SBIR-STTR Award

TFF Pharmaceuticals (TFFP) is developing a shelf-stable thin-film freeze (TFF) dry powder universal flu vaccine. Commercialization of this product would provide the first vaccine that is at least 75% effective against symptomatic influenza virus infection, with the added benefit of easy delivery and storage at room temperature to facilitate broad, cost-effective distribution. With NIAID's Collaborative Influenza Vaccine Innovation Center funding, the University of Georgia (UGA) has developed a recombinant vaccine against all influenza virus hemagglutinin (HA) proteins and demonstrated its efficacy in mice and ferret models. If shown to be effective in humans, it could provide broad protection against both known and previously unrecognized strains of influenza virus, establishing a new standard of protection against seasonal viruses while heading off the emergence of novel strains in the future. A traditional liquid version of this vaccine would provide enormous benefits relative to the current seasonal vaccines, but they require cold-chain handling that increases costs and presents substantial barriers to establishing a stockpile or distributing the vaccine in underdeveloped areas. To address these challenges, UGA is collaborating with TFFP to develop a dry powder formulation of the universal vaccine. Using a thin-film freezing (TFF) technique, TFFP can formulate and manufacture dry powder vaccines that maintain immunogenicity while withstanding unintentional freezing. The vaccine powder can be stored and shipped free of cold-chain handling with extended stability for stockpiling. Our preliminary studies demonstrate that a reconstituted TFF-formulated version of UGA's HA vaccine elicited the same level of immunogenicity and achieved the same protective efficacy as the original liquid vaccine in BALB/c mice. A follow up study in ferrets confirmed the efficacy of the TFF-HA vaccine in reducing viral titers in nasal swabs and preventing weight loss. In this Direct to Phase II SBIR, TFFP and UGA propose to evaluate different adjuvants for intranasal and pulmonary inhalation delivery and confirm the stability, immunogenicity, and efficacy of the TFF-formulated HA vaccine in ferrets, the gold standard for influenza virus vaccine testing (Aim 1). Aim 2 will scale-up manufacturing of the inhaled TFF-HA dry powder vaccine for subsequent toxicology studies in rats (Aim 3); we will also develop GMP formulation and manufacturing for clinical trials. This project is expected to provide all required IND- enabling studies to prepare an IND package and ultimately advance to human testing. A dry powder vaccine would eliminate challenges in shipping and storage, reducing the cost and complexity of vaccine stockpiles and vaccination campaigns. A shelf-stable universal influenza virus vaccine would also revolutionize the public health approach to influenza, providing a low-cost, broadly disseminable vaccine that is at least 75% effective against sympotmatic influenza virus infections regardless of which viral strain emerges each year.

Public Health Relevance Statement:
PROJECT NARRATIVE Each year, seasonal influenza viruses are responsible for hundreds of thousands of deaths and hundreds of billions of dollars in costs worldwide. This study is designed to advance the development of a shelf-stable dry powder formulation of a novel universal influenza virus vaccine that is more than 75% effective against symptomatic influenza virus infection and protects against groups I and II influenza A viruses, the form of virus that has historically given rise to all known influenza pandemics and that contributes to seasonal flu each year. If successful, this work could provide a first-in-class stable, easy-to-transport and easy-to-stockpile vaccine that would overcome the vaccine failures that result from mishandling, mismatches between predicted and actual seasonal flu strains, and evolutionary changes in influenza viruses across the season.

Project Terms:
Inhalation Administration; Inhalation Route of Drug Administration; Respiratory Drug Administration; Inhalation Drug Administration; Antibodies; immunogen; Antigens; Body Temperature; Body Weight; Clinical Trials; Cessation of life; Death; Ferrets; Follow-Up Studies; Followup Studies; Freeze Drying; Freeze Dryings; Lyophilization; Freezing; Future; Goals; Hemagglutinin; Human; Modern Man; Hypersensitivity; Allergy; Immunity; Influenza; Grippe; influenza virus vaccine; Influenza Vaccines; flu vaccine; flu virus vaccine; vaccine against flu; vaccine against influenza; Intramuscular Injections; intramuscular drug administration; Lung; Lung Respiratory System; pulmonary; Medically Underserved Area; medically under served area; Methods; Inbred BALB C Mice; BALB C Mouse; BALB/c; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; Powder dose form; Powders; Proteins; Public Health; Rattus; Common Rat Strains; Rat; Rats Mammals; Recombinant Vaccines; Safety; Seasons; Solubility; Temperature; Testing; Thinness; Leanness; Toxicology; Universities; Vaccination; Vaccines; Virus; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; Work; Film; Immunology; Titrations; Guidelines; Area; Phase; Variation; Variant; Funding; Collaborations; Cold Chains; NOAEL; No-Observed-Adverse-Effect Level; Immunological response; host response; immune system response; immunoresponse; Immune response; fluid; liquid; Liquid substance; Intramuscular; Reaction; Techniques; Viral; success; Toxic effect; Toxicities; Structure; novel; Appearance; Modeling; Influenza A virus; Influenza A; Influenza Viruses Type A; Influenzavirus A; Orthomyxovirus Type A; Type A Influenza; evaluate vaccines; vaccine screening; vaccine testing; vaccine evaluation; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; preventing; prevent; influenzavirus; Influenza Virus; ST14 gene; HAI; MT-SP1; MTSP-1; MTSP1; PRSS14; SNC19; ST14; TADG-15; TADG15; Address; Dose; Dryness; International; National Institute of Allergy and Infectious Disease; NIAID; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Vaccine Antigen; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Process; Adjuvant; Shipping; Development; developmental; Influenza A Virus, H3N2 Subtype; H3N2; H3N2 Virus; Influenza A Virus, H1N1 Subtype; H1N1; H1N1 Virus; safety study; flu virus pandemic; influenza virus pandemic; pandemic flu; pandemic strain of influenza; pandemic influenza; cost; Advanced Development; immunogenicity; flu serotype; flu strain; flu subtype; flu viral strain; flu virus strain; influenza serotype; influenza strain; influenza subtype; influenza viral strain; influenza virus strain; flu prevention; Influenza prevention; designing; design; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; scale up; cost effective; innovate; innovative; innovation; Influenza HA; flu HA; flu hemagglutinin; influenza viral HA; influenza viral hemagglutinin; influenza virus HA; influenza virus hemagglutinin; Influenza Hemagglutinin; Impairment; reconstitute; reconstitution; commercialization; vaccine candidate; protective efficacy; commercial scale manufacturing; manufacturing ramp-up; scale up batch; scale up production; upscale manufacturing; manufacturing scale-up; seasonal flu; seasonal influenza; Formulation; universal flu vaccine; universal influenza virus vaccine; universal vaccine against flu; universal vaccine against influenza; universal influenza vaccine; universal vaccine; Inhaling; Inhalation; preservation; first in man; first-in-human; flu infection; flu virus infection; infected with flu; infected with flu virus; infected with influenza; infected with influenza virus; influenza virus infection; influenza infection; deploy vaccines; distribute vaccines; vaccine deployment; vaccine roll-out; vaccine rollout; vaccine distribution; nasal swab; vaccine failure; vaccine immunogenicity; vaccine immune response; manufacture