Limited Predictability of Amino Acid Substitutions in Seasonal Influenza Viruses

Abstract

Seasonal influenza viruses repeatedly infect humans in part because they rapidly change their antigenic properties and evade host immune responses, necessitating frequent updates of the vaccine composition. Accurate predictions of strains circulating in the future could therefore improve the vaccine match. Here, we studied the predictability of frequency dynamics and fixation of amino acid substitutions. Current frequency was the strongest predictor of eventual fixation, as expected in neutral evolution. Other properties, such as occurrence in previously characterized epitopes or high Local Branching Index (LBI) had little predictive power. Parallel evolution was found to be moderately predictive of fixation. While the LBI had little power to predict frequency dynamics, it was still successful at picking strains representative of future populations. The latter is due to a tendency of the LBI to be high for consensus-like sequences that are closer to the future than the average sequence. Simulations of models of adapting populations, in contrast, show clear signals of predictability. This indicates that the evolution of influenza HA and NA, while driven by strong selection pressure to change, is poorly described by common models of directional selection such as travelling fitness waves.

Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination

“…However, the pace of antigenic selection varies over time for influenza A virus (IAV) subtypes and influenza B virus (IBV) lineages due mainly to population-level fluctuations in immune pressure. This confounds vaccine strain selection, which relies on the prediction of antigenic evolution 3 . To facilitate bi-annual selection of candidate vaccine viruses, the WHO Global Influenza Surveillance and Response System (GISRS) coordinates influenza surveillance from 138 National Influenza Centers (NICs) and diagnostic and reference laboratories in 108 countries 4 .…”

Phylogenetic identification of influenza virus candidates for seasonal vaccines

“…However, recently, Barrat-Charlaix et al. ( 50 ) found that mutations at the epitope sites in ( 36 ) fixed in the population less often than would be expected under neutral drift.…”

“…Barrat-Charlaix et al. ( 50 ) recently found that consensus strains are as close or closer to future populations than strains with a high local branching index, motivating the comparison to consensus strains. Figure 5 shows the epitope and amino acid distances (epitope site–only amino acid Hamming distance and whole-sequence amino acid Hamming distance, respectively).…”

Unbiased likelihood-based estimation of Wright-Fisher diffusion processes

“…A question of interest in applications is whether a newly appeared mutation is likely to sweep over the population. Think, for instance, in seasonal flu vaccine planning, where interest lies in predicting the most prevalent genetic variant a year ahead of time, so that effective vaccines can be designed before the next season, see, e.g., [3], [4], [5], [6]. In order to study deviations from neutrality, accurate inferences on are needed.…”