Issue #63: Virus variants, the different dynamics

Written by Nobel Laureate Professor Peter Doherty

Viruses use a diversity of survival strategies that allow them to persist and ‘succeed’ in nature. This survival game can be broken down into two broad themes. The first concerns those characteristics that facilitate transmission of the infection between individuals, while the second deals with the molecular mechanisms viruses have evolved so they can multiply and persist within us. Of course, these aren’t necessarily mutually exclusive functions, but it is a useful separation as we think about how virus mutants emerge (#6, #48).

Standing against viruses in the higher vertebrates (bony fish, reptiles, birds and mammals) is the highly specific adaptive immune system with its antibodies (or immunoglobulins, Igs) and ‘helper’ CD4+ T cells and ‘killer’ CD8+ T cells (#18, #21, #41). All these vertebrate species can potentially be vaccinated though that human-directed strategy is, of course, restricted to us and to species (pets, racehorses, working animals, farmed fish, birds and mammals) that are part of our sustaining system. In each case, vaccine protection (or resistance to reinfection) is mediated by protective Ig molecules in mucus, blood and other body fluids that attach to surface proteins on free virus particles, or virions. Coating the key sites on the virus with neutralising Igs inhibits binding to cell-surface receptors (ACE2 for SARS-CoV-2) that enable entry into the cells the parasitising viral genomes ‘take over’ and turn into virus production factories.

That interaction between virus and immune Ig is a key determinant of virus mutant selection. Just a few nucleic acids (#6) need to change to allow the emergence of novel variants that can potentially bypass vaccine-mediated protection. The job of the CD8+ killer T cells, which can also select virus mutants though at much lower frequency, is to destroy the infected factories and help terminate the infection. On the other hand, the CD4+ helpers ‘nurture’ – by providing secreted lymphokines that promote lymphocyte proliferation and differentiation in the lymph nodes – the dividing B cells and T cells (#42 #45).

When it comes to the three types of RNA viruses (#6) we’ve been discussing in this series, the coronaviruses (SARS-CoV-2), the myxoviruses (influenza) and the retroviruses (HIV), it’s only the much bigger coronaviruses that have any proof-reading mechanism to limit the emergence of mutants (#46, #61). What’s interesting here is that while variant SARS-CoV-2 strains have emerged over the past 18 months, with all those mutations effecting the receptor binding domain (RBD) that attaches to the ACE-2 molecule, they are still being blocked reasonably effectively by vaccine-induced antibodies direct at the RBD of the original (wild-type) Wuhan strain. That’s quite unlike HIV and influenza, where the variants that come to our attention are immune escape mutants that, for influenza, require new vaccines annually and make the production of an HIV vaccine a very difficult, if not impossible, task (#62).

Maybe the situation could be different in nations like Brazil where COVID-19 has been allowed to run riot, but there is a general sense that we are, in most places, seeing what looks much like a ‘virgin soil’ outbreak, where most people still have no immune protection as a consequence of prior SARS-CoV-2 infection (#21, #25). That equation is, of course, being rapidly changed in countries like Israel, the UK and the USA that have been aggressively vaccinating. The original SARS-CoV-2 mutant of concern was the UK variant (B1.1.7), which is now referred to as ‘alpha’, while the South African strain (B.1.351, now beta) that was originally regarded with great trepidation has not ‘taken over’ anywhere. Of the more recent delta and kappa viruses that are considered to have originated in India it seems that, while both are blocked about equally by neutralising antibodies measured in vitro (meaning, in the laboratory) it’s the delta variant that’s the predominant strain circulating in the substantially vaccinated UK population. People who have had two doses of either the AstraZeneca or the Pfizer are more than 90 per cent protected from the need for hospitalisation.

My personal sense is that all these (alpha to kappa) variants have come to prominence because they produce more infectious progeny, which could reflect that they take over greater numbers of respiratory epithelial cells faster and/or that each invaded cell is a more efficient production ‘factory’.  What they don’t look like is the type of immune escape mutants that we are accustomed to encountering with HIV and influenza. Though it’s early days, we haven’t been seeing new mutants emerge in the more vaccinated countries and, in fact, the alpha to kappa mutants have been around since December 2020.

That raises an important question re COVID-19. Both the influenza viruses and HIV produce enormous numbers of random variants to give a massive pool from which high-growth immune escape mutants will be selected in a substantially immune (to the original strain) population. And, at least with influenza, the disease they cause is no less severe than that experienced the year previously with the ‘wild-type’ virus. Such selection happens within the persistently infected person for HIV and, though the influenza viruses are usually eliminated within 10-14 days of initial exposure, we can see the same continuous emergence of variants in people who are immunosuppressed for some reason (genetic immunodeficiency, cancer chemotherapy) and are unable to clear the virus. The question is, will comparable, high growth immune-escape variants emerge for SARS-COV-2, a virus that throws off many fewer viable mutants? I’ll leave you with that thought, which we’ll discuss next week.