COVID-19: How the Doherty Institute keeps a step ahead
On COVID-19, we are in an enviable position. This is the inside story of how Australian scientists got the jump on the world.
“This virus doesn’t want to kill us. It has no brain, no will. It just wants to grow and reproduce, to obey the laws of evolution and natural selection.” So says Professor Peter Doherty, a man who knows a thing or two about unpicking a virus. If the virus that causes COVID-19 did have a brain it would probably avoid coming up against the 79-year-old, Brisbane-raised, Nobel prize-winning immunologist who in the mid-1990s unlocked the secret of how our body’s immune system gives viruses a good kicking. His name has suddenly been thrust into the spotlight again as patron of the research and public health organisation that bears his name, the Peter Doherty Institute for Infection and Immunity. No organisation in Australia has been more prominent in tackling COVID-19, not only in the lab but in shaping government policy through the findings of its public health scenario modellings. “I’d just written my retirement book,” Doherty laughs down the phone from his home in Melbourne, where his age means he’s under strict isolation. “I thought I was fading into the distance and now suddenly I’m back as a talking head.”
There’s a lot to talk about. If we are in an enviable position in this war against COVID-19, with the tantalising prospect of life returning to normal seeming closer every day, it’s in part due to the early work of scientists at the Doherty Institute.
It’s easy to forget those early days back in January, when bushfires preoccupied the country and no one suspected a mysterious virus in China would within two months result in unimaginable global upheaval. But in the age of globalisation, viruses can move faster than even the news cycle, and so can those who fight them. Within hours of Australia’s first confirmed case of COVID-19 landing on our shores, the Doherty Institute had grown the virus in culture and shared it with the world (the first lab outside China to do so), sequenced the entire genome of the virus, mapped the human body’s immune response to the infection and was supplying the modelling that informed the Federal Government’s response in imposing the lockdown restrictions. Now its scientists are collaborating on a vaccine and testing possible treatments. Things have happened so fast that you could almost swear they were waiting for this virus.
Actually, they were. Doherty director Sharon Lewin calls it “peacetime preparations”: all the work that goes on when you’re not in the grip of a pandemic, when you’re not sure what sort of infectious disease will hit next but you know it will and you’d better be ready for it. It was SARS that primed the institute for COVID-19, but its bread-and-butter work is annual outbreaks of influenza, tracking cases in the community and developing new vaccines and treatments. “SARS was very infectious but the difference was people would only spread the virus when they were unwell,” says Lewin, “so you knew who was spreading it because they were sick and usually in hospital. But nothing like this new coronavirus has ever affected us.”
A collaboration between The University of Melbourne and Royal Melbourne Hospital, the Doherty Institute was born out of another disaster – the Global Financial Crisis – as a recipient of the Rudd government’s 2009 stimulus splash in the tertiary sector. It was established to deal with the exact sort of crisis we’re in right now.
The first cases of a mysterious pneumonia-like illness emerged from the wet markets of Wuhan, China in late December. It was soon confirmed to be a new type of coronavirus, and on January 7 China revealed to the world its genetic sequence – like sharing a fingerprint from a crime scene. “That’s when people started getting nervous,” says Lewin. “It was different to SARS. It set alarms off around the world.” The impetus for countries outside China was then on designing a diagnostic molecular test (called a PCR assay), so they’d know if the virus washed up on their shores. But Australia was a step ahead. We already had the test.
“The tests were designed in the wake of SARS and MERS, predicting that this would happen again and we’d need a test capable of detecting an unknown coronavirus,” says Mike Catton, director of the Doherty Institute’s Victorian Infectious Diseases Reference Laboratory (VIDRL).
Having the virus’s genetic sequence meant Catton and his team could quickly tailor their test to the new virus. From January 15 they started testing samples from anyone arriving from Wuhan displaying cold-like symptoms. Catton jokes that if anything urgent is going to happen, it’ll be on the Friday night before a long weekend. On Friday January 24, the lab got a call from Monash Hospital. Another return traveller from China had presented with coronavirus symptoms and a sample from the patient was taken back to the lab for testing. By 2am they had preliminary results, and by 4am had completed the entire genome sequencing, confirming the matter beyond all doubt that the fingerprints matched. COVID-19 was here.
Getting a positive ID was just the beginning. The next step was to try to grow the virus in cell culture. If growing a virus is an art form then Julian Druce is the artist. Druce is the senior scientist at VIDRL’s viral identification laboratory, where he tends to cultures in flasks with the tender touch of the finest orchid grower. Other labs had failed to get it to sprout, but Catton says if anyone in the world could grow it, Druce could. The practice of growing cultures was once de rigueur, but is now almost antiquated since the molecular test revolutionised virology in the late 1980s. While a molecular test will place your suspect at the crime scene, only by having a viable virus strain grown in culture can you fully interrogate the virus and learn its nature and characteristics, allowing you to potentially design antiviral drugs and vaccines.
