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At first, we only had the human body and its inherent ability to fight disease. Then – at some point after we left the pristine marsh, the development of an opposable thumb and the picking of our first therapeutic herb – we got medicine. And now we have a world in which diseases are found and fought in laboratories thousands of miles from any suffering human body.
On the spectrum between primordial darkness and the Petri dish, vaccines occupy all points of the scale. They are at the forefront of medical science – they are our most sophisticated hope for a solution to the COVID-19 pandemic – and yet they fundamentally depend on the most basic resource of the human body: its ability to recover from , and eventually resist, the disease.
Amidst all of the extraordinary battles raging against the new SARS-CoV-2 coronavirus around the world right now, none is more important than the one waged by scientists. It’s a battle on two fronts: finding treatments to cure or alleviate the disease that affects millions of people; and develop a vaccine that will potentially protect billions of people.
Currently, there are more than 100 possible vaccines in development around the world, many of which are sponsored by the World Health Organization and CEPI (Coalition for Epidemic Preparedness Innovations, an international organization founded in 2016 to fund the development of vaccines against emerging infectious diseases). Australia’s place in this maelstrom is both small, but potentially important, which is a familiar position for Australian science. Despite our small population, Australian scientists “are constantly overweight,” says Anna-Maria Arabia, CEO of the Australian Academy of Science, “both in terms of the quality of our research and the publication rate 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, both work in vaccine technology. “There could very well be Australians fighting this thing,” says Frazer, a Brisbane-based immunologist who co-created the HPV vaccine, which since 2006 has protected some 300 million women from cervical cancer. ‘uterus.
“We have very talented people. We have immunologists, virologists, protein chemists and cellular biologists. “
“We really have good science here,” said Doherty, who won the Nobel Prize in Physiology or Medicine in 1996 for his work on human T-cell immunity. “For our money, compared to the United States, where I worked for a long time, we are doing very well. We have very good people. In fact, I don’t think I really appreciated how good they are so far. “
In January, Australian scientists (at the Doherty Institute in Melbourne, named after the great man himself) were the first outside of China to sequence the COVID-19 genome, develop the virus and share it with others. the international.
Several laboratories and hospitals across the country are studying drugs like remdesivir (an Ebola antiviral), tocilizumab (an immunosuppressant used primarily for rheumatoid arthritis), the HIV drug Kaletra, and the antimalarial treatment hydroxychloroquine to treat COVID-19. At the same time, REMAP-CAP, a multi-factor trial underway in Australia at more than 100 sites around the world that typically examines treatments for severe pneumonia, has pivoted to test drugs on COVID-19 patients, with the ability to modify them on the basis of continuous analysis.
“We have a lot of drugs that we are trying to reuse,” says Frazer. “And maybe some of them will work – but for now, it would be fair to say that the trials are … empirical. In other words, we are guessing. “
“We have a lot of drugs that we are trying to reuse. And maybe some of them will work – but for now, it would be fair to say that the trials are … empirical. In other words, we are guessing. “
Immunologist Ian Frazer.
“Drugs are good,” says Doherty. “But unlike a vaccine, no drug can immunize you. Even convalescent sera [antibodies extracted from recovered patients’ blood and given therapeutically] and monoclonal antibodies [lab-grown versions of antibodies] are only temporary. You should continue to take them, just like a medicine, because their protection gradually disappears. “
Even vaccines are not without problems. In the past, work on vaccines against other coronaviruses (such as MERS and SARS) has raised questions about the strength and longevity of the immunity produced by the vaccine; and the negative effects of a vaccine on the immune system. There has even been a debate about the possibility of a vaccine against COVID-19, since no vaccine against human coronavirus has ever been produced.
