Back in January when scientists at the University of Queensland received funding to rapidly develop and test new vaccines, the goal was to help stop the world’s next epidemic.
Faced with the growing and urgent threat of emerging infectious diseases, the Coalition for Epidemic Preparedness (CEPI) backed the UQ team and their ‘molecular clamp’ technology to supercharge vaccine production.
“The World Health Organisation … recognises that new epidemics can arise from known and unknown viruses — the latter referred to as ‘Disease X’,” Paul Young, project co-lead and professor of virology, said at the time.
Just days later, Disease X had a name: SARS-CoV-2, and Professor Young and his team quickly got to work trying to develop a coronavirus vaccine in partnership with biotech company CSL.
The researchers’ patented-clamp — which essentially boosts a vaccine’s ability to stimulate an immune response — had shown promise in trials targeting influenza, Ebola and Middle Eastern Respiratory Syndrome.
But on Friday, following 11 months of painstaking work and promising early signs, the vaccine trial was abandoned after multiple participants returned false-positive HIV tests.
While there was no possibility that the vaccine could cause HIV infection, the decision was made to halt the trial to maintain public confidence in the vaccine process.
The decision has “devastated” the research team, Professor Young said. But he added the vaccine, while no longer being pursued for coronavirus, had elicited a robust response to the virus and had a strong safety profile.
“We’re not going to progress this particular vaccine approach… but the underlying platform should be applicable to a wide range of virus threats,” he said speaking on a conference call after the decision was made public on Friday.
So, with the threat of infectious diseases now clearer than ever, how might the technology be used to fight other pathogens in the future?
How does the molecular clamp work?
UQ’s COVID-19 vaccine is known as a subunit vaccine. These work by introducing a fragment of the virus — in the case of COVID-19, the “spike” protein — to the body.
The idea behind the subunit vaccine is that when the body recognises the protein, it creates specialised immune cells that block the receptors and effectively shut the door to infection.
But the challenge is getting the body to recognise the virus fragment as enough of a threat to create an effective immune response. And injecting the spike protein alone isn’t enough to do that.
“On its own, the SARS-CoV-2 spike protein is unstable. It needs to be ‘locked’ into shape to ensure that the vaccine is inducing the right immune response to the COVID-19 virus if someone is exposed,” Professor Young said.
“That’s achieved with a molecular clamp.”
The clamp technology, pioneered and patented by the UQ team back in 2018, uses two fragments of a protein known as glycoprotein 41 (gp41), which is found in the human immunodeficiency virus (HIV) but is not able to infect people or replicate.
On its own, gp41 is harmless. But adding it to the coronavirus spike protein helps to stabilise the key part of the virus so that the immune system can recognise it, said virologist Adam Taylor.
“There is a particular way the [spike] protein folds when it’s about to attach to the calls and start an infection … which is thought to produce a better antibody response,” said Dr Taylor of the Menzies Health Institute Queensland.
What went wrong and how it could be tweaked
Phase 1 human trials of the UQ vaccine found it successfully elicited a robust immune response.
But the data also showed those who received the vaccine produced a partial antibody response to the molecular clamp (specifically the gp41 protein) — which has the potential to interfere with HIV screening tests that look for those same antibodies. This is what led to participants’ false positive HIV test results.
Subsequent tests confirmed no HIV virus was present, and on Friday, the researchers stressed there were no adverse health implications and no possibility that the vaccine could cause HIV infection.
But the researchers, CSL and the Federal Government agreed the risk to public confidence in vaccines was too great if the UQ vaccine were to be approved in its current form.
The decision was therefore made not to progress the trial because it was not practical to redesign the vaccine in the timeframe needed for COVID-19 (it would take at least 12 months), and because there are multiple other vaccine candidates now reaching the final stages of development.
Professor Young said despite the decision not to move forward, the clinical data on safety and efficacy was a “testament to the power of the [molecular clamp] technology”.
In the future, he said researchers could either tweak the existing clamp used in this vaccine, so it did not create cross-reactive antibodies and confuse HIV tests, or develop a different clamp using an alternative to gp41.
“The intention is that we will explore additional options and that’s what we were in the phase of doing before this particular pandemic arose, and we had to progress with what we had,” he said.
The researchers knew back in January there was a remote possibility the vaccine would generate cross-reactive antibodies, but they chose to progress with the vaccine because of the urgency of the pandemic.
“The HIV [protein] was chosen because it provided the greatest stability in early studies, but we haven’t exhausted all the possibilities,” Professor Young said.
Early on, the researchers tweaked the clamp so that parts known to elicit significant antibody responses to gp41 were removed. Now, they might look at ways to reduce its antigenicity even more — in other words, try to completely hide the gp41 protein from the immune system while the spike protein is still on show.
But the more likely path, according to Professor Young, is to find “similar bundled proteins” and engineer them to achieve the same levels of stability.
Dr Taylor said those alternatives don’t have to be viral proteins per se: “It’s just whether a protein has the molecular properties desirable to hold these [spike] proteins in place.”
Technology holds promise for future epidemics
Both Professor Young and Dr Taylor agreed that the molecular clamp technology has applicability to other viruses, particularly respiratory viruses, which “operate in a similar manner in terms of their infection”.
“The benefits of this and how rapidly they’ve been able to adapt and produce the vaccine, to get it to the stage where it’s at now, shows you the promise of the technology,” Dr Taylor said.
Next-generation vaccine technologies, including UQ’s molecular clamp and the mRNA approach being used by Pfizer and Moderna, are going to be critical to addressing emerging pathogens and pandemic threats, he said.
Heidi Drummer, who leads the Disease Elimination program at the Burnet Institute, said the molecular clamp technology was highly appealing as a vaccine technology because it is scalable.
“A prerequisite for any recombinant [subunit] protein vaccine is your ability to manufacture it,” she said. “You need to be able to make hundreds of milligrams of this protein, purify it and then administer it to people.”
The clamp technology reduces the amount of antigen (the spike protein) needed for each vaccine, and enables more doses to be manufactured more rapidly.
“It’s a very useful technology for expressing otherwise difficult to express proteins at a very high level, and that makes it tractable for manufacture and immunisation,” Professor Drummer said.
Although there’s more work to be done to understand how to dampen the immune responses to gp41, Professor Drummer said the UQ’s vaccine still had utility and “a lot of promise”.
“Let’s say there’s a MERS outbreak and we rapidly need a vaccine,” she said.
“You could take the similar region to what they used for COVID-19 — the spike protein — and add that to the clamp … to see whether you can use this as a vaccine.
“Or if Disease X comes around the corner again and it turns out this technology is the best, maybe the gp41 component is not such a big deal in the context of the benefit you get from vaccination.”
The UQ team is two years into a three-year funding program from CEPI, and intends to keep developing the molecular clamp technology.
“We should be proud of Paul Young and his team’s huge effort to get the vaccine to this point, and see it as an opportunity to improve on in the future, for the next pandemic that’s coming around the corner,” Professor Drummer said.