Specific Aims Rift Valley fever (RVF), a mosquito-borne zoonotic viral disease affecting ruminants and humans endemic to sub-Saharan Africa, Egypt, Saudi Arabia and Yemen, is classified as Category A Priority Pathogen by the NIH/NIAID and the Blueprint priority disease by the World Health Organization. With One Health approach, a control of infected animals and mosquitoes are important to eradicate RVF from specific areas, whereas vaccinated humans will support overall activities including the handling of infected animals. There are, however, no licensed RVF vaccines for human use. Live-attenuated MP-12 vaccine, which was conditionally licensed in 2013 as a veterinary RVF vaccine in the U.S., had Investigational New Drug (IND) vaccine status, it has now been replaced with weakly immunogenic inactivated RVF candidate vaccine under IND. To develop a highly immunogenic and safe RVF candidate vaccine for human use, we have generated a novel live-attenuated candidate vaccine for RVF, termed ?RVax-1?, which encodes more than 500 silent mutations throughout the open reading frame and a truncation of 78kD/NSm genes. Our central hypothesis is that the RVax-1 candidate vaccine is highly immunogenic in mice and marmosets via the intramuscular route with a single dose, highly attenuated in pregnant rat placenta and in infant mice, and disseminate poorly in mosquito vectors. The overall objective is characterize the immunogenicity, safety, and efficacy of the RVax-1 candidate vaccine in mice, rats, and marmosets, and to determine the level of viral dissemination in mosquitoes, in order to fill the gaps in knowledge regarding this candidate vaccine and move forward into IND-enabling preclinical and, subsequently, clinical evaluation. The work environment is ideal because the high containment facilities at the University of Texas Medical Branch are suitable for animal experiments, and SUNY Upstate Medical University supports mosquito experiments. The long-term goal of our study is to move the RVax-1 vaccine forward into preclinical evaluation, production under Good Manufacturing Practice, and Phase 1/2 trials.
Specific Aim 1 : To characterize the attenuation, immunogenicity, and protective efficacy of RVax-1 in a mouse model.
Specific Aim 2 : To characterize the mosquito dissemination of RVax-1.
Specific Aim 3 : To characterize the attenuation, immunogenicity, and protective efficacy of RVax-1 in a marmoset model.
Specific Aim 4 : To characterize the attenuation of RVax-1 in rat placenta. Successful completion of proposed project will qualify RVax-1 for further characterization in preclinical and clinical evaluation.
Safe and efficacious vaccines for Rift Valley fever are not available for humans. We will characterize a novel live-attenuated candidate vaccine, termed RVax-1, in several key animal models and mosquitoes for the attenuation, immunogenicity, and protective efficacy.