“There is one for chickens!” said Doherty, betraying his veterinary origins. “My wife and I worked there about 50 years ago!” He’s laughing. “But no, seriously, you hear about” no coronavirus vaccine “, but in fact, they were making a lot of progress with the MERS and SARS vaccines. The reason they didn’t go anywhere was basically because the SARS had burned, and although MERS continues to grumble, it only infects about 200 people a year. There is simply no big boost at this level of infection. “
He’s laughing. “I am a very simplistic thinker. But the fact is that all drug treatments are plugs. What we want for COVID-19 is a vaccine. And I think we will have one, and it will work well. . “
Rightly, the oldest inoculation records come from the source of the new global pandemic – China. The first disease contained by vaccination was smallpox. Devastating, incurable, with a death toll of 20 to 60% and the survivors often left blind and horribly marked, smallpox was – as old-fashioned as it was – a pathogen much more dangerous than the coronavirus. But in the 1500s (and perhaps much earlier), Chinese doctors had realized that if the sick could only survive the first onslaught of smallpox, they never caught it again. After the first attack, something in the survivors’ bodies permanently protected them.
Going back from this conclusion, the doctors took the healing crusts from the smallpox pustules and crushed them into powder. Then they blew up the powder in the noses of healthy patients. There was also a second technique, which may have originated in India, in which pus from smallpox wounds was scraped into incisions in the skin of healthy people with a needle. (No one said the drug looked good.) In both cases, the people treated contracted a milder form – at least in theory – of the disease, from which they could recover more easily.
These strategies, in particular the needle technique, known as variolation, worked in a surprising number of cases: in the 18th century, only one or two out of a hundred patients died of deliberately induced smallpox. These chances – although horrible for the modern mind – were so much better than risking disease without an intermediary that variola spread from China to the Arab world. Eventually, in the 1700s, it reached England, the United States, and Australia.
Variolation was practiced on princesses and kings, but its most important application was perhaps the arm of a schoolboy from Gloucestershire. Edward Jenner, now recognized as the father of immunology, was varied during his childhood, and therefore – rather against all odds of the 18th century – did not contract smallpox. Instead, he grew up to develop the world’s first vaccine.
Jenner realized that using pus from lesions in bovine smallpox, a much less serious disease that nonetheless offered effective immunity against smallpox, was a much safer treatment than traditional variola. At the time of his death in 1823, hundreds of thousands of people had undergone a “vaccination” (the word comes from the Latin vaccinus which means “from a cow”), and a direct line can be drawn from his work towards the final eradication of smallpox from the earth in 1980: the greatest triumph of vaccination, and the most successful medical intervention , in terms of lives saved, in human history.
We have come a long way ever since Jenner built a “Vaccine Temple” in her English garden, but for pandemic experts, it often seems like we haven’t made any progress. Professor Trevor Drew, Director of the Australian Center for Disease Preparedness (CDP) at CSIRO Melbourne, spent years dealing with the fact that before COVID-19 the man on the street simply couldn’t believe that a pandemic would never really happen. “For most countries in the world, it was a terrible shock,” he said, only to sound a little sad. “But we, infectious diseases, have known for years that it’s not a question of if, but when. We didn’t know what it would be or where it would come from, but we knew it was going to happen. “
However, it was not until January of this year that the CDP signed a contract with CEPI to conduct trials on potential COVID-19 vaccines. This was before virtually nothing was known about the virus, including its lethality – and the CDP is one of the few laboratories in the world designated BSL-4 (biosafety level 4), authorized to treat the most pathogenic agents dangerous on earth. – like Ebola, Marburg and hantaviruses.
“It was an extremely important challenge,” admits Drew, with a scientist’s understatement. “We had to be extremely agile, and it’s a huge tribute to my team that we were able to get organized so quickly.”
COVID-19’s social distancing measures have created many headaches in recruiting labs and organizing teams – Drew is speaking from his spare bedroom, no doubt a typical site for breakthroughs in all areas of human activity these days – but no one on his team has flinched. “I am so proud of them. They all started. “
The CDP is a world leader in the use of animal testing in the development of vaccines. Its scientists were the first in the world to confirm, for example, that ferrets were sensitive to COVID-19, thanks to the fact that they have a similar lung cell receptor, ACE 2, to that of humans. It is this receptor that the now famous “cutting edge protein” of COVID-19 plugs into to infect cells. Thus, ferrets, like us, can get a coronavirus (although, unlike us, their worst symptom is a mild cough).
