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.

多供体抗体是疫苗设计所关注的，因为原则上它们可以通过一组通用的免疫原在一般人群中引发。对于流行性感冒，已观察到针对血凝素（HA）茎的多供体抗体，但没有针对免疫优势的HA头。在这里，我们确定和表征针对HA头的多供体抗体类（LPAF-a类）。此类表现出针对H1N1 A /加利福尼亚04/2009（CA09）病毒的有效病毒进入抑制作用。LPAF-a类抗体衍生自HV2-70基因，并包含“ Tyr-Gly-Asp”基序，该基团与HA的共晶体结构揭示了HA-唾液酸结合位点。生殖系还原抗体和成熟LPAF抗体均能有效中和CA09病毒，并且对CA09 HA具有纳摩尔亲和力。此外，单次接种疫苗后，在人体内发现LPFA-a类抗体的频率增加。总的来说，这项工作突出了鉴定多类供体的头型流感中和抗体，并描述了其在人类中反复诱发的机制。