Identification and Structure of a Multidonor Class of Head-Directed Influenza-Neutralizing Antibodies Reveal the Mechanism for Its Recurrent Elicitation
Crystal Sao‐Fong Cheung, Alexander Fruehwirth, Philipp Paparoditis, Chen‐Hsiang Shen, Mathilde Foglierini, Michael Joyce, Kwanyee Leung, Luca Piccoli, Reda Rawi, Chiara Silacci-Fregni, Yaroslav Tsybovsky, Raffaello Verardi, Lingshu Wang, Shuishu Wang, Eun Sung Yang, Baoshan Zhang, Yi Zhang, Gwo‐Yu Chuang, Davide Corti, John R. Mascola, Lawrence Shapiro, Peter D. Kwong, Antonio Lanzavecchia, Tongqing Zhou
Abstract
Multidonor antibodies are of interest for vaccine design because they can in principle be elicited in the general population by a common set of immunogens. For influenza, multidonor antibodies have been observed against the hemagglutinin (HA) stem, but not the immunodominant HA head. Here, we identify and characterize a multidonor antibody class (LPAF-a class) targeting the HA head. This class exhibits potent viral entry inhibition against H1N1 A/California/04/2009 (CA09) virus. LPAF-a class antibodies derive from the HV2-70 gene and contain a "Tyr-Gly-Asp"-motif, which occludes the HA-sialic acid binding site as revealed by a co-crystal structure with HA. Both germline-reverted and mature LPAF antibodies potently neutralize CA09 virus and have nanomolar affinities for CA09 HA. Moreover, increased frequencies for LPFA-a class antibodies are observed in humans after a single vaccination. Overall, this work highlights the identification of a multidonor class of head-directed influenza-neutralizing antibodies and delineates the mechanism of their recurrent elicitation in humans.