Strategically Engineered Multi-Antigen KSHV Vaccine: Integrating Humoral and Cellular Immunity for Effective Protection

Project Summary/Abstract Infection of Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is estimated to account for 34,000 new cancer cases each year, presenting a significant healthcare challenge globally. Typically, KSHV infection in healthy infected individuals results in weak neutralizing antibody responses and low T cell immunity. This modest immunity during natural infection calls for a vaccine that can circumvent the immune evasion mechanisms of KSHV, effectively priming the immune system to generate robust and reliable immunity across individuals. Such a vaccine would not only protect against initial infections but also help individuals maintain better control over persistent infection, thereby reducing the risk of developing KSHV- associated diseases. This is particularly vital for high-risk populations, including individuals with an increased likelihood of HIV-1 infection, transplant patients receiving immunosuppressive therapy, and people living in resource-limited endemic regions of Africa. Our proposal addresses this critical medical need. Our proposal outlines a comprehensive and innovative vaccine strategy against KSHV, harnessing antibody and T cells to establish strong antiviral immunity. Aim 1 focuses on generating potent humoral antibody responses through structure-guided immunogen design, leading to neutralizing and non-neutralizing activities that block infection and mediate the immune clearance of infected cells. Aim 2 is dedicated to enhancing vaccine- induced T cell immunity targeting latently infected cells by utilizing innovative RNA-based adjuvants. These RNA- adjuvanted T cell responses are designed to complement antibody-mediated antiviral effects. Aim 3 seeks to integrate these strategies by combining vaccine components that simulate both antibody and T cell responses while maintaining the immunogenicity of each antigen. This aim will also address species differences in terms of dendritic cell activation and inflammatory responses after receiving our combined vaccine. Overall, through this multidisciplinary effort, we aspire to develop a prototype vaccine for KSHV that provides broad and effective immunity.