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In the beginning, we had only the human body and its inherent ability to fight disease. Then – at some point after we emerged from the primeval swamp, developed an opposable thumb, and picked our first therapeutic herb – we had medicine. And now we have a world in which diseases are found and fought in laboratories a thousand miles from any suffering human frame.
On the spectrum between primordial murk and Petri dish, vaccines occupy all points on the scale. They lie at the very forefront of medical science – they are our most sophisticated hope for a solution to the pandemic of COVID-19 – and yet they rely fundamentally on the most basic resource of the human body: its ability to recover from, and thereafter resist, disease.
Amid all the extraordinary battles raging against the novel coronavirus SARS-CoV-2 around the world at this moment, none is more important than that being fought by scientists. It’s a battle on two fronts: to find treatments to cure or mitigate the disease affecting millions of people; and to develop a vaccine that will potentially protect billions.
Currently, there are more than 100 possible vaccines in development globally, many under the aegis of the World Health Organisation and CEPI (the Coalition for Epidemic Preparedness Innovations, an international body founded in 2016 to finance vaccine development against emerging infectious diseases). Australia’s place in this maelstrom is both small, yet potentially significant, which is a familiar position for Australian science to occupy. Despite our small population, Australian scientists consistently “punch above their weight”, says Anna-Maria Arabia, the CEO of the Australian Academy of Science, “both in terms of the quality of our research and publication rates per capita”.
This expertise is particularly notable in the fields of immunology and vaccine development. Two of our most famous Australians, Peter Doherty and Ian Frazer, are both still working in vaccine technology. “It very well could be Australians who beat this thing,” says Frazer, a Brisbane-based immunologist who co-created the HPV vaccine, which since 2006 has protected some 300 million women against cervical cancer.
“We have very talented people. We have the immunologists, the virologists, the protein chemists and cell biologists.”
“We’ve got really good science here,” agrees Doherty, who won the 1996 Nobel Prize in Physiology or Medicine for his work on human T-cell immunity. “Bang for buck, compared with the US, where I worked for a long time, we do extremely well. We’ve got some really good people. In fact, I don’t think I’ve really appreciated how good they are until now.”
In January, Australian scientists (at the Doherty Institute in Melbourne, named after the great man himself) were the first outside China to sequence the COVID-19 genome, grow the virus, and share it internationally.
Multiple labs and hospitals around the country are investigating drugs like remdesivir (an Ebola antiviral), tocilizumab (an immunosuppressive used mainly for rheumatoid arthritis), the HIV drug Kaletra and malaria treatment hydroxychloroquine to treat COVID-19. At the same time, REMAP-CAP, an ongoing Australian-based multifactorial trial at more than 100 sites around the world that usually looks into treatments for severe pneumonia, has pivoted to testing drugs on COVID-19 patients, with the ability to alter their medication on the basis of ongoing analysis.
“We’ve got a lot of drugs that we’re trying to repurpose,” explains Frazer. “And maybe some of them will work – but at the moment it would be fair to say the trials are … empiric. In other words, we’re guessing.”
“We’ve got a lot of drugs that we’re trying to repurpose. And maybe some of them will work – but at the moment it would be fair to say the trials are … empiric. In other words, we’re guessing.”
Immunologist Ian Frazer.
“Drugs are good,” says Doherty. “But unlike a vaccine, no drug can give you immunity. Even convalescent serums [antibodies extracted from recovered patients’ blood and given therapeutically] and monoclonal antibodies [lab-grown versions of antibodies] are only temporary. You have to keep taking them, just like a drug, because their protection gradually disappears.”
Even vaccines are not without problems. In the past, work on vaccines for other coronaviruses (such as MERS and SARS) has raised questions regarding the strength and longevity of vaccine-produced immunity; and about the negative impacts of a vaccine on the immune system. There has even been debate about whether a vaccine is possible for COVID-19, given no human coronavirus vaccine has ever been produced.
“There’s one for chickens!” says Doherty, betraying his veterinary origins. “My wife and I both worked on it about 50 years ago!” He laughs. “But no, seriously, you hear this thing about ‘no vaccines for coronavirus’, but in fact they were making a lot of progress with both MERS and SARS vaccines. The reason they didn’t go anywhere was basically because SARS burnt out, and although MERS still grumbles away, it only infects about 200 people a year. There’s just no big impetus with that level of infection.”
