Zika virus (ZIKV) has recently emerged as an explosive pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives; thus, development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) containing modified nucleosides is emerging as a versatile and highly effective vaccine platform, which generates potent T follicular helper (Tfh) cell and neutralizing antibody responses to diverse viral pathogens. In this study, we developed a nucleoside-modified mRNA-based vaccine against ZIKV and determined its immunogenicity and protective efficacy in mice and non-human primates.
Nucleoside-modified mRNA encoding the pre-membrane (prM) and envelope (E) glycoproteins from a 2013 ZIKV outbreak strain (H/PF/2013) was transcribed with T7 phage RNA polymerase using 1-methylpseudouridine triphosphate in place of UTP. mRNA was purified by HPLC and incorporated into lipid nanoparticles (LNPs). Mice and rhesus macaques were immunized once intradermally with prM-E mRNA-LNPs. Serology was followed by IgG ELISA and three types of neutralization assay: plaque and focus reduction neutralization tests and reporter viral particle assay. Animals were challenged with ZIKV PRVABC59 (Puerto Rico, 2015) and viral loads were followed by quantitative RT-PCR.
High and stable levels of Zika E-specific IgG and neutralizing antibody were generated after a single immunization of ZIKV mRNA-LNPs in both mice and rhesus macaques. Neutralizing titers in multiple assays exceeded levels that previously protected animals in passive transfer experiments. A single immunization with 30 μg of ZIKV mRNA-LNPs protected mice from detectable viremia (<200 copies/ml) following a ZIKV challenge at 2 weeks (short-term) or 5 months (long-term) post-vaccination. A single low-dose immunization with 50 μg (0.02 mg/kg) protected rhesus macaques from detectable viremia (<50 copies/ml) following a challenge at 5 weeks post-vaccination.
The ZIKV prM-E nucleoside-modified mRNA-LNP vaccine is potently immunogenic in mice and rhesus macaques. This vaccine platform requires only a single administration of a low dose of mRNA to generate a rapid, long-lived, and protective immune response, which is mediated by potent Tfh cell induction. Nucleoside-modified mRNA-LNP represents a new and advantageous vaccine candidate for a global public health campaign against ZIKV, with ongoing expansion to other pathogens.