Genetic Adjuvants for RNA Vaccines

Topic Area addressed by the proposed research project: Emerging Infectious Diseases. Rationale: RNA vaccine platforms are promising tools for rapid response to emerging infectious diseases. However, mirroring the magnitude and durability of protective immunity induced by many conventional vaccines is a challenge for RNA-based vaccines, likely requiring the addition of immune-stimulating adjuvants specifically designed for use in RNA vaccines. Innovation: We propose the development and testing of novel genetically adjuvanted RNA vaccines, in which key immune genes typically induced by traditional adjuvants are incorporated directly into the vaccine RNA. Hypothesis: By directly upregulating relevant immune pathways in this manner, we believe we can enhance and diversify RNA vaccine-induced immunity and mimic the comprehensive, durable responses induced by live-attenuated vaccines. Study Design: We will test these hypotheses using the re-emerging Yellow Fever virus (YFV) as a model system. Yellow Fever is an ideal model system for studies of immune responses to vaccination as YF-17D, the existing live-attenuated YFV vaccine, induces exemplary durable protective responses that have been extensively characterized. We will start by characterizing the immune responses to VEEV-YFV-PrM-E, a self-replicating RNA-based yellow fever vaccine encoding the YF-17D envelope proteins in an alphavirus-based replicon, using a mouse model system. We will then create a set of genetically adjuvanted yellow fever vaccine candidates that add immune-stimulating chemokine, cytokine, and/or pathogen-associated molecular pattern genes to this vaccine backbone. Finally, we will test these genetically adjuvanted vaccines' ability to stimulate strong and durable protective immune responses similar to the responses to YF-17D in our mouse model. Expected Results: We expect the addition of genetic adjuvants to the RNA vaccine platform to enhance and diversify immune responses in our mouse model, improving both acute virus neutralizing antibody titers and cytotoxic CD8+ T cells, as well as durability of vaccine responses. The anticipated outcome of this work is a strategy for genetically adjuvanting RNA vaccines, which may allow RNA vaccines to induce durable and robust protection similar to that of traditional vaccines. If successful, this novel approach to adjuvanting RNA vaccines will establish a new paradigm for RNA vaccine development. Future Work: Our anticipated results will be (a) the development of an easily manufactured, potentially shelf-stable candidate YFV vaccine ready for advanced preclinical testing in nonhuman primates to address worldwide YFV vaccine shortages, and (b) preliminary data for future work focused on further optimization and advanced preclinical testing of a genetically adjuvanted RNA vaccine platform easily adaptable to emerging infectious diseases. Less