| R01AI185516↗ | Department of Health and Human Services | STATENS SERUM INSTITUT | PROJECT GRANT (B) | 2026-08-25 | 2026-08-25 | 1 | DISSECTING THE ROLE OF VACCINE-PROMOTED TH17 CELLS IN PROTECTIVE IMMUNITY AGAINST TUBERCULOSIS - ABSTRACT AN EFFECTIVE VACCINATION STRATEGY IS URGENTLY NEEDED TO COMBAT TUBERCULOSIS (TB), INCLUDING IN THE UNITED STATES, WHERE INCIDENCE IS INCREASING, AND MILLIONS LIVE WITH LATENT MYCOBACTERIUM TUBERCULOSIS (MTB) INFECTION. LACK OF KNOWLEDGE ON PROTECTIVE IMMUNITY REMAINS A MAJOR BOTTLENECK FOR RATIONAL DESIGN, TESTING, AND DOWN-SELECTION OF NEW CANDIDATES. ALTHOUGH TH1-PRODUCED IFNΓ IS ESSENTIAL, IT IS INSUFFICIENT FOR VACCINE PROTECTION, AND NOVEL IMMUNE RESPONSES NOT INDUCED EFFICIENTLY BY MTB INFECTION MAY BE NEEDED FOR OPTIMAL BACTERIAL CONTROL. TH17 CELLS HAVE GAINED ATTENTION AS VACCINE TARGETS DUE TO PROTECTION SIGNALS IN MICE AND NON-HUMAN PRIMATES, BUT THEIR ROLE IN TB REMAINS UNRESOLVED. MOREOVER, VALIDATED BIOMARKERS FOR DOSE OPTIMIZATION, PROGRESSION TO EFFICACY TRIALS, AND PIPELINE DECISION-MAKING ARE STILL LACKING. TO ADDRESS THIS GAP, WE DEVELOPED H107E/CAF®, A CLINICAL-STAGE SUBUNIT VACCINE DESIGNED TO MAXIMIZE TH1/TH17 INDUCTION IN HUMANS AND ACROSS SPECIES. THIS PROPOSAL WILL USE H107E/CAF® AS A TRANSLATIONAL TOOL TO DEFINE HOW VACCINE-INDUCED TH17 CELLS ORGANIZE LUNG IMMUNITY, SUSTAIN PROTECTION, AND GENERATE BIOMARKERS THAT CAN GUIDE TB VACCINE DEVELOPMENT. THE FOREIGN COMPONENT IS SCIENTIFICALLY NECESSARY BECAUSE H107E/CAF® WAS DEVELOPED AT STATENS SERUM INSTITUT (SSI), WHERE KEY SUPPORTING DATA, TRANSLATIONAL EXPERTISE, AND VALIDATED TH17-FOCUSED ANIMAL MODELS RESIDE. PLANS ARE IN PLACE TO MAKE H107E/CAF® AVAILABLE WHERE NEEDED; THUS, THIS WORK LINKS NIH-FUNDED DISCOVERY TO A VACCINE CANDIDATE WITH A REALISTIC PATH TOWARD PUBLIC-HEALTH USE, WHILE STRENGTHENING COLLABORATION BETWEEN SSI AND U.S. TB INVESTIGATORS. BUILDING ON PRELIMINARY DATA SUGGESTING THAT TH17 CELLS ACCOUNT FOR ≥50% OF H107E/CAF®- INDUCED PROTECTION IN MICE, THIS PROPOSAL WILL DETERMINE HOW VACCINE-INDUCED TH17 CELLS ORGANIZE AND MAINTAIN EFFECTIVE LOCAL IMMUNITY AND IDENTIFY SIGNATURES OF TH17-MEDIATED PROTECTION. BECAUSE TH17 CELLS HAVE UNIQUE CHARACTERISTICS, THEY MAY CONTRIBUTE TO TB VACCINE PROTECTION THROUGH SEVERAL NON-REDUNDANT ROLES. IN AIM 1, WE WILL DETERMINE THE CONTRIBUTION OF VACCINE-INDUCED TH17 CELLS TO ACCELERATED T-CELL PRIMING, TESTING WHETHER EARLY NEUTROPHIL RECRUITMENT MEDIATES TRAFFICKING OF BACTERIA TO THE DRAINING LYMPH NODE AND WHETHER LATER IFNΓ RESPONSES DOWN-REGULATE NEUTROPHILS AND PREVENT TISSUE DESTRUCTION. IN AIM 2, WE WILL ASSESS THE ROLE OF VACCINE-INDUCED TH17 CELLS IN LONG-TERM PROTECTION, TESTING WHETHER TH17 CELLS OUTCOMPETE NON- TH17 CELLS THROUGH INCREASED IN VIVO ANTIGEN RECOGNITION, PROLIFERATION, AND/OR RESISTANCE TO APOPTOSIS, AND WHETHER LONG-TERM PROTECTION DEPENDS ON PLASTICITY TOWARD IFNΓ-PRODUCING CELLS. IN AIM 3, WE WILL DETERMINE THE ROLE OF VACCINE-INDUCED TH17 CELLS IN FORMING HIGHENDOTHELIAL VENULES WITHIN TB LESIONS, TESTING WHETHER THESE MEDIATE EFFICIENT TRAFFICKING AND LOCALIZATION OF IMMUNE CELLS. TOGETHER, THIS PROJECT WILL USE A VACCINE IN CLINICAL TRIALS TO ELUCIDATE TH17-MEDIATED VACCINE IMMUNITY TO TB, IDENTIFY BIOMARKERS OF PROTECTION, SUPPORT H107E/CAF® DEVELOPMENT, AND GENERATE KNOWLEDGE RELEVANT TO PROTECTING INDIVIDUALS IN THE UNITED STATES AT RISK OF TB. | $712.6K |