Rabies still presents a public health threat causing more than 70,000 human deaths each year. Humans are infected with rabies virus (RV) mostly through bites from rabid domestic or wild animals. Controlling RV infection in domestic and wildlife animals, therefore not only reduces the mortality in these animals but also reduces the risk of human exposure. Pre-exposure vaccinations for people who are constantly at risk further prevent human rabies, as do post-exposure immunization for people who are bitten by rabid or suspected rabied animals. Currently, inactivated RV vaccines are used to immunize domestic pet animals. Purified and inactivated RV vaccines are used for humans in pre- or post-exposure settings. Although inactivated RV vaccines are efficacious, they have problems. First and for most, multiple doses of vaccines over a long period of time are required to stimulate protective immune responses. Furthermore, current tissue culture vaccines are expensive, thus most people in need of vaccination (in developing countries) cannot afford them. Hence, there is a need to develop more efficacious and affordable RV vaccines. In the previous funding period, we made constructs with mutation on both the glycoprotein and the nucleoprotein, resulting in reduced ability to replicate and spread in the nervous system. Here we propose to continue developing avirulent live RV vaccines by constructing mutant RV with enhanced ability to induce innate immune responses (by inserting IFN or chemokine genes into the RV genome), using the state-of-the-art reverse genetics technology. Our proposal is based on our recent findings. Attenuated RV induces strong innate immune responses, particularly IFN and chemokines, thus limiting virus spread within the CNS. The rationale for construction of recombinant RV expressing IFN or chemokines is that such altered RV most likely will have enhanced immunogenicity and can be used as live avirulent vaccines for humans and animals. Furthermore, induction of innate immune responses will not only have a direct anti-viral functions, but also recruit inflammatory cells that can kill infected cells. Such characterists will make these recombinant RV vaccines particularly suitable for post-exposure treatment.
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