A Single Shot Measles Vectored Rabies Vaccine for Children - Abstract: Rabies virus (RABV) is nearly 100% lethal once symptoms appear. Dogs are the primary source of 99% of human rabies infections, and about 40% of bite victims are children under 15. Rabies prevention in dogs has been focused on animal control and mass dog vaccinations. Despite these efforts, rabies still kills approximately 59,000 people annually worldwide. The human RABV vaccine is highly effective against RABV. However, this vaccine is cost-prohibitive for inclusion in childhood immunization regimens. The availability of an alternative, lower-cost vaccine would be a major step forward in our ability to prevent human RABV infections. A promising candidate toward this goal is based on the live-attenuated measles virus (MV), which is both highly effective and affordable. The MV vaccine has been administered to millions of children for over 50 years, providing long-lived immunity with very few side effects. The recombinant MV vaccine platform has been well- established to deliver and confer immunity to foreign antigens from viruses such as Lassa, Zika, etc. Therefore, we propose to develop a modified MV vaccine strain that can circumvent pre-existing immunity as a viral vector to immunize children of all ages against RABV, without the need to replace the current commercial MV vaccine. We previously generated two MV vectored RABV vaccines that express a non-neurotropic RABV glycoprotein (RV-G333) from two different positions within the MV genome: i) MV-RVG2, between N, P genes, and ii) MV- RVG6, between H, L genes. Although the MV-RVG6 virus induced higher RABV virus neutralizing antibody (VNA) titers than the MV-RVG2 virus, both were above the World Health Organization protective threshold. Whereas the commercial rabies vaccine could not protect these mice against an intranasal RABV challenge, immunization with one dose of MV-RVG2 conferred 60% protection, and one dose of MV-RVG6 conferred 100% protection. These data suggest that our MV-RABV vaccines may be inducing both high VNA titers and additional protective responses. For our 2nd-generation improved vaccine, we generated a MV vectored RABV-only vaccine, MVΔFH-RVGF, by replacing the MV fusion and hemagglutinin proteins with a chimeric RV-G. Our preliminary data suggest that one shot of MVΔFH-RVGF induces robust RV-G antibody titers. In Aim 1, we will test the safety profile, assess the effect of pre-existing MV immunity on RABV efficacy in mice, and evaluate the long-term efficacy of the single-shot MVΔFH-RVGF vaccine in mice and hamsters. In Aim 2, we will compare MVΔFH-RVGF, MV-RVG6, and the commercial RABV vaccine to assess the induction of plasma and T-cell responses and analyze the mechanism of protection by performing sera and/or T-cell transfer studies before RABV challenge. Further, we will perform single-cell sequencing of the PBMCs from vaccinated/control young rhesus macaques to delineate the signatures of long-term vaccine-mediated protection. Lastly, in Aim 3, we will test the post-exposure efficacy in hamsters of one to four shots of MVΔFH-RVGF, with/without human rabies Immunoglobulin, when administered 4 or 48 hours after RABV challenge.