CSIRO is currently conducting animal trials using ferrets for two vaccines – one from the US biotechnology company Inovio Pharmaceuticals and the other from the University of Oxford. The two were sent there because they looked particularly promising. “Our job is to assess the data and send it back to CEPI and WHO,” says Drew. “Then they will decide if they are worth taking the next step.”
Animal testing is still crucial to determine whether the candidate vaccines are safe and effective. But in the case of COVID-19, Drew and his team can help solve two other problems. One is temporary immunity, which means that several doses of vaccine may be needed (a big problem if you are potentially dealing with billions of people); the other is that some deaths from COVID-19 seem to be caused not by the virus but by the body’s response to it: a wild immune over-stimulation known as the cytokine storm.
“For these two problems, our trials are examining different routes of vaccine delivery – oral, intramuscular – to see if it might affect these results,” says Drew. “The vaccine route could lead to a different level of immunity. It could also be important for avoiding immune-mediated diseases. “
“Scientists are always collaborative, but these levels of cooperation – this global response – are truly unprecedented. But then, these are unprecedented times. Our competition is against the virus, not against each other. “
Professor Trevor Drew, Director of the Australian Center for Disease Preparedness.
So far, things look promising: ferrets have had no adverse effects on both vaccines and they will have been exposed to the virus before this article went to press. And so, by the time you read this story, up to 6,000 people in the UK may have received the vaccine in a safety trial. If this happens, this human trial may take place, in part, through animal testing by CSIRO.
“It’s a real global effort,” concludes Drew. “Scientists are always collaborative, but these levels of cooperation – this global response – are truly unprecedented.” He pauses. “But then, these are unprecedented times. Our competition is against the virus, not against each other. “
Professor Nigel Curtis sits in his office at the Murdoch Children’s Research Institute (MCRI) at the Royal Children’s Hospital in Melbourne. As head of the Infectious Diseases and Microbiology Research Group at MCRI and Professor of Pediatric Infectious Diseases at the University of Melbourne, he works not only in the laboratory, but with patients, and the weekend of January 27 , he thought of the hospital switchboard. accidentally sounded her day off.
“I answered the phone and said,” Look, I’m afraid I’m not on call today. “And they said,” No, he’s the special medical adviser from the World Health Organization, who calls from Geneva. “So I said, ‘Oh, right, I’ll take that call.’ “
WHO contacted Curtis regarding COVID-19. This is not a new innovative technique for this equally new virus, but its expertise in one of the oldest known vaccines, the BCG tuberculosis vaccine.
In the 19th century, tuberculosis – often called “consumption” – would have killed one in seven of the people who would never have lived. The BCG vaccine was developed by two French bacteriologists at the beginning of the 20th century (their work continued during the First World War with the help of the occupying German veterinarians) and was administered for the first time in 1921. It was administered to more than 4 billion people and is still used to vaccinate more than 100 million children a year. “It is incredibly safe and extremely well studied – although the amazing thing is that we still don’t really know how it works,” Curtis laughs.
Of course, BCG is not a vaccine for COVID-19. But the WHO is interested in its off-target effects; its “accidental benefits,” as Curtis calls them, which can affect the severity of COVID-19. Indeed, in hundreds of studies, many by Curtis and colleagues, BCG has been shown to significantly boost general immunity. Babies who receive BCG, for example, regardless of their TB protection, are also less likely to get sick with other things, such as diarrhea, sepsis, or respiratory illnesses. “It can reduce all-cause mortality by 30 to 40 percent,” says Curtis. “It is a dramatic reduction.
“It seems to work in different ways, but the main thing that we think is happening is that the vaccine provides immune training to the innate immune system.”
