Rapid response to pandemic influenza via multi-antigen RNA-based vaccine

通过基于多抗原 RNA 的疫苗快速应对大流行性流感

• 批准号: 10491533
• 负责人: Christian W. Mandl
• 金额: $ 28.49万
• 依托单位: TIBA BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491533
• 关键词: Adjuvant; Amines; Antibody Response; Antigens; Avian Influenza; B-Lymphocytes; Behavior; Benchmarking; Biological Assay; CD69 antigen; Cell Culture Techniques; Cell surface; Cells; Code; Codon Nucleotides; Combined Vaccines; Control Groups; Dendrimers; Development; Disease Outbreaks; Dose; Dyes; Economics; Encapsulated; Ensure; Enzyme-Linked Immunosorbent Assay; Equilibrium; Evaluation; Exclusion; Female; Formulation; Gel; Generations; Goals; Gold; H7 hemagglutinin; Hemagglutinin; Human; Immune response; Immunologics; In Vitro; Inbred BALB C Mice; Individual; Influenza; Influenza A Virus, H7N9 Subtype; Influenza A virus; Lead; Lipids; Measures; Memory; Messenger RNA; Methods; Molecular; Mus; NP protein; National Institute of Allergy and Infectious Disease; Neutralization Tests; Nucleic Acid Vaccines; Nucleic Acids; Outcome; Performance; Phase; Preparation; Prevention; Proteins; RNA; RNA Degradation; RNA vaccine; Replicon; Ribonucleases; Risk; ST14 gene; Sepharose; Serum; Splenocyte; Stains; Structural Protein; System; T-Lymphocyte; Technology; Testing; Time; TimeLine; Vaccines; Validation; Virion; Virus; Zoonoses; antibody detection; arm; base; density; design; experimental study; expression vector; flexibility; high risk; immunogenic; immunogenicity; in vivo; influenza virus vaccine; innovation; interest; light scattering; lipid nanoparticle; male; mortality; mouse model; nanoparticle; novel; nucleic acid delivery; pandemic disease; pandemic influenza; potency testing; prototype; respiratory; response; scale up; seasonal influenza; uptake; vaccine candidate; vaccine development; vaccine formulation; vector

Project Summary The proposal is to develop an RNA-based, rapid-response influenza vaccine prototype, supporting NIAID’s call for nucleic acid-based vaccines that protect against pandemic influenza threats. Avian influenza A H7N9 causes severe respiratory illness with a high mortality rate. The virus’ high zoonotic capacity has raised serious concerns over the possibility of a pandemic, with the risk being potentially similar to that of H5 strains. While progress has been made in the development of H5 influenza vaccines, H7 products have lagged. The proposed H7N9 vaccine will be innovative in two respects. 1) H7N9 vaccines typically focus on the hemagglutinin (HA) protein as the main immunogen, but immune responses to HA H7, while protective, are weaker than those against other HAs in humans. Therefore, Tiba will develop a multi-antigen approach, specifically including optimized ratios of the virion proteins HA, NA, M1, and NP. This approach is expected to increase the immunogenicity and heterotypic protective potential of the vaccine. 2) Conventional lipid nanoparticles (LNPs), which are the mainstay of nucleic acid delivery, require a large proportion of “structural” lipid, resulting in a relatively low RNA content. Tiba has developed a modified dendrimer nanoparticle system that maximizes the delivered RNA mass content, protecting RNA from degradation, and enables efficient uptake by cells in vivo. The prototype composition developed here will serve as a platform into which any outbreak antigen sequences could be rapidly implemented. Tiba will meet the near-term goal of developing a prototype HA/NA/M1/NP vaccine to advance toward live virus challenge experiments and IND-enabling studies in Phase 2 by completing three Phase 1 Aims. The first is to validate performance of a H7 HA replicon RNA-based expression construct in vivo. This will be generated and formulated with Tiba’s delivery system and tested in BALB/c mice at 0.2 µg, 2.0 µg, and 20 µg to measure cellular and humoral 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 replicon candidates, validating their performance in vivo at similarly increasing doses by T cell ELISpots and, for NA, also by ELISA to measure antibody responses. The final Aim is to compose a multi-antigen prototype vaccine combining the optimal balance of HA replicon RNA with NA, M1, and NP RNAs by co-encapsulating the four payloads in a single nanoparticle formulation. This multi-antigen candidate vaccine will be tested in male and female BALB/c mice, in comparison to HA-only and irrelevant antigen-coding control vaccines to determine if immunogenicity is retained against all components, and if anti-HA responses benefit from inclusion of the additional virion proteins. The candidate prototypes will be compared to state-of-the-art LNP formulations to evaluate the performance of Tiba’s delivery technology compared to the current gold-standard for RNA vaccines.

项目总结