In a sprawling laboratory in Melbourne, an army of robots is joining the fight against COVID-19. The mission? To scan hundreds of thousands of chemical compounds, faster than humanly possible, searching for the “needle in the haystack” – the one that can be turned into a lifesaving drug against a dangerous and fast-moving new virus.

Meanwhile, further down the corridors of the Walter and Eliza Hall Institute (WEHI), scientists are preparing to test not just how an existing drug might slow the new infection – but whether it can stop it taking hold altogether. And, next door at the Royal Melbourne Hospital and the Peter Doherty Institute for Infection and Immunity, a huge trial is kicking off that will mean most patients diagnosed with COVID-19 in Australia and New Zealand can already opt in to an experimental treatment.

A robot scans chemical compounds at the Walter & Eliza Hall Institute.

This is just one stretch of the global frontline against COVID-19. The quest for a vaccine offering immunity from the new coronavirus has already been labelled this century’s space race, such is its speed. But moving just as fast is the hunt for a drug to treat it.

Nobel-prize winning immunologist Professor Peter Doherty is hopeful the world will get its jab of immunity soon. But even the most optimistic predictions put a vaccine roll out into 2021. While we wait, treatments, ranging from existing drugs repurposed from the medicine cabinet to those that can stop the new virus infecting people in the first place, offer another road out of danger, he says.

So what are the main therapy strategies and the most promising trials? And what about Donald Trump's drug of choice: hydroxychloroquine?

What are the options for a COVID-19 drug?

This virus has never been seen before in humans. There's still a lot we don't know about it and the illness it causes COVID-19, and most of our cells know even less. We don't have any natural immunity to fight it off and there's no known medical treatment or cure. "None yet, anyway," says virologist and director at the Doherty Institute Professor Sharon Lewin.

But there are two main ways to defeat a virus, she explains. You can stop it in its tracks directly with a drug that disrupts how the microbe hacks into our cellular machinery. Or you can help our bodies cope with the invasion, ramping up or, more commonly in the case of a new unfamiliar pathogen, dampening down the immune system’s response as required.

This stops the virus either overwhelming our body’s defences or sparking an overreaction, the kind that can spiral into what’s known as a "cytokine storm" as too many virus-fighting antibodies are called to the fight and our organs become collateral damage. This storm is already playing out in hospital wards across the world as patients' lungs and even hearts and kidneys start to fail under COVID-19.

Some drugs could work on both the virus and our immune response, Lewin says. That includes the much-hyped anti-malarial drug hydroxychloroquine. Infectious disease clinician Professor Marc Pellegrini admits that, while the drug is already used safely to treat auto-immune conditions such as lupus and rheumatoid arthritis, researchers still aren't completely clear how it works. "We think it can modulate the immune system so it might stop that initial blunderbuss immune defence we know can often do more harm than good, particularly in the case of a new virus," Pellegrini says. "But in the lab it's also been shown to stop the virus replicating in cells."

Still, like those overzealous antibodies, against COVID-19 hydroxychloroquine could do more harm than good (and two early trials have raised concerns it may not be safe to use on cases of the new virus at all). It's among the therapies being considered because the fastest route to treating a new virus is to find an existing drug that can do the job, one already widely used with its own well-understood applications (and side-effects).

The World Health Organisation launched an international "mega trial" known as SOLIDARITY on March 18, testing the four drugs it ruled had the most promise: an antiviral called Remdesivir that failed on Ebola but has shown some of the most encouraging early results against COVID-19; the anti-HIV drug combo Lopinavir/Ritonavir known as Kaletra; Inteferon, which is used to regulate the immune system and treat multiple sclerosis; and a late addition, following hype from the media and the US President, hydroxychloroquine.

The trials are not double-blinded, the preferred gold standard, meaning patients taking part will know if they get an experimental treatment or if they're in "the control group" with just the current supportive care options. But scientists say the need for a fast roll-out and the large size of the new trials trump the risk of a placebo effect. They expect they will have meaningful results within months, even weeks.

Could a tablet to stop an infection?

There's another less talked about possibility. In the race for either a vaccine or a treatment, scientists may find a therapy that can do both by stopping the virus taking hold in the first place. As Pellegrini explains: "If you find a drug that stops the virus replicating and you give it to someone early enough, you can actually stop them getting infected."

Doherty agrees such drugs, which he likens to the preventative tablets taken to stop HIV infections, could be a gamechanger, offering a protective shield for at-risk groups such as the elderly or healthcare workers while the world waits for a vaccine.

"The earliest I've heard [for a vaccine] is still looking like 2021, we can't lock down that long," he says. "Treatments, but also something that prevents the infection, like the HIV PreP [pre-exposure prophylaxis] drugs you take twice a day, could get us out of this earlier."

Trials are now underway all around the world to find such a dual-action chemical. In some, healthcare workers are given a course of hydroxychloroquine over many weeks or months, at a lower dose than in trials testing the drug on infected patients.

