In a recent study posted to the medRxiv* preprint server, researchers used a simple phenomenological model to investigate the role of immunocompromised hosts in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigenic development. They showed that in the absence of epistasis, antigenic evolution happens rapidly independent of the population’s immunocompromised members.
The fact that the SARS-CoV-2 Delta variant (B.1.617.2) showed no antigenic changes during the coronavirus disease 2019 (COVID-19) pandemic is perplexing. Understanding how and when variants of SARS-CoV-2, the causal agent of COVID-19, are likely to evolve is critical to managing the pandemic’s future.
About the study
The researchers in the present study modified Gog and Grenfell’s model of antigenic evolution to include immunocompromised patients and epistasis. The model assumes that there are 30 variants evenly spaced along a line, each with a single mutation separating them.
Hosts are classified as either completely susceptible or completely immune to a variation. As a result, cross-immunity between variations is polarizing.
Discussion and conclusion
With the help of a basic model of antigenic evolution, the researchers demonstrated that chronic infections of immunocompromised patients allow viruses to accumulate enough mutations to overcome epistasis at the between-host level, allowing the creation of novel immune escape variants.
Indeed, the model implies that when epistasis is weak, new immunological escape variants emerge quickly. Immunocompromised individuals play a significant role in antigenic evolution when epistasis is stronger, limiting transmissibility for variants between fitness peaks. This effectively allows the pathogen to traverse the fitness valley and reach a new peak. It is worth noting that, unlike epistasis, faster within-host adaptation in immunocompromised individuals accelerates the rate of antigenic evolution, but it has no qualitative impact on the outcome. The researchers have also shown that enhancing immunocompromised patients’ care can drastically lower the risk of new variants arising.
While the model does not fully represent the complexities of antigenic evolution, it has significant implications for the knowledge of future SARS-CoV-2 immune escape variants. The model also suggests that the absence of antigenic development by Delta followed by the appearance of Omicron is consistent with immunological escape being constrained by epistasis, but that epistasis can be overcome when immunocompromised individuals are infected for long enough. As a result, rather than just speeding up antigenic evolution, extended infections of immunocompromised patients may be crucial for immunological escape variant evolution.
The within-host paradigm led us to believe that the pace of antigenic change during infection was constant. As immunocompetent hosts normally clear infection within two weeks, there is little time for novel variants to arise for onward transmission, slowing adaptation and preventing epistatic mutations from accumulating. However, the co-evolutionary dynamics between the virus and the host immune system could allow numerous mutations to accumulate in immunocompromised hosts, who may have much longer infections. Interestingly, earlier theoretical and experimental studies have shown that coevolution can both speed up adaptation and allow a pathogen to transcend fitness valleys induced by epistasis.
The researchers focused on viral evolution in immunocompromised persons as a source of immune escape variants like Omicron in this study, but there are two other possibilities. The first is that Omicron emerged in an isolated population early in the pandemic before spreading globally in late 2021. However, the combination of a large number of spike protein mutations and strong selection for immune escape in the general population makes this explanation unsatisfactory, as it does not explain why these mutations did not appear in places where mutation supply and immune pressure were both high.
The second theory is Omicron originating in an animal host after being transmitted from humans, then re-crossing the species barrier and infecting humans. This is a realistic scenario, but it necessitates crossing the species barrier twice and selection to favor mutations that benefit both animal and human species. The researchers believed that Omicron originated in an immunocompromised individual, especially because the longitudinal sequencing of within-host evolution supports this hypothesis.
In conclusion, rather than stigmatizing immunocompromised persons, the findings highlight the importance of global health equality. Controlling the COVID-19 pandemic will require improving the availability of vaccines and treatments, particularly in low- and middle-income countries, as well as permitting wider surveillance for new variants.
Our model was motivated by the surprising lack of antigenic evolution arising from the Delta lineage in 2021.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.