Paludisme associé à la grossesse : défis et perspectives pour les stratégies de prévention

Pregnancy associated malaria (PAM) is characterized by infected erythrocytes (IE) sequestration in the intervillous spaces of the placenta leading to devastating pregnancy outcomes. These sequestrations are mediated by VAR2CSA to chondroitin sulphate A(CSA). Pregnant women gain protection against PAM in a parity dependent manner. Recently, a new variant of P.flaciparum was identified to infect multigravid women living in Benin. In the absence of a licensed PAM vaccine, the World Health Orgainzation in recommends a monthly administration of intermittent preventive treatment of malaria in pregnancy(IPTp) with sulfadoxine-pyrimethamine(SP) starting from the second trimester of pregnancy. Although IPTp-SP continuous to be clinically efficacious, it's faced with a number of challenges. This study aims to assess the coverage and impact of the revised IPTp-SP policy on pregnancy and neonatal outcomes, identify some of the challenges facing the IPTp-SP policy and determine antibody functionality against the new P.falciparum variant so to advise on the way forward in PAM vaccine development. In the first study, we enrolled two different groups of pregnant women in Ghana attending either the first antenatal consultation or delivery. Using patient's information and liquid chromatography coupled to tandem mass spectrometer to assay for SP uptake, we were able to show that the new IPTp-SP policy is well implemented in Ghana and translates to an observed improved birth weight (article under Revision). However, genotyping SP resistance markers among parasite isolates indicated a high prevalence of septuple pfdhfr/pfdhps post-treatment compared to first ANC. In the second study, we established and followed a preconceptional cohort of women seeking to become pregnant for the first time in Benin. This study allowed us to show high prevalence of P. falciparum infection in the first trimester of pregnancy when current prevention tools can not yet be deployed. We identified that most of these infections occurring during the first trimester of pregnancy, were derived from persistent asymptomatic and submicroscopic infections prior to conception. This study established for the first time the role of persistent sub-patent infections as a major reservoir of PAM in early pregnancy and further justifying the need for new prevention strategies that can cover this period of pregnancy. Notwithstanding these challenges, we have, in a third study, deciphered the analysis of IgG subclasses in the stoppam cohort that was made up of pregnant women of various parasitemia. The major finding here was that high levels of cytophilic IgG 3 correlate with protection against the negative effects of placental malaria, which suggest that prospective PAM vaccine should target the elicitation of cytophilic IgG's (Manuscript In preparation). In the last study, we have undertaken to characterize the functional properties of the new variant of var2csa (WR80-like) expressed by isolates capable of infecting multigradidae. Results indicate that the parasites with var2csa belonging to this type (WR80-like) are able to recognize and bind to CSA, although to low extent compared to those from FCR3 and 3D7 variants and that IgG specific to FCR3 and 3D7 var2csa were unable to inhibit their interaction to CSA (Manuscript In preparation). Conclusion: The work carried out during this thesis reinforces the fact that the TPI-SP still faces major difficulties, particularly on the coverage of the first trimester of pregnancy, where the prevalence of infections is very high. The development of parasitic mutations associated with more resistance calls into question the effectiveness of the use of MS in the long run. In addition, current efforts to develop a vaccine against placental malaria will likely require a combination of alleles to obtain an effective vaccine on field isolates.Le paludisme placentaire se caractérise par la séquestration des érythrocytes infectés dans les espaces intervilleux du placenta, entraînant de graves conséquences sur la mère et le foetus. La séquestration des érythrocytes ainsi infectés est médiée par VAR2CSA à la chondroïtine sulfate A (CSA) et acquisition d'une protection ont été montré dépendent de la parité. Pourtant, récemment, il a été identifié une autre variante de P.falciparum qui infecte les femmes multigestes vivant au Bénin. En l'absence d'un vaccin homologué, l'Organisation mondiale de la santé (OMS) a recommandés de façon mensuelle administrée le traitement préventif intermittent du paludisme pendant la grossesse (TPIg) avec la sulfadoxine-pyriméthamine (SP) à partir du deuxième trimestre de grossesse. Ce travail de thèse vise à évaluer la couverture et le bénéfice clinique de la nouvelle politique du TPI-SP, à identifier certains des défis auxquels cette nouvelle politique serait confrontée et enfin à déterminer la fonctionnalité des anticorps dirigés contre le candidat vaccin VAR2CSA afin de faciliter le développement du vaccin efficace contre le paludisme placentaire. Dans la première étude, nous avons recruté dans une approche transversale deux groupes de femmes enceintes au Ghana qui arrivaient soit à leur première consultation prénatale ou pour l'accouchement. En exploitant les informations sur les sujets inclus et en effectuant le dosage des niveaux de SP ainsi que la détection du parasite dans le sang, nous avons été en mesure de montrer que la mise en place du nouveau régime de TPI et son utilisation par les femmes enceintes est effective au Ghana. Les résultats se traduisant par une amélioration du poids de l'enfant à la naissance. Cependant, le génotypage des marqueurs de résistance parasitaire à la SP a indiqué une forte prévalence de l'haplotype quadruple dhfr/dhps et une émergence de mutations aux codons 581 et 613 de la pfdhps. Ces mutations pourraient entrainer rapidement l'apparition de phénotypes parasitaires super résistants à la SP dans nos zones d'étude et par conséquent réduire l'efficacité du TPI. Dans la deuxième étude, nous avons suivi une cohorte pré-conceptionnelle de femmes au Bénin et observé que la plupart des infections à P. falciparum survenant pendant le premier trimestre de la grossesse, sont issues d'infections asymptomatiques et submicroscopiques présentes chez celles-ci bien avant la conception. Cette étude a établi pour la première fois le rôle du portage asymptomatique des infections persistantes comme un réservoir majeur du paludisme placentaire en début de grossesse. Une troisième étude portant sur l'analyse des sous classe d'IgG acquises par les femmes enceintes du Bénin contre la région de VAR2CSA présentant un intérêt vaccinal, montre que les sous-classes IgG 3 sont particulièrement corrélés avec la protection contre la survenue de faibles poids de naissance. Les résultats de cette étude suggèrent que le vaccin en développement à base de la protéine VAR2CSA devrait favoriser l'obtention d'IgG cytophile de type 3. Dans une dernière étude, nous avons entrepris de caractériser les propriétés fonctionnelles des variants majeurs de la région id1-id2 de VAR2CSA, cible vaccinale du candidat vaccin PAMVAC. Les résultats indiquent que le variant (WR80) récemment impliquée dans l'infection des multigestes interagit avec la CSA avec une plus faible affinité comparativement à ceux des variants FCR3 et 3D7. De plus les IgG spécifiques induits chez la souris contre les 3 variants montrent des différences majeures dans la reconnaissance croisée. Les travaux réalisés au cours de cette thèse renforcent le fait que le TPI-SP reste confronté à de difficultés majeures notamment sur la couverture du premier trimestre de grossesse où les prévalences d'infections sont très élevées. Le développement de mutations parasitaires associées à plus de résistance remet en question l'efficacité de l'utilisation de la SP à terme

