Primary human influenza B virus infection induces cross-lineage hemagglutinin stalk-specifc antibodies mediating antibody-dependent cellular cytoxicity

Influenza A virus (IAV) and influenza B virus (IBV) cause substantial morbidity and mortality during annual epidemics. Two distinct lineages of IBV are distinguished, based on variation in hemagglutinin (HA): B/Victoria/2/87-like (B/Vic) and B/Yamagata/16/88-like (B/Yam). Here, we show that, in humans, primary IBV infection with either lineage induces HA-specifc antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. IBV infection induced antibodies specifc to the HA head and stalk, but only HA stalk-specifc antibodies mediated ADCC efciently and displayed cross-reactivity with IBV of both lineages. This corresponds to recent fndings that 2 points of contact between the eflector and target cell (ie, HA and sialic acid, respectively, and the fragment crystallizable [Fc] domain and Fcfl receptor IIIa, respectively) are required for efcient ADCC activity and that antibodies specifc for the receptor-binding site located in the head domain of HA therefore fail to mediate ADCC. Potentially, ADCC-mediating antibodies directed to the HA stalk of IBV contribute to cross-protective immunity to IBV of both lineages.