What role does cross-reactive immunity play in the spread of a novel SARS-CoV-2 variant?

In a recent study posted to the medRxiv* preprint server, researchers used mathematical modeling to examine the effect of cross-reactive immunity from previous infections on an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant and explored the probability of the novel variant causing widespread infection or fading out.

Study: The impact of cross-reactive immunity on the emergence of SARS-CoV-2 variants. Image Credit: Lightspring/Shutterstock


Two factors determine whether an emergent SARS-CoV-2 variant can cause widespread infection in a population — introduction and invasion. A de novo mutation or a dispersal from another area introduces the variant into the host population. The variant must then infect many individuals to get established in a population, which is known as an invasion.

Apart from increased transmissibility, one of the factors that influence the invasion risk of a new variant is the level of background immunity generated due to infections from previous variants. Mathematical models have been used during the coronavirus disease 2019 (COVID-19) pandemic to estimate the transmissibility and infectiousness of emergent variants such as Alpha, Beta, and Gamma, and to project the course of the outbreak of new, highly transmissible variants.

Recent studies have demonstrated that humoral immunity derived from a combination of vaccines and previous infections is more successful in protecting against emerging SARS-CoV-2 variants. There have also been conflicting results from other studies showing that immunity from previous infections is associated with increased severity during subsequent infections.

About the study

In the present study, researchers used mathematical modeling to understand the effect of previous SARS-CoV-2 infections on the risk of novel SARS-CoV-2 variants invading the population. Two viruses were considered in the study — a novel SARS-CoV-2 variant and a variant that has previously infected the population and was antigenically related to the novel variant.

The study considered scenarios where the immunity from the previous infection partially or completely protected against the novel variant or was detrimental during infection by the novel variant. The researchers also investigated the role of the introductory pathway in the probability of invasion by the novel variant.

A simple mathematical model with the viral infectious period following an exponential distribution was used in this study. Cross-reactive immunity levels were also assumed to be fixed for previously infected individuals. The authors believe that, in reality, epidemiological periods follow a gamma distribution, and cross-reactive immunity is heterogenous in a population. They aim to incorporate these factors in a more complex mathematical model in a future study.


The results indicate that if the humoral immunity from a previous infection is complete, the novel variant needs to be more infectious than the previous variant to invade the host population. Weak or partial immunity from previous infections does not prevent the establishment of a novel variant in a population. Partial cross-reactive immunity presents a large pool of susceptible individuals for the novel variant to infect.

On the other hand, even novel variants with low transmissibility can invade a population if prior infections promote subsequent infections. The authors mention a few experimental studies demonstrating these detrimental effects of previous infections.

Furthermore, the pathway of the introduction of the novel variant also influences the probability of invasion. If the novel variant has dispersed from another location, the chances of the traveler carrying this variant having had a previous infection from an antigenically related variant are low. This increases the probability of the novel variant invading the host population. Conversely, if the new variant results from a de novo mutation, the immune status of the first person infected with this variant determines its invasion of the population.


To summarize, the study used mathematical modeling to understand the effects of cross-reactive immunity derived from infection from a previous antigenically related variant on the invasion of the host population by a novel SARS-CoV-2 variant.

The findings indicate that complete cross-reactive immunity grants protection against infection and prevents invasion by the new variant. Partial immunity leaves a large portion of the population susceptible to infection from the new variant, increasing the chances of invasion. In contrast, if previous infections make the population more susceptible to new variants, even variants with low transmissibility can get established in the host population.

The study highlights the importance of assessing cross-reactive immunity in ensuring that the emerging SARS-CoV-2 variants do not cause widespread and severe outbreaks of COVID-19.

*Important notice

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.

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