Research Project
8253240
DESCRIPTION (provided by applicant): For the Phase I SBIR grant we constructed a Plasmodium falciparum (Pf) 3D7 protein microarray containing 2,320 individual polypeptides representing 1,200 known and hypothetical proteins, or ~23 % of the entire Pf proteome. We showed that the individual proteins printed on those arrays captured antibodies present in sera from infected individuals and the amount of captured antibody could be quantified using fluorescent secondary antibody. In this way, the complete profile of antibodies that results after natural or experimental exposure or immunization can be determined. We probed the array with serum from people residing in Mali and identified a panel of potential vaccine antigen candidates against which antibodies were significantly elevated in protected children compared to age-matched susceptible children from the same village. In another study, we described a panel of biomarkers and potential vaccine antigens that were preferentially recognized in sera of protected volunteers immunized by the bite of irradiated Pf sporozoites infected mosquitoes as compared to similarly vaccinated but unprotected subjects. These results validate the utility of the Pf proteome microarray developed in the Phase I grant to identify antibodies associated with immune protection. In this Phase II application, we propose to apply an expanded version of the proteome microarray developed in Phase I (containing 4,253 Pf proteins) to determine antibody response in individuals enrolled in several attenuated sporozoite vaccine clinical trials. By comparing the antibody profiles from vaccinees which are protected with those who are not, we aim to identify surrogate antibody biomarkers associated with sporozoite vaccine mediated protection. There is now a major effort led by our collaborator, Sanaria Inc., to develop purified metabolically active, aseptic, vialed, and cryopreserved Pf sporozoite (PfSPZ) vaccines that prevent infection and transmission and are administered by needle and syringe injection. The first such PfSPZ vaccine has been attenuated by irradiation and is called the PfSPZ Vaccine. Recently, the group at Radboud University Nijmengen Medical Center (RUNMC) published on achieving complete protection against Pf by immunizing volunteers by the bite of mosquitoes carrying viable (non-irradiated) PfSPZ while taking chloroquine chemoprophylaxis to prevent parasitemia. This protection has now been shown to be sustained for 2 years. Together, Sanaria and RUNMC have shown that they can infect volunteers by needle and syringe administration of viable PfSPZ, and studies to immunize chloroquine treated volunteers with purified viable PfSPZ to determine if they can duplicate the protection seen after administration by mosquito bite are pending. Approximately 1,500 serum specimens from these trials will be used for the biomarker discovery project proposed here. The aim will be to identify and validate these surrogate biomarkers of protection and to develop a validated test intended to be used as a pivotal FDA-required assay to support licensure of the sporozoite vaccine. PUBLIC HEALTH RELEVANCE: An effective malaria vaccine would greatly benefit millions of infants, children, pregnant women and others at risk of malaria disease and death throughout the malaria-endemic world, but thus far efforts to develop recombinant protein and viral vector vaccines have been disappointing despite intense efforts. This proposal takes advantage of recent discoveries showing that several live attenuated whole organism vaccines can provide robust protection from infection by the parasite. The study proposed here aims to probe a microarray containing 4,253 Pf proteins with hundreds of sporozoite vaccine clinical trial specimens to identify and validate surrogate antibody biomarkers of protection and to develop a validated test intended to be used as a pivotal FDA-required assay to support licensure of the sporozoite vaccine.
