The proposal is to develop an RNA-based, rapid-response influenza vaccine prototype, supporting NIAID's callfor nucleic acid-based vaccines that protect against pandemic influenza threats. Avian influenza A H7N9 causessevere respiratory illness with a high mortality rate. The virus' high zoonotic capacity has raised serious concernsover the possibility of a pandemic, with the risk being potentially similar to that of H5 strains. While progress hasbeen made in the development of H5 influenza vaccines, H7 products have lagged. The proposed H7N9 vaccinewill be innovative in two respects. 1) H7N9 vaccines typically focus on the hemagglutinin (HA) protein as themain immunogen, but immune responses to HA H7, while protective, are weaker than those against other HAsin humans. Therefore, Tiba will develop a multi-antigen approach, specifically including optimized ratios of thevirion proteins HA, NA, M1, and NP. This approach is expected to increase the immunogenicity and heterotypicprotective potential of the vaccine. 2) Conventional lipid nanoparticles (LNPs), which are the mainstay of nucleicacid delivery, require a large proportion of "structural" lipid, resulting in a relatively low RNA content. Tiba hasdeveloped a modified dendrimer nanoparticle system that maximizes the delivered RNA mass content, protectingRNA from degradation, and enables efficient uptake by cells in vivo. The prototype composition developed herewill serve as a platform into which any outbreak antigen sequences could be rapidly implemented. Tiba will meetthe near-term goal of developing a prototype HA/NA/M1/NP vaccine to advance toward live virus challengeexperiments and IND-enabling studies in Phase 2 by completing three Phase 1 Aims. The first is to validateperformance of a H7 HA replicon RNA-based expression construct in vivo. This will be generated and formulatedwith Tiba's delivery system and tested in BALB/c mice at 0.2 µg, 2.0 µg, and 20 µg to measure cellular andhumoral immunogenicity. These studies will establish the minimum dose required for subsequent experiments.In the second Aim, Tiba will generate and test individual formulations of NA, M1, and NP mRNA and repliconcandidates, validating their performance in vivo at similarly increasing doses by T cell ELISpots and, for NA, alsoby ELISA to measure antibody responses. The final Aim is to compose a multi-antigen prototype vaccinecombining the optimal balance of HA replicon RNA with NA, M1, and NP RNAs by co-encapsulating the fourpayloads in a single nanoparticle formulation. This multi-antigen candidate vaccine will be tested in male andfemale BALB/c mice, in comparison to HA-only and irrelevant antigen-coding control vaccines to determine ifimmunogenicity is retained against all components, and if anti-HA responses benefit from inclusion of theadditional virion proteins. The candidate prototypes will be compared to state-of-the-art LNP formulations toevaluate the performance of Tiba's delivery technology compared to the current gold-standard for RNA vaccines.
Public Health Relevance Statement: Project Narrative
Development of a vaccine against Avian Influenza A H7N9, which has a high mortality rate in
humans and has raised concerns over its pandemic potential, will have a major impact on
prevention of pandemic disease and its associated economic disruption. We propose to produce
a multi-antigen RNA-based vaccine against H7N9, utilizing a novel and innovative modified-
dendrimer delivery method that will solve many challenges hindering conventional pandemic
vaccine development, such as long lead-times for scale-up and the need for flexibility to allow
substitution of alternative sequences to match emerging strains. The proposed vaccine product
is expected to confer greater protection by incorporating multiple influenza virion antigens
simultaneously, and its modular design allows it to be easily applied to other high-risk Influenza
pandemic or seasonal strains.
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