He laughs. “I’m a very simplistic thinker. But the fact is, all the drug treatments are stopgaps. What we want for COVID-19 is a vaccine. And I think we’ll get one, and that it will work fine.”
Fittingly, the oldest records of inoculation come from the source of the world’s newest pandemic – China. The first disease ever contained by vaccination was smallpox. Devastating, incurable, with a 20 to 60 per cent death toll and survivors often left blind and horribly scarred, smallpox was – unfashionable as it is to point out – a far more dangerous pathogen than coronavirus. But by the 1500s (and possibly far earlier), Chinese doctors had realised that if sufferers could only survive the first onslaught of smallpox, they never caught it again. After the first attack, something in survivors’ own bodies permanently protected them.
Working backwards from this conclusion, doctors took the scabs from healing smallpox pustules and ground them into powder. Then they blew the powder up healthy patients’ noses. There was also a second technique, which may have originated in India, in which pus from smallpox sores was scratched into incisions in the skin of healthy people with a needle. (Nobody said medicine was pretty.) In both cases, those treated contracted a milder form – in theory at least – of the disease, from which they could more easily recover.
These strategies, particularly the needle technique, known as variolation, worked in a surprising number of cases: by the 18th century, only one or two patients in every hundred were dying from deliberately induced smallpox. These odds – though horrifying to the modern mind – were so much better than risking the unmediated disease that variolation spread from China throughout the Arab world. Eventually, in the 1700s, it reached England, the US and Australia.
Variolation was practised on princesses and kings, but perhaps its most important application was to the arm of a Gloucestershire schoolboy. Edward Jenner, now recognised as the father of immunology, was variolated during his childhood, and thus – rather against 18th-century odds – did not contract smallpox. Instead, he grew up to develop the world’s first vaccine.
Jenner realised that using the pus from lesions of cowpox, a much less serious illness that nonetheless provided effective immunity against smallpox, was a far safer treatment than traditional variolation. By the time of his death in 1823, hundreds of thousands of people had undergone “vaccination” (the word comes from the Latin vaccinus meaning “from a cow”), and a direct line can be drawn from his work to the final eradication of smallpox from the earth in 1980: the greatest triumph of vaccination, and the single most successful medical intervention, in terms of lives saved, in human history.
We’ve come a long way since Jenner built a “Temple to Vaccinia” in his English backyard, but to experts in pandemic diseases, it must often seem as if we’ve made no progress at all. Professor Trevor Drew, the director of the Australian Centre for Disease Preparedness (CDP) at the CSIRO in Melbourne, has spent years dealing with the fact that, pre-COVID-19, the man on the street simply couldn’t believe that a global pandemic would ever, really and truly, happen. “To most of the world it has come as a terrible shock,” he says, managing to sound only slightly rueful. “But we in infectious diseases have known for years that it was a question not of if, but when. We didn’t know what it would be, or where it would come from, but we knew it was coming.”
Nonetheless, it was only in January this year that the CDP signed a contract with CEPI to run animal trials on potential COVID-19 vaccines. This was before virtually anything was known about the virus, including its lethality – and the CDP is one of only a handful of labs in the world designated as BSL-4 (biosafety level 4), authorised to deal with the most dangerous pathogens on earth – the likes of Ebola, Marburg and hantaviruses.
“It’s been an extremely big challenge,” admits Drew, with a scientist’s feel for understatement. “We’ve had to be extremely agile, and it’s a huge tribute to my team that we’ve been able to get organised so fast.”
COVID-19 social distancing measures have created many headaches in staffing labs and organising teams – Drew is talking from his spare bedroom, no doubt a typical site of breakthroughs in all fields of human endeavour these days – but nobody on his team has flinched. “I’m so proud of them. They all just got on with it.”
The CDP is a world leader in the use of animal testing in vaccine development. Its scientists were first in the world to confirm, for instance, that ferrets were susceptible to COVID-19, thanks to the fact that they have a similar lung cell receptor, ACE 2, to that of humans. It’s this receptor that the now-famous “spike protein” of COVID-19 plugs into to infect cells. So ferrets, like us, can catch coronavirus (though, unlike us, their worst symptom is a mild cough).
