Asynchrony between virus diversity and antibody selection limits influenza virus evolution.

Dylan H Morris,Colin A Russell,Edyth Parker,Simon A Levin,Richard A Neher,Fernando W Rossine,Bryan T Grenfell,Velislava N Petrova

doi:10.7554/elife.62105

Abstract

Seasonal influenza viruses create a persistent global disease burden by evolving to escape immunity induced by prior infections and vaccinations. New antigenic variants have a substantial selective advantage at the population level, but these variants are rarely selected within-host, even in previously immune individuals. Using a mathematical model, we show that the temporal asynchrony between within-host virus exponential growth and antibody-mediated selection could limit within-host antigenic evolution. If selection for new antigenic variants acts principally at the point of initial virus inoculation, where small virus populations encounter well-matched mucosal antibodies in previously-infected individuals, there can exist protection against reinfection that does not regularly produce observable new antigenic variants within individual infected hosts. Our results provide a theoretical explanation for how virus antigenic evolution can be highly selective at the global level but nearly neutral within-host. They also suggest new avenues for improving influenza control.

Highlights

Antibody-mediated immunity exerts evolutionary selection pressure on the antigenic phenotype of seasonal influenza viruses (Hensley et al, 2009; Archetti and Horsfall, 1950)
New antigenic variants like those that result in antigenic cluster transitions (Smith et al, 2004) and warrant updating the composition of seasonal influenza virus vaccines are likely to be produced in every infected host
To assess the importance of transmission bottlenecks, initial virus diversity, and sIgA antibody neutralization in virus evolution, we model the point of transmission as a series of stochastic events which may lead to one of more virions invading cells and initiating an infection

Summary

Introduction

Antibody-mediated immunity exerts evolutionary selection pressure on the antigenic phenotype of seasonal influenza viruses (Hensley et al, 2009; Archetti and Horsfall, 1950). Influenza virus infections and vaccinations induce neutralizing antibodies that can prevent reinfection with previously encountered virus antigenic variants, but such reinfections occur (Clements et al, 1986; Memoli et al, 2020; Javaid et al, 2020). At the human population level, accumulation of antibody-mediated immunity creates selection pressure favoring antigenic novelty. New antigenic variants like those that result in antigenic cluster transitions (Smith et al, 2004) and warrant updating the composition of seasonal influenza virus vaccines are likely to be produced in every infected host. Seasonal influenza viruses have high polymerase error rates (on the order of 10À5 mutations/nucleotide/replication [Nobusawa and Sato, 2006]), reach large within-host virus population sizes (as many as 1010 virions [Perelson et al, 2012]), and can be altered antigenically by single amino acid substitutions in the hemagglutinin (HA) protein (Koel et al, 2013; Linderman et al, 2014)

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