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Principal Investigator: Christian W. Mandl
Organization: TIBA BIOTECH, LLC
Fiscal Year: 2022
Award: $284,906
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <AIM antigen><AIM molecule><Adjuvant><Agarose><Amines><Antibody Response><Antigens><Assay><Avian Influenza><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BALB C Mouse><BALB/c><Behavior><Benchmarking><Best Practice Analysis><Bioassay><Biologic Assays><Biological Assay><Bird Flu><Blood Serum><CD69 antigen><Cell Body><Cell Culture Techniques><Cell surface><Cells><Code><Coding System><Codon><Codon Nucleotides><Coloring Agents><Combination Vaccines><Combined Vaccines><Control Groups><Dendrimers><Dendritic Compounds><Dendrons><Development><Disease Outbreaks><Dose><Dyes><ELISA><Economics><Encapsulated><Ensure><Enzyme-Linked Immunosorbent Assay><Equilibrium><Evaluation><Exclusion><Female><Formulation><Fowl Pest><Fowl Plague><Gel><Generations><Goals><Gold><Grippe><H7 hemagglutinin><H7N9><HAI><Hemagglutinin><Human><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Inbred BALB C Mice><Individual><Influenza><Influenza A><Influenza A Virus, H7N9 Subtype><Influenza A virus><Influenza Vaccines><Influenza Viruses Type A><Influenzavirus A><Lead><Leu-23 antigen><Lipids><MT-SP1><MTSP-1><MTSP1><Measures><Memory><Messenger RNA><Methods><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><NIAID><NP protein><National Institute of Allergy and Infectious Disease><Neutralization Tests><Non-Polyadenylated RNA><Nucleic Acid Vaccines><Nucleic Acids><Orthomyxovirus Type A><Outbreaks><Outcome><PRSS14><Pb element><Performance><Phase><Preparation><Prevention><Proteins><RNA><RNA Degradation><RNA Gene Products><RNA Nucleases><RNA vaccine><RNA-based vaccine><RNase><Replication Unit><Replicon><Ribonuclease Family Protein><Ribonucleases><Ribonucleic Acid><Risk><SNC19><ST14><ST14 gene><Sepharose><Serum><Splenocyte><Staining method><Stains><Structural Protein><System><T-Cells><T-Lymphocyte><TADG-15><TADG15><Technology><Testing><Time><TimeLine><Type A Influenza><Vaccines><Validation><Virion><Virus><Virus Particle><Zoonoses><Zoonotic><Zoonotic Infection><activation antigen EA1><activation inducer molecule antigen><amine><antibody based detection><antibody detection><antibody neutralization test><arm><avian flu><balance><balance function><base><cell culture><cell cultures><density><design><designing><detect antibodies><develop a vaccine><develop vaccines><development of a vaccine><developmental><early T-cell activation antigen p60><early activation antigen CD69><early activation antigen EA1><enzyme linked immunoassay><experiment><experimental research><experimental study><expression vector><flexibility><flexible><flu vaccine><flu virus pandemic><flu virus vaccine><heavy metal Pb><heavy metal lead><high risk><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><in vivo><influenza in birds><influenza virus pandemic><influenza virus vaccine><innovate><innovation><innovative><interest><light scattering><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><male><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><novel><nucleic acid delivery><nucleic acid-based vaccine><pandemic><pandemic disease><pandemic flu><pandemic influenza><pandemic strain of influenza><potency testing><prototype><respiratory><response><scale up><seasonal flu><seasonal influenza><thymus derived lymphocyte><uptake><vaccine against flu><vaccine against influenza><vaccine candidate><vaccine development><vaccine formulation><vector>