Paludisme associé à la grossesse : défis et perspectives pour les stratégies de prévention

Pregnancy associated malaria (PAM) is characterized by infected erythrocytes (IE) sequestration in the intervillous spaces of the placenta leading to devastating pregnancy outcomes. These sequestrations are mediated by VAR2CSA to chondroitin sulphate A(CSA). Pregnant women gain protection against PAM in a parity dependent manner. Recently, a new variant of P.flaciparum was identified to infect multigravid women living in Benin. In the absence of a licensed PAM vaccine, the World Health Orgainzation in recommends a monthly administration of intermittent preventive treatment of malaria in pregnancy(IPTp) with sulfadoxine-pyrimethamine(SP) starting from the second trimester of pregnancy. Although IPTp-SP continuous to be clinically efficacious, it's faced with a number of challenges. This study aims to assess the coverage and impact of the revised IPTp-SP policy on pregnancy and neonatal outcomes, identify some of the challenges facing the IPTp-SP policy and determine antibody functionality against the new P.falciparum variant so to advise on the way forward in PAM vaccine development. In the first study, we enrolled two different groups of pregnant women in Ghana attending either the first antenatal consultation or delivery. Using patient's information and liquid chromatography coupled to tandem mass spectrometer to assay for SP uptake, we were able to show that the new IPTp-SP policy is well implemented in Ghana and translates to an observed improved birth weight (article under Revision). However, genotyping SP resistance markers among parasite isolates indicated a high prevalence of septuple pfdhfr/pfdhps post-treatment compared to first ANC. In the second study, we established and followed a preconceptional cohort of women seeking to become pregnant for the first time in Benin. This study allowed us to show high prevalence of P. falciparum infection in the first trimester of pregnancy when current prevention tools can not yet be deployed. We identified that most of these infections occurring during the first trimester of pregnancy, were derived from persistent asymptomatic and submicroscopic infections prior to conception. This study established for the first time the role of persistent sub-patent infections as a major reservoir of PAM in early pregnancy and further justifying the need for new prevention strategies that can cover this period of pregnancy. Notwithstanding these challenges, we have, in a third study, deciphered the analysis of IgG subclasses in the stoppam cohort that was made up of pregnant women of various parasitemia. The major finding here was that high levels of cytophilic IgG 3 correlate with protection against the negative effects of placental malaria, which suggest that prospective PAM vaccine should target the elicitation of cytophilic IgG's (Manuscript In preparation). In the last study, we have undertaken to characterize the functional properties of the new variant of var2csa (WR80-like) expressed by isolates capable of infecting multigradidae. Results indicate that the parasites with var2csa belonging to this type (WR80-like) are able to recognize and bind to CSA, although to low extent compared to those from FCR3 and 3D7 variants and that IgG specific to FCR3 and 3D7 var2csa were unable to inhibit their interaction to CSA (Manuscript In preparation). Conclusion: The work carried out during this thesis reinforces the fact that the TPI-SP still faces major difficulties, particularly on the coverage of the first trimester of pregnancy, where the prevalence of infections is very high. The development of parasitic mutations associated with more resistance calls into question the effectiveness of the use of MS in the long run. In addition, current efforts to develop a vaccine against placental malaria will likely require a combination of alleles to obtain an effective vaccine on field isolates.Le