Identification of Hemagglutinin Residues Responsible for H3N2 Antigenic Drift during the 2014-2015 Influenza Season

Abstract

Influenza vaccines must be updated regularly because influenza viruses continuously acquire mutations in antibody binding sites of hemagglutinin (HA). The majority of H3N2 strains circulating in the Northern Hemisphere during the 2014-2015 season are antigenically mismatched to the A/Texas/50/2012 H3N2 vaccine strain. Recent H3N2 strains possess several new HA mutations, and it is unknown which of these mutations contribute to the 2014-2015 vaccine mismatch. Here, we use reverse genetics to demonstrate that mutations in HA antigenic site B are primarily responsible for the current mismatch. Sera isolated from vaccinated humans and infected ferrets and sheep had reduced hemagglutination inhibition and in vitro neutralization titers against reverse-genetics-derived viruses possessing mutations in the HA antigenic site B. These data provide an antigenic explanation for the low influenza vaccine efficacy observed during the 2014-2015 influenza season. Furthermore, our data support the World Health Organization's decision to update the H3N2 component of future vaccine formulations.

Figure 1. Genetically distinct H3N2 viruses circulated during 2014–2015 influenza season in the United States

(A) HA sequences deposited on the GISAID database were analyzed. All sequences deposited by United States laboratories were included in the analysis. Shown are % of viruses that belong to each HA clade (as defined in the text). (B) The H3 structure (Protein Data Bank entry 1HGG) is shown with residues from Table 1 shown in yellow. (C-D) ELISAs were completed with plates coated with VLPs containing A/Texas/50/2012-WT HA (A/TX/12-WT), A/Texas/50/2012-F159S HA (A/TX/12-F159S), or A/Port Chalmers/1/1973 HA (A/PC/73). ELISAs were completed with A/Texas/50/2012 ferret anti-sera (C) or the F49 mAb (D) that binds to a conserved region of the HA stalk. Shown are mean and SEM of triplicate samples. Data are representative of 2 independent experiments.