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A Zika Vaccine Generated Using the Chimeric Insect-Specific Binjari Virus Platform Protects against Fetal Brain Infection in Pregnant Mice.

ABSTRACT: Zika virus (ZIKV) is the etiological agent of congenital Zika syndrome (CZS), a spectrum of birth defects that can lead to life-long disabilities. A range of vaccines are in development with the target population including pregnant women and women of child-bearing age. Using a recently described chimeric flavivirus vaccine technology based on the novel insect-specific Binjari virus (BinJV), we generated a ZIKV vaccine (BinJ/ZIKA-prME) and illustrate herein its ability to protect against fetal brain infection. Female IFNAR-/- mice were vaccinated once with unadjuvanted BinJ/ZIKA-prME, were mated, and at embryonic day 12.5 were challenged with ZIKVPRVABC59. No infectious ZIKV was detected in maternal blood, placenta, or fetal heads in BinJ/ZIKA-prME-vaccinated mice. A similar result was obtained when the more sensitive qRT PCR methodology was used to measure the viral RNA. BinJ/ZIKA-prME vaccination also did not result in antibody-dependent enhancement of dengue virus infection or disease. BinJ/ZIKA-prME thus emerges as a potential vaccine candidate for the prevention of CSZ.

SUBMITTER: Hazlewood JE

PROVIDER: S-EPMC7564101 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A Zika Vaccine Generated Using the Chimeric Insect-Specific Binjari Virus Platform Protects against Fetal Brain Infection in Pregnant Mice.

Hazlewood Jessamine E JE Rawle Daniel J DJ Tang Bing B Yan Kexin K Vet Laura J LJ Nakayama Eri E Hobson-Peters Jody J Hall Roy A RA Suhrbier Andreas A

Vaccines 20200902 3

Zika virus (ZIKV) is the etiological agent of congenital Zika syndrome (CZS), a spectrum of birth defects that can lead to life-long disabilities. A range of vaccines are in development with the target population including pregnant women and women of child-bearing age. Using a recently described chimeric flavivirus vaccine technology based on the novel insect-specific Binjari virus (BinJV), we generated a ZIKV vaccine (BinJ/ZIKA-prME) and illustrate herein its ability to protect against fetal br ...[more]

PMID: 32887302

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Project description:Zika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms, but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. Creating an effective vaccine against ZIKV is a public health priority. We describe the protective effect of an already licensed attenuated yellow fever vaccine (YFV, 17DD) in type-I interferon receptor knockout mice (A129) and immunocompetent BALB/c and SV-129 (A129 background) mice infected with ZIKV. YFV vaccination provided protection against ZIKV, with decreased mortality in A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in BALB/c mice. The A129 mice that were challenged two and three weeks after the first dose of the vaccine were fully protected, whereas partial protection was observed five weeks after vaccination. In all cases, the YFV vaccine provoked a substantial decrease in the cerebral viral load. YFV immunization also prevented hippocampal synapse loss and microgliosis in ZIKV-infected mice. Our vaccine model is T cell-dependent, with AG129 mice being unable to tolerate immunization (vaccination is lethal in this mouse model), indicating the importance of IFN-γ in immunogenicity. To confirm the role of T cells, we immunized nude mice that we demonstrated to be very susceptible to infection. Immunization with YFV and challenge 7 days after booster did not protect nude mice in terms of weight loss and showed partial protection in the survival curve. When we evaluated the humoral response, the vaccine elicited significant antibody titers against ZIKV; however, it showed no neutralizing activity in vitro and in vivo. The data indicate that a cell-mediated response promotes protection against cerebral infection, which is crucial to vaccine protection, and it appears to not necessarily require a humoral response. This protective effect can also be attributed to innate factors, but more studies are needed to strengthen this hypothesis. Our findings open the way to using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak.

Project description:BackgroundZika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV.Methodology/principle findingsWe have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge.Conclusions/significanceThese studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

Dataset Information

A Zika Vaccine Generated Using the Chimeric Insect-Specific Binjari Virus Platform Protects against Fetal Brain Infection in Pregnant Mice.

Publications

A Zika Vaccine Generated Using the Chimeric Insect-Specific Binjari Virus Platform Protects against Fetal Brain Infection in Pregnant Mice.

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