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Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that block Plasmodium parasite development in the mosquito midgut, thus preventing mosquitoes from becoming infectious. While the Pro-domain and first of fourteen 6-Cysteine domains (Pro-D1) of the Plasmodium gamete surface protein Pfs230 are known targets of transmission-blocking antibodies, no studies to date have discovered other Pfs230 domains that are functional targets. Here, we show that a murine monoclonal antibody (mAb), 18F25.1, targets Pfs230 Domain 7. We generated a subclass-switched complement-fixing variant, mAb 18F25.2a, using a CRISPR/Cas9-based hybridoma engineering method. This subclass-switched mAb 18F25.2a induced lysis of female gametes in vitro. Importantly, mAb 18F25.2a potently reduced P. falciparum infection of Anopheles stephensi mosquitoes in a complement-dependent manner, as assessed by standard membrane feeding assays. Together, our data identify Pfs230 Domain 7 as target for transmission-blocking antibodies and provide a strong incentive to study domains outside Pfs230Pro-D1 as TBV candidates., (© 2023. The Author(s).)

During its life cycle, Plasmodium, the malaria parasite, is exposed to the human and mosquito complement systems. Early experiments demonstrated that activation of complement can pose a serious threat to parasites, but recent studies revealed complement-evasion mechanisms important for parasite survival. Blood-stage parasites and gametes recruit regulators to neutralize human complement activation, while ookinetes inhibit mosquito complement by disrupting epithelial nitration in response to midgut invasion. Here we provide an in-depth overview of the evasion mechanisms currently known and speculate on the existence of others not yet identified. Finally, we discuss how these mechanisms could provide novel targets for urgently needed malaria vaccines and therapeutics., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Ltd.)