This part of the immune system is rarely involved in the action of the vaccine, as it has nothing to do with antibodies, which are a function of B cells in the adaptive immune system. But “this is the front line defense, if you will: it holds the fort until the adaptive system acts. And what we have shown, with our partners in the Netherlands, is that BCG modifies some of your immune cells, so that your initial and innate response is more intense, deeper. And so we think that if you have recently had BCG, the response of your innate immune system when you receive COVID-19 will be faster and stronger. This will kill the virus and reduce the viral load. “
In January, WHO asked Curtis and his colleagues if they would conduct a study using BCG on health workers in Wuhan, China, to see if it would protect them from the new and threatening coronavirus known to circulate there. “In the end, there was complete chaos in Wuhan at the time, and it was just too difficult to start a study,” says Curtis. “But a few months later, when it became clear that the virus was going to spread around the world, my whole research team met on a Sunday and we said, ‘Okay, let’s stop everything we do and put all our effort in this. “
It was March 8. Usually, a large randomized control trial – the most rigorous and reliable form of gathering scientific evidence – takes at least six to 12 months to start. But three weeks later, with the entire MCRI team working “seven days a week and very long hours,” they were ready. The first participants in the so-called BRACE trial – all Australian health workers – were recruited at the end of the same month.
It works via an application, which tracks each illness experienced by the participants using a daily log of symptoms and progression of the illness. At the time of writing, the trial had just received $ 10 million from the Bill & Melinda Gates Foundation to increase the number of its participants to 10,000 and expand its trial sites abroad: the largest philanthropic donation to an Australian initiative COVID-19 to date. BRACE has also been personally approved by the Director-General of WHO, Dr Tedros Adhanom Ghebreyesus.
Intermediate results are expected next month, and
Curtis is hoping what they could show. “If I didn’t think it would work, I wouldn’t have worked 24/7 for the past month to start this study!” he said a briefing a few weeks ago. “But in science, we need RCTs. Large randomized studies with controls are the only way to know if something is working. “
“The great thing is that if it Is work, it can be delivered incredibly quickly and safely, ”he says now. “It is already readily available in many WHO accredited laboratories around the world – even if we have to leave children vulnerable to tuberculosis without a vaccine – so that production can be increased rather than started from scratch. For those who were vaccinated when they were children, they can take the vaccine again: indeed, the effects can be amplified by a second dose. There are also very strict indications for use outside of testing, so people won’t rush and get vaccinated, like with chloroquine. “
And finally – and significantly – the use of BCG as a proven therapy can be important not only for COVID-19, but for the next global health crisis, and the next, and the next.
“Who knows when the next pandemic will come,” says Curtis. “But it will come. Many of us have been saying this for years and no one was listening. UK and US both failed readiness 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 are afraid of not learning the lesson: we will not be ready. Next time it will be something different; possibly much more lethal than COVID-19. We have to be prepared. We may need a cap until we develop a vaccine. And maybe that is the thing that we can use. “
The most advanced possibility in Australia for a homemade vaccine for COVID-19 did not start dramatically. Senior researcher Dr. Keith Chappell started as a “side project” after returning to Brisbane from Madrid nine years ago. “He came back to my laboratory and asked me if he could continue watching it,” recalls Professor Paul Young, director of the University of Queensland (UQ) school of chemistry and molecular biosciences. “And he came up with the idea of what is now our vaccine technology.”
The problem Chappell, Young and his fellow researcher, Dr. Dan Watterson (who now jointly hold the patent), had to solve is a fundamental characteristic of the behavior of the virus: their nature to change shape. “Viral proteins undergo many shape changes,” says Young, which makes them difficult to enclose in a stable vaccine form. “If we take COVID-19 as an example, when the virus enters the body, it is in what is called a form of pre-fusion: it is very unstable. It is a bit like a mousetrap in the spring.
“Then, when it enters the host cell, it goes through this very dramatic change, which fuses it to the host cell so that it can begin to replicate. [No virus can reproduce on its own: it must hijack a host cell for replication.] So if you can block this step, it is a very effective way to prevent infection. We have developed what we call molecular forceps, which acts like a bulldog clip on the mousetrap, blocking it and preventing it from spurting out. “This bulldog clip, or molecular clip, is the basis of the UQ vaccine.