paludisme placentaire se caractérise par la séquestration des érythrocytes infectés dans les espaces intervilleux du placenta, entraînant de graves conséquences sur la mère et le foetus. La séquestration des érythrocytes ainsi infectés est médiée par VAR2CSA à la chondroïtine sulfate A (CSA) et acquisition d'une protection ont été montré dépendent de la parité. Pourtant, récemment, il a été identifié une autre variante de P.falciparum qui infecte les femmes multigestes vivant au Bénin. En l'absence d'un vaccin homologué, l'Organisation mondiale de la santé (OMS) a recommandés de façon mensuelle administrée le traitement préventif intermittent du paludisme pendant la grossesse (TPIg) avec la sulfadoxine-pyriméthamine (SP) à partir du deuxième trimestre de grossesse. Ce travail de thèse vise à évaluer la couverture et le bénéfice clinique de la nouvelle politique du TPI-SP, à identifier certains des défis auxquels cette nouvelle politique serait confrontée et enfin à déterminer la fonctionnalité des anticorps dirigés contre le candidat vaccin VAR2CSA afin de faciliter le développement du vaccin efficace contre le paludisme placentaire. Dans la première étude, nous avons recruté dans une approche transversale deux groupes de femmes enceintes au Ghana qui arrivaient soit à leur première consultation prénatale ou pour l'accouchement. En exploitant les informations sur les sujets inclus et en effectuant le dosage des niveaux de SP ainsi que la détection du parasite dans le sang, nous avons été en mesure de montrer que la mise en place du nouveau régime de TPI et son utilisation par les femmes enceintes est effective au Ghana. Les résultats se traduisant par une amélioration du poids de l'enfant à la naissance. Cependant, le génotypage des marqueurs de résistance parasitaire à la SP a indiqué une forte prévalence de l'haplotype quadruple dhfr/dhps et une émergence de mutations aux codons 581 et 613 de la pfdhps. Ces mutations pourraient entrainer rapidement l'apparition de phénotypes parasitaires super résistants à la SP dans nos zones d'étude et par conséquent réduire l'efficacité du TPI. Dans la deuxième étude, nous avons suivi une cohorte pré-conceptionnelle de femmes au Bénin et observé que la plupart des infections à P. falciparum survenant pendant le premier trimestre de la grossesse, sont issues d'infections asymptomatiques et submicroscopiques présentes chez celles-ci bien avant la conception. Cette étude a établi pour la première fois le rôle du portage asymptomatique des infections persistantes comme un réservoir majeur du paludisme placentaire en début de grossesse. Une troisième étude portant sur l'analyse des sous classe d'IgG acquises par les femmes enceintes du Bénin contre la région de VAR2CSA présentant un intérêt vaccinal, montre que les sous-classes IgG 3 sont particulièrement corrélés avec la protection contre la survenue de faibles poids de naissance. Les résultats de cette étude suggèrent que le vaccin en développement à base de la protéine VAR2CSA devrait favoriser l'obtention d'IgG cytophile de type 3. Dans une dernière étude, nous avons entrepris de caractériser les propriétés fonctionnelles des variants majeurs de la région id1-id2 de VAR2CSA, cible vaccinale du candidat vaccin PAMVAC. Les résultats indiquent que le variant (WR80) récemment impliquée dans l'infection des multigestes interagit avec la CSA avec une plus faible affinité comparativement à ceux des variants FCR3 et 3D7. De plus les IgG spécifiques induits chez la souris contre les 3 variants montrent des différences majeures dans la reconnaissance croisée. Les travaux réalisés au cours de cette thèse renforcent le fait que le TPI-SP reste confronté à de difficultés majeures notamment sur la couverture du premier trimestre de grossesse où les prévalences d'infections sont très élevées. Le développement de mutations parasitaires associées à plus de résistance remet en question l'efficacité de l'utilisation de la SP à terme

