Maurer Daniel P, Vu Mya, Ferreira Ramos Ana Sofia, Dugan Haley L, Khalife Paul, Geoghegan James C, Walker Laura M, Bajic Goran, Schmidt Aaron G
Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Sci Adv. 2025 Apr 25;11(17):eadu9140. doi: 10.1126/sciadv.adu9140. Epub 2025 Apr 23.
Monoclonal antibodies (mAbs) targeting the influenza hemagglutinin (HA) can be used as prophylactics or templates for next-generation vaccines. Here, we isolated broad, subtype-neutralizing mAbs from human B cells recognizing the H1 or H3 HA "head" and a mAb engaging the conserved stem. The H1 mAbs bind the lateral patch epitope on HAs from 1933 to 2021 and a prepandemic swine H1N1 virus. We improved neutralization potency using directed evolution toward a contemporary H1 HA. Deep mutational scanning of four antigenically distinct H1N1 viruses identified potential viral escape pathways. For the H3 mAbs, we used cryo-electron microscopy to define their epitopes: One mAb binds the side of the HA head, accommodating the N133 glycan and a pocket underneath the receptor binding site; the other mAb recognizes an HA stem epitope that partially overlaps with previously characterized mAbs but with distinct antibody variable genes. Collectively, these mAbs identify conserved sites recognized by broadly-reactive mAbs that may be elicited by next-generation vaccines.
靶向流感血凝素（HA）的单克隆抗体（mAb）可用作预防性药物或下一代疫苗的模板。在此，我们从人B细胞中分离出了识别H1或H3 HA“头部”的广谱、亚型中和性mAb，以及一种结合保守茎部的mAb。这些H1 mAb可结合1933年至2021年的HAs以及一种大流行前的猪H1N1病毒上的侧向斑块表位。我们通过针对当代H1 HA的定向进化提高了中和效力。对四种抗原性不同的H1N1病毒进行深度突变扫描确定了潜在的病毒逃逸途径。对于H3 mAb，我们利用冷冻电子显微镜确定了它们的表位：一种mAb结合HA头部的侧面，容纳N133聚糖和受体结合位点下方的一个口袋；另一种mAb识别一个HA茎部表位，该表位与先前鉴定的mAb部分重叠，但具有不同的抗体可变基因。总的来说，这些mAb确定了可能由下一代疫苗引发的广泛反应性mAb所识别的保守位点。
