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Principal Investigator: Jesse Hong-Sae Erasmus
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $2,091,310
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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