A novel synthetic DNA vaccine elicits protective immune responses against Powassan virus

Author summary Powassan virus (POWV) is an emerging RNA virus, belonging to the tick-borne flavivirus family and transmitted to humans through the bite of an infected tick. Infection can produce severe neurological manifestations, including meningitis and encephalitis, leading to death. Despite the potential for its emergence, currently antiviral therapies are not available to treat or prevent this emerging infection. This situation calls for concern and needs to be addressed. In this study, we have designed and produced a consensus, synthetic enhanced vaccine (SEV) against POWV (POWV-SEV) that focuses on regions of the envelope protein. The effectiveness of this vaccine was evaluated murine models. We have tested the antigen-specific humoral responses to the POWV-SEVs including the induction of neutralizing antibody responses. In addition, cellular immunogenicity including identification of dominant epitopes and polyfunctionality of cytokine-producing T-cells were characterized in POWV-SEV administered mice. Finally, we assessed the protective efficacy of POWV-SEV using a murine challenge natural infection model of POWV. These studies are highly novel and support the feasibility of developing an envelope-based synthetic enhanced DNA vaccine to aid in mitigating the public health threat emerging tick-borne viruses may pose to outdoor pets and humans in endemic areas. Powassan virus (POWV) infection is a tick-borne emerging infectious disease in the United States and North America. Like Zika virus, POWV is a member of the family Flaviviridae. POWV causes severe neurological sequalae, meningitis, encephalitis, and can cause death. Although the risk of human POWV infection is low, its incidence in the U.S. in the past 16 years has increased over 300%, urging immediate attention. Despite the disease severity and its growing potential for threatening larger populations, currently there are no licensed vaccines which provide protection against POWV. We developed a novel synthetic DNA vaccine termed POWV-SEV by focusing on the conserved portions of POWV pre-membrane and envelope (prMEnv) genes. A single immunization of POWV-SEV elicited broad T and B cell immunity in mice with minimal cross-reactivity against other flaviviruses. Antibody epitope mapping demonstrated a similarity between POWV-SEV-induced immune responses and those elicited naturally in POWV-infected patients. Finally, POWV-SEV induced immunity provided protection against POWV disease in lethal challenge experiments.