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Introduction: Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates., Methods: In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pf s230 ( Pf s230c and Pf s230D1M) and Pf s48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment., Results: Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pf s230c, Pf s48/45 and Pf s230D1M varied across study sites at enrolment ( p < 0.001 ), as did IgG seroprevalence for anti- Pf s230c and D1M IgG ( p < 0.001 ), but not for anti- Pf s48/45 IgG ( p = 0.159 ). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens ( Pf s230c OR [95% CI], p : 1.70 [1.10, 2.62], 0.017 ; Pf s48/45: 1.45 [0.85, 2.46], 0.174 ; Pf s230D1M: 1.70 [1.03, 2.80], 0.037 ), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pf s230c OR [95% CI], p : 1.09 [1.02, 1.17], 0.008 ; Pf s48/45: 1.05 [0.98, 1.13], 0.185 ; Pf s230D1M: 1.07 [0.99, 1.14], 0.071 )., Conclusion: Pf s230 and Pf s48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum ., Competing Interests: J-AC served as a guest editor for Frontiers in Cellular and Infection Microbiology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 O’Flaherty, Chan, Cutts, Zaloumis, Ashley, Phyo, Drew, Dondorp, Day, Dhorda, Fairhurst, Lim, Amaratunga, Pukrittayakamee, Hien, Htut, Mayxay, Faiz, Mokuolu, Onyamboko, Fanello, Takashima, Tsuboi, Theisen, Nosten, Beeson, Simpson, White and Fowkes.)