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Cell Rep. 2018 Nov 6;25(6):1385-1394.e7. doi: 10.1016/j.celrep.2018.10.031.

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2
California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA; Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
3
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
4
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
5
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
6
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
7
Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
8
California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA.
9
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
10
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu.
11
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: drobbiani@rockefeller.edu.

Abstract

Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.

KEYWORDS:

antibodies; antibody dependent enhancement; crystal structure; epitope; escape; flavivirus; macaques; prophylaxis; protection

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