Over the weekend Druce and Catton watched their virus grow, sometimes in the lab during the day, sometimes in the middle of the night. When unable to sleep, they would periodically open the laptop and hook into a webcam pointed at the flask back at the office. “It was really exciting,” says Catton, adding drolly: “if that’s your idea of excitement.” By the time Australians were back at work on the Tuesday, VIDRL had uploaded the genome sequence to an international database and were spreading the virus round the world, but in a good way, with the hope it could still be contained.
Sharing the virus before having it accepted into an academic journal was a bold and unusual move. Researchers will usually keep their discoveries closely guarded until the findings can be published. It’s possible that at least two other labs around the world had grown the virus before the Doherty Institute, but were sitting on it. Julian Druce says they didn’t have time for that. “We wanted to get the genie back in the bottle. It was clear to us here that public health came before publication.”
Collaboration would also come before commercialisation, with the COVID-19 crisis heralding an unprecedented flurry of global scientific co-operation through the sharing of information, materials, expertise and facilities. “I think it sent a message to the world about how we should be playing this thing,” says Catton.
Immediately after sharing the virus, VIDRL focused on helping public health labs, diagnosing samples sent in from New Zealand and states without local capacity. Throughout March the focus was on getting Victorian hospitals and community pathology labs set up with their own testing programs. Australia now has the highest per capita testing rate in the world.
Having a viable virus in the lab meant that labs around the world could start work designing antiviral drugs to treat patients, test vaccine candidates and begin serology testing to detect antibodies deployed by our immune system to fight the virus.
At the same time as VIDRL was growing the virus, the institute was claiming another world-first. An early patient had her immune response to the virus scrutinised, providing vital information on how the body fights COVID-19. The 47-year-old woman from Wuhan became the first person in Australia to be tested under a platform called Sentinel Travellers and Research Preparedness Platform for Emerging Infectious Disease (SETREP-ID). Doherty Institute infectious disease physician Irani Thevarajan helped set up SETREP-ID two years ago, around the time when the world was getting jumpy over new diseases such as ebola and zika. The platform – with pre-approved ethics – allows for testing and research of any travellers returning to the country with an emerging infectious disease. “We set it up knowing that new infections could walk through the door any day,” says Thevarajan. “So we wanted to be able to do immediate detection and research, to gain an understanding of it when it arrived.”
Thevarajan activated SETREP-ID on January 7, back when the world wasn’t even sure if human to human transmission was possible, and calibrated it to recruit data from any return travellers from China. When the woman arrived at hospital in late January and tested positive to COVID-19, a team led by Dr Oanh Nguyen and Dr Katherine Kedzierska immediately started taking blood samples and mapping her immune system response.
“We wanted to know right away what the immune system does when it sees this new coronavirus, because no one knew at that stage,” Thevarajan says. It was mild case of COVID-19 but the study revealed valuable information about the immune response. However, Thevarajan says a vital part of the puzzle is still missing. “What we don’t fully understand is what’s driving the really severe disease. We don’t yet fully understand why most people recover but some don’t.”
Nor do we fully understand what we stand to lose as collateral damage in the battle against COVID-19. On February 3, a collaboration of researchers led by the Doherty Institute convened a workshop with the Office of Health Protection and jurisdictional representatives in Canberra to discuss modelling the impact of COVID-19 on our health system.
Modelling was released to the public on April 7, two months after being provided to the Federal Government, which used it to inform its public health response. It’s this modelling and the delay in releasing it to the public that’s subsequently become the most controversial and debated element of the early initiatives, and the one that may prove to have the most serious long-term consequences. Doherty director of epidemiology Jodie McVernon led the team that built the model. She says at that early meeting the team proposed a “very broad brush set of initial scenarios based on influenza pandemic preparedness assumptions about severity, which was then highly uncertain”.
Back in 2009, McVernon had led a team of modellers responding to the H1N1 influenza pandemic that killed half a million people globally. So when COVID-19 came along and a preparedness model was needed in a hurry they brought out the influenza plan as a template, updating data specific for COVID-19 as it came in. “It’s our business to be surprised. That’s what emergencies are about,” says McVernon. “The reason this [modelling] could be done so fast was because the government had invested in preparedness for a very long time. So the toolkit, the thinking and the strategies were ready, but as the data came in it became clear this was beyond the influenza scenarios.”
The modelling, though, came in for criticism for basing its assumptions on overseas data, for not taking into account Australia’s case numbers, different demographics, geography and health care system. Australia never saw the widespread virus transmission of places like Italy, Spain and New York. Some say this is because of the strict social distancing measures the government put in place. Others say it’s because Australia never had the effective reproduction number (the number of people infected by each person carrying the virus) that Wuhan did, our population isn’t as elderly as Italy’s, our rate of smoking is relatively low, we don’t have high-density slums, and a thousand other differences that mean a one-size-fits-all model was never going to be an accurate representation.
