The impact of cross-reactive immunity on the probability that a newly introduced SARS-CoV-2 variant will invade the host population

By Pooja Toshniwal PahariaJan 17 2023Reviewed by Danielle Ellis, B.Sc.

In a recent study published in Frontiers in Immunology, researchers investigated the effect of cross-protective immunological responses on novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence by mathematical modeling, considering newly emerged SARS-CoV-2 variant transmission occurred post-transmission of an antigenically similar virus in the population.

Background

The continual emergence of novel SARS-CoV-2 variants has shaped the epidemiological dynamics of coronavirus disease 2019 (COVID-19). However, not all variants have transmitted extensively to infect a considerable percentage of the population. Most of the novel variants have faded out, with a few variants accounting for the enormous number of COVID-19 case counts. Immunity against novel SARS-CoV-2 variants might be affected by prior exposure to related SARS-CoV-2 variants and seasonal CoVs, and the levels of cross-protective immunity conferred by the exposures.

About the study

In the present study, researchers performed mathematical modeling, considering a newly emerged variant of SARS-CoV-2 and a virus with similar antigenicity that has priorly been transmitted among persons, to identify the factors impacting the risk of novel variant invasion in the population.

The team assumed that SARS-CoV-2 infection with priorly circulating variants affected novel variant transmission, considering different scenarios wherein previous infections either completely or partially protected against infection or were detrimental. The risk of novel variant emergence was calculated based on numerical equations, considering SARS-CoV-2 transmission from a single infected person to the population, confirming that the mathematically simulated approximations matched invasion probability estimates.

For the model simulations, the size of the local population (N) was 100,000. The average latency period for the novel SARS-CoV-2 variant (1/γ) was 5.0 days and the average infectivity period (1/µ) was 8.0 days. The priorly circulating virus reproduction value (R_0p) was 1.5, such that the population assumed to be infected with the priorly circulating virus (N_p) comprised 58,281 persons, covering 58.0% of the host population. R_0n denoted the reproduction number of the new variant, β denoted the new variant transmission rate, α denoted the diminution or elevation in susceptibility to new variant infection due to cross-protective immunity, and ϵ denoted the diminution or elevation in new variant infectivity due to cross-protective immunity.

In the scenario wherein previous antigenically similar virus infection was protective against new variant infection, α > 0, and in the scenario wherein prior infection by the antigenically similar virus was fully protective against the newly emerged variant, α = ϵ = 1.0. In the scenario wherein prior infection by the antigenically similar virus did not impact the newly emerged variant dynamics (i.e., α = ϵ = 0), the risk of invasion by the newly emerged variant was irrespective of whether the infected person had been previously infected with the antigenically related viral organism.

The new variant spread dynamics were also modeled based on SEIR modeling, with two key differences. SEIR modeling included consideration of the cross-protective immunity provided by the antigenically related virus. Gillespie stochastic modeling, including novel variant infection or fading out from the population for every model simulation, was performed.

The team individually assessed the impact of the infectiousness- and susceptibility-altering effects of cross-protective immunity on the new variant invasion probability. They assumed COVID-19 development to fail based on a branching process, such that failure of a variant to establish required the infecting SARS-CoV-2 variant from both currently infected hosts to fail independently.

Results

The findings indicated that in the case of complete cross-protective immunity, the newly emerged variant would require greater transmissibility compared to the priorly circulating virus to invade the host population. In other words, the R_0n value would have to be greater than that of the antigenically similar virus for population invasion by the new SARS-CoV-2 variant.

However, in the case of partial cross-protective immunity, the newly emerged variant could invade the population even in case of lower transmissibility compared to viruses previously in circulation since incomplete cross-protective immunity efficiently enhances the susceptible host pool available for the newly emerged variant, in comparison to fully cross-protective immunological responses.

In the case of prior infection with the antigenically related viral organism promoted novel variant infection (low R_0n values, including <1.0), even variants with very low transmission potential could invade the population. In addition, the probability of novel variant infection would be greater in case the initial SARS-CoV-2 infection occurred in persons priorly infected with the antigenically similar virus. If the priorly circulating viral organism confers negligible protection against infection, the new variant invasion risks would not be affected by the antigenically-related virus outbreak.

Higher peaks and lesser duration in COVID-19 cases occurred if antigenically similar virus infection promoted novel variant infection. The immunological status of the initially infected person would affect the new variant transmission risks in the population. Population invasion by the new variant was more likely to occur if the initially infected person would infect several persons.

Beginning from one infected person without previous infection with the antigenically similar virus (e.g., variant introduction in the population variant by an incoming passenger), only the susceptibility-modifying immunity (α) would affect variant transmission by the initially infected person.

Contrastingly, in case the initially infected person was infected with the antigenically similar virus (i.e., variant introduction due to mutations from a related virus), the infectiousness-modifying immunity (ϵ) would affect all probable variant transmissions by the initially infected person.

Conclusion

Overall, the study findings showed that the cross-protective immunity levels for novel SARS-CoV-2 variants and antigenically related viral organisms are key determinants of the risk of novel variant invasion into the population.