Project Grant R01AI181218

IMMUNOTHERAPEUTIC APPROACH FOR THE PREVENTION OF SECONDARY INFECTION WITH DRUG-RESISTANT TB - PULMONARY INFECTIONS WITH MYCOBACTERIUM TUBERCULOSIS (M.TB) ACCOUNT FOR A STAGGERING AMOUNT OF MORBIDITY AND MORTALITY WORLDWIDE. A HIGHLY EFFECTIVE VACCINE ABLE TO PREVENT (I) ACTIVE DISEASE, (II) RELAPSE AFTER CHEMOTHERAPY, AND (III) REINFECTION, REMAINS ELUSIVE EVEN IN THE FACE OF CONCERTED GLOBAL EFFORTS. ONE OBSTACLE HINDERING THE COMPARISON OF VACCINE CANDIDATES AND THEIR PROGRESSION IN THE PIPELINE IS A LACK OF CONSENSUS IN THE FIELD ON IMPORTANT IMMUNOLOGICAL ENDPOINTS TO INCLUDE IN PRECLINICAL STUDIES AND CLINICAL TRIALS. THE RESEARCH PROPOSED HERE AIMS TO LEVERAGE CORE MODELS WITH A SUBOPTIMAL DRUG TREATMENT REGIMEN TO RESOLVE DIFFERENCES IN RELAPSE RATES WITH OR WITHOUT CONCURRENT VACCINE CANDIDATE IMMUNIZATIONS. RELAPSE AND REINFECTION ARE CLEARLY DEFINED OUTCOMES FOR TB PATIENTS, AND WE AIM TO DEVELOP NOT ONLY AN EFFECTIVE THERAPEUTIC VACCINE BUT ALSO BETTER SCREENING METHODS FOR UNDERSTANDING EFFICACY ENDPOINTS IN PRECLINICAL MODELS. TO ACHIEVE THESE GOALS, WE WILL SCREEN SIXTEEN VACCINE CANDIDATES CONSISTING OF FOUR SUBUNIT ANTIGENS (INCLUDING CLINICALLY PROVEN M72 AND ID93 ANTIGENS, A PROMISING THERAPEUTIC CANDIDATE ID91, AND A NOVEL TB SUBUNIT (TBSU) CANDIDATE) FORMULATED WITH FOUR ADJUVANT CANDIDATES THAT DIFFER IN THEIR MODES OF ACTION, WHICH WILL BE SCREENED USING INNOVATIVE THERAPEUTIC ANIMAL MODELS (IN MICE AND GUINEA PIGS). M72 WITH AN AS01E-LIKE ADJUVANT, CO-DEVELOPED BY OUR TEAM, WILL BE INCLUDED AS A COMPARATOR IN THESE STUDIES, WHICH WILL ADD SCIENTIFIC RIGOR AS THIS IS THE FIRST DEFINED VACCINE TO SHOW PROTECTION IN PREVIOUSLY M.TB INFECTED INDIVIDUALS. WE HYPOTHESIZE THAT COMBINED WITH A DRUG TREATMENT REGIMEN, AN OPTIMIZED THERAPEUTIC VACCINE CANDIDATE PROTEIN + ADJUVANT CAN REDUCE RELAPSE AND REINFECTION BY ELICITING A MULTIFACETED ANTIGEN- SPECIFIC IMMUNE RESPONSE. IN AIM 1 16 VACCINE CANDIDATES WILL BE ASSESSED USING SAFETY AND EFFICACY ENDPOINTS BOTH IN VITRO AND IN VIVO. WE WILL ALSO CHOOSE AN ANTIGEN DOSE THAT IS EFFECTIVE AND SAFE FOR USE IN AIM 2. AIM 2 WILL BE DEVOTED TO EVALUATING THE FULL COMPLEMENT OF 16 CANDIDATES (4 ANTIGENS X 4 ADJUVANTS) FOR THERAPEUTIC PROTECTION FROM RELAPSE IN THE MOUSE MODEL. FOLLOWING A MOUSE RELAPSE SCREEN, VACCINE CANDIDATES WILL BE FURTHER DOWNSELECTED. FINALLY, 2 LEAD VACCINE COMBINATIONS THAT SHOW EFFICACY (SURVIVAL, RELAPSE, AND PROTECTION FROM DRUG-RESISTANT M.TB) IN BOTH SEXES WILL BE ADVANCED INTO THE GUINEA PIG THERAPY MODEL WHERE THEY WILL BE ASSESSED FOR DURABLE TREATMENT SUCCESS AS MEASURED BY A REDUCTION IN BACTERIAL COUNTS (IN THE LUNG AND SPLEEN), REDUCTION IN LUNG PATHOLOGY, PREVENTION OF DISEASE RNA SIGNATURES, CLINICAL SCORING (INCLUDING WEIGHTS), AND ENHANCED SURVIVAL OVER DRUG TREATMENT ALONE, TO SELECT THE FINAL CANDIDATE FOR ADVANCEMENT TO AIM 3. IN AIM 3, WE WILL EXAMINE THE LEAD CANDIDATE FOR THERAPEUTIC EFFICACY OF PROTECTION FROM REINFECTION FOLLOWING PRIMARY TB INFECTION. WE WILL ALSO INVESTIGATE THE MECHANISMS OF THERAPEUTIC EFFICACY BY SYSTEMATICALLY INTERROGATING IMMUNE CORRELATES OF PROTECTION BY EXAMINING DETAILED GENETIC MECHANISMS USING A SERIES OF COLLABORATIVE CROSS GENOTYPES.