Development of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone

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.

Next generation agents (synthetic agents): Emerging threats and challenges in detection, protection, and decontamination

“…The 10.8 kb genome of ZIKV encodes a single polyprotein that, upon action of host and viral proteases, forms three structural proteins (C, PrM, and E) and seven nonstructural proteins (NS1-5 NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (Ye et al, 2016). Numerous approaches are being employed to develop live attenuated virus (Shan et al, 2017), inactivated whole virus (Sumathy et al, 2017), subunit DNA/RNA vaccines (Pardi et al, 2017;To et al, 2018), virus like particles (Espinosa et al, 2018;Salvo et al, 2018), over virus vectored (Xu et al, 2018), and chimeric ZIKV (Kum et al, 2018;Li et al, 2018) vaccines pertaining to several benefits including economical and long-term immunity. But only a few of them have generated appropriate prophylactic responses in tested in vivo models.…”

Zika virus vaccines

“…Studies from a number of groups have reported the protective efficacy of inactivated virus vaccines, DNA vaccines, viral vector-based vaccines and mRNA vaccines 54–56,68,70–76 (Table 1). DNA vaccines expressing variations of the prM-ENV antigen were quickly developed and tested successfully for efficacy in both mice and monkeys 70 .…”

“…mRNA vaccines expressing wild-type or modified prM-ENV antigens, leading to the generation of sub-viral particles were able to protect mice with a single dose as low as 10 µg 54 or 50 µg for monkeys 55 . Several live-attenuated vaccines have also been developed, based on the Yellow Fever Virus (YFV) YF17D model, the JEV vaccine SA14–14-2 backbone, or attenuated through systematic deletions in the 3′UTR region in the ZIKV genome 74–76 . All live-attenuated ZIKV vaccines have proved immunogenic and protective in mice and monkeys.…”

“…The development of immunodeficient mouse pregnancy models for ZIKV infection has led to important advances due to the increased viral replication and impact on the central nervous system 89,90 , and the first prevention of fetal malformations and demise was observed using mRNA and live-attenuated ZIKV vaccines 56,76,91 . However, even though a statistically significant impact on fetal demise was observed, the protection was not sterilizing.…”

“…ZIKV RNA was still detected in the maternal brain and spleen as well as in the placenta and fetal heads in the majority of animals. Interestingly, pups born to mothers vaccinated with a LAV were protected against lethal intracranial challenge with ZIKV 76 . Further research is needed to assess the impact of low level viremia in fetal and maternal compartments.…”