The CSIRO is now running animal trials using ferrets for two vaccines – one from American biotech company Inovio Pharmaceuticals, and one from Oxford University. Both were sent there because they looked particularly promising. “Our job is to assess the data and send it back to CEPI and WHO,” explains Drew. “Then they’ll decide if they’re worth taking to the next stage.”
Animal trials are always crucial in establishing whether candidate vaccines are safe and efficacious. But in the case of COVID-19, Drew and his team may help to solve two other problems. One is temporary immunity, which means more than one vaccine dose may be necessary (a big deal if you’re potentially dealing with billions of people); the other is that some COVID-19 deaths appear to be caused not by the virus but by the body’s response to it: a wild immune overstimulation known as a cytokine storm.
“For both those problems, our trials are looking at different routes of administering the vaccine – orally, intramuscularly – to see if that might affect those outcomes,” explains Drew. “Vaccine route might prompt a different level of immunity. It might also be important in avoiding immune mediated disease.”
“Scientists are always collaborative, but these levels of co-operation – this global response – are really unprecedented. But then, these are unprecedented times. Our competition is against the virus, not against each other.”
Professor Trevor Drew, director of the Australian Centre for Disease Preparedness.
Things so far look promising: the ferrets have had no adverse effects to either vaccine, and they’ll have been exposed to the virus before this article goes to press. And so, by the time you read this story, as many as 6000 people in the UK may have been given the vaccine in a safety trial. Should it happen, this human trial will be able to proceed, in part, thanks to the animal testing carried out by the CSIRO.
“It’s a real global effort,” concludes Drew. “Scientists are always collaborative, but these levels of cooperation – this global response – are really unprecedented.” He pauses. “But then, these are unprecedented times. Our competition is against the virus, not against each other.”
Professor Nigel Curtis is sitting in his office at the Murdoch Children’s Research Institute (MCRI) in the Royal Children’s Hospital in Melbourne. As head of the infectious diseases and microbiology research group at the MCRI and professor of paediatric infectious diseases at the University of Melbourne, he works not only in the lab, but with patients, and on the weekend of January 27, he thought the hospital switchboard was accidentally ringing him on his day off.
“I answered the phone and said, ‘Look, I’m afraid I’m not on call today.’ And they said, ‘No, it’s the special medical adviser from the World Health Organisation, calling from Geneva.’ So I said, ‘Oh, right, I’ll take that call.’ ”
The WHO was contacting Curtis about COVID-19. Not about an innovative new technique for this equally novel virus, but for his expertise in one of the oldest known vaccines, the BCG vaccine for tuberculosis.
By the 19th century, TB – often called “consumption” – was estimated to have killed one in seven of all the people who had ever lived. The BCG vaccine was developed by two French bacteriologists in the early years of the 20th century (their work continued through World War I thanks to the help of occupying German veterinary surgeons) and was first administered in 1921. It has been given to more than 4 billion people and is still used to vaccinate more than 100 million children annually. “It’s incredibly safe and extremely well studied – although the extraordinary thing is we still don’t really know how it works,” laughs Curtis.
Of course, BCG is not a vaccine for COVID-19. But the WHO is interested in its off-target effects; its “accidental advantages”, as Curtis calls them, which may impact on the severity of COVID-19. This is because in hundreds of studies, including many by Curtis and his colleagues, BCG has been shown to significantly boost general immunity. Babies given BCG, for instance, quite apart from their protection against TB, are also less likely to get sick with other things, including diarrhoea, sepsis or respiratory illness. “It can reduce all-cause mortality by between 30 and 40 per cent,” explains Curtis. “That’s a dramatic reduction.
“It seems to work in a number of different ways, but the main thing we think is happening is that the vaccine provides immune training for the innate immune system.”
This part of the immune system is rarely involved in vaccine action, because it has nothing to do with antibodies, which are a function of B cells in the adaptive immune system. But “it’s the frontline defence, if you like: it holds the fort until the adaptive system gets its act together. And what we’ve shown, along with our partners in the Netherlands, is that BCG changes some of your immune cells, so that your initial, innate response is more intense, more profound. And so we think that if you’ve had BCG recently, the response of your innate immune system when you get COVID-19 will be faster and stronger. It will kill the virus and reduce the viral load.”
