Abstract
The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine. Here we report the development and characterization of a recombinant chimeric ZIKV vaccine candidate (termed ChinZIKV) that expresses the prM-E proteins of ZIKV using the licensed Japanese encephalitis live-attenuated vaccine SA14-14-2 as the genetic backbone. ChinZIKV retains its replication activity and genetic stability in vitro, while exhibiting an attenuation phenotype in multiple animal models. Remarkably, immunization of mice and rhesus macaques with a single dose of ChinZIKV elicits robust and long-lasting immune responses, and confers complete protection against ZIKV challenge. Significantly, female mice immunized with ChinZIKV are protected against placental and fetal damage upon ZIKV challenge during pregnancy. Overall, our study provides an alternative vaccine platform in response to the ZIKV emergency, and the safety, immunogenicity, and protection profiles of ChinZIKV warrant further clinical development.
Highlights
The global spread of Zika virus (ZIKV) and its unexpected association with congenital defects necessitates the rapid development of a safe and effective vaccine
Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flavivirus genus of the Flaviviridae family, which includes other important human pathogens such as yellow fever virus (YFV), dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV)
The chimera expressed the structural proteins of ZIKV and the non-structural proteins of JEV as verified by immunostaining (Fig. 1b and Supplementary Fig. 1a) and western blotting (Supplementary Fig. 1b), respectively
Summary
We tested the neurovirulence of ChinZIKV in 1-day-old suckling BALB/c mice following intracerebral (i.c.) inoculation, in comparison with the same doses of wild type ZIKV and the two licensed live-attenuated vaccines YFV 17D and JEV SA14-14-2. The levels of multiple cytokines including IL-2, IL-Ra, RANTES (regulated on activation, normal T cell expressed and secreted; CCL-5), and eotaxin showed a divergent profile between ChinZIKV-immunized and PBS-inoculated animals following ZIKV challenge (Supplementary Fig. 8b), which may SFU/million PBMC SFU/million PBMC SFU/million PBMC. Extensive placental injury and fetal demise were observed in PBS-immunized mice at E18, whereas all pups were delivered at term with normal viability from the ChinZIKVimmunized group (Fig. 5f, g) These results demonstrate that preconception maternal immunity induced by ChinZIKV immunization efficiently prevented vertical ZIKV transmission during pregnancy and protected the fetuses from ZIKV infection
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