Where is the next SARS-CoV-2 variant of concern?

The COVID-19 pandemic has been characterised by successive waves of new variants of concern sweeping the population. The ultimate source of these variants is not known with certainty, but preliminary evidence suggests at least some have emerged from long-term SARS-CoV-2 infections, such as those observed in immunocompromised patients.¹ As a result, it is of the utmost urgency that those with long-term infections should be able to access quality health care and be prioritised for curative therapy because a failure to properly manage these infections poses a risk to the individual and to public health.

Immunocompromised patients, such as those infected with HIV or recipients of organ transplants, can have difficulty eliminating SARS-CoV-2 infections.² Preliminary data suggest that infections often persist for many months with viruses acquiring new mutations over time³ as they presumably evade immune-mediated neutralisation⁴ and hone their ability to infect human cells. Because the virus population size within persistent infections is not limited by bottlenecks at transmission, the rate of mutation is accelerated in comparison with the population at large, so these infections typically generate considerable genetic novelty. Although the evolutionary pressures on a virus within an individual host might be different from the adaptation to transmit between hosts, it is reasonable to assume that the next variant of concern could arise from a virus population with a high degree of genetic diversity and containing mutations allowing infection of resistant individuals.

The alpha (B.1.1.7) variant arose during a period of intense surveillance in the UK and was readily seen to be highly divergent from its nearest common ancestor, having accumulated a constellation of mutations with worrisome properties more rapidly than the rest of the virus population.¹ The omicron (B.1.1.529) variant arose under similar circumstances and had about 45 mutations that separated it from its ancestor at a time when the distantly related delta (B.1.617.2) variant was dominant.¹ The beta (B.1.351) and gamma (P.1) variants are similarly divergent from their closest relatives, consistent with comparable origins.¹ The possibility of SARS-CoV-2 evolving resistance to existing therapies during such infections is real.⁵ Hence, curing COVID-19 infections in immunocompromised individuals is of crucial importance as it is possible that an existing patient might harbour the next variant, a highly transmissible new variant of concern that challenges immunity and existing therapeutics.