05 Jul 2021
Issue #64: Immune escape variants: will they be a major problem in COVID-19?
Written by Nobel Laureate Professor Peter Doherty
As mentioned several times through this series, much of our initial thinking about SARS-CoV-2 and COVID-19 has been influenced by our long experience with influenza (#37, #46). That’s been useful in some respects, but it has also, at times, made our interpretation of COVID-19 somewhat blinkered. It took us a while, for example, to realise that COVID-19 is both a respiratory and a systemic (viraemic) disease, with virus distributed via the blood directly infecting cells in the heart, kidneys, vascular epithelium and so forth. As a consequence, COVID-19 can present as a primary coagulopathy characterised by small and large blood clots that interfere with oxygen exchange in the terminal alveoli of the lung, or occlude larger vessels and cause strokes. Neither viremia nor vascular blockage are prominent characteristics of the acute stage in human influenza.
Though it’s not absolutely proven, I have the sense that COVID-19 vaccines work so much better than flu vaccines (#49) because, as the immune system operates optimally (#21) to maintain high levels of neutralising antibody in blood, stopping the systemic phase prevents much of the more extreme pathology caused by the coronavirus. While vaccinated people may be SARS-CoV-2 PCR positive in the nose and even experience ‘coughs and sneezes’, they aren’t all that sick because any virus that gets into the blood is immediately neutralised by high levels of circulating, spike protein-specific, antibody. And, even if local antibody levels remain low in the upper respiratory tract, any virus-infected epithelial cells may, perhaps, be quickly eliminated by the ‘recall’ of the vaccine primed SARS-CoV-2 spike-induced CD8+ ‘killer’ T cell response (#34). If that’s insufficient, newly made infectious virus that drains to the adenoids, tonsils and cervical lymph nodes will stimulate ‘naïve’ CD8+ T cells responding to peptides from additional proteins that are present in the virus, but not the vaccine (#38, #49). Some of these will differentiate to be the ‘killer’ T cells that, leaving the lymphoid tissue, circulate in the blood, and exit back into the nose where they destroy any virus producing factory cells though not, perhaps, until the infected individual has been sniffling for a few days.
What worries many in the broader community is that, as with influenza, we are in constant danger that our hard-won vaccine-induced immune protection will be overwhelmed by a virulent, SARS-CoV-2 immune-escape mutant. Working out of national Reference Laboratories that feed to the six WHO Collaborating Centres for Reference and Research on Influenza, the leaders of that influenza surveillance community – including Kanta Subbarao and Ian Barr from our Institute – meet twice a year in Geneva to decide on the emerging variants that go into commercial influenza vaccines for the year to come. The best-case scenario is, of course, that we keep ahead of the game by providing a new product annually that protects against novel variants. Will that also be needed for SARS-CoV-2? I’m not convinced, but we shall see.
As discussed last week (#63), the COVID-19 mutants that have been significant so far have all emerged because they grow better and spread more rapidly in ‘virgin soil’ populations that are largely immunologically naïve. Their greater transmission (versus the original ‘wild type’ Wuhan strain) likely reflects some modification of the spike protein RBD (receptor binding domain) that allows the variant to attach better to the human ACE-2 receptor and, as a consequence, infect cells more readily to give increased virus production. But, while changes that improve infectivity may diminish the tightness of (vaccine-induced) antibody binding, the variants we’re seeing so far do not look like immune escape mutants. Still, as vaccination becomes the rule, might immune-escape mutants indeed emerge? If we were to look closely at large numbers of infected, but vaccinated subjects, which we could do using a ‘broader spectrum’ PCR, it’s likely that we would find such variants. But will they be a threat? A likely scenario is that most, if not all, will suffer a ‘fitness cost’ that diminishes their replicative capacity and thus transmission. In short, will they become established in a human transmission cycle, or flame briefly, and disappear?
Each year, across the planet, the influenza viruses must be throwing-off enormous numbers of mutants, though we normally see only one or two variants that emerge and go on to cause widespread and severe disease in previously-infected, or vaccinated populations (#52). Similarly, in HIV/AIDS, where this persistent virus undergoes sequential, immune-defeating mutations within the infected individual, these escape variants don’t normally take over when it comes to transmission between people (#61). This presumably reflects that the original (wild-type) HIV strain has not had to ‘pay a price’ to avoid virus neutralisation and, as a consequence, still retains a greater level of fitness.
So there lies the question for SARS-CoV-2: is the much lower (than for flu or HIV) prevalence of mutation for the CoVs sufficient to provide immune escape variants that can both change at the RBD site to avoid neutralisation (blocking of binding to ACE-2) while providing a modified RBD that still enables a high level of infection, replication and transmission? The answer is, of course, that we don’t know. And what is equally certain is that we will be ‘instructed by nature’ and find out. Next week, we’ll discuss possible scenarios suggested by this type of reasoning.