Scientists are making no promises – a chemical that can kill the virus in a test tube will not necessarily stop it replicating in a human throat, says Pellegrini, who is leading one such prevention trial on more than 2000 healthcare workers in Melbourne for WEHI, which is double-blinded. (And, as outlined below, one major study has since found the drug was no more effective than a placebo in stopping the infection).

But, if they succeed, will we all take one tablet a day to keep coronavirus at bay?

Not according to researchers. Such a prevention drug would likely only be given to those deemed high risk or already exposed, the way the antiviral Tamiflu is sometimes given to people in close contact with an influenza case.

"Side effects from hydroxychloroquine are rare but all drugs have them, especially if given to a big population," Pellegrini says. "So, especially now the virus is not spreading as widely here in the community, if we find something that works and that's safe, you'd still want to target it to mini-outbreaks like the McDonald's cluster or people at risk, say, in aged care homes or healthcare workers."

Still US President Donald Trump is not waiting until the results are in - on May 19, the day before Pellegrini's trial opened, he revealed he had already been taking hydroxychloroquine himself for more than a week after hearing about healthcare workers using the drug proactively as an experimental preventer. "Here's my evidence: I've been getting a lot of positive calls about it...I'm still here." Trump said a doctor had not suggested the treatment, but given it on the president's request - he was also taking a daily zinc supplement and a daily dose of the antibiotic azithromycin sometimes used as a preventative. (Antibiotics do not work against COVID-19 as it is not caused by bacteria).

UPDATE: On June 3 a major study into the use of hydroxychloroquine in preventing infection delivered disappointing results - when tested on about 400 people recently exposed to COVID-19 the drug did not reduce the chance of developing the infection any more than a placebo (which was given to another 400-odd people at risk). The good news was hydroxychloroquine, when taken as a preventer in this way, did not cause any harmful side effects. The same day, the White House physician released a report on Trump, saying the President's cardiac health had been closely monitored while he took a two-week course of hydroxychloroquine, and he had now completed it "safely and without side effects".

As for patients already sick with COVID-19, another large retrospective study published in The Lancet in late May at first sparked further alarm when it linked the drug to a higher risk of death and heart complications. The WHO even temporarily paused its hydroxychloroquine arm of the SOLIDARITY trial to review the evidence. But days later, the organisation ruled it was safe to continue testing the drug - as concerns about the study's data piled up. On June 4, the authors of the study retracted it entirely, acknowledging they had been unable themselves to verify the data from the 96,000 patients involved. Researchers at the Doherty Institute confirmed on June 4 they will also continue with the hydroxychloroquine arm of their large ASCOT trial (detailed below) on patients hospitalised in Australia and New Zealand.

Could using blood from recovered patients help?

Then there's work underway into whether immunity could be temporarily "borrowed" from recovered patients via antibodies in their blood. Successfully fighting off a virus leaves us armed with these tiny warrior proteins in case it comes back, usually conferring at least a period of immunity (if not always a lifelong shield). The idea is you could perform a kind of transfusion from survivor to patient, spinning out the blood plasma with the antibodies inside.

There are lingering questions about just how many antibodies our bodies produce against COVID-19 and how long they last. But hospitals in the US are already running trials of blood plasma donations from survivors for critically ill patients. Of course, if it works, there will be another hurdle to pass – supply. The current survivors, however generous, cannot donate enough blood plasma to inoculate the world.

In Australia, biotech giant CSL has started "investigational" work on a possible blood plasma treatment for the most critically ill patients. Australians who have recovered from COVID-19 more than 28 days ago can donate via Lifeblood - but its estimated about 800 donations will be needed to treat 50 to 100 patients in a clinical trial.

"We could make antibodies specific for the virus, we do [that] all the time," Doherty adds. "We grow them in enormous quantities in vats."

Creating our own custom antibodies against COVID-19 comes with its own lengthy testing – and takes us back into the realm of vaccine development. At the very least, survivors of the virus now carry in their veins crucial molecular clues for both inoculation and drug therapy.

What are they testing on COVID-19 in Australia?

To find out which drugs will work best against a new pathogen, scientists have to first play detective. Professor Mark von Itzstein, who heads the Institute for Glycomics at Griffith University, says designing a drug to kill off the virus directly means finding a good target for the attack – usually the protein that the virus uses to break into human cells and start making copies of itself. In this case, the much talked about spike protein.

A number of drugs have since emerged that show promise against the virus and its spiky weapon – killing it off at least in test tubes.

"We've been screening a lot of those, and already getting some hits," von Itztein says. "We've got some low-hanging fruit I'm desperate to evaluate immediately. If we can show drugs are not toxic at the doses needed to kill this virus [or] get prevention drugs up too to protect our first responders from infection, we could save lives.”

A huge clinical trial led by the Doherty Institute has now been assembled across 70 hospitals in Australia and 11 in New Zealand, meaning most COVID-19 patients in the region will be able to opt in for an experimental treatment. Dubbed the ASCOT trial, it will test two drugs, at least to start with: hydroxychloroquine and the HIV therapy Kaletra. Both have been shown to stop the virus replicating in the lab and have been approved for "compassionate use" by doctors with nothing else in their toolkit in some parts of the world including the US. At least 75 per cent of the trial participants will be given one of the drugs. Of those, a third will get a combination of the two, which researchers hope might improve the odds.

