Project Grant R61AI169132

DEVELOPMENT OF NOVEL MRNA VACCINES AGAINST MYCOBACTERIUM TUBERCULOSIS - PROJECT SUMMARY/ABSTRACT TUBERCULOSIS REMAINS ONE OF THE TOP TEN LEADING CAUSES OF DEATH WORLDWIDE (1). BASED ON THE MOST CURRENT INFORMATION FROM WHO 2020 REPORT, IN 2019 AN ESTIMATED 1.4 MILLION PEOPLE DIED FROM TB AND APPROXIMATELY 10,000,000 FELL ILL (2). THE COVID-19 PANDEMIC HAS LED TO MASSIVE DECREASES IN TB CASE IDENTIFICATION AND STOP TB ESTIMATES AN ADDITIONAL 1.4 MILLION TB DEATHS WILL BE REGISTERED OVER THE NEXT 4 YEARS (3, 4). THIS, TOGETHER WITH THE GROWING THREAT OF DRUG-RESISTANT TB AND THE CO-EPIDEMICS OF TB WITH HIV AND DIABETES MAKES ENDING THE TB EPIDEMIC MORE CRUCIAL THAN EVER BEFORE. A VACCINE THAT PREVENTS ADOLESCENTS AND ADULTS FROM ACQUIRING, DEVELOPING, AND TRANSMITTING TB WOULD BE THE SINGLE MOST COST-EFFECTIVE TOOL IN ENDING THE TB EPIDEMIC (5). THE TUBERCULOSIS VACCINE INITIATIVE (TBVI) AND TREATMENT ACTION GROUP (TAG) TB VACCINE PIPELINES REPORT TWELVE SUBUNIT VACCINES INCLUDING RECOMBINANT PROTEIN/ADJUVANT AND VIRAL VECTOR VACCINES SPANNING FROM PRECLINICAL THROUGH PHASE 3 DEVELOPMENT (6, 7). OF THESE, NINE INCLUDE AG85 (AG85A OR B) AND SIX INCLUDE ESAT6. THE HIGHLY LIMITED ANTIGENIC AND IMMUNOLOGICAL DIVERSITY PRESENT IN THE PIPELINE IS A SIGNIFICANT GAP IN EFFORTS TO DEVELOP A NOVEL, EFFECTIVE VACCINE. THE PROPOSED RESEARCH IS INTENDED TO BRING NEEDED ANTIGENIC AND PLATFORM DIVERSITY TO THE PRE-CLINICAL TB VACCINE PIPELINE USING MODERNA'S CUTTING-EDGE MRNA VACCINE TECHNOLOGY AND EXPERTISE. WITHIN THE R61 PHASE OF THIS PROGRAM, WE WILL FIRST OPTIMIZE MYCOBACTERIAL ANTIGEN SEQUENCES FOR EXPRESSION IN MAMMALIAN CELLS USING MODERNA'S PROPRIETARY LEARNINGS AND ALGORITHMS. THESE PRINCIPLES WILL BE APPLIED TO THE DEVELOPMENT OF THREE CANDIDATE MRNA VACCINES, INCLUDING 1) AN ANTIGEN CASSETTE PREVIOUSLY SHOWN TO INDUCE PROTECTION IN ANIMAL MODELS WHEN DELIVERED AS A PROTEIN PLUS ADJUVANT, 2) A NEW ANTIGEN CASSETTE INCLUDING NOVEL ANTIGENS, AND 3) THE M72 ANTIGEN SHOWN TO INDUCE PROTECTION IN HUMANS WHEN DELIVERED AS RECOMBINANT PROTEIN WITH THE AS01E ADJUVANT. WE WILL THEN USE DATA FROM MURINE IMMUNOGENICITY AND PROTECTION STUDIES TO SELECT THE TWO BEST CANDIDATES FOR ADVANCEMENT INTO THE R33 PHASE. WITHIN THE R33 PHASE, WE WILL USE THE GUINEA PIG CHALLENGE MODEL TO DOWNSELECT TO A FINAL LEAD CANDIDATE FOR FURTHER ADVANCEMENT. ONCE A FINAL LEAD CANDIDATE IS SELECTED, ADDITIONAL STUDIES WILL BE CONDUCTED TO FURTHER CHARACTERIZE THE CANDIDATE, INCLUDING PROTECTION IN GENETICALLY DIVERSE MICE AND AN IMMUNOGENICITY STUDY IN NONHUMAN PRIMATES TO OPTIMIZE THE VACCINATION REGIMEN FOR CLINICAL USE. BY THE END OF THIS PROGRAM, WE WILL HAVE A NOVEL LEAD VACCINE CANDIDATE READY FOR ADVANCEMENT INTO IND- ENABLING STUDIES AND EARLY DEVELOPMENT AS A VACCINE TO PREVENT TB DISEASE IN ADULTS AND ADOLESCENTS.