Project 2: mRNA vaccine development against Bunyaviruses, Paramyxoviruses and Picornaviruses

Project Summary/Abstract – Project 2: mRNA Vaccine Development against Bunyaviruses, Paramyxoviruses and Picornaviruses As the emergence of new pathogenic outbreaks in the future is not a matter of “if”, but of “when”, development of prophylactic vaccines against viruses with high pandemic potential prior to actual outbreaks is a reasonable

strategy to contribute to global pandemic preparedness. The lipid nanoparticle (LNP)-formulated nucleoside- modified mRNA platform is particularly suitable for vaccine development against viral pathogens because it can efficiently generate T follicular helper cell responses associated with the induction of durable and broadly

protective antibody responses. Beside potency, this novel, synthetic vaccine platform has important advantages over other vaccine types, including rapid, scalable production that does not require complicated infrastructure (such as mammalian cell culture and protein purification systems). Additionally, the enormous flexibility of the

mRNA-LNP platform allows the co-formulation of several antigen-encoding mRNAs into a single vaccine regimen to elicit more potent and/or broadly protective immune responses. The overall goal of Project 2 of this U19 Program is to develop potent mRNA-based vaccines against select members of Bunyaviruses, Paramyxoviruses

and Picornaviruses, capable of inducing protective immune responses and evaluate them in animal models. In Aim 1.1, we will design and produce nucleoside-modified mRNA immunogens targeting select members of Bunyaviruses, Paramyxoviruses and Picornaviruses. In Aim 1.2, we will collaborate with Project 1 (Felgner Lab)

on LNP-formulation of the mRNA immunogens using various lipids. In Aim 1.3, in vitro characterization (confirmation of protein production from each mRNA) of mRNA-LNP vaccines will be performed using HEK293T cells. Evaluation of the immunogenicity of Bunyavirus, Paramyxovirus and Picornavirus mRNA-LNP vaccines

will be performed in Aims 2.1, 2.2 and 2.3, respectively. In all 3 subaims, antibody responses (antigen-specific IgG, virus neutralization) as well as T and B cell (T follicular helper cell, CD8+ T cell, germinal center B cell, memory B cell and plasma cell) responses will be evaluated. The durability of antibody responses will also be

assessed. Based on the results of challenge experiments (performed by Projects 3-5), multivalent vaccines will be generated and tested for immunogenicity and protective efficacy. If the multivalent formulations provide high levels of protection in mice (tested by Projects 3-5), they will be evaluated in nonhuman primates by the

Translational Immunology Core. The proposed work will yield “prototype” vaccines that can be tested in clinical trials and quickly be adjusted to a pandemic pathogen and be produced and distributed at large scale. These deliverables have an immediate translational potential and will significantly contribute to our pandemic preparedness against Bunyaviruses,

Paramyxoviruses and Picornaviruses with high pandemic potential.