As of 29 June, 2020, the World Health Organization (WHO) had, since January, recorded 10,021,401 ‘official’ cases of COVID-19, with 499,913 deaths globally. These numbers are certainly too low. ‘End of life’ is unmistakeable, so those counts may prove to be no more than two-fold out when we later see annual excess death statistics. But case numbers must inevitably reflect differential capacities to identify asymptomatic and mild infections by expensive PCR testing.

Until we have reliable, cheap serological assays that can be used at very large scale to detect the antibody ‘footprints’ of past infection, it is possible that the real ‘case numbers’ globally could be as much as 5 to 10-fold higher than the WHO figures. Following the extreme ‘10x-too- low’ scenario, a simple calculation tells us that 98 per cent of the global population is still vulnerable. Most epidemiologists think that ‘herd immunity’ should cut-in for COVID-19 when about 60 per cent of people have been infected. Some regions, like Brazil, where there has been minimal intervention by government will hit that earlier than others. Such ‘natural experiments’ are being closely watched. But it’s obvious that, for many countries, there is a way to go. This may only come to an end for most with the roll-out of effective vaccines to boost ‘herd immunity’ across the planet.

Real viruses don’t move themselves. They don’t blow across the oceans like dust plumes from the Saharan Air Layer and they are not, like computer ‘viruses’ and conspiracy theories, disseminated via 5G networks. SARS- CoV-2, the virus that causes the disease COVID-19, flew around the world in people travelling in Boeings and Airbuses. Could the global spread of this virus have been slowed, even stopped, if there had been an early decision to shut down non-essential international air travel and impose quarantine restrictions on incoming passengers and flight crew? The thinking of responsible bodies like the WHO and the public health authorities advising national governments was, I suspect, conditioned by the influenza mantra, that it isn’t possible to block the global spread of respiratory viruses by stopping the planes. But is that true?

Prof. Peter Doherty

We now know, particularly from the Australian and New Zealand experience of confining newly arrived travellers in supervised hotels, that a properly monitored 14-day quarantine can greatly limit virus entry. The influenza model was, perhaps, more historical and ‘conviction- based’ than fact-based. Both influenza and COVID-19 can be transmitted by people who are pre-symptomatic and, in the case of the coronavirus, we can add ‘remain asymptomatic’ to that. The R0 (the basic reproductive number for a virus, essentially, how infectious the disease is) for a highly infectious influenza A virus and for SARS- CoV-2 is about 2.5, so what works for one should work for the other.

Influenza is an old and familiar disease, and we don’t stop the world for it. But one of the lessons we could learn from COVID-19 is that if an influenza A virus strain that’s as bad as the 1918-19 ‘Spanish flu’ virus comes out of nature sometime in the near to distant future, it would make sense to put strict controls on internal and international travel fast. Then, with SARS-CoV-2 being the third bat coronavirus to cause a human epidemic in the past 20 years, we are acutely aware that bats host many more coronaviruses, along with known human pathogens in the henipavirus, ebolavirus and rhabdovirus lineage. Of course, not all of these have obvious pandemic potential.

Is COVID-19 telling us that, without effective and agreed global policies, jet planes and cruise ships may be as dangerous to humanity as the sailing ships that, from the 15th century, transported Europeans to the remote ‘New Worlds’ of the Americas and Australasia? Smallpox, measles, yellow fever and so forth travelled with those adventurers to wipe-out large numbers of the immunologically naïve, and totally vulnerable, Indigenous peoples. What we are doing now with such large population sizes and food stress in our connected (yet massively unequal) world is to ‘sample’ the remotest corners of the earth for novel, pandemic pathogens.

Pandemic influenza A viruses may be novel but, as I will discuss later, there can be significant cross-protective immunity resulting from prior exposure to other flu strains. The thought may come as a surprise, but COVID-19 could, in fact, be the first global pandemic caused by a completely new (to humans) respiratory virus since modern science began in the 17th century. As such, it joins the human immunodeficiency (HIV) viruses that so dramatically impacted on us from the early 1980’s, though there’s now reasonable evidence that these retrovirus infections were grumbling away in West Africa for the previous 50 years. Like SARS-CoV-2, they were disseminated globally by jet air travel. Of course, HIV and COVID-19 pose different levels of threat. Changing behaviour and cleaning up the blood supply stops HIV transmission, but we can’t decide not to breathe!

Peter Doherty receiving the Nobel Prize for Physiology or Medicine from King Carl XVI Gustav of Sweden on 10 December 1996, the 100th anniversary of Alfred Nobel’s death.

