Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and correlate with recovery from infection. To examine the human antibody response to HBV, we screened 124 vaccinated and 20 infected, spontaneously recovered individuals. The selected individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection but selected for resistance mutations in mice with prior established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with an HBsAg peptide epitope revealed a stabilized hairpin loop. This structure, which contains residues frequently mutated in clinical immune escape variants, provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.

尽管尚无法有效治愈慢性乙型肝炎病毒（HBV）感染，但抗体具有保护性，并与感染的恢复相关。为了检查人对HBV的抗体反应，我们筛选了124位接种疫苗的人和20位受感染的自发恢复的个体。选定的个体产生了针对HBV S抗原（HBsAg）上3个非重叠表位的广泛中和抗体（bNAb）的共享克隆。单个bNAb可以保护人源化小鼠免于感染，但可以选择已建立感染的小鼠进行耐药性突变。相比之下，感染是通过靶向非重叠表位的bNAb组合来控制的，这些bNAb对人类感染期间常见的突变具有互补的敏感性。具有HBsAg肽表位的bNAb之一的共晶体结构显示出稳定的发夹环。这种结构包含在临床免疫逃逸变体中经常突变的残基，为为什么对HBV感染的免疫疗法可能需要补充bNAb的组合提供了分子解释。