Malaria Transmission Blocking Vaccine Discovery

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Antigen discovery has focused on using human serum samples collected from individuals that are naturally exposed to malaria and appear to develop effective immunity that prevents gametocytemia or blocks parasite transmission to mosquitoes, as tools to identify candidate vaccine antigens. Specifically, serum samples or antibodies that have activity of interest are compared to sera/antibodies that lack this activity, for their ability to select or recognize individual recombinant proteins constructs of P. falciparum. Recombinant proteins identified through differential screening are then prepared as immunogens and tested for their ability to induce effective anti-gametocyte or transmission-blocking antibodies. From our publications this year, we report the following advances in FY2023: Simons LM, Ferrer P, Gombakomba N, Underwood K, Herrera R, Narum DL, Canepa G, Acquah F, Amoah L, Duffy PE, Barillas-Mury C, Long C, Lee SM, Locke E, Miura K, Williamson KC. Extending the range of Plasmodium falciparum transmission blocking antibodies. 2023. Vaccine. Apr 24:S0264-410X(23)00453-X. doi: 10.1016/j.vaccine.2023.04.042. Using flow cytometry to efficiently screen for P. falciparum gamete/zygote surface reactivity, this collaborative study led by USUHS colleagues identified 82 antibodies that bound live P. falciparum gametes/zygotes. Eight of these antibodies elicited significant TRA via standard membrane feeding assay, and do not recognize epitopes present in any of the current recombinant transmission-blocking vaccine candidates, Pfs230D1M, Pfs48/45.6C, Pf47 D2 and rPfs25. One TRA mAb immunoprecipitates two surface antigens, Pfs47 and Pfs230, that are expressed by both gametocytes and gametes/zygotes. These two proteins have not previously been reported to associate and the recognition of both by a single TRA mAb suggests the Pfs47/Pfs230 complex is a new vaccine target. In total, Pfs230 was the dominant target antigen, with five of the eight TRA mAbs and 8 of 11 nonTRA gamete/zygote surface reactive mAbs interacting with Pfs230. Of the three remaining TRA mAbs, two recognized non-reduced, parasite-produced Pfs25 and one bound non-reduced, parasite-produced Pfs48/45. None of the new TRA epitopes are linear. The identification of eight new TRA mAbs that bind epitopes not included in any of the constructs currently under advancement as transmission-blocking vaccine candidates may provide new targets worthy of further study. Dickey TH, Gupta R, McAleese H, Ouahes T, Orr-Gonzales S, Ma R, Muratova O, Hume JCC, Lambert LE, Duffy PE, Tolia NH. Design of a stabilized non-glycosylated Pfs48/45 antigen enables a potent malaria transmission-blocking nanoparticle vaccine. 2023. npjVaccines. Feb 18;8(1):20. doi: 10.1038/s41541-023-00619-9. Pfs48/45 is a promising antigen in development as a transmission blocking vaccine (TBV)This collaborative project led by Tolia lab implemented a SPEEDesign computational design and in vitro screening pipeline to create a stabilized non-glycosylated Pfs48/45 D3 antigen with improved manufacture characteristics for vaccine manufacture.