A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations

By Qiao Wang, E. Michailidis, Yingpu Yu, Zijun Wang, A. Hurley, D. Oren, C. Mayer, A. Gazumyan, Zhenmi Liu, Yunjiao Zhou and 22 more. 2020

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SUMMARY Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and constitute clinical correlates of recovery from infection. To examine the human antibody response to HBV in individuals with potent serum neutralizing activity, we screened 144 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 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. Co-crystals of one of the bNAbs with a 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.

Subfields: Epidemiology, Hepatology, Virology