Strategic Design of a Vaccine for Tumor-Associated Herpesviruses

Human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV) are associated with malignancies, which are directly linked to viral latency. Therefore, the goal of vaccination for gammaherpesviruses is to prevent the establishment of latent infection. There are urgent needs for effective and safe vaccines against gammaherpesviruses, particularly for high risk groups, such as na�ve transplant patients and individuals at high risk for HIV-1 infection. Vaccines based on live attenuated viruses enable the presentation of a full repertoire of antigens and generation of long-lasting memory responses by mimicking an infection. A safe live gammaherpesvirus vaccine candidate should be highly attenuated and unable to persist in the host. We propose a rational design by eliminating viral antagonists of type I interferon (IFN-I) to achieve attenuation while maintaining immunogenicity. IFN-I not only provides immediate defense against infection but also regulates the development of memory immunity. In this proof of principle study, we used murine gammaherpesvirus-68 (MHV-68), closely related to EBV and KSHV, as a model system to test the vaccine candidate and study the underlying protective immune mechanisms against the establishment of viral persistence. We engineered a recombinant MHV-68 by targeted mutations at immune evasion genes, including the viral antagonists of IFN-I, and eliminated the latency locus responsible for persistent infection. This design results in a highly attenuated virus that demonstrates no measurable replication capacity, latent infection or persistence in immunocompetent hosts, C57BL/6. This highly attenuated virus stimulates robust innate immunity, drives the differentiation of antiviral memory T cells and elicits neutralizing antibodies. Vaccination using this live attenuated virus induces durable protective immunity that can inhibit the establishment of latent infection from challenge infection six months post vaccination. In this study, we establish the first strategy to inactivate viral IFN-I antagonists as a rational design of a herpesvirus vaccine to achieve both safety and immunogenicity