Issue #120: Are we coming to the end of COVID-19?

Written by Nobel Laureate Professor Peter Doherty

The answer is, of course, that we don’t know. We would all like it to be over but wishing (or saying) that it is so does not make it so. At least in Australia, it does seem clear that the BA5 phase is winding down, with new case numbers falling dramatically in Victoria, along with the number of hospitalised patients. People are still dying, but there’s generally a lag phase before those counts also drop away.

Our national borders are now fully open, and COVID-19 is, of course, a global problem. A different variant from the Omicron lineage (BA2.7.5) is prevalent in India, but there’s a general sense that this may be a milder infection. That’s what we’ve all been hoping for, of course, that SARS-CoV-2 would just mutate to become one of the ‘colds and croup’ human coronaviruses (HuCoVs). There are already four of those circulating at least somewhere on the planet, two that we’ve known about for decades and two more that were first identified in the 21st century. If SARS-CoV-2 settles to that status, it will just be a member of a ‘club of 100 or more’ (#12). that can cause inconvenient respiratory infections in, predominantly, the colder months. Such viruses are responsible for a lot of productivity loss and occasional severe disease. That’s one reason that we will, I think, see an increasing R&D focus on ‘blow up your nose’ products that use contemporary molecular strategies to drive non-specific (for a particular pathogen) innate immune responses in the upper respiratory tract.

We might also be a little tentative in accepting the view that BA2.7.5 – which has been detected a number of times in Australia but does not seem to have ‘taken off’ – causes a mild form of COVID-19. The withdrawal of government funding for extensive SARS-CoV-2 PCR testing and genomic surveillance across the planet means that we are ‘comparing apples and oranges’ when we contrast the incidence data we’re seeing now with the case numbers for 2021 and early 2022. And that may be exacerbated by a general community weariness that has led some to either avoid using (or not report) a RAT test for a mild respiratory illness. The real measure will be the numbers of people that require hospitalisation with COVID-19. The first answer to the ‘is it over’ question will likely come from what happens through the northern hemisphere winter.

Looking at the history of COVID-19, successive pandemic waves were, until Omicron, caused by variants (#63) that seemed to originate de novo from the original Wuhan virus, the one that the vaccines are made to counter. The last of these was Delta, which was the first (at least in NSW and Victoria) to break out of the ‘ring of steel’ plus lockdown strategy established by our public health authorities. The more recent Omicron strains are mutants in the same lineage (#64) that have, with progression, expressed spike proteins (the vaccine target) that are more and more distant from that of the Wuhan strain.

The consequence is that even three or four vaccine doses do not stop people being infected, though the general message from the infectious disease, respiratory and critical care physicians who have been caring for patients is that vaccination still helps to limit the incidence of severe disease and death (#106). The grim exception is, of course, for the immunocompromised and frail elderly. We’ve discussed through this series why it is so difficult to keep high levels of protective antibodies (#18-22), or immunoglobulins (Igs) - even if they are of the right specificity - in the mucus (#10) that bathes the nasal epithelia (#89, #90).

Antibodies generally recognise unique 3D (conformational) structure determined by the amino acid sequence of folded proteins (#18, #64). In COVID-19, the virus mutates to escape from the blocking effect of Ig binding to the viral spike protein that prevents attachment to the ACE-2 molecule on the surface of susceptible cells. For SARS-CoV-2, it seems, there is a spectrum of structural options that enable the Ig/spike interaction The question re BA5 is whether it has brought us to the limit for the Omicron lineage.

The residual protective effect regrading progression and late-stage disease could reflect the recall (to effector function) of memory CD4+ ‘helper’ and CD8+ ‘killer’ T cells that, as they recognise sequences of 10-12 or so amino acids presented in the tip of ‘self’ transplantation antigens (#33, #34), are less subject to critical mutation change. Both CD4 and CD8 T cells can function by delivering mixes of cytokines to sites of virus growth, while the primary role of the CD8s is to function as specifically-targeted ‘assassins’ that eliminate the virus-producing cell ‘factories’ and bring the infection to an end.

Talking of endings, I’ve decided to stop producing what has been a weekly essay for this series. Like many of us, I badly need a break and I’ve been neglecting other issues I need to deal with. The further problem for me is that, in trying to write useful, in depth ‘explainers’ around key aspects of COVID-19, the scientific data just isn’t out there. Many systematic studies are in progress, but they aren’t yet published, even in preprint form. Cases in point relate to Long COVID (#105-118) and Hybrid Immunity. Time to back off! At least for the next few months, I’ll be limiting my effort to an occasional contribution.