Research Project 3: Rapid-Response Roadmap for RNA vaccines

Abstract RNA vaccines have dramatically altered the landscape of vaccine development, affording an unparalleled ability to rapidly counteract emerging infectious diseases, as evidenced by the swift generation of effective RNA vaccines in response to the COVID-19 pandemic. However, despite these major achievements, there remain substantial gaps, challenges, and limitations to RNA vaccines, especially reactogenicity and limited durability and breadth of protection, requiring further research, development, and optimization. First, the selection of appropriate sub-cellular targeting moieties is crucial to antigen expression, influencing the folding, processing, and presentation of the expressed antigen to the immune system; the generalizability of these targeting motifs across virus targets is an open question. Second, there is a need to balance reactogenicity and immunogenicity, as RNA vaccines may precipitate dose-dependent adverse reactions while eliciting potent immune responses, particularly in the context of multi-antigen RNA vaccination requiring higher total RNA doses. Finally, there is a lack of knowledge regarding the generalization of antigen design and safety parameters across different virus groups, both within a specific family and across broader taxa. Project 3 in the PROVIDENT consortium aims to address these challenges with three specific aims. (1) The first aim is to optimize antibody responses to RNA-encoded prototypic nairovirus, hantavirus, and paramyxovirus structural proteins, leveraging high-throughput and structure-guided methodologies to screen for ideal cell-surface expression. These optimized designs will be subsequently applied to related viruses; (2) The second objective is to ascertain whether vaccine efficacy can be augmented by complementing antibody responses targeting the main antigen with secondary immune responses to additional antigens, using a multi-antigen vaccine composition. These multi-antigen designs will also be applied to related viruses; (3) The third objective is to characterize the differential innate immune responses and reactogenicity profiles to RNA-encoded protein variants using traditional mRNA, and next-generation self-amplifying replicon RNA platforms. This aim will provide crucial insights into the reactogenic characteristics associated with RNA-encoded pathogenic proteins and virus-like particles, delivered by a variety of platforms, as well as the safety profiles of lead vaccine candidates. Anticipated findings from this project hold significant potential to contribute to the refinement of RNA vaccine strategies, particularly concerning nairoviruses, hantaviruses, and paramyxoviruses but also extending to other pandemic potential virus groups. Ultimately, this project will equip vaccine developers with a robust toolbox and a predictable, rapid vaccine development road map against related viruses.