Asynchrony between virus diversity and antibody selection limits influenza virus evolution

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.

Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination

“…Most transmission occurs within a day or two of peak viral load, near the onset of symptoms 49 , 50 . The small founding populations and short time to peak load afford little time for escape variants to appear via mutation and rise to appreciable abundance, especially if viral loads are suppressed owing to residual immunity from vaccination 51 – 56 . Past work on influenza has found no evidence of selection for escape variants during infection in vaccinated hosts 57 .…”

An Antigenic Thrift-Based Approach to Influenza Vaccine Design

“…One approach used to induce stem-targeted antibodies, as outlined in Nachbagauer et al, involved designing a vaccine with chimeric HA constructs that contained the head domain of a non-human-circulating avian HA subtype and an H1 stem [ 61 , 67 ]. Exposure to the same stem domain whilst varying avian head domains generated a potent antibody response against the stem in ferrets [ 61 , 68 , 69 , 70 ].…”

“…Analogously, differing intensities of selection in various stages of infection dynamics were observed for influenza and proposed as factors affecting influenza diversity patterns [ 58 , 59 ]. Whereas most influenza models focus on between-host dynamics, a few have explicitly modelled within-host evolution of influenza [ 59 , 60 , 61 ]. Notably, a recent study by Morris et al [ 60 ] modelled both within- and between-host influenza dynamics and assumed that influenza strains undergo asynchronous selective pressure during transmission and replication.…”

Current and prospective control strategies of influenza A virus in swine

“…Lacking a proof-reading function, diversity in the viral genome gradually accumulates, providing a source of variation for the forces of natural selection to be imposed on, in a process known as antigenic drift (Fig. 1 b) [ 24 ]. The viruses that can transmit between hosts and replicate within a host most efficiently then become pervasive by superior propagation.…”

“…Antibody binding with HA interferes with its ability to bind to the host receptor SA, preventing endocytic uptake and therefore viral infection and transmission. However, as the exposed head region of HA is heterogenous (25% genetic distinction within subtypes) and has a high mutation rate, positive selection of swIAV that do not have an HA match with an antibody promotes evolution of swIAV virions that circumvent the vaccine induced immune response [ 24 ]. This evolution is a major cause of low vaccine efficacy rates and reason why vaccines must continually be updated and modified to match circulating strains.…”