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Antibodies in the Absence of Neutralizing Antibody-Dependent Cellular Cytotoxicity Cross-Reactive Influenza-Specific

A better understanding of immunity to inﬂuenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemo-kines. ADCC Abs may target more conserved inﬂuenza virus Ags compared with neutralizing Abs. There has been minimal interest in inﬂuenza-speciﬁc ADCC in recent decades. In this study, we developed novel assays to assess the speciﬁcity and function of inﬂuenza-speciﬁc ADCC Abs. We found that healthy inﬂuenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 inﬂuenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and invitro elimination ofinﬂuenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 inﬂuenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivityof inﬂuenza-speciﬁc ADCC Abs in seropositive humans. Targeting cross-reactive inﬂuenza-speciﬁc ADCC epitopes by vaccination could lead to improved inﬂuenza vaccines. The Journal of Immunology , 2013, 190: 000–000.