Single dose of chimeric dengue-2/Zika vaccine candidate protects mice and non-human primates against Zika virus

Whitney R Baldwin,Ginger Young,Holli A Giebler,Claire Y.-H Huang,Jill A Livengood,Kelly J Bohning,Hansi J Dean,Janae L Stovall

doi:10.1038/s41467-021-27578-w

Whitney R Baldwin, Ginger Young + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-27578-w

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Abstract

The development of a safe and effective Zika virus (ZIKV) vaccine has become a global health priority since the widespread epidemic in 2015-2016. Based on previous experience in using the well-characterized and clinically proven dengue virus serotype-2 (DENV-2) PDK-53 vaccine backbone for live-attenuated chimeric flavivirus vaccine development, we developed chimeric DENV-2/ZIKV vaccine candidates optimized for growth and genetic stability in Vero cells. These vaccine candidates retain all previously characterized attenuation phenotypes of the PDK-53 vaccine virus, including attenuation of neurovirulence for 1-day-old CD-1 mice, absence of virulence in interferon receptor-deficient mice, and lack of transmissibility in the main mosquito vectors. A single DENV-2/ZIKV dose provides protection against ZIKV challenge in mice and rhesus macaques. Overall, these data indicate that the ZIKV live-attenuated vaccine candidates are safe, immunogenic and effective at preventing ZIKV infection in multiple animal models, warranting continued development.

Highlights

Introduction of EQ465R and E-I484T into the D2/ZK-V0 construct resulted in viable virus recovery from Vero cells, indicating at least one of the substitutions was critical for Vero cell adaptation (Fig. 1b). the D2/ZK-V2 virus replicated well, a mixed plaque phenotype was observed after a single round of amplification inVero cells, suggesting the virus was still evolving
The Zika virus (ZIKV) live-attenuated vaccine (LAV) candidates reported in this study are based on the chimeric dengue virus serotype-2 (DENV-2) PDK-53 vaccine platform that we previously developed for several flavivirus LAVs, including a tetravalent
Following the similar construct design for chimeric D2/WNV8, we generated recombinant cDNA clones containing the prM-E genes of a contemporary ZIKV isolate in the dengue viruses (DENVs)-2 PDK-53 vaccine or parental 16681 genetic backbone to derive chimeric D2/ZK-V or

Summary

Introduction

Introduction of EQ465R and E-I484T into the D2/ZK-V0 construct (designated D2/ZK-V2) resulted in viable virus recovery from Vero cells, indicating at least one of the substitutions was critical for Vero cell adaptation (Fig. 1b). the D2/ZK-V2 virus replicated well, a mixed plaque phenotype was observed after a single round of amplification inVero cells, suggesting the virus was still evolving. Q465R and E-I484T into the D2/ZK-V0 construct (designated D2/ZK-V2) resulted in viable virus recovery from Vero cells, indicating at least one of the substitutions was critical for Vero cell adaptation (Fig. 1b). Genome sequencing of multiple plaque isolates of the D2/ZK-V2 virus identified a total of 6 AA substitutions in E, NS1, NS2A, and NS4A. E-I493F, NS2A-K99N and NS4A-D23N appeared to be most significant for Vero cell adaptation, based on their higher frequency of occurrence and association with isolates producing uniform plaques. Six additional chimeric clones containing various combinations of the substitutions at E-465, E-484, E-493, NS2A99 and NS4A-23 were generated to investigate their relative significance in Vero cell adaptation. We determined E-Q465R and E-I493F to be the most critical substitutions, as chimeric constructs lacking either substitution resulted in rapid evolution of the virus to regain that specific substitution within a single

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