De Chiara, Arianna (2025) Uncovering Genetic Adjuvants to Maximize mRNA Vaccines Potential Against Infectious Diseases and Cancer. [Tesi di dottorato]

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Abstract

Over the past three decades, we assisted to the development of a novel vaccine technology called Genetic Vaccination (GV) which uses genes encoding the antigen(s) rather than the antigen in its proteinaceous form. Unlike classical vaccines, which are potent inducers of humoral response, GV elicits both humoral and cell-mediated immune responses, especially CD8 T lymphocyte immunity, leading to high prophylactic level or even therapeutic efficacy. During the recent SARS-CoV-2 outbreak, several genetic vaccines based on viral vectors or mRNA demonstrated remarkable safety and efficacy, paving the way for the rapid development of novel genetic vaccines against infectious diseases and cancer. However, despite being the subject of clinical studies for decades, it was only with the administration of billions of doses during the COVID-19 pandemic that some limitations of genetic vaccines became apparent. In particular, for mRNA based GV, the main challenges are the low immunogenicity in immunocompromised patients (e.g., cancer patients), the unbalanced B- vs. T cell response, and the relatively short-term protection, requiring multiple doses to be administered. The immune system is a complex network of biological pathways that change over time and space. To establish a more potent and durable adaptive immunity, we set up a novel strategy of co-delivering the antigen of interest with a protein with immunomodulatory activity, both of them administered as mRNA formulated in lipo-nanoparticles (mRNA-LNP) to ensure a spatio-temporal coordinated expression in vivo. By interpolating single cell data from immune cells with a bioinformatics analysis, we selected N protein factors as potential immunomodulatory candidates to be screened in vivo in the form of mRNA-LNP. In this way, we have identified several immunomodulators that significantly enhance the immunogenicity of genetic vaccines for cancer and infectious diseases. These data confirm the feasibility of using mRNA encoded immunomodulatory molecules to improve immunogenicity and efficacy of mRNA vaccines. Through an in-depth analysis of the mechanisms of action of the immunomodulators, we aim to develop a comprehensive map of the molecular circuits involved in the induction of optimal adaptive immunity by mRNA based genetic vaccination.

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