Through this Notice of Funding Opportunity Announcement (NOFO), the National Cancer Institute (NCI) intends to expand the research scope and leverage the gains made through the NOFO entitled Investigation of the Transmission of KSHV (RFA-CA-18-013 and RFA-CA-20-046) to support basic and translational research that will guide the development of a prophylactic or therapeutic Kaposi sarcoma herpesvirus (KSHV) vaccine. A prophylactic KSHV vaccine could prevent primary KSHV infection, transmission, and subsequent development of KS and other KSHV-associated syndromes such as multicentric Castleman disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS) or ameliorate the severity of disease. A therapeutic KSHV vaccine could be helpful in preventing or treating KSHV disease in people who are already infected with KSHV. Research areas could include, but are not limited to: (1) Identification and evaluation of KSHV structural and non-structural targets for a potential KSHV vaccine; (2) Development of animal models to study a prototype KSHV vaccine or vaccines; (3) Development and testing of a candidate KSHV vaccine or vaccines; (4) Studies to assess how the efficacy of a promising KSHV vaccine can be optimized for PWH; (5) Research to better define the initial steps of infection with KSHV and the primary means of person-to-person transmission in different populations that can be targeted with a vaccine; and (6) Optimization and/or standardization of KSHV detection methods.