Recognition of Plasmodium falciparum mature gametocyte-infected erythrocytes by antibodies of semi-immune adults and malaria-exposed children from Gabon

Abstract

BackgroundTransmission of malaria from man to mosquito depends on the presence of gametocytes, the sexual stage of Plasmodium parasites in the infected host. Naturally acquired antibodies against gametocytes exist and may play a role in controlling transmission by limiting the gametocyte development in the circulation or by interrupting gamete development and fertilization in the mosquito following ingestion. So far, most studies on antibody responses to sexual stage antigens have focused on a subset of gametocyte-surface antigens, even though inhibitory Ab responses to other gametocyte antigens might also play a role in controlling gametocyte density and fertility. Limited information is available on natural antibody response to the surfaces of gametocyte-infected erythrocytes.MethodsAb responses to surface antigens of erythrocytes infected by in vitro differentiated Plasmodium falciparum mature gametocytes were investigated in sera of semi-immune adults and malaria-exposed children. In addition, the effect of immunization with GMZ2, a blood stage malaria vaccine candidate, and the effect of intestinal helminth infection on the development of immunity to gametocytes of P. falciparum was evaluated in malaria-exposed children and adults from Gabon. Serum samples from two Phase I clinical trials conducted in Gabon were analysed by microscopic and flow-cytometric immunofluorescence assay.ResultsAdults had a higher Ab response compared to children. Ab reactivity was significantly higher after fixation and permeabilization of parasitized erythrocytes. Following vaccination with the malaria vaccine candidate GMZ2, anti-gametocyte Ab concentration decreased in adults compared to baseline. Ab response to whole asexual stage antigens had a significant but weak positive correlation to anti-gametocyte Ab responses in adults, but not in children. Children infected with Ascaris lumbricoides had a significantly higher anti-gametocyte Ab response compared to non-infected children.ConclusionThe current data suggest that antigens exposed on the gametocyte-infected red blood cells are recognized by serum antibodies from malaria-exposed children and semi-immune adults. This anti-gametocyte immune response may be influenced by natural exposure and vaccination. Modulation of the natural immune response to gametocytes by co-infecting parasites should be investigated further and may have an important impact on malaria control strategies.

Low Levels of Human Antibodies to Gametocyte-Infected Erythrocytes Contrasts the PfEMP1-Dominant Response to Asexual Stages in P. falciparum Malaria

“…Interestingly, when the IE membrane was removed from the gametocytes, human antibodies recognized native antigens expressed on the gametocyte membrane itself, consistent with other reports on permeabilized gametocyte-IEs (13). Major gametocyte surface antigens include Pfs230 and Pfs48/45, which are targeted by human antibodies and associated with transmission-blocking activity through mosquito feeding assays [reviewed in (9)].…”

“…One study reported naturally-acquired antibodies recognized the surface of immature gametocyte-IEs (10). In contrast, other studies reported a lack of antibodies to immature stages, but some antibodies to mature stage V gametocyte-IEs (11–13). The target of these antibodies is unknown.…”

Immune Responses to the Sexual Stages of Plasmodium falciparum Parasites

“…Naturally occurring antibodies targeting Pfs230 and Pfs45/48 have been observed in field studies in The Gambia, Kenya, and Cameroon and were associated with reduced malaria transmission (30, 45). However, other studies reported that transmission reduction correlated with antibody responses to Pfs230 only (46) or with anti-Pfs48/45 antibodies only (6, 42, 43). These conflicting results may be due to differences in the history of exposure of study participants or existence of other co-infections.…”

“…Second, it is not known what ingested antibody levels in the mosquito are required that would lead to a subsequent transmission blockade. The identification and validation of gametocyte surface antigens as vaccine candidates with transmission reducing activity (TRA) directly measurable in the human host will overcome these challenges, complement and strengthen current transmission blocking vaccine efforts (6, 52).…”

“…Transmission blocking interventions either targeting gametocytes while in the human host or gametes in the mosquito are considered an essential part of malaria control strategies especially in the quest to eradicate malaria (5, 6). Malaria parasites (sporozoites) are transmitted through the bite of Anopheline mosquitoes.…”