Project Grant R43AI179364

EVALUATION OF A NEXT GENERATION SCHISTOSHIELD VACCINE - ABSTRACT SCHISTOSOMIASIS IS A MAJOR PARASITIC DISEASE WHICH COULD IMPACT ONE BILLION PEOPLE WITH 252 MILLION CURRENTLY INFECTED AND 779 MILLION AT RISK TO ACQUIRE THE INFECTION IN 74 COUNTRIES. CURRENT CONTROL STRATEGIES HAVE RELIED ON REPEATED TREATMENTS WITH THE DRUG PRAZIQUANTEL ALONE - HOWEVER, THIS STRATEGY HAS PROVEN INADEQUATE DUE TO MINIMAL REDUCTION OF DISEASE TRANSMISSION, REINFECTION, AND THE INHERENT THREAT OF DRUG RESISTANCE. OVER THE COURSE OF 20 YEARS, WE HAVE DEVELOPED A POTENT SCHISTOSOMIASIS VACCINE, TERMED SCHISTOSHIELD, TARGETING A FUNCTIONALLY IMPORTANT ANTIGEN, SM-P80, FORMULATED IN THE TLR4-TARGETED ADJUVANT, GLA-SE. SCHISTOSHIELD HAS BEEN EXHAUSTIVELY TESTED IN NUMEROUS ANIMAL MODELS AND HAS CONSISTENTLY EXHIBITED PROTECTION AT ALL PARASITE LIFE STAGES. WE ARE NEAR COMPLETION OF A PHASE 1 SAFETY AND DOSE-RANGING HUMAN CLINICAL TRIAL WITH SCHISTOSHIELD IN THE US - WITH NO SERIOUS SAFETY SIGNALS REPORTED - AND WILL BEGIN PHASE 1B TRIALS IN Q3 OF 2023 WITH A PHASE 2 TRIAL CURRENTLY FUNDED AS WELL BY THE BILL AND MELINDA GATES FOUNDATION. DESPITE THE PROMISE OF SCHISTOSHIELD, IT IS IMPORTANT TO READY A NEXT-GENERATION FOLLOW-ON CANDIDATE THAT BUILDS A PIPELINE AND SERVES AS AN ALTERNATIVE SHOULD WE ENCOUNTER PROBLEMS DOWN THE ROAD IN TERMS OF E.G. SCALABILITY, COST, OR FIELD EFFICACY. TO ADDRESS THESE CONCERNS, WE ARE PROPOSING TO EVALUATE TWO NEW VARIATIONS ON THE CURRENT SCHISTOSHIELD VACCINE: THE FIRST BEING A REDESIGNED SM-P80 PROTEIN ANTIGEN, WHILE THE SECOND BEING A NOVEL RNA DELIVERY PLATFORM VERSION OF THE SM- P80 ANTIGEN. FOR THE REDESIGN, WE REMOVED THE HYDROPHOBIC AND OTHER IRRELEVANT (OUTSIDE OF THE CATALYTIC TRIAD DOMAIN) REGIONS OF THE ~85 KDA SM-P80 ANTIGEN RESULTING IN A SMALLER, AND MORE ANTIGENICALLY FOCUSED, ~44 KDA ANTIGEN WHICH WE HAVE TERMED CATALYSIS-TARGETED CONSTRUCTS (CATACO). CATACO IS SIMILAR TO SM-P80 IN THAT DOMAINS REQUIRED FOR ENZYMATIC ACTIVITY ARE MAINTAINED WHILE SOLUBLE PRODUCTION YIELDS ARE IMPROVED. COMPARED TO SM- P80, CATACO EXHIBITS MINIMAL AGGREGATION AND LESS DEGRADATION -- A POTENTIAL PROBLEM WITH THE CURRENT ANTIGEN THAT WAS FLAGGED BY THE FDA FOR POTENTIAL IMPROVEMENT. IN MICE, CATACO ELICITS COMPARATIVELY HIGH TITERS IN MICE, BINDS TO ANTI-SM-P80 MONOCLONAL ANTIBODIES (MABS), AND IS DETECTED BY SERA FROM MICE AND BABOONS IMMUNIZED WITH SCHISTOSHIELD. WITH THE INCREASED USE OF RNA VACCINES, WE WILL ALSO PRODUCE AND EVALUATE BOTH CATACO AND SM-P80 AS RNA VACCINES USING A PROPRIETARY TECHNOLOGY INVENTED BY OUR PARTNERS AT HDT BIO. HDT RECENTLY USED THIS TECHNOLOGY FOR THEIR COVID-19 VACCINE HDT-301, WHICH IS SIMILAR TO THE COVID-19 VACCINES FROM MODERNA AND PFIZER/BIONTECH. THE HDT-301 PLATFORM CONSISTS OF A SELF-REPLICATING RNA (REPRNA) ADSORBED AND STABILIZED ON A LIPID INORGANIC NANOPARTICLE (LION) CARRIER. THIS VACCINE RECEIVED EMERGENCY USE APPROVAL IN INDIA - THE ONLY SELF-AMPLIFYING PLATFORM TO BE APPROVED IN HUMANS. INTRODUCTION OF THE REPRNA INTO CELLS RESULTS IN ONGOING BIOSYNTHESIS OF ANTIGEN-ENCODING RNA RESULTING IN MARKEDLY HIGHER PROTEIN CONCENTRATIONS IN VIVO LEADING TO ENHANCED HUMORAL AND CELLULAR IMMUNE RESPONSES AND - PERHAPS MOST IMPORTANTLY - A DOSE SPARING EFFECT. THE HDT-301 VACCINE HAS BEEN EVALUATED IN BOTH PHASE 1 AND PHASE 2 HUMAN CLINICAL TRIALS TRIAL IN BRAZIL AND THE US AND HAS BEEN SHOWN TO BE SAFE WHILE ELICITING HIGH ANTI-COVID-19 TITERS. IN THIS SBIR, WE PROPOSE TO PRODUCE BOTH CATACO AND SM-P80 AS REPRNA/LION VACCINES AS WELL AS THE CATACO ANTIGEN, IMMUNIZE THEM INTO MICE, AND CHALLENGE WITH S. MANSONI DIRECTLY COMPARING EACH TO THE EXISTING SCHISTOSHIELD VACCINE. SUCCESSFUL COMPLETION OF THIS GRANT WILL ADDRESS TWO KEY QUESTIONS: 1) IS AN RNA VACCINE FOR SCHISTOSHIELD FEASIBLE OR SUPERIOR TO THE EXISTING VACCINE, AND 2) WHETHER THE REDESIGNED CATACO ANTIGEN IS AN IMPROVEMENT FOR THE NEXT GENERATION SCHISTOSHIELD.