Cell Rep . Identification and Structure of a Multidonor Class of Head-Directed Influenza-Neutralizing Antibodies Reveal the Mechanism for Its Recurrent Elicitation

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Cell Rep


. 2020 Sep 1;32(9):108088.
doi: 10.1016/j.celrep.2020.108088.
Identification and Structure of a Multidonor Class of Head-Directed Influenza-Neutralizing Antibodies Reveal the Mechanism for Its Recurrent Elicitation


Crystal Sao-Fong Cheung ¹ , Alexander Fruehwirth ² , Philipp Carl Georg Paparoditis ² , Chen-Hsiang Shen ¹ , Mathilde Foglierini ² , M Gordon Joyce ¹ , Kwanyee Leung ¹ , Luca Piccoli ² , Reda Rawi ¹ , Chiara Silacci-Fregni ² , Yaroslav Tsybovsky ³ , Raffaello Verardi ¹ , Lingshu Wang ¹ , Shuishu Wang ¹ , Eun Sung Yang ¹ , Baoshan Zhang ¹ , Yi Zhang ¹ , Gwo-Yu Chuang ¹ , Davide Corti ² , John R Mascola ¹ , Lawrence Shapiro ⁴ , Peter D Kwong ⁵ , Antonio Lanzavecchia ⁶ , Tongqing Zhou ⁷



Affiliations

• PMID: 32877670
• DOI: 10.1016/j.celrep.2020.108088

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.

Keywords: Influenza; X-ray crystal structure; elicitation frequency; germline-reverted; hemagglutinin; multidonor antibody class; neutralizing antibodies; recurrent elication; sialic acid-binding site; vaccination.