KSHV Subunit Vaccine Candidates to Elicit Potent Humoral Immune Reponses against KSHV Infection

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PROJECT SUMMARY Kaposi sarcoma-associated herpesvirus (KSHV) has been classified as a direct carcinogen by the International Agency for Research on Cancer because of its ability to cause Kaposi sarcoma (KS) and two rare types of B-cell lymphoma. KS frequently occurs among iatrogenic or HIV/AIDS-induced immunosuppressed individuals. To date, there is no licensed KSHV vaccine that can prevent primary infection and subsequent malignancies. Our objective in this application is to optimize the inclusion of key KSHV glycoproteins (gps), which are involved in epithelial, endothelial, fibroblast and B-cell entry, into multivalent subunit vaccine candidates that can stimulate neutralizing antibody (nAb) immune responses to prevent or limit KSHV infection and KSHV+ cancers in vivo. This application builds on my recently completed NCI K01 CA184388-05 research on KSHV entry mechanisms and vaccine development. Recently, we showed that in vitro, the KSHV glycoprotein gH is essential for viral infection of epithelial, endothelial, and fibroblasts cells, but not B cells. Notably, we and other have also shown that both monoclonal and polyclonal Abs to KSHV glycoproteins K8.1, gB, and gH/gL can neutralize KSHV infection of diverse permissive human cells in vitro. Building on this success, we have generated quadrivalent virus-like particles (KSHV-LPs) incorporating the four glycoproteins critical for viral entry (K8.1, gB and gH/gL). In this application we will use wild-type and humanized mice and common marmoset (Callithrix jacchus) models to test the hypothesis that purified KSHV-LPs delivered directly or through immunization with a modified vaccinia Ankara vector (MVA-KSHV-LPs) will elicit robust protective nAb responses to KSHV infection and its associated malignancies. The premise of our proposal is built on strong evidence that 1) infection with KSHV does not occur during early childhood, as is typical for other herpesviruses, opening a window of opportunity for vaccination and 2) Abs against the KSHV glycoproteins K8.1, gB, and gH/gL can neutralize KSHV infection. Furthermore, the permissiveness of humanized mice and marmosets to KSHV infection offers an ideal platform to test candidate vaccines. Thus, a polyvalent vaccine that induces prophylactic neutralizing Abs responses will not only be an invaluable candidate vaccine in preventing KSHV infection, but also of utmost importance in preventing KSHV-associated diseases. We will provide evidence for the safety of our candidate KSHV vaccine based on three pre-clinical animal models as prerequisite data for an IND application for a phase I clinical trial. In the long term, the success of our approach will introduce a new vaccine to the market with a potential for reducing global incidence of KSHV+ malignancies (>44,000 cases/year), and the possibility of limiting KSHV infection and associated malignancies in developing countries or eradicating them from developed countries where KSHV seroprevalence is <10%.