This proposal is to develop a high potency, low-dose Powassan virus (POWV) RNA vaccine candidateusing Tiba Biotech's innovative replicon RNA delivery system. As the geographical range of ticks growsdue to climate change, the incidence of Tickborne Diseases such as POWV is expected to increase, posing aperennial epidemic threat. There are no specific medical interventions for illness caused by POWV, which canlead 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 technologyallows 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 systemthat maximizes RNA mass content while protecting the nucleic acids from degradation and mediating cellularuptake, 2) inclusion of highly potent replicon RNA payloads to promote single-dose efficacy through their inherentadjuvant activity and persistent expression. In addition, the dendrimer-based formulation strategy proposed hereeliminates the need for structural lipid excipients that are used in competing RNA vaccine products, streamliningproduction and enhancing safety. Two replicon POWV vaccine RNAs will be produced for evaluation in thisPhase I project, one based on an alphavirus genome, and one based on the natural flaviviral genome of POWVitself. The output of this study will be in vivo-validated lead vaccine candidates, which will be developed by performing3 aims. The first Aim is to clone, synthesize, and test the two candidate POWV RNA replicon RNAs in vitro. Thesecond Aim is to establish the optimal nanoparticle formulations for these RNAs using Tiba's high-capacitymodified dendrimer encapsulation platform. The formulations will be evaluated in a preliminary murineimmunogenicity trial, measuring antibody responses to select the lead candidates. In the final proposed Aim, thebest performing candidate formulations identified in Aim 2 will be advanced to a small-scale challenge study, inwhich mice will be infected with POWV subcutaneously. Survival and serum viremia will be monitored to evaluatevaccine efficacy. Evidence of protective capacity for a candidate replicon RNA POWV vaccine will serve as thebasis for a Phase II project proposal to advance this lead to further preclinical development and in-depthimmunological characterization.
Public Health Relevance Statement: There are no specific medical interventions for illness caused by POWV, and infection can lead to life-
threatening encephalitis, meningitis, and long-term neurological complications. As with other flaviviruses,
POWV comprises an RNA genome that can undergo rapid mutation with epidemic potential. To bolster
pandemic preparedness against this virus, Tiba Biotech proposes to develop a novel nucleic acid POWV
vaccine candidate using our modular delivery platform, based on highly potent self-amplifying RNA payloads
and a dendrimer-based delivery formulation that can be easily adapted to include sequences of other
flaviviruses.
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