the required efficacy threshold. VacEquity Global Health was shut down but VaxEquity was kept alive and charged with carrying out a longer-term strategy for self-amplifying RNA.
VaxEquity’s co-founder, Robin Shattock, a professor of immunology and infectious diseases at Imperial, together with Michael Watson, the company’s chief executive, set the new course. They were assisted by co-founder Morningside Ventures, a life science investor. Dr Watson is a physician with more than two decades of vaccine R&D experience. In 2020 he worked as a consultant to Moderna Inc, helping that company develop its mRNA vaccine for Covid-19.
In an interview, Dr Watson said his new job at VaxEquity is to push the research agenda forward, potentially into new RNA constructs and applications. “It’s an unusual situation to be in, effectively a start-up [company] that already has clinical data,” he commented. Not long after the Phase 1 trial completed, VaxEquity started to work on fixes to its vaccine candidate. This led to an overture from AstraZeneca Plc which had expressed an interest in the project. On 23 September 2021, AstraZeneca announced an equity investment, together with Morningside Ventures, in VaxEquity. The size of the investment wasn’t disclosed but it was part of a research and development deal between AstraZeneca and VaxEquity that involves using the self amplifying RNA platform to start projects against up to 26 drug targets. The milestone payments could potentially reach $195 million per programme.
Proponents of self-amplifying RNA say the technology has the potential to express proteins for longer, resulting in higher protein levels per dose of vaccine. The mRNA vaccines developed by Moderna and Pfizer-BioNTech SE are non amplifying, meaning that they only code for the antigen of interest. The self-amplifying RNA codes for the antigen of interest and makes multiple copies of itself. But there is at least one caveat: the self-amplifying RNA vaccine delivers a much bigger piece of RNA and is more easily detected by the innate immune system.
In its Phase 1 study, VaxEquity found that its vaccine candidate was well tolerated with no serious adverse events, but that seroconversion rates were lower than expected. “Seventy per cent of people who got the vaccine had an immune response but 30% did not. That was the issue really. There seemed to be a proportion that weren’t responding,” Dr Watson said.
The company therefore went back to the drawing board and worked out a strategy for improving the vaccine’s design. “We can’t modify the RNA but what we can do is also produce proteins that modulate the innate immune response. So now essentially the self-amplifying RNA is doing three things: it’s delivering replicatory machinery; it’s delivering the gene of interest; and it’s also delivering a protein which modulates the innate immune response so that a large piece of RNA can pass under the radar and get on with its job of making protein without the body shutting itself down,” the executive said. The new candidate vaccine is in preclinical development with a framework for measuring success. “We’ve got the Covid benchmark so we know what ‘better’ looks like,” he added.
VaxEquity is not the only company with an interest in self-amplifying RNA. In 2012, researchers at the Novartis Institutes for BioMedical Research in the US published the results of a study of a self-amplifying RNA vaccine specifically looking at delivery. They concluded that a vaccine delivered in a lipid nanoparticle rather than a viral vector was a promising strategy.
Arcturus Therapeutics
More recently, US-based Arcturus Therapeutics Inc reported data for two investigational self-amplifying vaccines, ARCT 154 and ARCT-165. Both are in Phase 1/2 development in the US and Singapore as primary vaccines and boosters. Preliminary immunogenicity results from the booster trial showed an “encouraging increase” in neutralising antibody titers, the company said on 16 December 2021.
Arcturus is also studying ARCT-154 in a pivotal trial in Vietnam sponsored by the Vietnamese conglomerate Vinbiocare Biotechnology. The study is set to enrol 19,400 participants and compare ARCT-154 against placebo and against the AstraZeneca Covid-19 vaccine Vaxzevria. The goal is to file for an emergency use authorisation for the vaccine in Vietnam.
According to Dr Watson, the advantages of self-amplifying RNA are clear. “The benefit of self-amplifying RNA is that you can use smaller doses to achieve the same effect [as a conventional RNA vaccine] because it continues to produce proteins for days and weeks. And that gives you a bigger area under the curve,” he said.
“Of course there are some hurdles to get over, but once we’re over those, there is a huge potential for what is essentially a digital approach to medicines. It’s delivering the code to the body and letting the body do what it does very, very well everyday which is make proteins,” the executive commented.
This article was prepared by the MedNous editor on the basis of an interview and literature search.