McVernon says they had no choice but to use overseas data, as that’s where the epidemics were occurring. She says they simply didn’t have time to wait. “We’re acutely attuned to the fact we have to contextualise this to our local setting,” she says, “but you have to start with what you have. Yes, there were uncertainties, but the model is there to help you come to a consistent set of decisions. You ask yourself if any of those uncertainties would change your decisions.”
The modelling revealed that an unmitigated COVID-19 epidemic in Australia would have been a disaster, quickly overwhelming the health system. Suddenly “flattening the curve” became a phrase every Australian was familiar with. The curve was soon flattened, but at what cost? We won’t know until later the legacy of shutting down the economy, consigning so many Australians to the unemployment queue, or the other social impacts. One million Australians have become unemployed, and the Federal Government’s economic support packages are costing the country $320 billion.
McVernon admits she’s nervous about the collateral damage but stands by the measures. She says it was their job to avert a crisis. “It’s not a stretch to compare COVID-19 with the plague. People are saying that public health is being allowed to run the government. Well, I think there was definitely a need for public health to lead the charge to avert a catastrophe. That was our single task.”
The world waits for a vaccine. Doherty Institute virologist Dr Damian Purcell says more than 100 vaccine concepts are being worked on. “It doesn’t take a lot of time to produce a vaccine candidate,” he says, “what really takes time is the testing.” The institute’s collaboration with the University of Queensland to design a vaccine is one of those 100. Purcell says UQ started the work on January 20 and it’s now being tested on ferrets in the Netherlands prior to human trials. Elsewhere overseas, other vaccine candidates are already at the human trial stage. In-house, the institute is working on its own vaccine candidates, thanks to a $3.2 million donation from the Jack Ma Foundation. Meanwhile, two international groups, one from Britain’s Oxford University and another from US group Inovio, are testing vaccine candidates at the CSIRO in Geelong. CSIRO has partnered with the Coalition for Epidemic Preparedness Innovations (CEPI), part of a global alliance aiming to speed up the development of vaccines, and in April was given $220 million by the Federal Government to upgrade its biosecurity research facilities and help expedite the quest for a vaccine.
Purcell says international collaboration and funding are the keys to unlocking a vaccine. “Funding is the thing that fires up the rocket sled. But things are highly accelerated now because people are sharing information in real time. A lot of the problems with vaccine development is it’s so expensive to manufacture at a high grade and going through the larger scale testing, so we’re speeding up the process of the early phase testing. As soon as things look remotely good and we get the safety signals, we pull the trigger and manufacture.”
If it sounds simple, don’t kid yourself. Developing a vaccine is one thing, but working out how to safely mass produce what is a very complex biological product for the consumption of millions, to fight a virus we still don’t know a lot about, and doing it by yesterday, requires navigating seemingly insurmountable problems. Purcell believes we will get a vaccine, but he’s just not sure if it will be the elixir the world is expecting. “It may be difficult to achieve effective vaccination of the elderly, we just don’t know. Therapeutic antibodies or anti-viral drugs may turn out to be more important. That’s why we need to advance all fronts.”
Other fronts include a trial led by the institute involving 2500 people in more than 80 hospitals in Australia and New Zealand (called the ASCOT trial) to assess the effectiveness of two antiviral drugs, lopinavir/ritonavir (used to treat HIV) and hydroxychloroquine, the antimalarial drug touted by Donald Trump and Clive Palmer. It’s also partnering with Monash University on a study of the anti-parasitic drug Ivermectin. Early experiments done at the Doherty Institute days after the virus was identified in Australia showed that Ivermectin killed SARS-CoV-2, the virus that causes COVID-19, within 48 hours in cell culture. Dr Kylie Wagstaff from Monash Biomedical Discovery Institute says anecdotal evidence is good, but getting the dosing right is the key before human trials in Australia can start.
Peter Doherty, who still has a key research advisory role with the institute, remains relaxed and grounded, an endearing everyman infected with an incurable case of humility. On April 27 he tweeted what was meant to be a Google search: “Dan Murphy opening hours.” Even strict isolation comes with occasional caveats. Rather than delete the tweet, he let it stay and gather likes and laughs. “Only flawed humans can be loved,” he later tweeted. “And I certainly qualify.”
The real work is more sobering. Doherty says the worst virus he’s ever seen is smallpox. It killed about 300 million people in the 20th century, about 30 per cent of those it infected. Ironically, it’s also the only human infectious disease ever to be eradicated, the last case occurring in 1978. “We’re probably not going to eradicate COVID-19,” says Doherty. “So whatever people think of what’s being done, we need to build up the armamentarium against this thing. It’s lethal.”