A broadly protective antibody that targets the flavivirus NS1 protein

Naphak Modhiran(The University of Queensland), Hao Song(Chinese Academy of Sciences), Lidong Liu(First Affiliated Hospital of Guangzhou Medical University), Cheryl Bletchly(Queensland Health), Lou Brillault(The University of Queensland), Alberto A. Amarilla(The University of Queensland), Xiaoying Xu(Chinese Academy of Sciences), Jianxun Qi(Chinese Academy of Sciences), Yan Chai(Chinese Academy of Sciences), Stacey T. M. Cheung(The University of Queensland), Renee Traves(The University of Queensland), Yin Xiang Setoh(The University of Queensland), Summa Bibby(The University of Queensland), Connor A. P. Scott(The University of Queensland), Morgan E. Freney(The University of Queensland), Natalee D. Newton(The University of Queensland), Alexander A. Khromykh(The University of Queensland), Keith J. Chappell(The University of Queensland), David A. Muller(The University of Queensland), Katryn J. Stacey(The University of Queensland), Michael J. Landsberg(The University of Queensland), Yi Shi(Chinese Academy of Sciences), George F. Gao(Chinese Academy of Sciences), Paul R. Young(The University of Queensland), Daniel Watterson(The University of Queensland)
Science
January 7, 2021
10.1126/science.abb9425
Cited by 121

Abstract

There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.

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