7. Project Summary/Abstract Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family that causes fever, rash, and arthralgia in humans, leading to debilitating illness and poor quality of life. In the past 20 years, CHIKV has greatly expanded its geographic distribution in part due to climate changes as well as its adaptation to Aedes albopictus mosquitoes and remains a global health threat due to its high rate of infectivity and the severity of disease it causes. Estimates indicate that over 1.3 billion people reside in areas at risk for CHIKV transmission, with over 114,181 cases and 43 deaths reported to date in 2023 alone. Despite CHIKV’s classification as a category C priority pathogen and its recent identification as a prototype pathogen for NIAID’s Plan for Pandemic Preparedness, there are currently no licensed vaccines or therapeutics to protect against CHIKV infection. While a few vaccine candidates have progressed to advanced stages of development, manufacturing challenges exist for complex vaccine compositions for enveloped viruses. This is compounded by an incomplete understanding of virally-induced chronic CHIKV disease mechanisms that can introduce adverse event risks, especially for replication-competent vaccines. Alternate vaccines utilizing methods that can offer better safety profiles as well as benefits in manufacturing are warranted. We have developed a promising recombinant subunit CHIKV vaccine that induces high levels of neutralizing antibodies, prevents viral replication in immunocompetent mice and protects immunocompromised mice from lethal challenge. The role of antibodies in protection was demonstrated in a passive transfer study where immune sera was injected into naïve immunocompromised mice and full protection was achieved after lethal virus challenge. The overall goal of the current Phase IIB renewal research is to support preclinical efforts to further advance the CHIKV E2/E1 recombinant subunit vaccine candidate formulated with the next-generation adjuvant SLA-LSQ. These efforts will enable human clinical trial evaluation and further the potential for commercialization. The proposed research aims to 1) Evaluate the E2/E1 vaccine in chronic disease and durability studies; 2) Prepare cGMP lots of E2/E1 vaccine antigen; 3) Submit a pre-IND package to FDA for review and conduct a rabbit toxicology study; and 4) Prepare and submit IND to the FDA. Completion of the proposed work will promote the clinical advancement of a safe and stable vaccine alternative using an established recombinant protein manufacturing platform that can combat the significant disease threat posed by CHIKV.