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The 2017–2018 influenza epidemic was particularly severe, resulting in over 30,000 laboratory-confirmed, influenza-associated hospitalizations in the U.S., according to reports from the Centers for Disease Control and Prevention ( https://www.cdc.gov/flu/weekly/index.htm ). Vaccination is the most effective healthcare intervention to prevent influenza virus infection. Seasonal influenza vaccines contain either three (trivalent) or four (tetravalent) influenza virus components: two influenza A viruses and one to two influenza B viruses. Decisions on which strains to incorporate into the vaccine are made months in advance and are based on predictions as to which strains will be circulating in the forthcoming influenza season. Although supported by the compilation of widespread surveillance data, this process is not perfect, and therefore predictions can be incorrect, resulting in mismatches between vaccine and circulating influenza virus strains. In the 2017–2018 influenza season, the predominant circulating strain was an H3N2 virus, which has unfortunately been associated with a higher-than-average number of hospitalizations and deaths. The seasonal influenza vaccines for 2017–2018 included an H3N2 component, generated using the same vaccine strains as the 2016–2017 vaccine, in which adaptations of the H3N2 virus during egg-based vaccine manufacture resulted in a loss of glycosylation at an antigenic site in the hemagglutinin (HA) head domain (). This adaptation mutation in the vaccine strain meant that neutralizing antibody (NAb) responses in vaccinees were impaired in their ability to recognize the HA head of H3 in circulating strains. In a similar manner, alternative substitutions in egg-passaged human H3N2 viruses, such as the L194P mutation, have also been proposed to contribute to low vaccine effectiveness (). This mutation leads to an increase in the flexibility of an immunodominant H3 antigenic site proximal to the receptor binding site, resulting in altered antigenicity and reduced immunogenicity (). Interim estimates of vaccine effectiveness for the 2017–2018 vaccine have been reported to be as low as 25% in the U.S. for the H3 component (). However, it is currently unclear if the egg-adaptation mutation associated with the 2016–2017 vaccine has also contributed to reduced vaccine effectiveness for 2017–2018. Furthermore, it is now apparent that the poor effectiveness of H3N2 vaccines may be more complex than issues related solely to egg adaptation. A recent study reported that poor vaccine immunogenicity for the H3N2 component in the 2012–2013 influenza season, previously attributed to egg-adaptation mutations, may have been due to poor vaccine immunogenicity in certain individuals ().