Project Grant R44AI167158

RAPID RESPONSE TO PANDEMIC INFLUENZA VIA MULTI-ANTIGEN RNA-BASED VACCINE - PROJECT ABSTRACT AVIAN INFLUENZA A H7N9 CAUSES SEVERE RESPIRATORY ILLNESS WITH A HIGH MORTALITY RATE, AND ITS ZOONOTIC CAPACITY HAS RAISED SERIOUS CONCERNS OVER THE POSSIBILITY OF A PANDEMIC. THE VALUE OF VACCINES FOR PANDEMIC-POTENTIAL VIRUSES HAS BEEN DEMONSTRATED BY THE DEVASTATING EFFECTS OF COVID-19 ON HUMAN HEALTH AND THE ECONOMY. DEVELOPMENT OF H7 INFLUENZA VACCINES HAS LAGGED, AS PANDEMIC INFLUENZA VACCINES HAVE GENERALLY BEEN DEVELOPED WITH TRADITIONAL TECHNOLOGIES, AND LOW IMMUNOGENICITY FOR H7 PRODUCTS IN HUMANS HAS BEEN REPORTED. THE HIGH THREAT PRESENTED BY THIS STRAIN REPRESENTS A SUBSTANTIAL MARKET GAP FOR NEWER TECHNOLOGIES TO FILL. THE COVID-19 PANDEMIC ILLUSTRATED THE POTENTIAL OF RNA VACCINES AS A RAPID-RESPONSE PLATFORM, BUT ALSO DEMONSTRATED THEIR LIMITATIONS. CURRENT GENERATION VACCINES RELYING ON LIPID NANOPARTICLE (LNP) DELIVERY ARE KNOWN TO ELICIT UNWANTED ACUTE INFLAMMATORY RESPONSES AND REQUIRE ULTRA-LOW TEMPERATURES FOR LONG-TERM STORAGE AND STABLE REFRIGERATION AT THE POINT-OF-CARE, HIGHLIGHTING THE NEED FOR NEW DELIVERY APPROACHES. IN PHASE I STUDIES, TIBA BIOTECH ESTABLISHED PROOF-OF-PRINCIPLE THAT AN INTRAMUSCULAR IMMUNIZATION OF BALB/CJ MICE WITH A NOVEL, LESS INFLAMMATORY FORMULATION CONTAINING A PROPRIETARY DELIVERY MOLECULE AND HIGHLY IMMUNOGENIC RNA REPLICONS ENCODING THE H7N9 HEMAGGLUTININ (HA), NEURAMINIDASE (NA) AND NUCLEOPROTEIN (NP) AT A 1:1:1 MASS RATIO INDUCED IMMUNE RESPONSES AGAINST ALL ANTIGENS. THIS APPROACH IS EXPECTED TO INCREASE THE IMMUNOGENICITY AND HETEROTYPIC PROTECTIVE POTENTIAL OF THE VACCINE, AND THE RNABL PLATFORM THAT IS UTILIZED MAXIMIZES THE SAFELY DELIVERED RNA MASS CONTENT, PROTECTS RNA FROM DEGRADATION, AND ENABLES EFFICIENT UPTAKE BY CELLS IN VIVO. IN PHASE II, TIBA BIOTECH PLANS TO FURTHER DEVELOP THE PROTOTYPE H7N9 VACCINE BY EVALUATING DIFFERENT RATIOS OF RNAS AND DELIVERY MATERIALS FROM TIBA'S ENHANCED RNABL LIBRARY, DEVELOPING MANUFACTURING, SCALE UP AND QUALITY CONTROL PROCESSES FOR THE RNA COMPONENTS OF THE VACCINE, DETERMINING OPTIMAL DOSING IN A MOUSE MODEL, ESTABLISHING PROTECTIVE EFFICACY IN A HIGHLY RELEVANT FERRET CHALLENGE MODEL, AND PERFORMING PRELIMINARY SAFETY ASSESSMENTS AND BIODISTRIBUTION STUDIES IN RATS. THESE STUDIES WILL ENABLE A REQUEST FOR A PRE-IND MEETING, AND THIS MEETING WILL BE USED TO INFORM FURTHER EXPERIMENTS PRIOR TO IND FILING AND CLINICAL TRIALS. ULTIMATELY, THIS VACCINE PRODUCT WILL HAVE THE POTENTIAL FOR COMMERCIALIZATION AND USE IN VACCINE STOCKPILING, ENABLING PREPAREDNESS IN THE CASE OF A H7N9 INFLUENZA PANDEMIC. IN ADDITION, THE PROTOTYPE COMPOSITION DEVELOPED HERE WILL SERVE AS A PLATFORM INTO WHICH ANY OUTBREAK ANTIGEN SEQUENCES COULD BE RAPIDLY IMPLEMENTED.