One of the beauties of 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. The success was such that in 2018, the team was only the second university organization in the world to be funded by CEPI.
This funding was aimed at developing a “rapid response immunization system”. With partners such as CSIRO, the Doherty Institute and the Australian National University, the idea was to organize molecular clamp technology to use it as a universal vehicle, into which they could stick any protein pathogenic. Barely a year after the funds arrived – and, like CSIRO, much earlier than they expected – they were asked by CEPI for COVID-19.
“Everyone has been working 24/7 for three months, so we’re all exhausted, but we’re all thrilled at the same time.”
Professor Paul Young, Director of the School of Chemistry and Molecular Biosciences at the University of Queensland.
“CEPI’s initial funding request specified that you would be able to have a vaccine ready for clinical trials within 16 weeks,” recalls Young. “And at that time, everyone said,” Well, it’s just crazy. »» The 60s mumps vaccine – the fastest in history – took four years. “But it’s a good goal to have; and in fact, we are confident we will get there.”
This confidence is based on the fact that, first, the key aspect of their technology – the molecular clamp – is ready to work. In addition, they specifically studied ways to speed up the standard vaccine pipeline.
“Traditionally, vaccine development has been a linear sequence over several years,” says Young. “Discovery, development, preclinical animal experimentation, then human trials in phases [small safety trials, larger studies for efficacy, then really large populations]. Only then do you go to a regulatory authority; and only if this is the manufacturer intervenes. “
So how do you speed up this process without sacrificing science or security? UQ decided to focus on manufacturing. “We have separated the manufacturing component from the whole process,” says Young. “So we are continuing our preclinical studies, while preparing for manufacturing.”
This is a high risk strategy because it literally means producing a vaccine that may not work. But the fact, says Young, is that it’s a financial risk, “not a security risk. You could devote a lot of resources to something that might not happen, it’s true. But we are convinced that it will be. “
When we talk in late April, the UQ vaccine has just passed an important step: it induces an extremely powerful immune response in animals. In the field of cell culture, tests by the Doherty Institute have shown that it stimulates an even better antibody response than that of patients who have recovered from COVID-19 (who have developed their own antibodies against the living virus).
The next steps are to challenge ferrets and hamsters tested with the live virus (just as Trevor Drew does at CSIRO), complete standard toxicology studies, and keep the manufacturing schedule on track for this year. “We are already producing reagents and organizing the infrastructure for large-scale production, and we are currently in discussions with the manufacturers,” says Young. “There are actually not many companies in the world capable of dealing with a global vaccine. Hundreds of millions of doses – only the big pharmaceutical companies can do it. “
Young admits he is “relieved” that the vaccine has been so successful so far and says he is optimistic about its future.
“Our schedule is next month, possibly July for human trials,” he said. “And we are on the right track.” Ideally, the UQ vaccine could be ready for production in September and available for widespread use in early 2021.
It is clear that Young, who speaks from his home in Brisbane, feels both the responsibility and the pleasure of this position. He and his team may be about to change the world. “The laboratory is simply incredibly excited,” he admits. “Everyone has been working 24/7 for three months, so we’re all exhausted, but we’re thrilled at the same time.”
The months since COVID-19 appeared have been memorable for most people on earth. Like the scientists at COVID-19, we have all learned a lot since this microscopic spark of destruction emerged from the alleged wet market in China. Unlike scientists, it is not clear if we will remember any of them. But one thing will surely remain with us. We now understand, in a way we have never known before, that vaccines are not just a daily detail of modern health care, but a miracle of human ingenuity: a miracle that allows us to deceive the dead.
Paul Young, comme tous les scientifiques de cette histoire, est modeste, amical et inspirant confiance. Mais il peut détenir le pouvoir de la vie et de la mort pour des millions de personnes dans son laboratoire, et il le sait.
«La plupart des gens entrent dans ce genre de science pour faire une différence», dit-il. “Dans nos cœurs, c’est ce que nous désirons tous. Et nous sommes dans l’un de ces rares moments de l’histoire où c’est vraiment possible. “