Project Grant R01AI186073

LONG-TERM SAFETY AND EFFECTIVENESS OF DENGVAXIA IN THE PHILIPPINES - ABSTRACT THE FOUR SEROTYPES OF DENGUE VIRUS (DENV1-4) ARE THE LEADING CAUSE OF MOSQUITO-BORNE VIRAL DISEASES IN HUMANS. DENGVAXIA, THE FIRST LICENSED DENGUE VACCINE, WAS RECOMMENDED FOR INDIVIDUALS AGED 9-45 YEARS IN 2016. IN THE PHILIPPINES, A SCHOOL-BASED VACCINATION PROGRAM WAS LAUNCHED IN APRIL 2016 WITH >830,000 CHILDREN RECEIVING DENGVAXIA WITHOUT PRIOR SEROLOGICAL TESTING. SUBSEQUENTLY, DENV-SERONEGATIVE CHILDREN WHO RECEIVED DENGVAXIA DEVELOPED SEVERE DISEASE AFTER BREAKTHROUGH DENV INFECTION (BTDI). THIS RESULTED IN THE REVISED RECOMMENDATION IN 2018 THAT DENGVAXIA BE ADMINISTERED ONLY TO DENV-SEROPOSITIVE INDIVIDUALS. THUS, THOUSANDS OF FILIPINO CHILDREN ARE AT HIGHER RISK OF SEVERE DENGUE DISEASE. STUDIES HAVE SHOWN THE EFFICACY OF DENGVAXIA WANED OVER TIME ESPECIALLY AMONG BASELINE DENV-SERONEGATIVE RECIPIENTS, UNDERSCORING A CRITICAL NEED FOR ELUCIDATION OF ANTIBODY AND T-CELL RESPONSES INDUCED BY DENGVAXIA. OUR UNDERSTANDING OF DENGVAXIA WAS PRIMARILY BASED ON EFFICACY TRIALS WITH 3-DOSE REGIMEN. A KNOWLEDGE GAP EXISTS REGARDING THE RISK OF SEVERE DISEASE AND EFFECTIVENESS IN THE REAL WORLD, WHERE MOST INDIVIDUALS RECEIVED ONLY 1 OR 2 DOSES AND PRESENTED WITH BTDI. IN COLLABORATION WITH THE RESEARCH INSTITUTE FOR TROPICAL MEDICINE, OUR RECENT STUDY DEMONSTRATED THE FEASIBILITY OF OUR DENV1-4 NONSTRUCTURAL PROTEIN 1 (NS1) IGG ELISA TO DETERMINE THE BASELINE DENV SEROSTATUS OF DENGVAXIA RECIPIENTS DURING BOTH BTDI AND OTHER FEBRILE ILLNESS (OFI) IN THE PHILIPPINES. OUR LONG-TERM GOAL IS TO FACILITATE THE DEVELOPMENT OF NEXT-GENERATION DENGUE VACCINES AND TO REDUCE THE GLOBAL DISEASE BURDEN OF DENGUE. THE OBJECTIVE IS TO UNDERSTAND THE LONG-TERM EFFECTS OF DENGVAXIA, A CHIMERIC YELLOW FEVER TETRAVALENT DENGUE VACCINE, AND THE IMMUNE RESPONSES INDUCED IN THE FILIPINO POPULATION. THE CENTRAL HYPOTHESIS IS THAT DENGVAXIA INDUCES ANTIBODY AND T-CELL RESPONSES INFERIOR TO NATURAL INFECTION, LEADING TO LIMITED TYPE-SPECIFIC NEUTRALIZING ANTIBODIES, WEAK T-CELL RESPONSES AND WANING VACCINE EFFICACY ESPECIALLY FOR BASELINE DENV-NAIVE RECIPIENTS. THE FIRST AIM IS TO DETERMINE THE BASELINE DENV SEROSTATUS OF DENGVAXIA RECIPIENTS IN THE PHILIPPINES AND ASSESS THE LONG-TERM SAFETY AND EFFECTIVENESS OF DENGVAXIA. THE SECOND AIM IS TO CHARACTERIZE ANTIBODY AND T-CELL RESPONSES INDUCED BY DENGVAXIA PRIOR TO AND AFTER BTDI. THE PROPOSED RESEARCH IS INNOVATIVE AS IT COMBINES RT-PCR AND IGM ELISA USED IN ROUTINE DENGUE FEVER SURVEILLANCE AND OUR RECENTLY VALIDATED DENV14 NS1 IGG ELISA TO DETERMINE BASELINE DENV SEROSTATUS UNDER FIELD CONDITIONS AND PROVIDES NEW INSIGHTS INTO THE SAFETY AND EFFECTIVENESS OF DENGVAXIA AFTER MASS VACCINATION THROUGH A MANUFACTURER-INDEPENDENT STUDY AS OPPOSED TO THAT DERIVED FROM VACCINE EFFICACY TRIALS. GIVEN THAT PREVIOUS IMMUNOGENICITY STUDIES OF DENGVAXIA PRIMARILY FOCUSED ON NEUTRALIZING ANTIBODY TITERS, OUR IN-DEPTH STUDY OF ANTIBODY RESPONSES BOTH QUALITATIVELY AND QUANTITATIVELY AND T-CELL RESPONSES TO STRUCTURAL AND NONSTRUCTURAL PROTEINS IS HIGHLY SIGNIFICANT. THIS INFORMATION IS TRANSLATIONAL AND WILL FACILITATE THE DEVELOPMENT OF NEXT-GENERATION LIVE-ATTENUATED TETRAVALENT DENGUE VACCINE OR OTHER CHIMERIC VACCINES.