A single-shot measles vaccine expressing the rabies virus glycoprotein confers dual protection against rabies virus and measles virus.

Rabies (RABV) is a neglected tropical disease responsible for ~59,000 global human deaths annually, 99% of these being due to dog bites. Efforts to control RABV in the dog population have been unsuccessful due to insufficient dog vaccinations and animal population control. The current RABV vaccine is 100% effective at preventing RABV deaths when administered correctly, but the average cost of human RABV pre & post-exposure vaccines is currently ~$108, which precludes its widespread use in low-income RABV endemic countries. To address these challenges, we harnessed the potential of the measles virus (MV) vaccine vector (Edmonston B strain), which is cheap to produce. We generated two recombinant MVs expressing a codon-optimized (co) RABV glycoprotein (RV-G) containing the R333E mutation (to abrogate neurotropism), from two different positions within the MV genome: i) MV-RVG2(between N &P), and ii) MV-RVG6(between H &L). Both the MV-RABV vaccines induced significantly higher RABV- and MV-specific IgG ELISA and neutralizing titers than the commercial RABV vaccine and the MMR vaccine, respectively. Interestingly, a single shot of the MV-RVG6 vaccine conferred 100% protection when hCD46-IFNAR-/- mice were intranasally challenged with CVS-N2C, whereas two shots of MV-RVG2 were required for the same protection. Furthermore, MV-RVG6 conferred 100% MV protection in a cotton rat model of MV infection. Lastly, the MV-RABV vaccines induced plasma cell responses and long-term RABV and MV neutralizing responses in mice similar to the commercial RABV vaccine, RabAvert. These findings suggest that further development of MV-RVG6 could lead to an effective dual vaccine against RABV and MV.