Low-dose RNA vaccine platform for tickborne flaviviruses

This proposal is to develop a high potency, low-dose Powassan virus (POWV) RNA vaccine candidate using Tiba Biotech’s innovative replicon RNA delivery system. As the geographical range of ticks grows due to climate change, the incidence of Tickborne Diseases such as POWV is expected to increase, posing a perennial epidemic threat. There are no specific medical interventions for illness caused by POWV, which can lead to life-threatening encephalitis, meningitis, and long-term, potentially fatal neurological complications. Nucleic acid vaccines are an ideal approach to addressing the threat of such flaviviruses, as this technology allows rapid response to emergent outbreaks of related strains without alteration to the manufacturing process. Tiba’s vaccine will be innovative in two respects: 1) application of a proprietary dendrimer-based delivery system that maximizes RNA mass content while protecting the nucleic acids from degradation and mediating cellular uptake, 2) inclusion of highly potent replicon RNA payloads to promote single-dose efficacy through their inherent adjuvant activity and persistent expression. In addition, the dendrimer-based formulation strategy proposed here eliminates the need for structural lipid excipients that are used in competing RNA vaccine products, streamlining production and enhancing safety. Two replicon POWV vaccine RNAs will be produced for evaluation in this Phase I project, one based on an alphavirus genome, and one based on the natural flaviviral genome of POWV itself.The output of this study will be in vivo-validated lead vaccine candidates, which will be developed by performing 3 aims. The first Aim is to clone, synthesize, and test the two candidate POWV RNA replicon RNAs in vitro. The second Aim is to establish the optimal nanoparticle formulations for these RNAs using Tiba’s high-capacity modified dendrimer encapsulation platform. The formulations will be evaluated in a preliminary murine immunogenicity trial, measuring antibody responses to select the lead candidates. In the final proposed Aim, the best performing candidate formulations identified in Aim 2 will be advanced to a small-scale challenge study, in which mice will be infected with POWV subcutaneously. Survival and serum viremia will be monitored to evaluate vaccine efficacy. Evidence of protective capacity for a candidate replicon RNA POWV vaccine will serve as the basis for a Phase II project proposal to advance this lead to further preclinical development and in-depth immunological characterization.