Vaccine scientists at forefront of the war on COVID-19

The world waits and prays as women and men in white coats wage war on the virus.

A researcher works to formulate a vaccine for use against COVID-19 at Copenhagen University in Denmark. Picture: AFP

To paraphrase the stirring wartime language of Boris Johnson’s hero: Never has so much hope been invested by so many in so few.

Like Winston Churchill long before him, the recovering British Prime Minister has made more than his share of mistakes, deliberately shaking hands with infected patients chief among them after he initially played down the threat of COVID-19.

This week, it was up to the masked and gloved few in the intensive care unit to save him. Johnson would probably appreciate the irony, had he not been so desperately ill.

But if we look to the big picture that captivated Churchill — lionised in a shamelessly self-serving 2014 book Johnson wrote to preface his own rise to power — another select group comes to the fore. As brave and dedicated as the doctors and nurses are on the frontline, this war can be won only in the lab. COVID-19 won’t be defeated until a vaccine is found by medical scientists.

Some Australian researchers involved in the worldwide R&D effort insist it’s a matter of when, not if, this happens. Let’s hope they’re right. The strategy to “flatten the curve” of infections is a trade-off that has a punishing cost to the economy and day-to-day life to keep the outbreak manageable and the health system functioning until an answer emerges in the form of a vaccine.

It cannot last. In the absence of a vaccine, there are two alter­natives, both means to a deeply confronting end. Option one is ongoing mitigation, a normalisation of some of the disruptive social-distancing measures and shutdowns now in force. Implicitly, this accepts that people will continue to catch the virus and die, albeit at a much slower pace than would be the case without intervention.

Yet, across time, the graph of the managed infection rate would start to converge with the “let it rip” scenario, which is option two. Unthinkable as it seems, this has been partially embraced by Sweden through its “flexible” response to the pandemic and will be the default position of impoverished nations in Africa, the Middle East, south and central Asia and the ­Pacific because of a heart-rending lack of resources.

Yes, the disease would burn through the population faster, leaving those who contracted a mild or even asymptomatic dose protected against reinfection alongside the severely stricken survivors — the endgame of herd immunity. But would Australians be prepared to accept the fearful cost in lives?

Leaving aside the Stygian circumstances of Iran, Italy, Spain, France, Britain and the US, where bungling governments locked the gate after the virus had bolted, consider what is happening at the clear-eyed instigation of Swedish authorities. Having allowed the citizenry to decide for themselves whether to stay at home or live it up in the still-open pubs and restaurants, a country with half the population of Australia and equally advanced health services now has 15 times the deaths — 793 as of Friday, and increasing at more than 100 a day. Johnson flirted with a similar approach until he was mugged by reality.

Tipping point

A vaccine, of course, sidesteps the otherwise grim Darwinian acquisition of herd immunity. No one can say for sure where it would cut in with COVID-19, given so much is still unknown about the disease and the virus that causes it. Chief Medical Officer Brendan Murphy’s best guess this week was that 50 to 60 per cent of the population would need to be immune, a standard tipping point. Other experts say the proportion could be closer to the 90 per cent that was required to check the more virulent measles virus.

The only certainty is that the combination of a vaccine and interim therapeutic treatments is the best hope — only hope, really — to get on top of COVID-19 in a socially and economically sustainable way. However, the cautious optimism voiced by Murphy, Scott Morrison and the premiers about the continued fall in the rate of new infections in Australia was tempered this week by warnings that a vaccine is between 12 and 18 months away — assuming one or more of the 35-odd platforms in development will work on live humans, which is by no means guaranteed.

The history of vaccine development hardly inspires confidence. Jane Halton, the former federal public service mandarin who chairs the Coalition for Epidemic Preparedness Innovations, the not-for-profit body co-ordinating and funding vaccine projects globally, says the challenge is akin to curing the common cold.

The Coalition for Epidemic Preparedness Innovations’ Jane Halton. Picture: Tracey Nearmy

Sounds easy, but after all these years no one has come up with a way to do it.

“If you said we pulled out all the stops and a vaccine was approved and deemed efficacious by the middle of next year, that would be unbelievably quick … we would be ecstatically overjoyed, delighted,” she explains.

“But I do think it is important not to create unrealistic expectations. No one has ever successfully developed a coronavirus vaccine, and we still don’t have a vaccine against HIV. I would never say never. But this is my point about an 18-month timeline: it is heroic, ­really tough.

“I am hoping with every fibre of my being that proves to be the case, but the truth of the matter is we do have to have a plan B on how we run the joint, how we protect as many people as we can, because with these sorts of things in science, nothing is certain.”

In the case of COVID-19, the common cold analogy is particular apt. Both infections are caused by a coronavirus — though SARS-CoV-2, as the name suggests, is a much closer match to severe acute respiratory syndrome and it is even more lethal than its Middle East-anchored cousin MERS, sharing up to 90 per cent of those viruses’ genetic material.