As we think about the lessons learned so far from COVID-19, a major consideration may be to work out how we ensure that a rapid, hopefully short, sharp lockdown of people-transfer between nations states could be implemented without causing major economic damage. That would cost all countries infinitely less than yet another, and likely much more severe, pandemic.

Humanity has been on a very steep learning curve since, reacting to a 31 December 2019 report from the Wuhan Municipal Health Commission that they were seeing an atypical pneumonia of unknown cause, the World Health Organization (WHO) published (5 January, 2020) the first Disease Outbreak Bulletin to alert the public health community and the global media to the disease we call COVID-19. From the outset, both the WHO and the local virologists were primed by the 2002/3 SARS-CoV-1 experience to think that a coronavirus might be involved.

That was confirmed when Chinese investigators isolated the SARS-CoV-2 virus that causes COVID-19 on 7 January and made the gene sequence available globally a couple of days later. Knowing the viral RNA sequence enabled those who already had appropriate ‘platform technologies’ to start right away with the job of making vaccines. It also allowed Mike Catton and Julian Druce of The Royal Melbourne Hospital’s Victorian Infectious Disease Reference Laboratory (VIDRL) that is part of our Institute to add a sensitive PCR (polymerase chain reaction) test specific for SARS-CoV-2 to the more broadly reactive assay established earlier to detect the SARS-CoV-1 and MERS viruses, neither of which caused disease in Australia. Variants of the SARS-CoV-2 PCR are the ‘tests’ that, as we all understand, have allowed the identification of currently infected individuals that facilitates targeted control strategies.

Arriving in Melbourne from China on 19 January, a returned resident very responsibly alerted authorities several days later to the fact that he was symptomatic and could be infected with this new virus. The diagnosis was immediately confirmed by PCR and, by Australia Day (26 January), Mike, Julian and teams had recovered infectious SARS-CoV-2 from him and announced that that the virus would be made available globally to legitimate laboratories. That was important: having fully infectious virus meant that researchers and diagnosticians could, for example, do virus neutralisation tests to measure protective antibodies in serum, screen chemical compounds (small molecules) for possible antiviral effects in tissue culture and challenge immunised animals to test for vaccine efficacy.

So, here are a couple of very big lessons that those of us who work in science understood but some in government and many in the broader community may not have fully appreciated.

The international co-operation that is essential for all science, and especially for public health science, functioned for COVID-19 from the outset and has, in fact, continued to work. The WHO did its job of alerting responsible individuals and agencies to the fact that there could be a problem, the Chinese gave out the gene sequence as soon as they had it, and our Institute was the first to provide the infectious virus globally for key laboratory tests. Locally, the communication mechanisms between public health professionals and elected officials proved fit for purpose. The Australian government was immediately aware of the potential threat and the Minister for Health, Greg Hunt, made a public announcement on 25 January that we had recorded our index case.

Additional to that, the very big lesson we should all take on board here is that modern science protects and serves us. Though everyone understood that the catastrophic influenza pandemic of 1918/19 was caused by a virus, diagnosis back then was all symptomatic, no human influenza virus was isolated until 1933 and it was only during World War 2 (1939-45) that the first, primitive influenza vaccines were rolled out to protect the troops against the possibility of a repeat pandemic that, thankfully, did not occur. When it comes to SARS- CoV-2 and COVID-19 we had a specific diagnostic test within days and, I will personally be very surprised if large-scale human vaccination is not in full swing by the second half of 2021.

Even so, the big lesson for the public is that, no matter how wonderful the laboratory science, actually getting products out there to protect people is a much more cumbersome process. Ensuring that a novel drug or vaccine is safe and efficacious takes time. Even though regulatory authorities have been comfortable with the idea that preliminary trials in animals and small numbers of human volunteers (Phase 1) can be conducted simultaneously, all that information must be evaluated before any product can be given to substantial numbers of people. Every possible effort is being made to ensure that all participants in large, closely monitored Phase 2 then Phase 3 trials will be protected, or at least safe, following community exposure to SARS-CoV-2.

Much of what had to be done over this first six months of the COVID-19 challenge was just plain hard work. An enormous effort was, for example, made within VIDRL to build testing capacity by helping other private and public laboratories get up to speed. And the Institute is still in the process of evaluating rapid person-side antibody tests that can be used for large-scale serological surveys. The obvious lesson here is that we are protected by having well-funded, high quality public laboratories and Institutions that can rapidly build capacity in the face of any pandemic threat. Next week, I’ll finish my assessment of the lessons we’ve learned so far, to return to that six months from now.