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Background: The effectiveness of community delivery of intermittent preventive treatment (C-IPT) of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine has been evaluated in selected areas of the Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria. We aimed to assess the effect of C-IPTp on the potential development of Plasmodium falciparum resistance to sulfadoxine-pyrimethamine, since it could threaten the effectiveness of this strategy., Methods: Health facility-based cross-sectional surveys were conducted at baseline and 3 years after C-IPTp implementation in two neighbouring areas per country, one with C-IPTp intervention, and one without, in the four project countries. Dried blood spots from children under five years of age with clinical malaria were collected. Sulfadoxine-pyrimethamine resistance-associated mutations of the P falciparum dhfr (Asn51Ile/Cys59Arg/Ser108Asn/Ile164Leu) and dhps (Ile431Val/Ser436Ala/Ala437Gly/Lys540Glu/Ala581Gly/Ala613Ser) genes were analysed., Findings: 2536 children were recruited between June 19 and Oct 10, 2018, during baseline surveys. Endline surveys were conducted among 2447 children between July 26 and Nov 30, 2021. In the Democratic Republic of the Congo, the dhfr/dhps IRNI/ISGEAA inferred haplotype remained lower than 10%, from 2% (5 of 296) at baseline to 8% (24 of 292) at endline, and from 3% (9 of 300) at baseline to 6% (18 of 309) at endline surveys in intervention and non-intervention areas respectively with no significant difference in the change between the areas. In Mozambique, the prevalence of this haplotype remained stable at over 60% (194 [64%] of 302 at baseline to 194 [64%] of 303 at endline, and 187 [61%] of 306 at baseline to 183 [61%] of 301 in endline surveys, in non-intervention and intervention areas respectively). No isolates harbouring the dhps ISGEAA genotype were found in Nigeria. In Madagascar, only five isolates with this haplotype were found in the non-intervention area (2 [>1%] of 300 at baseline and 3 [1%] of 300 at endline surveys). No isolates were found carrying the dhps ISGEGA genotype., Interpretation: C-IPTp did not increase the prevalence of molecular markers associated with sulfadoxine-pyrimethamine resistance after three years of programme implementation. These findings reinforce C-IPTp as a strategy to optimise the control of malaria during pregnancy, and support the WHO guidelines for prevention of malaria in pregnancy., Funding: UNITAID [2017-13-TIPTOP]., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Malaria in pregnancy is a major driver of maternal and infant mortality in sub-Saharan Africa. The WHO recommends the administration of intermittent preventive treatment with sulfadoxine pyrimethamine (IPTp-SP) at antenatal care (ANC) visits. Despite being a highly cost-effective strategy, IPTp-SP coverage and uptake remains low. A pilot project was conducted to assess the cost-effectiveness (CE) of community-based delivery of IPTp (C-IPTp) in addition to ANC delivery to increase IPTp uptake in the Democratic Republic of Congo (DRC), Madagascar (MDG), Mozambique (MOZ) and Nigeria (NGA)., Methods: Costs and CE estimates of C-IPTp were calculated according to two scenarios: (1) costs in 'programmatic mode' (ie, costs if C-IPTp was to be implemented by national health systems) and (2) costs from the pilot project. The effectiveness of C-IPTp was obtained through estimates of the averted disability-adjusted life-years (DALYs) associated with maternal clinical malaria and anaemia, low birth weight and neonatal mortality., Results: Net incremental costs of C-IPTp ranged between US$6138-US$47 177 (DRC), US$5552-US$31 552 (MDG), US$10 202-US$53 221 (MOZ) and US$667-US$28 645 (NGA) per 1000 pregnant women, under scenarios (1) and (2), respectively. Incremental cost-effectiveness ratios (ICERs) ranged between US$15-US$119 in DRC, US$9-US$53 in MDG, US$104-US$543 in MOZ and US$2-US$66 in NGA per DALY averted, under scenarios (1) and (2), respectively. ICERs fall below the WHO recommended CE threshold based on the gross domestic product per capita., Conclusion: Findings suggest that C-IPTp is a highly cost-effective intervention. Results can inform policy decisions on adopting and optimising effective interventions for preventing malaria in pregnancy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine is recommended at each antenatal care clinic visit in high-moderate transmission areas. However, its coverage remains unacceptably low in many countries. Community health workers can effectively deliver malaria preventive interventions. The aim of this study was to assess the effect of community delivery of IPTp (C-IPTp) on antenatal care and IPTp coverage., Methods: A community-based IPTp administration approach was implemented in four sub-Saharan countries: the Democratic Republic of the Congo (DR Congo), Madagascar, Mozambique, and Nigeria. A quasi-experimental before and after evaluation by cluster sampling was designed where C-IPTp was implemented in selected country areas in different phases. Baseline (before C-IPTp implementation), midline, and endline household surveys were carried out to assess IPTp intake in pregnant women in 2018, 2019, and 2021. Eligible participants of the household survey were women of reproductive age (13-50 years old, depending on the country) that had a pregnancy that ended (any pregnancy regardless of pregnancy outcome) in the 6 months before the interview. For the first baseline surveys, the target population was women who had a pregnancy that ended in the 12 months before the interview. The primary outcome from the household surveys was the proportion of women who reported having received at least three doses of IPTp during pregnancy. The trial is registered at ClinicalTrials.gov, NCT03600844., Findings: A total of 32 household surveys were conducted between March 15, and Oct 30, 2018, and data from 18 215 interviewed women were analysed. The coverage of at least three doses of IPTp (IPTp3+) increased after the first year of C-IPTp implementation in all project areas in DR Congo (from 22·5% [170/755] to 31·8% [507/1596]), Madagascar (from 17·7% [101/572] to 40·8% [573/1404]), and Nigeria (from 