The Dynamics of Naturally Acquired Immune Responses to Plasmodium falciparum Sexual Stage Antigens Pfs230 & Pfs48/45 in a Low Endemic Area in Tanzania

et al. (2010) The Dynamics of Naturally Acquired Immune Responses to Plasmodium falciparum Sexual Stage Antigens Pfs230 & Pfs48/45 in a Low Endemic Area in Tanzania. PLoS ONE 5(11): e14114. doi:10.1371/journal.pone.0014114 The Dynamics of Naturally Acquired Immune Responses to Plasmodium falciparum Sexual Stage Antigens Pfs230 & Pfs48/45 in a Low Endemic Area in Tanzania Teun Bousema 0 Will Roeffen 0 Hinta Meijerink 0 Harry Mwerinde 0 Steve Mwakalinga 0 Geert-Jan van 0 Gemert 0 Marga van de Vegte-Bolmer 0 Frank Mosha 0 Geoffrey Targett 0 Eleanor M. Riley 0 Robert 0 Sauerwein 0 Chris Drakeley 0 Lorenz von Seidlein, Menzies School of Health Research, Australia 0 1 Department of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine , London , United Kingdom , 2 Joint Malaria Programme, Moshi, Tanzania, 3 Department of Medical Microbiology, Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands , 4 TPC District Designated Hospital, Tanzania Plantation Company, Lower Moshi, Tanzania, 5 Department of International Health , Immunology, and Microbiology , University of Copenhagen , Copenhagen , Denmark , 6 Kilimanjaro Clinical Research Institute , Moshi , Tanzania Background: Naturally acquired immune responses against sexual stages of P. falciparum can reduce the transmission of malaria from humans to mosquitoes. These antigens are candidate transmission-blocking vaccines but little is known about the acquisition of sexual stage immunity after exposure to gametocytes, or their longevity and functionality. We conducted a longitudinal study on functional sexual stage immune responses. Methodology/Principal Findings: Parasitaemic individuals (n = 116) were recruited at a health centre in Lower Moshi, Tanzania. Patients presented with gametocytes (n = 16), developed circulating gametocytes by day 7 (n = 69) or between day 7 and 14 (n = 10) after treatment or did not develop gametocytes (n = 21). Serum samples were collected on the first day of gametocytaemia and 28 and 84 days post-enrolment (or d7, 28, 84 after enrolment from gametocyte-negative individuals). Antibody responses to sexual stage antigens Pfs230 and Pfs48/45 were detected in 20.7% (72/348) and 15.2% (53/348) of the samples, respectively, and were less prevalent than antibodies against asexual stage antigens MSP-119 (48.1%; 137/285) and AMA-1 (52.4%; 129/246)(p,0.001). The prevalence of anti-Pfs230 (p = 0.026) and anti-Pfs48/45 antibodies (p = 0.017) increased with longer duration of gametocyte exposure and had an estimated half-life of approximately 3 months. Membrane feeding experiments demonstrated a strong association between the prevalence and concentration of Pfs230 and Pfs48/45 antibodies and transmission reducing activity (TRA, p,0.01). Conclusions/Significance: In a longitudinal study, anti-Pfs230 and Pf48/45 antibodies developed rapidly after exposure to gametocytes and were strongly associated with transmission-reducing activity. Our data indicate that the extent of antigen exposure is important in eliciting functional transmission-reducing immune responses. - Funding: This study was supported by a Wellcome Trust research fellowship to CJD (#063516). JTB was supported by the European Union FIGHTMAL project, receiving funding from the European Communitys Seventh Framework Programme [FP7/20072013] under grant agreement PIAP-GA-2008-21816.4. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr Mwerinde works at a hospital within the TPC grounds but is not employed by them. He is employed by the government. This does not alter the authors adherence to all the PLoS ONE policies on sharing data and materials. Recent successes in eliciting transmission-reducing immune responses with malaria transmission-blocking vaccines (MTBV) in animal models [1,2,3,4] have fuelled interest in future deployment of these vaccines as part of malaria control and elimination strategies [5,6]. Understanding the dynamics of naturally acquired transmission reducing immune responses will assist in the future deployment of MTBV in endemic populations. The transmission of malaria depends on the presence of mature sexual stage parasites, gametocytes, in the human peripheral blood. Once ingested by a mosquito taking a blood meal, gametocytes will form male microgametes and female macrogametes that after fertilization and zygote formation develop into ookinetes that penetrate the mosquito midgut wall to form an oocyst underneath the basal lamina of the midgut. Each oocyst produces thousands of sporozoites, rendering the mosquito infectious to humans. The infectiousness of gametocytes to mosquitoes depends on their density [7,8,9] and level of maturation [10] but also on mosquito [11] and human immune responses [12]. Human transmissionreducing antibodies are ingested by Anopheline mosquitoes together with gametocytes and can interfere with zygote formation and, as a consequence, further development of parasites in the mosquito vector. MTBV are designed to induce such antibody responses to reduce the infectiousness of gametocytes to mosquitoes or even block transmission completely [6,13,14]. The three most promising MTBV candidates for Plasmodium falciparum so far are based on the induction of antibody responses against parasite antigens Pfs230, Pfs48/45 and Pfs25 [1,2,3,4,15]. Pfs48/45 and Pfs230 are expressed on the surface of gametes and are involved in the fertilization of macrogametocytes by microgametes [5]; Pfs25 is a postfertilisation antigen expressed on the surface of ookinetes [4], and plays a role in the traversal of the mosquito midgut epithelium [16]. The gamete surface molecules Pfs48/45 and Pfs230 are also expressed in gametocytes circulating in the human blood and antibody responses against these antigens are detected in naturally exposed individuals [12,17,18]. This makes it possible to study the nature and duration of sexual-stage specific immunity in naturally infected individuals [5]. Naturally acquired sexual stage-specific antibody responses may be acquired after exposure to gametocytes [12] and rapidly induced as part of the initial response to infection [19,20]. In contrast to antibodies against pre-erythrocytic and blood-stage antigens [19,21,22], the prevalence of sexual-stage specific antibodies does not increase with age [23,24]. Little is known about the rate of induction or longevity of sexual-stage antibody responses and this may be important for natural boosting of any vaccine induced response. Here, we determine the acquisition, longevity and functionality of sexual stage specific antibody responses in a longitudinal study in an area of low endemicity in Tanzania. Ethics permission was received from the ethical committees of the National Institute for Medical Research, the Kilimanjaro Christian Medical Centre, and the London S (...truncated)