Way back in March last year, I wrote a column for this newspaper called “The pandemic we had to have”. For the 18 months since, I’ve been very active as a Covid-19 communicator on traditional broadcast and social media, while also giving lectures, recording podcasts and taking part in panel discussions and Q&A formats, both locally and across the planet.
Early on, I decided to stick to what I know, so my focus has largely been on the nature of the disease we call Covid-19 and our virus specific “adaptive” immune response to the causative SARS-CoV-2 virus. Our institute’s epidemiologists and medical doctors have been active on various key committees, helping the chief health officers and providing analysis that informs politicians, so I’ve stayed away from commenting on public health directives, lockdowns and so forth.
Focusing on the disease, what has been the nature of the journey so far? Once the SARS-CoV-2 gene sequence was released on January 15, 2020, innovators in Britain, Europe and the United States started immediately to make the vaccines that, within months, were in clinical trials and, at least in the northern hemisphere, going into the arms of large numbers of people by the beginning of 2021.
On January 24, 2020, Mike Catton and Julian Druce, of the Victorian Infectious Disease Reference Laboratory – which is part of the Doherty Institute – used the SARS-CoV- 2-specific PCR test they’d developed from the sequence data to diagnose Australia’s first case in a self-aware traveller. PCR stands for polymerase chain reaction, and tests genetic material from a specific organism.
They also isolated the SARS-CoV-2 virus and, having had problems getting access to the SARS-CoV-1 virus in 2002-03, immediately made it available to any legitimate laboratory across the planet.
Why was that important? Researchers need infectious virus for the “benchmark” antibody neutralisation assay, to discover possible drug candidates by screening in virus-infected tissue culture, to test any promising therapeutic treatments in infected laboratory animals and to do the “preclinical” animal challenge studies that are mandated for vaccine development. Also at our institute, the Microbiological Diagnostic Unit led by Ben Howden switched some of their state-of-the-art gene-sequencing operation from bacteria to SARS-CoV-2. Tracking the minor mutations that a “barcode” virus isolates has facilitated the emergence of genomic epidemiology, which enables the public health people to trace the source of different clusters of infection.
Early on, we had the sense that Covid-19 was more lethal than it actually is. The reason was that using symptomatic disease for the initial “case definition” in major outbreaks suggested that the mortality rate following infection was in the 3-5 per cent range. From the outset, that severe toll was seen mainly in older people and in those with serious comorbidities, particularly diabetes, obesity, immunodeficiency and some forms of cardiovascular disease, a pattern that has endured. While the vaccines have worked remarkably well in the elderly, even full vaccination may not protect those who are very frail. Along with front-line healthcare workers, the aged-care community is where, following the example set first in Israel, we will soon see the rollout of a third vaccine “booster” shot.
Once public health authorities across the world started to deploy the SARS-CoV-2 PCR very broadly as a diagnostic tool to test anyone with coughs and sneezes, for contact-tracing and at airports and so forth, we soon realised that many suffer mild to asymptomatic infections with this virus. With PCR+ as the case definition, the mortality rate from Covid-19 was found to be more like 0.3-0.8 per cent, at least for those countries that can supply decent medical and hospital support, particularly oxygen to see people through their clinical crisis.
That was the good news. But the emerging bad news was that 10-20 per cent or more of those infected, including younger people with few symptoms early on, were suffering for at least three months from a debility list that included sporadic headaches, muscle pains, coughing, general weakness, lethargy and what is described as “brain fog”.
The emerging concern about what we now recognise as long Covid was driven initially by sufferers getting together on social media. As of August 1, some 970,000 people in private British households were identified as having some long Covid symptoms – about 1.5 per cent of the population. While there’s no doubt that long Covid is all too real, part of the continuing confusion around prevalence reflects that much of the data does come from self-reporting. It’s still early days, and better data will come out of sequential sampling studies in closely monitored clinical trials, a good example being the ADAPT study from Sydney’s St Vincent’s Hospital and UNSW Sydney. Such systematic analysis by professionals should help identify the underlying mechanisms and bring forward better treatments. The good news about long Covid is that it’s much less common, and of shorter duration, in children, and in vaccinated people who suffer breakthrough infections in the upper respiratory tract.
As time went by, we came to realise that the summary – “Covid-19 is like a very bad flu” – is basically wrong. The reason? Human influenza is a respiratory infection, with severe disease resulting when the virus gets deep into the lungs. We rarely find influenza virus in the blood of sick people. The respiratory tract can also be severely damaged by SARS-CoV-2, but what makes Covid-19 different from the flu is the fact the virus disseminates in the blood (viremia) to infect major organs such as the heart and kidneys.
Molecular mechanisms triggered by the spectrum of at times toxic cytokines and chemokines, secreted mostly but not exclusively by cells of the innate immune system in sites of inflammatory pathology (where white blood cells invade infected tissues), can activate the clotting cascade. In short, while Covid-19 is a pneumonia, it can also be a “coagulopathy”, with large blood clots causing strokes and heart attacks and micro-clots blocking gaseous exchange at the lung terminal alveoli. Once doctors understood this they started treating hospitalised patients early with anti-coagulant – low dose heparin – while also moderating any “cytokine storm” effects by giving those who are not getting better the anti-inflammatory drug dexamethasone. When that isn’t enough, some patients have been pulled back from the brink by blocking the pro-inflammatory cytokine IL-6 with a monoclonal antibody (tocilizumab). This is normally used to help arthritis sufferers and, as a consequence of Covid-19, is in short supply.
Heparin and dexamethasone are old, cheap drugs. By comparison, the monoclonal antibodies such as tocilizumab and sotrovimab, which neutralise the virus when given by intravenous infusion, are very expensive. That’s also true for the new oral antiviral drug molnupiravir, a ribonucleoside analogue from Merck which, when taken early, induces lethal mutations in the virus that stop it from replicating and causing damage. Our federal government has provisionally ordered 300,000 dose schedules of molnupiravir, which is still in clinical trial, as is the alternative Pfizer drug (PF-07321332, also on order), an oral protease inhibitor that again blocks viral replication.
It’s unlikely we’ll see either drug in clinical use here before 2022. Infinitely cheaper for society, and smarter for the individual in every sense, is one or other of the highly effective vaccines that are now readily available to all Australian residents who are 12 or older. Vaccines for younger children will likely be rolled out in the first quarter of 2022.
Some find it difficult to deal with the fact that vaccinated people can still suffer breakthrough infections, experience unpleasant symptoms, including loss of taste and smell for a while, and even transmit the infection. I never expected anything different. A vaccine injected into the arm gives high levels of antibody in the blood, which likely stops viremic spread to the body’s major organs and prevents the blood-clotting problem; but keeping enough antibody in the nose to stop incoming virus from infecting the epithelial cells there is a very big ask. Both the virus and the antibody molecules are inert particles, with no capacity to move themselves around. It’s a random and inefficient dating game.
A later vaccine strategy might be to puff a “booster shot” up the nose, but the optimal approach for now is to keep antibody levels high in blood so that there’s as much spillover as possible into the nose. The best thing any of us can do for ourselves, for those close to us and for our community is to be double vaccinated and get the booster when available. That will almost certainly keep us out of hospital, and we shouldn’t need the No. 3 dose for at least six months. Maybe younger people won’t need it at all.
This article was first published in the print edition of The Saturday Paper on October 30, 2021 as "Covid-19: what we’ve learnt so far".
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