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

  • Cell Host Microbe. 2020 Aug 12;28(2):335-349.e6. doi: 10.1016/j.chom.2020.05.010.
Qiao Wang  1 ,  Eleftherios Michailidis  2 ,  Yingpu Yu  2 ,  Zijun Wang  3 ,  Arlene M Hurley  3 ,  Deena A Oren  4 ,  Christian T Mayer  3 ,  Anna Gazumyan  3 ,  Zhenmi Liu  5 ,  Yunjiao Zhou  6 ,  Till Schoofs  3 ,  Kai-Hui Yao  3 ,  Jan P Nieke  3 ,  Jianbo Wu  6 ,  Qingling Jiang  5 ,  Chenhui Zou  7 ,  Mohanmmad Kabbani  2 ,  Corrine Quirk  2 ,  Thiago Oliveira  3 ,  Kalsang Chhosphel  3 ,  Qianqian Zhang  6 ,  William M Schneider  2 ,  Cyprien Jahan  2 ,  Tianlei Ying  6 ,  Jill Horowitz  3 ,  Marina Caskey  3 ,  Mila Jankovic  3 ,  Davide F Robbiani  3 ,  Yumei Wen  6 ,  Ype P de Jong  8 ,  Charles M Rice  2 ,  Michel C Nussenzweig  9
Affiliations
  • 1. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 2. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • 3. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
  • 4. Structural Biology Resource Center, The Rockefeller University, New York, NY 10065, USA.
  • 5. West China School of Public Health, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 7. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 8. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: [email protected].
  • 9. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
PMID: 32504577 DOI: 10.1016/j.chom.2020.05.010
Abstract

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.

Keywords
Hepatitis B infection; broadly neutralizing antibodies; crystal structure; elite neutralizing activity; escape mutations; humanized mice; passive immunotherapy; prophylaxis.
Products