Paludisme associé à la grossesse : défis et perspectives pour les stratégies de prévention

Le paludisme placentaire se caractérise par la séquestration des érythrocytes infectés dans les espaces intervilleux du placenta, entraînant de graves conséquences sur la mère et le foetus. La séquestration des érythrocytes ainsi infectés est médiée par VAR2CSA à la chondroïtine sulfate A (CSA) et acquisition d'une protection ont été montré dépendent de la parité. Pourtant, récemment, il a été identifié une autre variante de P.falciparum qui infecte les femmes multigestes vivant au Bénin. En l'absence d'un vaccin homologué, l'Organisation mondiale de la santé (OMS) a recommandés de façon mensuelle administrée le traitement préventif intermittent du paludisme pendant la grossesse (TPIg) avec la sulfadoxine-pyriméthamine (SP) à partir du deuxième trimestre de grossesse. Ce travail de thèse vise à évaluer la couverture et le bénéfice clinique de la nouvelle politique du TPI-SP, à identifier certains des défis auxquels cette nouvelle politique serait confrontée et enfin à déterminer la fonctionnalité des anticorps dirigés contre le candidat vaccin VAR2CSA afin de faciliter le développement du vaccin efficace contre le paludisme placentaire. Dans la première étude, nous avons recruté dans une approche transversale deux groupes de femmes enceintes au Ghana qui arrivaient soit à leur première consultation prénatale ou pour l'accouchement. En exploitant les informations sur les sujets inclus et en effectuant le dosage des niveaux de SP ainsi que la détection du parasite dans le sang, nous avons été en mesure de montrer que la mise en place du nouveau régime de TPI et son utilisation par les femmes enceintes est effective au Ghana. Les résultats se traduisant par une amélioration du poids de l'enfant à la naissance. Cependant, le génotypage des marqueurs de résistance parasitaire à la SP a indiqué une forte prévalence de l'haplotype quadruple dhfr/dhps et une émergence de mutations aux codons 581 et 613 de la pfdhps. Ces mutations pourraient entrainer rapidement l'apparition de phénotypes parasitaires super résistants à la SP dans nos zones d'étude et par conséquent réduire l'efficacité du TPI. Dans la deuxième étude, nous avons suivi une cohorte pré-conceptionnelle de femmes au Bénin et observé que la plupart des infections à P. falciparum survenant pendant le premier trimestre de la grossesse, sont issues d'infections asymptomatiques et submicroscopiques présentes chez celles-ci bien avant la conception. Cette étude a établi pour la première fois le rôle du portage asymptomatique des infections persistantes comme un réservoir majeur du paludisme placentaire en début de grossesse. Une troisième étude portant sur l'analyse des sous classe d'IgG acquises par les femmes enceintes du Bénin contre la région de VAR2CSA présentant un intérêt vaccinal, montre que les sous-classes IgG 3 sont particulièrement corrélés avec la protection contre la survenue de faibles poids de naissance. Les résultats de cette étude suggèrent que le vaccin en développement à base de la protéine VAR2CSA devrait favoriser l'obtention d'IgG cytophile de type 3. Dans une dernière étude, nous avons entrepris de caractériser les propriétés fonctionnelles des variants majeurs de la région id1-id2 de VAR2CSA, cible vaccinale du candidat vaccin PAMVAC. Les résultats indiquent que le variant (WR80) récemment impliquée dans l'infection des multigestes interagit avec la CSA avec une plus faible affinité comparativement à ceux des variants FCR3 et 3D7. De plus les IgG spécifiques induits chez la souris contre les 3 variants montrent des différences majeures dans la reconnaissance croisée. Les travaux réalisés au cours de cette thèse renforcent le fait que le TPI-SP reste confronté à de difficultés majeures notamment sur la couverture du premier trimestre de grossesse où les prévalences d'infections sont très élevées. Le développement de mutations parasitaires associées à plus de résistance remet en question l'efficacité