Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies.
Germinal center (GC) B cells at viral replication sites acquire specificity to poorly immunogenic but conserved influenza hemagglutinin (HA) epitopes. Here, high-throughput epitope mapping of local GC B cells is used to identify conserved HA epitope selecting cross-reactive antibodies that mediate heterosubtypic protection. A distinct feature of this epitope is an occlusion in the naive trimeric HA structure that is exposed in the post-fusion HA structure to occur under low pH conditions during viral replication. Importantly, systemic immunization by the post-fusion HA antigen results in GC B cells targeting the occluded epitope, and induces a class of protective antibodies that have cross-group specificity and afford protection independent of virus neutralization activity. Furthermore, this class of broadly protective antibodies develops at late time points and persists. Our results identify a class of cross-protective antibodies that are selected at the viral replication site, and provide insights into vaccine strategies using the occluded epitope.
Adachi, Y; Tonouchi, K; Nithichanon, A; Kuraoka, M; Watanabe, A; Shinnakasu, R; Asanuma, H; Ainai, A; Ohmi, Y; Yamamoto, T; Ishii, KJ; Hasegawa, H; Takeyama, H; Lertmemongkolchai, G; Kurosaki, T; Ato, M; Kelsoe, G; Takahashi, Y
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