Comment

Peter Doherty
What we got wrong about Covid-19

Right at the beginning of the Covid-19 pandemic, even as the informed science community was telling everyone that this was not influenza, we were, perhaps unconsciously, basing our approach on the assumption that the causative SARS-CoV-2 virus would tend to behave like the flu. After all, we’d been dealing with the flu since the terrible pandemic of 1918-19, when more than 50 million people died in a human population about a quarter the size of that today. Covid-19 was just another viral pneumonia, right?

Wrong, although it took us a while to work out that, unlike human influenza but like measles or polio, SARS-CoV-2 causes a systemic infection, with the virus being distributed to internal body organs via the blood. Beyond that, Covid-19 can have the added complication of being a coagulopathy, a blood-clotting disease, via mechanisms that are yet to be fully understood.

Still, protective mechanisms such as social distancing, quarantine and face masks, all of which were used to contain the 1918-19 flu pandemic, worked again in 2020. Years of research and development, plus the experience of further flu pandemics and seasonal epidemics, as well as the SARS-CoV-1 outbreak of 2002-03, had honed our skills and massively advanced the underlying science.

There were other lessons, too, which helped our response. Although AIDS is a very different type of disease, dealing with the continuing human immunodeficiency virus (HIV) pandemic from 1981 has taught us much. In particular, HIV/AIDS brought the importance of social sciences to the fore. Right now, Covid-19 is demonstrating very clearly how the vagaries of human behaviour influence the spread of disease.

What SARS-Cov-2, HIV and the influenza A and B viruses share is that they all transmit their genetic information as RNA.
We know from the study of individuals infected with HIV, and from flu cases in people with pre-existing immunosuppressive disease, that these viruses throw off novel variants with incredible speed. But HIV and flu have, when compared with SARS-CoV-2, relatively small genomes that lack any proofreading mechanism to limit the emergence of mutant strains. Many of us who aren’t virologists thought that mutational change would be much less of a problem in Covid-19, but we were wrong.

Clearly, we now understand that a highly infectious coronavirus (CoV) spreading globally in an at-first “virgin soil” situation can throw off new infectious variants with incredible speed. Since Delta, what we’ve likely been experiencing is the emergence of different immune-escape variants in the Omicron lineage. All these mutants are highly infectious and cause perhaps less severe clinical impairment than we saw with the early strains. Still, some people are becoming very ill, a few are dying, and others who are symptomatic but don’t require hospitalisation are developing the distressing long Covid syndrome.

More concerning is that, with a virus that tends to cause a relatively mild disease in the young – who readily transmit the infection – but tends to be more severe as people age, there is no obvious evolutionary reason why more severe strains could not emerge. We all hope that will not happen but, with the embedding of more relaxed attitudes regarding social distancing and mask-wearing, a change of that type could give us a nasty surprise. In the past, Australians benefited from prior warning of what was happening elsewhere but, when we head into our 2023 winter, that dynamic could reverse.

The influenza A viruses are basically infections of waterbirds. Bat populations act as “sustaining reservoirs” for many other CoVs, while paramyxoviruses/henipaviruses jump from bats to horses (Hendra virus) or pigs (Nipah virus) and then to us. The same is true for some filoviruses (e.g. Ebola) and rhabdoviruses (rabies-like), and other potentially pandemic viruses that are maintained in non-human primates (the origin of HIV) and rodent species (e.g. Lassa fever). Given the size of the human population and the massive increase in passenger air travel, especially to and from countries that sell wildlife and live birds in open markets, there can be no doubt that we will suffer further pandemics.

Before 2000, we knew of two human CoVs that had emerged since the 1960s, both of which cause colds and croup and were not considered to be especially problematic. Since 2000, five more have jumped across to infect us, with four of these still known to be in circulation. The 2002-03 SARS-CoV-1 virus infected about 8000 people and about 10 per cent died. That SARS epidemic was caused by a virus that jumped from bats into Himalayan civet cats, then to humans in a live animal market. In 2004, two new “cold and croup” CoVs were detected in Amsterdam and Hong Kong, both major air travel hubs. First found in 2012, the MERS CoV is known to have infected about 2500 people, with about a third of those dying from the disease. The likely transmission is from bats to camels to humans. And then, of course, there’s SARS-CoV-2, which may have a mortality rate as low as 0.1-0.3 per cent, but is so far known to have killed at least 6.6 million people.

