Integrated evaluation of antibody responses to mosquitoes and mosquito-borne pathogens using highly multiplexed serology

Vector-borne diseases (VBDs) are a leading cause of morbidity and mortality worldwide. Antigens driving host immune responses to pathogens and vectors can serve as vaccine candidates and biomarkers of previous exposure, but the immunogenicity of relevant proteomes remains undercharacterized. To comprehensively profile antibody responses to VBDs and the vectors themselves, we developed a highly multiplexed phage display library, VectorScan, containing more than 250,000 peptides derived from diverse arthropod vectors and prevalent vector-borne pathogens. We used phage immunoprecipitation sequencing to screen VectorScan against blood samples with experimental and natural exposures to arboviruses, malaria parasites, and mosquitoes. We analyzed quantitative measurements of peptide seroreactivity to identify epitopes driving viral serotype-level exposure signatures and mosquito sialome antigens. Mosquito-directed antibody responses were quantitatively associated with natural viral and parasite exposure. We leverage VectorScan to define the relationship between the intensity of mosquito exposure and the rate of malaria infection in children, demonstrating the public health utility of a tool for paired vector and pathogen serosurveillance.