Project Grant R01AI173567

ASSAYS FOR ACCELERATION: FROM FIT-FOR-PURPOSE MODELS TO SCALABLE ASSAYS OF BROAD SYSTEMIC AND MUCOSAL PROTECTION AGAINST ALL STRAINS OF GROUP A STREPTOCOCCUS - PROJECT SUMMARY/ABSTRACT THERE IS RENEWED INTERNATIONAL MOMENTUM TO DEVELOP VACCINES TO PREVENT INFECTIONS CAUSED BY THE HIGHLY ADAPTED, HUMAN-RESTRICTED BACTERIAL PATHOGEN GROUP A STREPTOCOCCUS (GAS). HOWEVER, THE LACK OF A KNOWN CORRELATE OF HUMAN IMMUNE PROTECTION AGAINST GAS INFECTION AND THE LIMITATIONS OF CURRENT IN VITRO ASSAYS AND PRECLINICAL MODELS HAVE IMPEDED DEVELOPMENT OF PROMISING PRECLINICAL VACCINE CANDIDATES AND THREATENS FUTURE INVESTMENT IN GAS VACCINE DISCOVERY AND DESIGN. TO OVERCOME THIS ROADBLOCK, WE WILL UNDERTAKE A CROSS- DISCIPLINARY COLLABORATIVE RESEARCH PROGRAM, DRAWING ON HIGHLY RELEVANT HUMAN SAMPLES AND DEVELOPING A NEW HUMAN EX VIVO TISSUE MODEL, TO DISCOVER BROADLY APPLICABLE POTENTIAL HUMAN CORRELATES OF PROTECTION THAT WILL INFORM DESIGN OF PRACTICAL IMMUNOASSAYS FIT FOR DEPLOYMENT IN CLINICAL VACCINE TRIALS. RATHER THAN ADHERING TO THE CONSTRAINTS OF HISTORICAL GAS IMMUNOASSAYS, WE ARE EXPLICITLY TARGETING PREFERRED CHARACTERISTICS FOR CLINICAL IMMUNOGENICITY ASSAYS TO SUPPORT VACCINE DEVELOPMENT, SUCH AS PRACTICALITY, ACCURACY AND BROAD APPLICATION TO RELEVANT SYNDROMES AND STRAINS. GAS NATURALLY INFECTS HUMANS ONLY, THEREFORE WE WILL TAKE A HUMAN-CENTRED APPROACH, PURPOSEFULLY MOVING AWAY FROM ANIMAL MODELS THAT DO NOT ADEQUATELY REPRESENT RELEVANT COMPLEXITIES OF THE HUMAN IMMUNE RESPONSE. WE WILL APPLY CUTTING EDGE IMMUNOLOGY APPROACHES TO STUDY DIVERSE HUMAN SAMPLES FROM PARALLEL RESEARCH PROGRAMS, INCLUDING FROM EXTERNALLY FUNDED TRIALS USING OUR OWN GAS HUMAN CHALLENGE MODEL TO EVALUATE VACCINE PROTECTION AGAINST PHARYNGITIS, THE PRIMARY TARGET INDICATION FOR VACCINE DEVELOPMENT EFFORTS. INITIAL PUBLISHED FINDINGS FROM THE GAS PHARYNGITIS HUMAN CHALLENGE MODEL SHOW THAT PROTECTION MAY BE ASSOCIATED WITH ROBUST EARLY MUCOSAL AND SYSTEMIC TH1 INFLAMMATORY RESPONSES, IN CLEAR ALIGNMENT WITH RECENT PRECLINICAL ANIMAL MODEL FINDINGS, AND HIGHLIGHTING VACCINE-INDUCED ANTIGEN-SPECIFIC TH1 RESPONSES AS A CORRELATE OF PROTECTION FOR MULTICOMPONENT VACCINES. WE WILL CHARACTERIZE THE TRANSCRIPTOMIC BASIS FOR THIS IMMUNE RESPONSE USING OUR EXISTING HUMAN SAMPLE COLLECTION. WE WILL DRAW ON OUR EXPERIENCE WITH HUMAN WHOLE BLOOD STIMULATION ASSAYS AND TISSUE MODELS TO ESTABLISH WHOLE-BLOOD AND ORGANOTYPIC TONSIL TISSUE MODELS AS OUR PRIMARY RESEARCH TOOLS. THIS APPROACH WILL ALLOW US TO INTERROGATE EX VIVO HUMAN IMMUNE RESPONSES TO WHOLE BACTERIA, CULTURE SUPERNATANT, AND VACCINE ANTIGENS TO DISCOVER POTENTIAL SYSTEMIC AND MUCOSAL CORRELATES OF PROTECTION. THESE BROAD-RANGING EFFORTS TO IDENTIFY IMMUNE PATHWAYS IMPLICATED IN VACCINE-INDUCED PROTECTION WILL INFORM THE DESIGN OF A PRACTICAL, SCALABLE, AND STRAIN-AGNOSTIC WHOLE-BLOOD IN-TUBE ASSAY (ANALOGOUS TO CYTOKINE RELEASE ASSAYS), AND A HIGH-THROUGHPUT FUNCTIONAL ORAL FLUID MUCOSAL ASSAY TO TEST IN FORTHCOMING CLINICAL TRIALS OF NOVEL GAS VACCINES.