Vaccination with different group 2 influenza subtypes alters epitope targeting and breadth of hemagglutinin stem–specific human B cells.

The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics. Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2. Here, we characterized the stem-specific repertoire of individuals vaccinated with one of three group 2 influenza subtypes (H3, H7, or H10). Epitope mapping revealed two epitope supersites on the group 2 stem. Antibodies targeting the central epitope were broadly cross-reactive, whereas antibodies targeting the lower epitope had narrower breadth but higher potency against H3 subtypes. The ratio of B cells targeting each of the supersites varied with the vaccine subtype, leading to differences in the cross-reactivity of the B cell response. Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains. Editor's summary: The hemagglutinin (HA) stem of influenza virus represents a key vaccine target, because it is relatively conserved across influenza strains. However, the specific regions on the HA stem that elicit immunity must be known to optimize vaccine design. Here, Mantus et al. evaluated HA stem–specific antibody responses elicited by three different vaccines targeting the H3, H7, and H10 group 2 influenza subtypes, respectively. They identified two epitopes, termed the central epitope and the lower epitope, that were targeted by vaccine-elicited antibodies. Vaccination against the H7 subtype favored central epitope antibodies, whereas the H3 and H10 vaccines elicited a more balanced response between the two epitopes. The authors further showed that antibodies against both epitopes conferred protection when given to mice before H3N2 infection, supporting development of vaccines that specifically elicit both central epitope- and lower epitope-reactive antibodies. —Courtney Malo [ABSTRACT FROM AUTHOR]