Another lesson that we should have learnt from Covid-19 is that it is in the interests of all of us to strengthen local public health response capacity, including laboratory capacity, while at the same time working towards more equitable, open and integrated national and global health systems. A further positive step would be to achieve general agreement between nation states that outgoing passenger flights should be stopped in any circumstance where a novel infection seems to be flaring.

Then, for those countries that maintain live wild animal and bird markets, it is clearly important to develop a monitoring system to hopefully identify any crossover of a potentially pathogenic virus into humans. The PCR test can, for instance, be designed to be very specific for a particular virus substrain, but it can also be “broad spectrum” to detect any novel CoV or henipavirus that might be infecting market workers. The same strategy can be used with rapid antigen tests (RATs), although it will be less sensitive than the PCR. Any positive result would then be followed up in a public health laboratory, using PCRs directed at known viruses and by isolating the causative virus in cell culture.

When it comes to protecting human populations, the HIV experience also has an important lesson for us. When vaccines don’t work because they are rapidly subverted by mutational change, small molecule therapeutics (chemical drugs) can be designed to block different molecular mechanisms in the virus replication pathway. Initially, because of the way the pharmaceutical industry is set up, these (as with Paxlovid for SARS-CoV-2) will be very expensive as the companies seek to make a profit while covering the high cost of the underlying research and development, then testing to ensure safety and efficacy. At least in the longer term there are ways around this by having cheap generics made in India for distribution to developing countries, as is the case with HIV.

The problem with HIV is that the virus hides by being copied (using a viral reverse transcriptase) back into the genome and (using present technology) can never be completely eliminated. Although there are hints that this might happen for bits of the SARS-CoV-2 genome (using endogenous, human reverse transcriptase) there’s no evidence that this could lead to the production of infectious virus. We also know that the various influenza viruses do not, given a functioning immune system, persist in us. The anti-influenza drug Tamiflu works against any influenza A or B virus – although, like Paxlovid, it has to be given early to be efficacious. The Covid-19 experience has shown us how to do that by the judicious use of PCR or RATs for immediate diagnosis, which must then be backed by a mechanism for rapid drug distribution.

Drugs are always an expensive way to go, compared with vaccination, but we could make antiviral, class-specific drugs to treat people infected with any novel CoV, henipavirus, filovirus and so forth. We know from the HIV experience and from cancer therapy that we need at least two different drugs in our armamentarium for each class of pathogen, to avoid mutational escape. How might these be tested ahead of time? Drugs can at first be assessed in virus-infected cell cultures, then used for preclinical safety and efficacy testing in animals. If a product looks promising, human phase 1 trials are just to ensure that the drug is safe to use in us. Then, for example, the relatively innocuous “cold and croup” CoV strains could be used to evaluate efficacy using carefully controlled and monitored human virus challenge studies. That approach has now been used for some time with influenza. The facilities to do such work are available and are being expanded.

Initiatives to develop specific antivirals for a spectrum of pathogens are currently under way across the world, but it will take major investment from governments, charitable foundations and the pharmaceutical industry to drive this work forward. Recently, the philanthropist Geoffrey Cumming donated $250 million to the University of Melbourne to establish the Cumming Global Centre for Pandemic Therapeutics, within the Doherty Institute. The intention is that all this money will go to research and development, not to building concrete edifices, and it will focus on novel approaches that might be beneath the radar of Big Pharma.

Maybe there’s a sci-fi novel to be written around the idea of a “global pandemics force” that, armed with a spectrum of great drugs, can be parachuted into an afflicted region as soon as there’s the hint of a potentially dangerous outbreak. During the peak of the Victorian Covid-19 experience, we deployed a lab-in-a-van and a shipping container lab, either of which could be loaded into a Lockheed Hercules or Starlifter. The modern reality is that we can extend the mantra of Rockefeller University microbiologist René Dubos – to think globally and act locally and globally. As both Covid-19 and climate change are showing us, we live in one world, on one small planet. Wars, blame games, conspiracy theories and other idiocies are not the way to go.

This article was first published in the print edition of The Saturday Paper on December 17, 2022 as "What we got wrong about Covid-19".

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