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Principal Investigator: Christian W. Mandl
Organization: TIBA BIOTECH, LLC
Fiscal Year: 2022
Award: $300,000
Funding agency: National Institute of Allergy and Infectious Diseases
This proposal is to develop a high potency, low-dose Powassan virus (POWV) RNA vaccine candidate
using Tiba Biotech’s innovative replicon RNA delivery system. As the geographical range of ticks grows
due to climate change, the incidence of Tickborne Diseases such as POWV is expected to increase, posing a
perennial epidemic threat. There are no specific medical interventions for illness caused by POWV, which can
lead to life-threatening encephalitis, meningitis, and long-term, potentially fatal neurological complications.
Nucleic acid vaccines are an ideal approach to addressing the threat of such flaviviruses, as this technology
allows rapid response to emergent outbreaks of related strains without alteration to the manufacturing process.
Tiba’s vaccine will be innovative in two respects: 1) application of a proprietary dendrimer-based delivery system
that maximizes RNA mass content while protecting the nucleic acids from degradation and mediating cellular
uptake, 2) inclusion of highly potent replicon RNA payloads to promote single-dose efficacy through their inherent
adjuvant activity and persistent expression. In addition, the dendrimer-based formulation strategy proposed here
eliminates the need for structural lipid excipients that are used in competing RNA vaccine products, streamlining
production and enhancing safety. Two replicon POWV vaccine RNAs will be produced for evaluation in this
Phase I project, one based on an alphavirus genome, and one based on the natural flaviviral genome of POWV
itself.
The output of this study will be in vivo-validated lead vaccine candidates, which will be developed by performing
3 aims. The first Aim is to clone, synthesize, and test the two candidate POWV RNA replicon RNAs in vitro. The
second Aim is to establish the optimal nanoparticle formulations for these RNAs using Tiba’s high-capacity
modified dendrimer encapsulation platform. The formulations will be evaluated in a preliminary murine
immunogenicity trial, measuring antibody responses to select the lead candidates. In the final proposed Aim, the
best performing candidate formulations identified in Aim 2 will be advanced to a small-scale challenge study, in
which mice will be infected with POWV subcutaneously. Survival and serum viremia will be monitored to evaluate
vaccine efficacy. Evidence of protective capacity for a candidate replicon RNA POWV vaccine will serve as the
basis for a Phase II project proposal to advance this lead to further preclinical development and in-depth
immunological characterization.
Terms: <Address><Adjuvant><After Care><After-Treatment><Aftercare><Agarose><Alpha Virus><Alphavirus><Antibody Response><Antigens><Automobile Driving><BAC clone><BACs><Bacterial Artificial Chromosomes><Benchmarking><Best Practice Analysis><Biotech><Biotechnology><Blood Serum><Brain Inflammation><Capsid><Capsid Proteins><Cell Body><Cells><Clinical Treatment Moab><Cloning><Co-Stimulator><Coat Proteins><Code><Coding System><Codon><Codon Nucleotides><Complementary DNA><Control Groups><Costimulator><Custom><DNA><DNA Recombination><Dendrimers><Dendritic Compounds><Dendrons><Deoxyribonucleic Acid><Detection><Disease><Disease Outbreaks><Disorder><Dose><ELISA><Encephalitis><Envelope Protein><Enzyme-Linked Immunosorbent Assay><Epidemic><Epidermal Thymocyte Activating Factor><Evaluation><Excipients><Exhibits><Fibroblasts><Flavivirus><Formulation><Gamma interferon><Gel><Gene Proteins><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Recombination><Genetic Transcription><Genetic defect><Genome><Geography><Group A Arboviruses><Group B Arbovirus><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-2><IL2 Protein><Immune Interferon><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Incidence><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intervention><Intervention Strategies><Ixodida><Lead><Life><Lipids><Lymphocyte Mitogenic Factor><MF59><Measures><Mediating><Medical><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Meningitis><Messenger RNA><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Monitor><Monoclonal Antibodies><Murine><Mus><Mutation><Neurologic><Neurological><Non-Polyadenylated RNA><Nucleic Acid Vaccines><Nucleic Acids><Outbreaks><Output><Pb element><Phase><Polyproteins><Powassan><Powassan virus><Production><Protein Gene Products><RNA><RNA Expression><RNA Gene Products><RNA Viruses><RNA amplification><RNA delivery><RNA vaccine><RNA-based vaccine><Reaction><Recombinants><Recombination><Replication Unit><Replicon><Ribonucleic Acid><Safety><Sampling><Sepharose><Serum><Spinal Column><Spine><Splenocyte><Sterility><Surface Proteins><System><T cell growth factor><T cell response><T-Cell Growth Factor><T-Cell Stimulating Factor><Technology><Testing><Thymocyte Stimulating Factor><Tick-Borne Diseases><Ticks><Transcript><Transcription><Transfection><Universities><Vaccines><Validation><Venezuelan Equine Encephalitis><Venezuelan Equine Encephalomyelitis><Venezuelan Equine Fever><Vertebral column><Viral Coat Proteins><Viral Diseases><Viral Genome><Viral Outer Coat Protein><Viremia><Virus><Virus Diseases><Virus-like particle><backbone><base><cDNA><climate change><climatic changes><cohort><driving><entire genome><env Antigens><env Gene Products><env Polyproteins><env Protein><enzyme linked immunoassay><evaluate vaccines><experiment><experimental research><experimental study><full genome><genome mutation><global climate change><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunogenicity><immunoresponse><in vivo><innovate><innovation><innovative><interventional strategy><lFN-Gamma><lead candidate><light scattering><mAbs><mRNA><mRNA vaccine><mRNA-based vaccine><manufacturing process><nano particle><nano-sized particle><nanoparticle><nanosized particle><novel><nucleic acid-based vaccine><pandemic preparedness><particle><post treatment><pre-clinical development><preclinical development><protective efficacy><replicon vaccine><response><sterile><subcutaneous><subdermal><success><tick-borne flavivirus><tick-borne illness><tickborne disease><tickborne flavivirus><tickborne illness><uptake><vaccine candidate><vaccine efficacy><vaccine evaluation><vaccine formulation><vaccine platform><vaccine screening><vaccine testing><vector><viraemia><viral RNA><viral infection><viral sepsis><virus RNA><virus genome><virus infection><virus-induced disease><virus-like nanoparticles><virusemia><viruslike particle><whole genome>