In vivo protection against ZIKV infection and pathogenesis through passive antibody transfer and active immunisation with a prMEnv DNA vaccine.

Jian Yan,Joel N. Maslow ,Sagar B. Kudchodkar ,J Joseph Kim,Karuppiah Muthumani,Laurent Humeau,Stephanie A. Booth ,Stephanie Ramos,Sangya Agarwal,Amelia A. Keaton ,Emma L. Reuschel ,Amir S. Khan ,Jingjing Jiang,Bryan D. Griffin ,Young K. Park ,Brian Lee,Kate E. Broderick ,Elizabeth K. Duperret ,Charles C. Reed ,Kimberly A. Kraynyak ,Trina Racine,Christopher Chung,Matthew P. Morrow ,Gary P. Kobinger ,David B. Weiner ,Kenneth E. Ugen ,Yinho K Kim,Hyeree Choi,Niranjan Y. Sardesai

doi:10.1038/npjvaccines.2016.21

Abstract

Significant concerns have been raised owing to the rapid global spread of infection and disease caused by the mosquito-borne Zika virus (ZIKV). Recent studies suggest that ZIKV can also be transmitted sexually, further increasing the exposure risk for this virus. Associated with this spread is a dramatic increase in cases of microcephaly and additional congenital abnormalities in infants of ZIKV-infected mothers, as well as a rise in the occurrence of Guillain Barre’ syndrome in infected adults. Importantly, there are no licensed therapies or vaccines against ZIKV infection. In this study, we generate and evaluate the in vivo efficacy of a novel, synthetic, DNA vaccine targeting the pre-membrane+envelope proteins (prME) of ZIKV. Following initial in vitro development and evaluation studies of the plasmid construct, mice and non-human primates were immunised with this prME DNA-based immunogen through electroporation-mediated enhanced DNA delivery. Vaccinated animals were found to generate antigen-specific cellular and humoral immunity and neutralisation activity. In mice lacking receptors for interferon (IFN)-α/β (designated IFNAR−/−) immunisation with this DNA vaccine induced, following in vivo viral challenge, 100% protection against infection-associated weight loss or death in addition to preventing viral pathology in brain tissue. In addition, passive transfer of non-human primate anti-ZIKV immune serum protected IFNAR−/− mice against subsequent viral challenge. This study in NHP and in a pathogenic mouse model supports the importance of immune responses targeting prME in ZIKV infection and suggests that additional research on this vaccine approach may have relevance for ZIKV control and disease prevention in humans.

Highlights

During the recent outbreak in South and Central America, microcephaly and other congenital abnormalities in infants have been observed in mothers who were infected by Zika virus (ZIKV) during pregnancy.[11,12,13]
A consensus sequence of ZIKV precursor of membrane (prM) (precursor membrane and Envelope (Env) genes (ZIKV-prME) was generated using prM and Env sequences from various ZIKV isolated between the years of 1952 and 2015, which caused infection in humans
The results show that the ZIKV-prME vaccination increased the proportion of bifunctional vaccine-specific T cells expressing TNF-α and IFN-γ

Summary

Introduction

Zika virus (ZIKV) is a single-stranded, positive sense RNA flavivirus,[1] spread primarily through the bite of infected Aedes mosquitos.[2,3,4] during the recent outbreak in South and Central America, novel mechanisms of ZIKV transmission have been described including sexual and transplacental transmission.[5,6,7] The virus is endemic in parts of Africa and Asia and has spread unabated through South America, Mexico and the Caribbean over the last 2 years.[8,9] Factors including increased global travel and an expansion of the range of Aedes mosquitos owing to climate change portend further spread of this virus, expanding its range in the southern United States over the few years.[5,9]ZIKV infection presents with a prodrome of myalgias, arthralgias, malaise and low-grade fever with a rash appearing approximately 7 days post infection that may occur with conjunctivitis and retro-orbital pain. Zika virus (ZIKV) is a single-stranded, positive sense RNA flavivirus,[1] spread primarily through the bite of infected Aedes mosquitos.[2,3,4] during the recent outbreak in South and Central America, novel mechanisms of ZIKV transmission have been described including sexual and transplacental transmission.[5,6,7] The virus is endemic in parts of Africa and Asia and has spread unabated through South America, Mexico and the Caribbean over the last 2 years.[8,9] Factors including increased global travel and an expansion of the range of Aedes mosquitos owing to climate change portend further spread of this virus, expanding its range in the southern United States over the few years.[5,9]. We describe the development and evaluation of a synthetic ZIKV prME DNA vaccine delivered by electroporation for its immunogenicity and its impact on ZIKV infection in a pathogenic animal challenge model

Methods

Results

Conclusion