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Naturally acquired immune responses target infected red blood cell surface antigens of immature malaria transmission stages. Targeting transmission: Effective malaria vaccines to block transmission of Plasmodium falciparum may require targeting of different antigens than those that are currently being studied. To identify candidate antigens, Dantzler et al. studied immune responses from large cohorts of people that had been infected with P. falciparum. They used multiple complementary assays to study how antibodies recognize different stages of gametocytes, the sexual stage that allows transmission from human blood into mosquitoes. Immune sera recognized immature but not mature gametocytes inside red blood cells. They further studied a selection of candidate antigens that are not present in other stages and are relatively conserved across P. falciparum strains. Strong natural immunity to these antigens indicates that a vaccine may be designed to induce protective immune responses that could potentially interfere with transmission. The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention. [ABSTRACT FROM AUTHOR]