Weight loss was analyzed by two-way ANOVA (***, P < 0.001). Survival data was analyzed by the log rank test (*, P < 0.05 ***, P < 0.001). Error bars indicate standard error the mean (SEM). Animals were monitored for survival ( I) and weight loss ( J). AG129 Mice were challenged at 6 weeks post vaccination with 10 4 PFU of ZIKV P6-740. The dashed lines indicate the limit of detection of the assay. EC50 and EC90 data were analyzed by a Kruskal-Wallis test with a multiple comparisons correction and compared to the placebo LNP vaccine (*, P < 0.05 ***, P < 0.001 ****, P < 0.0001). Data are a composite of two independent experiments with sera from each of the 10 animals per group. Each point represents the mean of two independent experiments per animal. Representative curves are shown ( F), and EC50 ( G) and EC90 ( H) values were calculated for individual animals in each group. Serum was collected at 6 weeks after vaccination and analyzed for neutralization of ZIKV by PRNT assay. Scheme of immunization of AG129 mice with one (prime) or two (prime-boost) doses of 2 or 10 μg with IgE sig prM-E or placebo mRNA LNP vaccines. HeLa cell supernatants were collected for Western blotting under non-reducing conditions with a mAb against the ZIKV E protein. One representative experiment of several is shown D. Low- and high-power images of purified SVPs are shown. HeLa cells were transfected with prM-E mRNA, and SVPs in the supernatant were purified and concentrated by ultracentrifugation and then subjected to electron microscopy and negative staining. In this construct, prM is directed into the ER using a heterologous IgE signal sequence (IgE sig) at the amino-terminus.
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An mRNA encoding the ZIKV prM/M and E structural genes was engineered ( bottom).
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ZIKV prM-E modified mRNA is packaged into LNPs for intramuscular delivery. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.ĭengue virus RNA vaccine Zika virus antibody neutralization flavivirus immunity pathogenesis protection.Ĭopyright © 2017 Elsevier Inc. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Electronic address: emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA Department of Pathology and Immunology, Washington University School of Medicine, St. Electronic address: 7 Department of Medicine, Washington University School of Medicine, St.
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