In January, the WHO asked Curtis and his colleagues if they would run a study using BCG on health workers in Wuhan in China, to see if it would help protect them against the new and threatening coronavirus known to be circulating there. “As it turned out, there was complete chaos in Wuhan at the time, and it was just way too hard to get a study going,” says Curtis. “But a few months later, when it became apparent that the virus was going to spread across the world, my whole research team got together one Sunday and we said, ‘Right, let’s stop everything we’re doing, and put all our effort into this.’ ”
That was on March 8. Usually a big randomised control trial – the most rigorous and reliable form of scientific evidence-gathering – takes at least six to 12 months to get going. But three weeks later, with the whole MCRI team working “seven days a week, and very long hours”, they were ready. The first participants in what’s known as the BRACE trial – all Australian health workers – were recruited at the end of the same month.
It works via an app, which is tracking every illness participants experience using a daily diary of symptoms and disease progression. At the time of writing, the trial had just received $10 million from the Bill & Melinda Gates Foundation to increase its participant numbers to 10,000 and expand its trial sites overseas: the single largest philanthropic donation to an Australian COVID-19 initiative to date. BRACE has also been personally endorsed by the WHO’s director-general, Dr Tedros Adhanom Ghebreyesus.
Interim results are expected next month, and
Curtis is hopeful about what they might show. “If I didn’t think it would work, I wouldn’t have been working 24/7 for the past month to get this study off the ground!” he told a briefing a few weeks ago. “But in science we need the RCTs. Big randomised studies with controls are the only way to know if anything works.”
“The great thing is that if it does work, it can be delivered incredibly quickly and safely,” he now explains. “It’s already readily available in many WHO-accredited labs around the world – though we must be careful not to leave TB-vulnerable children without the vaccine – so production could be scaled up rather than started from scratch. For those who were vaccinated as children, meanwhile, they can take the vaccine again: indeed, the effects may be enhanced by a second dose. There are also very strict indications for use outside trials, so you won’t get people rushing out and vaccinating themselves, as with chloroquine.”
And finally – and significantly – the use of BCG as a proven therapeutic may be important not just for COVID-19, but for the next global health crisis, and the next, and the next.
“Who knows when the next pandemic will come along,” says Curtis. “But it will come. Many of us have been saying it for years, and no one was listening. The UK and the US have both failed preparedness tests [the UK failed a major pandemic simulation exercise in 2016; and the US dissolved its White House Pandemic Office and connected funding in 2018]; even now I think many of us fear that we won’t learn the lesson: we won’t be ready. Next time round it will be something different; perhaps far more deadly than COVID-19. We need to be prepared. We may need a stopgap until we develop a vaccine. And this might be the thing we can use.”
Australia’s most advanced possibility for a home-grown vaccine for COVID-19 did not begin dramatically. Senior research fellow Dr Keith Chappell started it as a “sideline project” after he returned to Brisbane from Madrid nine years ago. “He came back to my lab and asked if he could continue looking at it,” recalls Professor Paul Young, head of the school of chemistry and molecular biosciences at the University of Queensland (UQ). “And he came up with the idea of what is now our vaccine technology.”
The problem Chappell, Young and fellow researcher Dr Dan Watterson (who now jointly own the patent) had to solve is a basic characteristic of virus behaviour: their shape-shifting nature. “The proteins on viruses undergo a lot of shape changing,” explains Young, which makes them hard to lock into a stable vaccine form. “If we take COVID-19 as an example, when the virus enters the body it’s in what’s called a pre-fusion form: it’s very unstable. It’s a bit like a mousetrap set to spring.
“Then, when it inserts itself into the host cell, it flips through this very dramatic change, which is what fuses it to the host cell so that it can begin replicating. [No virus can reproduce on its own: it must hijack a host cell for replication.] So if you can block that step, it’s a very efficient way to prevent infection. We’ve developed what we call a molecular clamp, which acts like a bulldog clip on the mousetrap, clamping down and stopping it from springing.” This bulldog-clip, or molecular clamp, is the basis of the UQ vaccine.
