Delineating antibody recognition against Zika virus during natural infection & a single injection of human neutralizing antibody protects against Zika virus infection and microcephaly in the developing fetuses in mice
Fei Gao1, Cui Li2,3, Lei Yu4, Ruoke Wang1, Fuchun Zhang4, Zhiheng Xu2,3, and Linqi Zhang1*
1Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084; 2State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; 3University of Chinese Academy of Sciences, Beijing 100101, China; 4Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510060, China
*Corresponding Author: Dr. Linqi Zhang (email@example.com)
Zika virus (ZIKV) is a newly emerged mosquito-transmitted flavivirus that can cause severe defects in the developing fetuses and newborns in humans and shares a considerable degree of homology with dengue virus (DENV).
Here, we examined longitudinal antibody response against ZIKV during natural infection in 2 convalescent individuals. By decomposing the antibody recognition into DI/DII and DIII of the E glycoprotein, we showed their development in humans followed a spatiotemporal hierarchy. Plasma binding to DI/DII appeared to peak and wane during early infection with extensive cross-reactivity with DI/DII of DENV. Binding to DIII, however, peaked early but persisted months into the infection without detectable cross-reactivity with DIII of DENV. A clear trend of increase in DIII-specific neutralizing activity was observed over the course of infection. The mAbs isolated during early infection are largely DI/DII specific, weakly neutralizing, and highly cross-reactive with DENV, while those from later infection are more diverse in recognition, potently neutralizing, and ZIKV specific.
To develop prophylactic and therapeutic agents against ZIKV, we investigated the protective potential of six human monoclonal antibodies with distinct neutralizing activity and epitope specificity isolated from a ZIKV convalescent individual above in one of the most stringent mouse models of microcephaly. By a single intraperitoneal injection of pregnant and non-pregnant mice prior to ZIKV infection, we showed that these antibodies afforded distinct levels of protection to the developing fetuses and adult animals, which closely mirrored their neutralizing activities in vitro. The most potent neutralizing antibody tested, ZK2B10, provided a complete protection in pre-exposure treatment and partial protection in post-exposure therapy against ZIKV infection with markedly reduced tissue pathology. Thus, ZK2B10 could serve as a promising candidate for antibody-based intervention and inform rational vaccine design against ZIKV infection.