DESCRIPTION (provided by applicant): There is major public health concern about the continuing spread of two viruses transmitted by mosquitoes that cause serious human diseases leading to extensive morbidity and mortality. These viruses are chikungunya virus (CHIKV, an alphavirus) and dengue virus (DENV, a flavivirus). These viruses are transmitted by the same mosquito vectors and are now co-circulating extensively in both the old and new worlds. There are currently no vaccines available to protect against either DENV or CHIKV infection. We have developed a chimeric, live attenuated vaccine vector based on a defective vesicular stomatitis virus (VSV) deleted for its surface glycoprotein gene (G), and instead expressing the CHIKV envelope proteins. This VSVΔG-CHIKV vector can be grown readily in tissue culture and induces high levels of CHIKV neutralizing antibodies. It also provides single-dose protection from CHIKV infection but lacks all pathogenicity including neurotoxicity. The goal of this project is to test the immunogenicity and safety of this vector expressing appropriate antigens from all four DENV serotypes to determine if it might be a candidate multivalent vaccine protecting against both CHIKV and all four DENV serotypes. Vaccine vectors based on live attenuated viruses are typically highly effective, but they also require extensive safety testing prior to clinical trials. Thus if a single safe and effective live vaccine vector for both CHIKV and DENV could be developed, it would greatly simplify the regulatory approval and clinical trial processes. It would also help limit the number of vaccinations required for people living or working in areas where both viruses are circulating.

PUBLIC HEALTH RELEVANCE: Chikungunya (CHIKV) and dengue (DENV) viruses cause severely debilitating and sometimes fatal human disease, and are co-circulating in much of the world, yet there are no vaccines available to protect against either virus. Development of a multivalent vaccine that would provide protection against both CHIKV and DENV is a high priority and would have a major impact on world health. This project will support proof-of- concept immunogenicity and safety studies to evaluate a novel, highly attenuated hybrid virus vector with the potential to serve as a multivalent vaccine protecting against both CHIKV and DENV.