de l'utilisation de la SP à terme.Pregnancy associated malaria (PAM) is characterized by infected erythrocytes (IE) sequestration in the intervillous spaces of the placenta leading to devastating pregnancy outcomes. These sequestrations are mediated by VAR2CSA to chondroitin sulphate A(CSA). Pregnant women gain protection against PAM in a parity dependent manner. Recently, a new variant of P.flaciparum was identified to infect multigravid women living in Benin. In the absence of a licensed PAM vaccine, the World Health Orgainzation in recommends a monthly administration of intermittent preventive treatment of malaria in pregnancy(IPTp) with sulfadoxine-pyrimethamine(SP) starting from the second trimester of pregnancy. Although IPTp-SP continuous to be clinically efficacious, it's faced with a number of challenges. This study aims to assess the coverage and impact of the revised IPTp-SP policy on pregnancy and neonatal outcomes, identify some of the challenges facing the IPTp-SP policy and determine antibody functionality against the new P.falciparum variant so to advise on the way forward in PAM vaccine development. In the first study, we enrolled two different groups of pregnant women in Ghana attending either the first antenatal consultation or delivery. Using patient's information and liquid chromatography coupled to tandem mass spectrometer to assay for SP uptake, we were able to show that the new IPTp-SP policy is well implemented in Ghana and translates to an observed improved birth weight (article under Revision). However, genotyping SP resistance markers among parasite isolates indicated a high prevalence of septuple pfdhfr/pfdhps post-treatment compared to first ANC. In the second study, we established and followed a preconceptional cohort of women seeking to become pregnant for the first time in Benin. This study allowed us to show high prevalence of P. falciparum infection in the first trimester of pregnancy when current prevention tools can not yet be deployed. We identified that most of these infections occurring during the first trimester of pregnancy, were derived from persistent asymptomatic and submicroscopic infections prior to conception. This study established for the first time the role of persistent sub-patent infections as a major reservoir of PAM in early pregnancy and further justifying the need for new prevention strategies that can cover this period of pregnancy. Notwithstanding these challenges, we have, in a third study, deciphered the analysis of IgG subclasses in the stoppam cohort that was made up of pregnant women of various parasitemia. The major finding here was that high levels of cytophilic IgG 3 correlate with protection against the negative effects of placental malaria, which suggest that prospective PAM vaccine should target the elicitation of cytophilic IgG's (Manuscript In preparation). In the last study, we have undertaken to characterize the functional properties of the new variant of var2csa (WR80-like) expressed by isolates capable of infecting multigradidae. Results indicate that the parasites with var2csa belonging to this type (WR80-like) are able to recognize and bind to CSA, although to low extent compared to those from FCR3 and 3D7 variants and that IgG specific to FCR3 and 3D7 var2csa were unable to inhibit their interaction to CSA (Manuscript In preparation). Conclusion: The work carried out during this thesis reinforces the fact that the TPI-SP still faces major difficulties, particularly on the coverage of the first trimester of pregnancy, where the prevalence of infections is very high. The development of parasitic mutations associated with more resistance calls into question the effectiveness of the use of MS in the long run. In addition, current efforts to develop a vaccine against placental malaria will likely require a combination of alleles to obtain an effective vaccine on field isolates

Characterization of T cell activation and regulation in children with asymptomatic Plasmodium falciparum infection

