Antigenic evolution of SARS-CoV-2 in immunocompromised hosts

Abstract

The apparent lack of antigenic evolution by the Delta variant (B.1.617.2) of SARS-CoV-2 during the COVID-19 pandemic is puzzling. The combination of increasing immune pressure due to the rollout of vaccines and a relatively high number of infections following the relaxation of non-pharmaceutical interventions should have created perfect conditions for immune escape variants to evolve from the Delta lineage. Instead, the Omicron variant (B.1.1.529), which is hypothesised to have evolved in an immunocompromised individual, is the first major variant to exhibit significant immune escape following vaccination programmes and is set to become globally dominant in 2022. Here, we use a simple mathematical model to explore possible reasons why the Delta lineage did not exhibit antigenic evolution and to understand how and when immunocompromised individuals affect the emergence of immune escape variants. We show that when the pathogen does not have to cross a fitness valley for immune escape to occur, immunocompromised individuals have no qualitative effect on antigenic evolution (although they may accelerate immune escape if within-host evolutionary dynamics are faster in immunocompromised individuals). But if a fitness valley exists between immune escape variants at the between-host level, then persistent infections of immunocompromised individuals allow mutations to accumulate, therefore facilitating rather than simply speeding up antigenic evolution. Our results suggest that better global health equality, including improving access to vaccines and treatments for individuals who are immunocompromised (especially in lower- and middle-income countries), may be crucial to preventing the emergence of future immune escape variants of SARS-CoV-2.

Immune Heterogeneity and Epistasis Explain Punctuated Evolution of SARS-CoV-2

“…In the presence of strong epistasis, gradual evolution towards a high fitness genotype can be blocked (see Figure 3–Figure supplement 1A). Conceptually, such gradual evolution under strong epistasis would correspond to traversing a deep valley in the fitness landscape by a series of small steps before reaching a peak ( Katsnelson et al, 2019 ; Smith and Ashby, 2022 ). However, such a fitness valley indicates the presence of deleterious mutations which impart a high probability of extinction of the lineage in question, preventing the fitness peak from being reached.…”

“…There are a few models in the literature that seek to address the connection between saltation, epistasis and the likelihood of emergence of new variants ( Katsnelson et al . ( 2019 ) and Smith and Ashby ( 2022 ), the latter of which is based on the model by Gog and Grenfell ( 2002 )). However, in contrast to existing theoretical studies, we address the empirical temporal development of diversity and propose a model which can directly replicate the main features of that distribution.…”

Antigenic escape accelerated by the presence of immunocompromised hosts

“…Because these hosts are at higher risk of infection than other hosts, a prioritized countermeasure In a recent study, Smith and Ashby considered a similar model and investigated the effect of immunocompromised hosts on antigenic evolution (Smith and Ashby, 2022). Under the assumption that there is some correlation between pathogen infectivity and antigenicity, they numerically simulated their model and showed qualitative prediction that the presence of immunocompromised hosts allows pathogens to overcome an otherwise insurmountable fitness valley.…”

“…However, few studies have examined the epidemiological dynamics of antigenic escape when heterogeneity in host traits, such as recovery rates, is present. Smith and Ashby’s stochastic simulations suggest that the presence of hosts with low recovery rates increases the l Composition of immunocompromised and immune-competent hosts in the infected ikelihood of overcoming the valley of the fitness landscape, but the impact of heterogeneity in host recovery rates on antigenic escape rates and epidemics in more general situations remains unresolved (Smith and Ashby, 2022).…”

Non-pharmaceutical interventions and the emergence of pathogen variants

“…Population heterogeneity and contact structure both affect pathogen transmission, and so are also likely to affect the initial spread of variants, potentially allowing variants to gain a foothold in a subset of the population. Conversely, a more complex genetic and phenotypic landscape would likely make it more difficult for variants to emerge, for example due to epistasis (Smith & Ashby, 2022). One could crudely model this by reducing the mutation supply in our model to mimic the lower rate of accumulating multiple mutations, which would quantitatively, but not qualitatively, change our results.…”