Vincent Venditto Scope: State Matching: Kentucky Network for Innovation & Commercialization (#KYNETIC#) Yr 5

Problem Description: Lipid-based mRNA vaccines represent a significant advance in public health. Although effective, the unwanted vaccine-induced reactogenicity that causes muscle aches and fever remains a barrier to adherence and limits the long-term efficacy due to off-target effects. Continued development of mRNA vaccines for various infectious agents and inflammatory diseases demands novel lipids that induce robust antigen-specific immunity, with minimal reactogenicity to improve the long-term vaccine-induced immunity. Intended Customer: Subjects at risk of moderate/severe systemic vaccine-induced reactogenicity. Approved flu and COVID vaccines result in ~30-70% of subjects experiencing moderate to severe systemic reactogenicity. This accounts for 50-100 million subjects in the US annually during non-endemic/pandemic years. The broad applicability of this technology suggests that the target market is larger than estimated here. Solution: Our data indicate that this lipid-based vaccine platform offers a state-of-the-art approach to generate mRNA vaccines. This innovative approach is based on in vitro and in vivo observations in which, our cationic lipid-based vaccine induces robust and balanced antigen-specific immunity toward a protein antigen, while inhibiting the cellular pathway responsible for off-target reactogenic responses. To optimize our potential for success, we validated a solid phase synthetic strategy to generate a combinatorial lipid library and demonstrated successful nucleic acid delivery, which support our efforts focused on mRNA vaccine development. Proposed work: The proposed experiments are designed to de-risk the technology at the developmental stage to increase the translational potential of the lipid-based vaccine platform. The experiments include: 1) in vitro and in vivo transgene expression and immunogenicity; 2) versatility testing; 3) detailed evaluation of the reactogenic and immunogenic responses; and 4) in vivo viral challenge studies. Milestones: We propose four milestones evaluating our lipid platform: (M1) mRNA-based transgene expression and antigen-specific immunity; (M2) evaluate the versatility of our vaccine platform across multiple mRNA-based antigens; (M3) in vivo characterization of the immunogenicity, reactogenicity, and toxicity using a clinically relevant target in a murine model; and (M4) viral challenge in a secondary small animal model of infection. Deliverables: The deliverables include: (M1) mRNA-based transgene expression and immunogenicity data, which is the most significant translational barrier. Subsequent milestones include (M2) indication of the versatility of the technology across multiple antigens. In vivo studies will (M3) examine the immune response, reactogencity, and toxicity, and (M4) efficacy of this platform in relevant animal models. Team: We are the first group to identify the immunomodulatory properties of triazine-based lipids to enhance the vaccine-induced immunogenicity. Our strong data places us in a unique position to leverage these findings to advance these molecules toward clinical translation. Dr. Venditto (PI) has a PhD in chemistry and postdoctoral training in liposomal vaccine design with an entrepreneurial mindset in project design