Production and Testing of a Novel Live-Attenuated Chikungunya Vaccine
The following work was focused on production and testing of a novel live-attenuated chikungunya virus (CHIKV) vaccine. To this end, multiple strategies were adapted from the IRES-based vaccine strategy first employed with VEEV vaccine strain, TC-83. The first strategy, CHIKV/IRESv1, was highly stable during cell culture passages in Vero cells, and was unable to replicate in mosquitoes. The vaccine was then tested for safety and efficacy in multiple mouse models. These tests demonstrated that CHIKV/IRESv1 had a highly attenuated phenotype and was able to produce a strong immunogenic response. The vaccine was also capable of protecting against a lethal challenge by wild-type CHIKV in multiple animal models. The use of immunocompromised animals became the focus of our testing due to the sensitivity of the type I IFN -/- receptor knockout mouse, A129, to CHIKV infection. In-depth studies were completed using this animal to measure the differences between wild-type CHIKV, CHIKV/IRESv1, and the prototypical 181/25 vaccine. These studies expanded on the safety and efficacy knowledge of the vaccines. The work also discerned the beneficial attributes of CHIKV/IRESv1 in comparison to the 181/25 vaccine, such as increased stability in vivo following serial brain passages and other safety concerns. Overall, the CHIKV/IRESv1 vaccine is safer than and similarly efficacious to the 181/25 vaccine, which progressed to phase II clinical trials.