Antigenic and virological properties of an H3N2 variant that will likely dominate the 2021-2022 Northern Hemisphere influenza season

Influenza viruses have circulated at very low levels during the COVID-19 pandemic, and population immunity against these viruses is low. Influenza virus cases have been increasing in the Northern Hemisphere involving an H3N2 strain (3C.2a1b.2a2) with a hemagglutinin (HA) that has several substitutions relative to the 2021-2022 H3N2 vaccine strain. Here, we show that one of these substitutions eliminates a key glycosylation site on HA and alters sialic acid binding. Using glycan array profiling, we show that the 3C.2a1b.2a2 H3 maintains binding to an extended bi-antennary sialoside and replicates to high titers in human airway cells. We found that antibodies elicited by the 2021-2022 Northern Hemisphere influenza vaccine poorly neutralize the new H3N2 strain. Together, these data indicate that 3C.2a1b.2a2 H3N2 viruses efficiently replicate in human cells and could potentially cause an antigenic mismatch if they continue to circulate at high levels during the 2021-2022 influenza season.