Single dose of a replication-defective vaccinia virus expressing Zika virus-like particles is protective in mice

Brittany Jasperse,Yuxiang Wang,Paulo H Verardi,Caitlin M O'Connell

doi:10.1038/s41598-021-85951-7

Brittany Jasperse, Yuxiang Wang + Show 2 more

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https://doi.org/10.1038/s41598-021-85951-7

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Abstract

Zika virus (ZIKV), a flavivirus transmitted primarily by infected mosquitos, can cause neurological symptoms such as Guillian–Barré syndrome and microcephaly. We developed several vaccinia virus (VACV) vaccine candidates for ZIKV based on replication-inducible VACVs (vINDs) expressing ZIKV pre-membrane (prM) and envelope (E) proteins (vIND-ZIKVs). These vIND-ZIKVs contain elements of the tetracycline operon and replicate only in the presence of tetracyclines. The pool of vaccine candidates was narrowed to one vIND-ZIKV containing a novel mutation in the signal peptide of prM that led to higher expression and secretion of E and production of virus-like particles, which was then tested for safety, immunogenicity, and efficacy in mice. vIND-ZIKV grows to high titers in vitro in the presence of doxycycline (DOX) but is replication-defective in vivo in the absence of DOX, causing no weight loss in mice. C57BL/6 mice vaccinated once with vIND-ZIKV in the absence of DOX (as a replication-defective virus) developed robust levels of E-peptide-specific IFN-γ-secreting splenocytes and anti-E IgG titers, with modest levels of serum-neutralizing antibodies. Vaccinated mice treated with anti-IFNAR1 antibody were completely protected from ZIKV viremia post-challenge after a single dose of vIND-ZIKV. Furthermore, mice with prior immunity to VACV developed moderate anti-E IgG titers that increased after booster vaccination, and were protected from viremia only after two vaccinations with vIND-ZIKV.

Highlights

Zika virus (ZIKV), a flavivirus transmitted primarily by infected mosquitos, can cause neurological symptoms such as Guillian–Barré syndrome and microcephaly
We developed several vaccine candidates expressing ZIKV E protein either alone or with prM to rapidly determine an antigen strategy that leads to high levels of E protein expression and virus-like particles (VLPs) secretion
Recombinant vINDs can be produced in a week, using our Efficient Purification by Parental Inducer Constraint (EPPIC) system[19], allowing the straightforward generation of multiple vaccine candidates that can be tested for expression, and if needed, immunogenicity

Summary

Introduction

Zika virus (ZIKV), a flavivirus transmitted primarily by infected mosquitos, can cause neurological symptoms such as Guillian–Barré syndrome and microcephaly. We developed several vaccinia virus (VACV) vaccine candidates for ZIKV based on replication-inducible VACVs (vINDs) expressing ZIKV premembrane (prM) and envelope (E) proteins (vIND-ZIKVs). These vIND-ZIKVs contain elements of the tetracycline operon and replicate only in the presence of tetracyclines. In late 2015, increasing numbers of infants born with microcephaly were reported, prompting the Brazil Ministry of Health to declare a Public Health Emergency of National Importance[8] and the World Health Organization to declare a Public Health Emergency of International Concern from FebruaryNovember 20169 Once it emerged in Brazil, ZIKV spread rapidly throughout Central and South America, leading to over 170,000 confirmed ZIKV cases across 48 countries and territories[3]. In the absence of inducer, expression of a fluorescence marker is detected in abortively-infected cells[13,14], indicating that even in the absence of viral replication, heterologous antigens are expressed

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