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

• Recent H3N2 strains are antigenically distinct in comparison to the 2014–2015 vaccine strain
• Most humans produce antigenic site B HA antibodies
• New mutations in antigenic site B of HA likely led to 2014–2015 vaccine mismatch

SummaryInfluenza 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.

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