One of the beauties of the molecular clamp is that it can be applied to a wide range of viruses. The UQ team has already demonstrated that it works on (among others) Ebola, MERS, influenza and herpes. It’s been so successful that in 2018, the team was only the second academic organisation in the world to be funded by CEPI.
This funding was aimed at developing a “rapid response vaccine system”. Along with partners including the CSIRO, the Doherty Institute and Australian National University, the idea was to organise the molecular clamp technology for use as a universal vehicle, into which they could slot whatever pathogen protein came along. Barely a year after the funding arrived – and, like the CSIRO, far sooner than they were expecting – they were called on by CEPI for COVID-19.
“Everyone has been working 24/7 for three months, so we’re all exhausted, but we’re all exhilarated at the same time.”
Professor Paul Young, head of the school of chemistry and molecular biosciences at the University of Queensland.
“The original funding application from CEPI specified that you be capable of having a vaccine ready for clinical trials within 16 weeks,” recalls Young. “And in those days, everyone said, ‘Well, that’s just crazy.’ ” The mumps vaccine of the 1960s – the fastest in history –took four years. “But it’s a good goal to have; and actually, we’re confident we’ll meet it.”
This confidence is based on the fact that, firstly, the key aspect of their technology – the molecular clamp – is ready to go. Also, that they have been specifically investigating ways to speed up the standard vaccine pipeline.
“Traditionally, vaccine development is a linear sequence over several years,” explains Young. “Discovery, development, preclinical animal testing, then humans trials by phases [small safety trials, larger studies for efficacy, then really large populations]. Only then do you go to a regulatory authority; and only if that’s granted does the manufacturer come in.”
So how do you speed up that process without sacrificing science or safety? UQ decided to focus on manufacturing. “We’ve uncoupled the manufacturing element from the whole process,” says Young. “So we’re continuing with our preclinical studies, while simultaneously setting up for manufacture.”
It’s a high-risk strategy, because it means, literally, producing a vaccine that may not work. But the point, says Young, is that it’s a financial risk, “not a safety risk. You could be devoting a lot of resources to something that may not get there, that’s true. But we’re confident it will.”
When we speak at the end of April, the UQ vaccine has just passed a significant milestone: it induces an extremely potent immune response in animals. In cell culture, meanwhile, tests at the Doherty Institute have shown it stimulates an even better antibody response than patients who’ve recovered from COVID-19 (who’ve developed their own antibodies to the live virus).
The next steps are to challenge the test ferrets and hamsters with the live virus (just as Trevor Drew is doing at the CSIRO), complete the standard toxicology studies, and keep the manufacturing timeline on track for this year. “We’re already generating reagents and getting the infrastructure organised that’s required for large-scale production, and we’re in discussions with manufacturers right now,” explains Young. “There are actually not that many companies in the world that can cope with a global vaccine. Hundreds of millions of doses – only large pharma can do that.”
Young admits he’s “relieved” the vaccine has done so well so far and says he’s optimistic about its future.
“Our timeline is next month, maybe July for human trials,” he says. “And we’re on track.” In the best-case scenario, the UQ vaccine could be ready for production in September, and available for widespread use by early 2021.
It’s clear that Young, who is speaking from his Brisbane home, feels both the responsibility and the thrill of this position. He and his team may be on the cusp, literally, of changing the world. “The lab is just incredibly excited,” he confesses. “Everyone has been working 24/7 for three months, so we’re all exhausted, but we’re exhilarated at the same time.”
The months since COVID-19 appeared have been memorable ones for most people on earth. Like the scientists of COVID-19, we’ve all learnt many things since that microscopic spark of destruction emerged from the putative wet market in China. Unlike the scientists, it’s not clear whether we’ll remember any of them. But one thing, surely, will stay with us. We now understand, in a way we never have before, that vaccines are not just a quotidian detail of modern health care, but a miracle of human ingenuity: a miracle which allows us to cheat death.
Paul Young, like all the scientists in this story, is modest, friendly and confidence-inspiring. But he may hold the power of life and death for millions of people in his laboratory, and he knows it.
“Most people enter this kind of science to make a difference,” he says. “In our hearts, that’s what we all desire. And we’re in one of those rare moments in history where that’s really possible.”