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A VSV-based Zika virus vaccine protects mice from lethal challenge.

ABSTRACT: Infection with Zika virus (ZIKV) is commonly mild in humans but has been associated with alarming negative health outcomes including Guillain-Barré syndrome in adults and microcephaly in fetuses. As such, developing a vaccine for ZIKV is a global public health priority. Recombinant vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) has been successfully used as a vaccine platform in the past. In this study, two novel VSV-ZIKV vaccines were generated utilizing the favorable immune targeting of the existing VSV-EBOV vector. In addition to the EBOV GP, these new vaccines express the full-length pre-membrane and envelope proteins or pre-membrane and truncated soluble envelope proteins as antigens. Efficacy testing of both of the VSV vectors against ZIKV was conducted in IFNAR-/- mice and resulted in uniform protection when a single dose was administered 28 days prior to lethal challenge. Furthermore, this vaccine is fast-acting and can uniformly protect mice from lethal disease when administered as late as 3 days prior to ZIKV challenge. Thus, VSV-ZIKV vectors are promising vaccine candidates and should move forward along the licensure pathway.

SUBMITTER: Emanuel J

PROVIDER: S-EPMC6056530 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A VSV-based Zika virus vaccine protects mice from lethal challenge.

Emanuel Jackson J Callison Julie J Dowd Kimberly A KA Pierson Theodore C TC Feldmann Heinz H Marzi Andrea A

Scientific reports 20180723 1

Infection with Zika virus (ZIKV) is commonly mild in humans but has been associated with alarming negative health outcomes including Guillain-Barré syndrome in adults and microcephaly in fetuses. As such, developing a vaccine for ZIKV is a global public health priority. Recombinant vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) has been successfully used as a vaccine platform in the past. In this study, two novel VSV-ZIKV vaccines were generated utilizing th ...[more]

PMID: 30038228

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Project description:Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2(-/-)) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1(-/-) mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2(-/-) mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2(-/-) mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2(-/-) mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2(-/-) mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2(-/-) mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2(-/-) mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.

Project description:West Nile virus (WNV) has caused multiple global outbreaks with increased frequency of neuroinvasive disease in recent years. Despite many years of research, there are no licensed therapeutics or vaccines available for human use. One of the major impediments of vaccine development against WNV is the potential enhancement of infection by related flaviviruses in vaccinated subjects through the mechanism of antibody-dependent enhancement of infection (ADE). For instance, the recent finding of enhancement of Zika virus (ZIKV) infection by pre-exposure to WNV further complicates the development of WNV vaccines. Epidemics of WNV and the potential risk of ADE by current vaccine candidates demand the development of effective and safe vaccines. We have previously reported that the domain III (DIII) of the WNV envelope protein can be readily expressed in Nicotiana benthamiana leaves, purified to homogeneity, and promote antigen-specific antibody response in mice. Herein, we further investigated the in vivo potency of a plant-made DIII (plant-DIII) in providing protective immunity against WNV infection. Furthermore, we examined if vaccination with plant-DIII would enhance the risk of a subsequent infection by ZIKV and Dengue virus (DENV). Plant-DIII vaccination evoked antigen-specific cellular immune responses as well as humoral responses. DIII-specific antibodies were neutralizing and the neutralization titers met the threshold correlated with protective immunity by vaccines against multiple flaviviruses. Furthermore, passive administration of anti-plant DIII mouse serum provided full protection against a lethal challenge of WNV infection in mice. Notably, plant DIII-induced antibodies did not enhance ZIKV and DENV infection in Fc gamma receptor-expressing cells, addressing the concern of WNV vaccines in inducing cross-reactive antibodies and sensitizing subjects to subsequent infection by heterologous flavivirus. This study provides the first report of a WNV subunit vaccine that induces protective immunity, while circumventing induction of antibodies with enhancing activity for ZIKV and DENV infection.

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A VSV-based Zika virus vaccine protects mice from lethal challenge.

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A VSV-based Zika virus vaccine protects mice from lethal challenge.

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