After SARS emerged in southern China in 2003, spreading to other countries in Asia and the Canadian city of Toronto, scientists thought they had cracked a vaccine. Initially, the animal models looked promising. But the prototype compounds were found to trigger such a powerful immune response that the danger was the vaccine would make people sicker than SARS could. When that epidemic, far smaller than today’s, was contained, the funding got pulled and the research was abandoned. The development of a vaccine for Zika, the dengue-like virus spread by mosquitoes, followed a similar path to oblivion.

But this time the net is cast far wider, reflecting the extent of the emergency. The research teams in government labs and private biotechs are ­scattered across the globe, from China to the US, Israel and Europe to here, where a partnership between the University of Queensland, Melbourne’s Peter Doherty Institute for Infection and Immunity and the CSIRO is driving the Australian program under CEPI’s umbrella.

Old-school approach

Some scientists are taking the old-school approach by creating a vaccine with live virus. The advantage is that the methodology is tried and tested, with established pathways through the regulatory maze to production. Yet the potential for unintended consequences remains: the live form can continue to evolve in the host to recapture some of its original potency, making the recipient ill. Often, higher or repeat doses of the inactivated virus are required for the vaccine to work, while dealing with infectious live agents is taxing for lab staff and can be a challenge to spin up into mass production.

The new-breed platforms achieve immunity differently by targeting the virus’s vulnerabilities at the genetic level, but the principle is broadly consistent. All vaccines present part or all of a pathogen to the human immune system to train it to go after the ­invader by producing antibodies to kill it.

Several of the emergent technologies, such as the candidate vaccine being developed by US biotech Novavax, have picked up the shelved research on SARS and MERS. The Maryland-based company uses nanoparticles to harness the protein spikes on the surface of SARS-CoV-2. The extracted genetic code helps stimulate an antibody response against the coronavirus.

Moderna Therapeutics, the first vaccine developer in the world to inject a prototype compound into the arm of a person in a phase one “safety and proving” trial in Seattle in the US, is building protection out of messenger RNA, the mechanism used by the virus to replicate ­itself in human cells.

At UQ, the team working on Keith Chappell’s molecular clamp — a “plug and play” vaccine designed to be reconfigured to deal with different pandemic pathogens, also targeting the virus’s protein spikes — have settled on a formulation that recently went to animal studies.

Phase one human trials are pencilled in for June, by which time Chinese biopharma Sinovac should have preliminary results on its process to inactivate whole virus particles with formaldehyde and an immune booster.

“In terms of getting a vaccine that we think will work, we think we are already there,” Chappell recently told Inquirer from the team’s Brisbane laboratory. “But getting a vaccine that’s available for seven billion people on the planet means … we have to move to scale and that’s a very different proposition.”

Halton says CEPI is in ­detailed discussion with a “significant number” of multinational drugmakers — the GSKs, Pfizers and Mercks of the world — as well as regulators including Australia’s Therapeutic Goods Administration to fast-track potential vaccine production, provided the scientists come through.

For once they have a useful ally in SARS-CoV-2. The virus may be 20 times clinically worse than seasonal influenza, in the estimation of Australia’s Nobel prize-winning immunologist Peter Doherty, namesake of the Melbourne research institute, but in key respects it is not a particularly formidable vaccine target because it is slow to change, unlike the ever-mutating flu virus. This means it is not very good at dodging the immune system, making the task of the vaccine developers easier.

Chappell and his colleagues at UQ point out that their platform provoked powerful immune responses in animal studies on seasonal influenza and MERS before the technology was repurposed.

“We don’t believe it is going to be more complicated than with influenza,” says Paul Young, the professor of molecular virology who supervised Chappell’s PhD research before joining the molecular clamp team. “In fact, it’s a little less complicated … because overall the coronaviruses don’t drift in their mutations as much as influenza virus does.”

Race against time

Halton says the new DNA and RNA-based platforms are best-placed to be deployed first against COVID-19, even though none has made it out of the lab to date, underlining her caution about the timeline. “RNA and DNA vaccines can be made quickly because they require no culture or fermentation, instead using synthetic processes,” argues a paper she co-authored recently for the prestigious New England Journal of Medicine. “Developers’ and regulators’ experience with these platforms for personal oncology vaccines can facilitate rapid testing and release.”

Funding is pouring in through CEPI, a fusion of private and public capital backed by the Bill and Melinda Gates Foundation, Britain’s Wellcome Trust and eight signatory countries, including Australia. Halton reels off the governments that answered CEPI’s call last month for top-up funding: £220m ($433m) kicked in by Britain, €130m ($224.5m) from the Germans, $C40m ($45m) from Ottawa. And Canberra’s contribution? “In relation to the current call, Australia hasn’t donated anything, though we are still hopeful,” she deadpans.

With an eye to the problematic history of vaccine development, Halton insists it will be “the more the merrier” for COVID-19. “We wouldn’t want to chance our arm on a single candidate … because fundamentally vaccines are hard to make and, depending on the technology, some vaccines are slow to make,” she says.

“If we were spoilt for choice and had 20 come through, that would be a different matter. But I don’t think that will happen at the end of the day. It would be better to have three than one, for example, because that means you could spread manufacturing around the world and get it to people sooner.”

Let’s leave the final word to Churchill: “This is not the end. It’s not even the beginning of the end. But it is, perhaps, the end of the ­beginning.”