Abstract Background Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. However, the relationship between Tregs, cellular activation and parasite control in asymptomatic malaria remains unclear. Methods In a cross-sectional study, the levels of Tregs and other T cell activation phenotypes were compared using flow cytometry in symptomatic, asymptomatic and uninfected children before and after stimulation with infected red blood cell lysates (iRBCs). In addition, the association between these T cell phenotypes and parasitaemia were investigated. Results In children with asymptomatic infections, levels of Tregs and activated T cells were comparable to those in healthy controls but significantly lower than those in symptomatic children. After iRBC stimulation, levels of Tregs remained lower for asymptomatic versus symptomatic children. In contrast, levels of activated T cells were higher for asymptomatic children. Strikingly, the pre-stimulation levels of two T cell activation phenotypes (CD8+CD69+ and CD8+CD25+CD69+) and the post-stimulation levels of two regulatory phenotypes (CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+) were significantly positively correlated with and explained 68% of the individual variation in parasitaemia. A machine-learning model based on levels of these four phenotypes accurately distinguished between asymptomatic and symptomatic children (sensitivity = 86%, specificity = 94%), suggesting that these phenotypes govern the observed variation in disease status. Conclusion Compared to symptomatic P. falciparum infections, in children asymptomatic infections are characterized by lower levels of Tregs and activated T cells, which are associated with lower parasitaemia. The results indicate that T cell regulatory and activation phenotypes govern both parasitaemia and disease status in paediatric malaria in the studied sub-Saharan African population

MOESM2 of Characterization of T cell activation and regulation in children with asymptomatic Plasmodium falciparum infection

Additional file 2. Linear regression analysis to determine the level of variation in parasitaemia using 4 T cell phenotypes

MOESM3 of Characterization of T cell activation and regulation in children with asymptomatic Plasmodium falciparum infection

Additional file 3. Diagnostic plots for the regression analysis described in the legend of Additional file 2

Impact of an Irrigation Dam on the Transmission and Diversity of Plasmodium falciparum in a Seasonal Malaria Transmission Area of Northern Ghana

Water bodies such as dams are known to alter the local transmission patterns of a number of infectious diseases, especially those transmitted by insects and other arthropod vectors. The impact of an irrigation dam on submicroscopic asexual parasite carriage in individuals living in a seasonal malaria transmission area of northern Ghana was investigated. A total of 288 archived DNA samples from two cross-sectional surveys in two communities in the Bongo District of Northern Ghana were analysed. Parasite density was determined by light microscopy and PCR, and parasite diversity was assessed by genotyping of the polymorphic Plasmodium falciparum msp2 block-3 region. Submicroscopic parasitaemia was estimated as the proportional difference between positive samples identified by PCR and microscopy. Dry season submicroscopic parasite prevalence was significantly higher (71.0%, p=0.013) at the dam site compared with the nondam site (49.2%). Similarly, wet season submicroscopic parasite prevalence was significantly higher at the dam site (54.5%, p=0.008) compared with the nondam site (33.0%). There was no difference in parasite density between sites in the dry season (p=0.90) and in the wet season (p=0.85). Multiplicity of infection (MOI) based on PCR data was significantly higher at the dam site compared with the nondam site during the dry season (p<0.0001) but similar between sites during the wet season. MOI at the nondam site was significantly higher in the wet season than in the dry season (2.49, 1.26, p<0.0001) but similar between seasons at the dam site. Multivariate analysis showed higher odds of carrying submicroscopic parasites at the dam site in both dry season (OR = 7.46, 95% CI = 3.07–18.15) and in wet season (OR = 1.73, 95% CI = 1.04–2.86). The study findings suggest that large water bodies impact year-round carriage of submicroscopic parasites and sustain Plasmodium transmission

Plasmodium falciparum VAR2CSA-Specific IgG Subclass Responses Reflect Protection Against Low Birth Weight and Pregnancy-Associated Malaria

International audienceSequestration of Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen in the placenta results in poor pregnancy outcomes, including low birth weight and maternal anemia. Antigen-specific antibody-mediated immunity is acquired during successive pregnancies. Thus, evaluating VAR2CSA-specific IgG profiles among pregnant women will increase knowledge on the immunological mechanisms associated with protection, and help in the development of VAR2CSA-based placental malaria vaccines. Using the PAMVAC candidate vaccine antigen, we assessed anti-VAR2CSA IgG subclass responses of a cohort of pregnant Beninese, and analyzed their relationships with pregnancy outcomes. Cytophilic IgG1 and IgG3 responses were the most frequent, with prevalences ranging from 28% (IgG3) up to 50% (IgG1). Elevated levels of VAR2CSA-specific total IgG and cytophilic IgG3 during pregnancy were consistently associated with higher birth weights, whilst high levels of IgG4 were associated with a reduced risk of placental infections. This suggests that protective anti-VAR2CSA IgG responses are coordinated between both cytophilic and noncytophilic antibodies

Seroprevalence of Antibodies against Plasmodium falciparum Sporozoite Antigens as Predictive Disease Transmission Markers in an Area of Ghana with Seasonal Malaria Transmission.