Associate Professor Steven Tong is leading the trial from the Royal Melbourne Hospital and says the team will be keeping a close eye on other trials and lab studies around the world. Drugs showing promise can be added into the mix, pending supply. Nothing has been shown to work yet, all researchers stress – it's not time to rush out to a pharmacy or doctor.

ASCOT had hoped to include another frontrunner, the intravenous drug Remdesivir, but was at first knocked back by the company that makes it, Gilead, due to supply issues. Gilead is rationing the drug for trials in countries with more patients, the Australian team says, but if more becomes available, it too might be tested here over the next 12-18 months. In May, the Australian government confirmed the company has since allowed some limited use of the drug on compassionate grounds rather than for trials in a small number of Australian hospitals. Professor Tong says it is very restricted use - only for seriously ill patients on ventilators.

The ASCOT trial is designed to adapt as more information comes to hand, he says - a drug performing well can be given to more patients while something reacting poorly or even causing harm can be dropped entirely.

Could we discover brand-new drugs against COVID-19?

Back to the robots. As with many labs around the world, WEHI is now drawing on huge chemical databases to see if a drug that can fight COVID-19 might already on its books, even from the scrap heap of previous medical trials. "Maybe there's a drug designed for a skin rash that didn't work on that but passed human trials," Pellegrini says. "It might just kill COVID-19 or keep a cell alive against it."

To find this coveted compound, researchers are turning to artificial intelligence, machines that can run around the clock on a miniaturised scale not possible for humans, mixing different chemicals with viruses and cells, and using computer algorithms to decide which reactions look promising. The institute's new National Drug Discovery Centre is home to the largest screening effort in Australia. Pellegrini likens it to a factory assembling cars.

“We can’t promise we’ll find a miracle drug, more likely it will help against the next pandemic,” he says.

While the drug candidates already in trials had been quickly picked out from a screening of "the usual suspects", he stresses much is still not understood about the way COVID-19 operates. “So we need to cast our net wide too, and search as much as we can. We're throwing everything at it.”

Further north in Queensland, Professor von Itzstein is taking a different approach to fast-track screening. "We're doing a broad look too, it may turn out to be really important," he says. "But I want to solve this disease now.'

In most labs around the world, drugs are screened against viruses using monkey cells, usually from the kidneys, he says. "That's fine so long as we assume they're just like human respiratory cells. We didn't want to assume. We're using human respiratory cells straight away as well as some lung cells too [taken from] volunteers and then grown in the lab."

In the dish, he says the cells have little hairs. They beat and breathe.

"They're beautiful, living beasts. This is what the virus sees. So when we're testing on them we can already say it's more likely to get a similar result in a human. Of course in people it might be different again but we think we can get there [without] having to go into animal models. We are far, far closer."

Von Itzstein's team at Griffith University is testing how drugs can protect live human respiratory cells (above) from the virus.

How could 'designer drugs' help?

Once he and his team zero in on some likely contenders, von Itzstein has more in mind than just human trials. He wants to figure out how he could make the existing drugs being tested in hospitals even better at fighting COVID-19. His team use 3D modelling to map viruses and design "plugs" or molecules that can slot between the microbe and our cells to stop it replicating. If it can't get into cells to duplicate, it can't survive.

"Of course, we'll have to go through clinical trials again just in case the tweaks we've made create anything [harmful] but we'll already know a lot about the [existing] drug, how it works...we'll have a headstart."

Doherty says the work shows real promise. "We might need something specifically designed for COVID-19."

Why weren't we prepared for COVID-19?

Unlike the last pandemic, swine flu in 2009, this time the world is almost starting from scratch. Back then, a vaccine against the new influenza strain also had to be hastily pulled together but the virus was at least a somewhat familiar foe. The foundations for an inoculation were already laid from seasonal flu and there were two strong antiviral drugs that worked against it. One of them was Relenza, the world's first designer influenza drug, created by von Itzstein.

“In 2009, the big difference was we had drugs that worked already in hospitals,” he says. "We didn't see the diaster we see now."

No vaccine exists for a coronavirus, not even against the other two dangerous strains to emerge in the modern era, SARS and MERS. And, as both have struggled to attract research funding as caseloads fell, there are no proven drug therapies either. But scientists had been warning for years that another SARS-like coronavirus would emerge in humans thanks to "spillovers" from the animal world which are happening more and more as people encroach on habitats and poach wildlife.

Doherty says that before COVID-19 burst onto the scene in December, the world had been taking some early steps towards preparing for its next pandemic, launching a rapid response vaccine program, CEPI, in 2017 for just such an event, with coronaviruses earmarked as priority. But in hindsight, he says there should have been a similar accelerator set up for reactive drug therapies too.

"It was something we've been missing that I mumbled about but I didn't shout about," Doherty says. "We've done all right with the vaccines but we should have kept testing drugs [for] SARS, right across the coronaviruses, even others like Hendra virus. There's a lot of lessons here."

This article was first published on April 23 and has been updated to include new research.