Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses

Abstract

Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.

Improving the Identification of Antigenic Sites in the H1N1 Influenza Virus Through Accounting for the Experimental Structure in a Sparse Hierarchical Bayesian Model

“…These results, which are summarized in Table , show a clear improvement for eSABRE over the models that were used in Harvey et al . ().…”

“…Here we have selected six proven, two plausible and one implausible, compared with four proven, no plausible and one implausible selected in Harvey et al . (). These results, which are summarized in Table , show a clear improvement for eSABRE over the models that were used in Harvey et al .…”

“…A similar method has also been applied by Harvey et al . () to influenza A(H1N1), using versions of the data sets that are used here.…”

“…Finally we apply biWAIC with eSABRE to the H1N1 data set and identify some known and potential antigenic sites, comparing the results with those of Harvey et al . ().…”

Association between Haemagglutination inhibiting antibodies and protection against clade 6B viruses in 2013 and 2015

“…Since its first emergence in 2009, pandemic A(H1N1) virus (H1N1pdm) has been undergoing constant genetic changes and it remains the predominate H1N1 virus worldwide [4, 5]. How genes changes the structure of virus epitopes and what its extrinsic impact is on human’s susceptibility are outstanding important questions in vaccine design [6]. Recent H1N1pdm viruses are most frequently clustered in genetic clade 6 and its contemporary subclades.…”