As an increasing number of malaria-endemic countries approach the disease elimination phase, sustenance of control efforts and effective monitoring are necessary to ensure success. Mathematical models that estimate anti-parasite antibody seroconversion rates are gaining relevance as more sensitive transmission intensity estimation tools. Models however estimate yearly seroconversion and seroreversion rates and usually predict long term changes in transmission, occurring years before the time of sampling. Another challenge is the identification of appropriate antigen targets since specific antibody levels must directly reflect changes in transmission patterns. We therefore investigated the potential of antibodies to sporozoite and blood stage antigens for detecting short term differences in malaria transmission in two communities in Northern Ghana with marked, seasonal transmission.Cross-sectional surveys were conducted during the rainy and dry seasons in two communities, one in close proximity to an irrigation dam and the other at least 20 Km away from the dam. Antibodies against the sporozoite-specific antigens circumsporozoite protein (CSP) and Cell traversal for ookinetes and sporozoites (CelTOS) and the classical blood stage antigen apical membrane antigen 1 (AMA1) were measured by indirect ELISA. Antibody levels and seroprevalence were compared between surveys and between study communities. Antibody seroprevalence data were fitted to a modified reversible catalytic model to estimate the seroconversion and seroreversion rates.Changes in sporozoite-specific antibody levels and seroprevalence directly reflected differences in parasite prevalence between the rainy and dry seasons and hence the extent of malaria transmission. Seroconversion rate estimates from modelled seroprevalence data did not however support the above observation.The data confirms the potential utility of sporozoite-specific antigens as useful markers for monitoring short term/seasonal changes in malaria transmission. It may however be essential to update models to allow for assessment of seasonal changes in malaria transmission, which usually occur within four to six months

Influence of α2-macroglobulin, anti-parasite IgM and ABO blood group on rosetting in <i>Plasmodium falciparum</i> clinical isolates and their associations with disease severity in a Ghanaian population

PURPOSE: The severity of Plasmodium falciparum infections is associated with the ability of the infected red blood cells to cytoadhere to host vascular endothelial surfaces and to uninfected RBCs. Host blood group antigens and two serum proteins α(2)-macroglobulin (α(2)M) and IgM have been implicated in rosette formation in laboratory-adapted P. falciparum. However, there is only limited information about these phenotypes in clinical isolates. METHODS: This was a hospital-based study involving children under 12 years-of-age reporting to the Hohoe Municipal Hospital with different clinical presentations of malaria. Parasite isolates were grown and rosette capabilities and characteristics were investigated by fluorescence microscopy. α(2)M and IgM were detected by ELISA. RESULTS: Rosette formation was observed in 46.8% (75/160) of the parasite isolates from all the blood groups tested. Rosettes were more prevalent (55%) among isolates from patients with severe malaria compared to isolates from patients with uncomplicated malaria (45%). Rosette prevalence was highest (30%) among patients with blood group O (30%) and B (29%), while the mean rosette frequency was higher in isolates from patients with blood group A (28.7). Rosette formation correlated negatively with age (r = −0.09, P= 0.008). Participants with severe malaria had a lower IgM concentration (3.683±3.553) than those with uncomplicated malaria (5.256±4.294) and the difference was significant (P= 0.0228). The mean concentrations of anti-parasite IgM measured among the clinical isolates which formed rosettes was lower (4.2 ±3.930 mg/mL), than that in the non rosetting clinical isolates (4.604 ±4.159 mg/mL) but the difference was not significant (P=0.2733). There was no significant difference in plasma α(2)M concentration between rosetting and non rosetting isolates (P=0.442). CONCLUSION: P. falciparum parasite rosette formation was affected by blood group type and plasma concentration of IgM. A lower IgM concentration was associated with severe malaria whilst a higher α(2)M concentration was associated with uncomplicated malaria