An antigenic mismatch between the vaccine and circulating H3N2 strains was hypothesized to contribute to the severity of the 2017–2018 season in North America.

Serum and nasal washes were collected from influenza positive and negative patients during the 2017–2018 season to determine neutralizing antibody (nAb) titers and for influenza virus sequencing, respectively.

The circulating and vaccine H3N2 virus strains were different clades, with the vaccine strain being clade 3C.2a and the circulating viruses being 3C.2a2 or 3C.3a. At enrollment, both the H3N2 negative and positive patients had greater nAb titers to the egg-adapted vaccine virus compared to the cell-grown vaccine but the H3N2-negative population had significantly greater titers to the circulating 3C.2a2. Among H3N2-positive patients, vaccination, younger age, and female sex were associated with greater nAb responses to the egg-adapted vaccine H3N2 virus but not to the cell-grown vaccine or circulating viruses.

For the 2017–2018 circulating viruses, mutations introduced by egg adaptation decreased vaccine efficacy. No increased protection was afforded by vaccination, younger age, or female sex against 2017–2018 circulating H3N2 viruses.