Project Grant R01AI183678

DEFINING THE IMMUNOGENIC LANDSCAPE OF EARLY MOSQUITO-STAGE P. FALCIPARUM TO ACCELERATE MALARIA TRANSMISSION-BLOCKING VACCINE DISCOVERY - PROJECT SUMMARY THE DISEASE MALARIA IS CAUSED BY VECTOR-BORNE PARASITES OF THE GENUS PLASMODIUM. WITH HUNDREDS OF MILLIONS OF INFECTIONS AND OVER HALF A MILLION DEATHS ANNUALLY, MALARIA REMAINS ONE OF THE FOREMOST GLOBAL HEALTH CHALLENGES. THE TWO WHO-RECOMMENDED MALARIA VACCINES HAVE ONLY MODERATE EFFICACY AGAINST SEVERE DISEASE AND DO NOT PROVIDE STERILIZING PROTECTION, NEITHER DO THEY PREVENT TRANSMISSION OF THE PARASITE TO THE MOSQUITO VECTOR THAT CARRIES IT BETWEEN HUMAN HOSTS. THE MAJORITY OF VACCINE DEVELOPMENT EFFORTS TO DATE HAVE FOCUSED ON MEANS TO PREVENT INFECTION OF HUMANS. HOWEVER, A COMPREHENSIVE MALARIA ERADICATION EFFORT ALSO REQUIRES BLOCKING TRANSMISSION WITH VECTOR-TARGETED INTERVENTIONS. COMPARED WITH VACCINES THAT PREVENT INFECTION BY TARGETING PRE- ERYTHROCYTIC AND ASEXUAL BLOOD STAGES OF THE PARASITE, VERY FEW CANDIDATE ANTIGENS HAVE BEEN IDENTIFIED FOR TRANSMISSION-BLOCKING VACCINES (TBVS) THAT TARGET THE TRANSMITTED FORMS OF THE PARASITE PRESENT IN THE MOSQUITO VECTOR STAGES. THIS DISPARITY ARISES IN PART BECAUSE THE COMPREHENSIVE CHARACTERIZATION OF PROTEIN EXPRESSION THAT INFORMS VACCINES AGAINST PRE-ERYTHROCYTIC AND ASEXUAL BLOOD STAGES HAS NOT BEEN PERFORMED FOR THE STAGES THAT DEVELOP IN THE MOSQUITO MIDGUT, I.E., GAMETES, ZYGOTES, AND OOKINETES. THE FEW TBV CANDIDATES THAT HAVE ENTERED CLINICAL TRIALS, INCLUDING PFS25, PFS48/45, AND PFS230, ARE SURFACE-EXPOSED ON THESE EARLY MOSQUITO-STAGE PARASITES. IMPORTANTLY, IT HAS BEEN DEMONSTRATED THAT ANTIBODIES AGAINST THESE PROTEINS CAN BE GENERATED IN THE VERTEBRATE HOST, CARRIED TO THE MOSQUITO VECTOR IN THE BLOOD MEAL, AND SUBSEQUENTLY INTERFERE WITH FERTILIZATION AND/OR SUCCESSFUL INFECTION OF THE MOSQUITO. WE HYPOTHESIZE THAT EARLY MOSQUITO-STAGE PARASITES EXHIBIT MANY MORE UNDISCOVERED SURFACE-EXPOSED PROTEINS, AND THAT THESE PROTEINS CAN BE TARGETED BY ANTIBODIES TO PREVENT TRANSMISSION OF THE MALARIA PARASITE TO THE MOSQUITO VECTOR. WE WILL USE MASS SPECTROMETRY-BASED PROTEOMICS TO PROVIDE THE FIRST COMPREHENSIVE CATALOG OF SURFACE-EXPOSED PROTEINS IN P. FALCIPARUM GAMETES, ZYGOTES, AND OOKINETES. IN PARALLEL, WE WILL IMMUNIZE ANIMALS WITH EARLY MOSQUITO-STAGE PARASITES AND IDENTIFY PARASITE PROTEINS THAT ELICIT AN IMMUNE RESPONSE. FROM THE SUBSET OF IMMUNOGENIC SURFACE-EXPOSED PARASITE PROTEINS, WE WILL IDENTIFY THE MOST PROMISING TBV CANDIDATES AND EVALUATE THEM AS ANTIGENS FOR TRANSMISSION-BLOCKING VACCINES BY QUANTIFYING THE ABILITY OF ANTIBODIES AGAINST THESE ANTIGENS TO PREVENT P. FALCIPARUM FROM INFECTING MOSQUITOES.