Abstract
The recent Zika virus (ZIKV) epidemic in the Americas led to an intense search for therapeutics and vaccines. Here we report the engineering of a chimeric virus vaccine candidate (YF-ZIKprM/E) by replacing the antigenic surface glycoproteins and the capsid anchor of YFV-17D with those of a prototypic Asian lineage ZIKV isolate. By intracellular passaging, a variant with adaptive mutations in the E protein was obtained. Unlike YFV-17D, YF-ZIKprM/E replicates poorly in mosquito cells. Also, YF-ZIKprM/E does not cause disease nor mortality in interferon α/β, and γ receptor KO AG129 mice nor following intracranial inoculation of BALB/c pups. A single dose as low as 1 × 102 PFU results, as early as 7 days post vaccination, in seroconversion to neutralizing antibodies and confers full protection in AG129 mice against stringent challenge with a lethal inoculum (105 LD50) of either homologous or heterologous ZIKV strains. Induction of multi-functional CD4+ and CD8+ T cell responses against ZIKV structural and YFV-17D non-structural proteins indicates that cellular immunity may also contribute to protection. Vaccine immunogenicity and protection was confirmed in other mouse strains, including after temporal blockade of interferon-receptors in wild-type mice to facilitate ZIKV replication. Vaccination of wild-type NMRI dams with YF-ZIKprM/E results in complete protection of foetuses against brain infections and malformations following a stringent intraplacental challenge with an epidemic ZIKV strain. The particular characteristic of YF-ZIKprM/E in terms of efficacy and its marked attenuation in mice warrants further exploration as a vaccine candidate.
Highlights
The recent outbreak of the Zika virus (ZIKV) in the Americas[1] affected over 80 countries
The resulting virus had acquired two mutations in the E gene leading to a serine-toleucine (S455L) and an alanine-to-threonine (A40T) change in the E protein [amino acid positions according to Theys et al.22]. (Supplementary Fig. 5 and Supplementary Table 2)
Reverse engineering of these tissue culture adapted (TCA) mutations into the non-adapted virus (NAV) (Supplementary Fig. 6a) or the mCherry-tagged variant thereof resulted in the rescue of the otherwise replication incompetent chimeric virus to full infectivity (Supplementary Fig. 6b)
Summary
The recent outbreak of the ZIKV in the Americas[1] affected over 80 countries. The World Health Organization (WHO) declared the epidemic a global health emergency in particular because of the high rates of ZIKV-induced congenital malformations. The ZIKV is a flavivirus; several other medically important pathogens such as the dengue (DENV), the Japanese encephalitis (JEV), the tick-borne encephalitis (TBEV), the West Nile (WNV), and the yellow fever viruses belong to this genus. The vaccine has been administered to an estimated 600 million people worldwide[3] and is, based on its legacy track record, generally considered safe with only rare (~1 per million) serious adverse side effects [i.e., in particular vaccineassociated viscerotropic disease] limited primarily to specific risk groups.[4] Several YFV-17D-based chimeric vaccines against the JEV5,6 (Imojev®), the DENV7 (Dengvaxia®), and the WNV8 (ChimeriVax-WN02) have been constructed wherein the prM/E genes of YFV-17D are replaced with each of the corresponding genes of the stated viruses
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