Evaluation of iDMV-1.0: A Single Dose Self-Amplifying Vaccine for SARS-CoV-2

Modified Project Summary/Abstract Section PROJECT SUMMARY: Devdoot Majumdar, PhD, Research Project Leader (RPL) Lipid nanoparticles (LNPs) are critical delivery vehicles for a range of therapeutic modalities, including vaccines and gene therapies; however, the precise mechanisms by which their physicochemical characteristics dictate the nature and magnitude of ensuing immune responses remain incompletely understood. This project will investigate the complex interplay between LNP properties and the immune system, with a focus on two key areas: (1) identifying the molecular pathways that LNPs encode a differential immune response by disrupting endosomes and (2) identifying which stromal cells are responsible for sensing and transducing that immune response. Differential responses by LNPs are imperative to understand, as precise tuning of the LNP response translates directly into the strength of adjuvancy. The research design utilizes CRISPR-Cas9 screens in relevant immune cell types to systematically uncover novel molecular regulators of LNP-induced immunogenicity. By dissecting these fundamental interactions, this research will identify key cellular and molecular determinants that govern LNP-immune system engagement. The anticipated outcomes of this work will provide crucial insights into LNP immunobiology, thereby facilitating the rational design of next-generation LNPs with precisely tailored immunological profiles. This knowledge is expected to significantly advance the development of safer and more effective LNP-based vaccines and therapeutics, ultimately benefiting public health by improving strategies for disease prevention and treatment.