Abstract Orthobunyaviruses are an understudied genus in the order Bunyavirales that has no vaccines or therapies in clinical development. One of the prototype pathogens within this genus, as recently identified by NIAID, is Cache Valley virus (CVV). CVV is an emerging arthropod-borne virus that induces spontaneous abortions and congenital malformations in ruminants and humans. Given CVV’s prevalence and its broad host range, coupled with the expanding geographical range of its diverse array of competent vectors, the epidemic potential of CVV continues to increase, reminiscent of what was previously observed for Chikungunya and Zika viruses. To date, there have been no reported vaccine development activities for this virus, and prototype approaches are urgently needed to develop road maps for vaccines against viruses within this genus should an epidemic occur in the future. With the rapid adoption of mRNA vaccine technology during the ongoing COVID-19 pandemic, coupled with the recent emergency use approval of HDT Bio’s self-amplifying mRNA vaccine platform, we propose to apply HDT’s technology to develop prototype vaccines for the orthobunyavirus genus with a proof-of-concept vaccine to prevent CVV infection in a novel murine model of CVV infection and disease. This innovative, timely, and critically important R21 aims to study the safety profile and protective efficacy of this vaccine, and identify the important antigens required for broad cross-reactive immunity post-vaccination, via two specific aims: 1. Evaluate the safety, immunogenicity, and optimal dosage regimen for a LIONTM-formulated, replicon- RNA vaccine for CVV. 2. Investigate the efficacy and correlates of protection of a LION-formulated, replicon-RNA vaccine for preventing CVV-induced disease in murine models. Considering a One Health approach, and recognizing the connection between the health of humans and animals, such a vaccine could have an immediate impact in the veterinary/agricultural market, simultaneously preventing economic damage, animal disease, and disease emergence in humans. In the event of epidemic emergence in humans, this approach could be rapidly adapted and scaled for human trials.

Narrative Cache Valley virus (CVV) is an important, zoonotic, arthropod-borne virus in North America that can potentially emerge and become a major pathogen of humans, wildlife and livestock. CVV emergence can result in potentially devastating consequences on our economy, food availability, human and animal health. To circumvent this threat, we will develop a lipid inorganic nanoparticle formulated, replicon-RNA vaccine that demonstrates exceptional immunogenicity and outstanding safety, and completely protects against all aspects of CVV disease, including viral-induced abortions and congenital birth defects.