Authors

M Cerone¹; CV Ukegbu¹; JA Cai¹; A Varkey¹; Z Yunyue¹; P Yen¹; D Noone¹; D Bubek¹; W Tham²; G Chistophides¹; D Vlachou¹;  ¹ Imperial College London, UK;  ² The Walter and Eliza Hall Institute of Medical Research, Australia

Discussion

Malaria remains one of the most pressing global health challenges, exacerbated by widespread mosquito resistance to insecticides, parasite resistance to antimalarial drugs, and climate-driven shifts in transmission dynamics. These pressures underscore the urgent need for innovative strategies that directly interrupt parasite development within mosquito vectors. Here, we introduce a new design paradigm for transmission-blocking interventions that harnesses human complement activity within the Anopheles gambiae midgut to selectively eliminate early Plasmodium falciparum stages. The human complement system provides rapid innate defence through antibody-antigen complexes that trigger a proteolytic cascade culminating in multiple effector mechanisms, including membrane attack complex formation and pathogen lysis. Importantly, active complement components are ingested during blood feeding and persist in the mosquito midgut for several hours, coinciding with vulnerable extracellular parasite stages. However, naturally occurring antibodies against mosquito-stage parasites are present at low titres in human blood and are insufficient to initiate robust complement activation within the mosquito blood bolus. To overcome this limitation, we engineered synthetic bifunctional recognition molecules capable of simultaneously binding P. falciparum sexual-stage antigens and recruiting human complement factors, thereby enabling targeted complement fixation on parasite surfaces within the mosquito. These molecules display high antigen specificity and efficient complement recruitment. When added to gametocytaemic blood, they induce strong transmission-blocking activity in A. gambiae, with significant reductions in midgut parasite development and onward transmission. Furthermore, when expressed in gene drivemodified mosquitoes, they lead to marked suppression of P. falciparum infection. Together, these findings establish a new paradigm for transmission-blocking interventions and define a scalable, genetically encodable platform for complement-mediated malaria transmission control.