12·7% [130/1027] to 35·2% [423/1203]), with increases between 145·6% (Madagascar) and 506·6% (Nigeria). IPTp3+ coverage increased between baseline and endline in all districts, except for Murrupula (Mozambique) and ranged between 9·6% and 533·6%. This pattern was similar in DR Congo, Madagascar, and Nigeria, and in Mozambique, the increase was lower than the other countries. Antenatal care attendance did not change or increased lightly in all study countries., Interpretation: C-IPTp was associated with an increase in IPTp uptake without reducing antenatal care attendance. The strategy might be considered for malaria control in pregnancy., Funding: UNITAID [2017-13-TIPTOP]., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Eotaxin-1 concentrations in plasma have been inversely associated with malaria exposure, malaria infection and pregnancy, but the effect of these conditions on the levels of the related chemokines eotaxin-2 and eotaxin-3 remains unknown., Methods: Eotaxin-2 and -3 concentrations were measured in 310 peripheral or placental plasma samples from pregnant and non-pregnant individuals from Papua New Guinea (malaria-endemic country) and Spain (malaria-naïve individuals) with previous data on eotaxin-1 concentrations. Correlations between eotaxin concentrations were examined with the Spearman's test. Differences in eotaxin concentrations among groups were evaluated with the Kruskal-Wallis or Mann Whitney tests. The pairwise Wilcoxon test was performed to compare eotaxin-2 concentration between peripheral and placental matched plasmas. Univariable and multivariable linear regression models were estimated to assess the association between eotaxins and Plasmodium infection or gestational age., Results: Eotaxin-2 concentrations in plasma showed a weak positive correlation with eotaxin-3 (rho = 0.35, p < 0.05) concentrations. Eotaxin-2 concentrations in the malaria-exposed non-pregnant group were significantly lower than the in the malaria-naive non-pregnant and the malaria-exposed pregnant groups. Eotaxin-3 plasma concentrations were lower in malaria-exposed than in non-exposed groups (p < 0.05), but no differences were found associated to pregnancy. Eotaxin-2 and eotaxin-3 plasma concentrations were negatively correlated with anti-Plasmodium IgG levels: PfDBL5ε-IgG (rho Eo2  = - 0.35, p = 0.005; rho Eo3  =- 0.37, p = 0.011), and eotaxin-3 was negatively correlated with PfDBL3x-IgG levels (rho Eo3  =- 0.36; p = 0.011). Negative correlations of eotaxin-2 and 3 in plasma were also observed with atypical memory B cells (rho Eo2  = - 0.37, p < 0.001; rho Eo3= - 0.28, p = 0.006), a B cell subset expanded in malaria-exposed individuals. In addition, a borderline negative association was observed between eotaxin-3 concentrations and Plasmodium infection (adjusted effect estimate, β = - 0.279, 95% CI - 0.605; 0.047, p = 0.091). Moreover, eotaxin-2 placental concentrations were significantly increased compared to peripheral concentrations in the malaria-exposed pregnant group whereas the contrary was observed in the non-exposed pregnant group (p < 0.005)., Conclusion: Although a clear epidemiological negative association is observed between eotaxins concentrations and malaria exposure and/or infection, pregnancy may alter this association for eotaxin-2. Further research is required to understand the role of these chemokines in this disease and in combination with pregnancy., (© 2022. The Author(s).)

Introduction: Intermittent preventive treatment in pregnancy with sulphadoxine pyrimethamine (IPTp) is a key malaria prevention strategy in sub-Saharan African countries. We conducted an anthropological study as part of a project aiming to evaluate a community-based approach to the delivery of IPTp (C-IPTp) through community health workers (CHWs) in four countries (the Democratic Republic of Congo, Madagascar, Mozambique and Nigeria), to understand the social context in order to identify key factors that could influence C-IPTp acceptability., Methods: A total of 796 in-depth interviews and 265 focus group discussions were undertaken between 2018 and 2021 in the four countries with pregnant women, women of reproductive age, traditional and facility-based healthcare providers, community leaders, and relatives of pregnant women. These were combined with direct observations (388) including both community-based and facility-based IPTp delivery. Grounded theory guided the overall study design and data collection, and data were analysed following a combination of content and thematic analysis., Results: A series of key factors were found to influence acceptability, delivery and uptake of C-IPTp in project countries. Cross-cutting findings include the alignment of the strategy with existing social norms surrounding pregnancy and maternal health-seeking practices, the active involvement of influential and trusted actors in implementation activities, existing and sustained trust in CHWs, the influence of husbands and other relatives in pregnant women's care-seeking decision-making, the working conditions of CHWs, pregnant women's perceptions of SP for IPTp and persistent barriers to facility-based antenatal care access., Conclusions: The findings provide evidence on the reported acceptability of C-IPTp among a wide range of actors, as well as the barriers and facilitators for delivery and uptake of the intervention. Overall, C-IPTp was accepted by the targeted communities, supporting the public health value of community-based interventions, although the barriers identified should be examined if large-scale implementation of the intervention is considered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy-parasitaemia and clinical disease-than adult women., Methods and Findings: An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian-Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value < 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value < 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data-12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia., Conclusions: In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: CM is a member of the Editorial Board of PLOS Medicine.

This qualitative study is part of a project aiming to evaluate a community-based approach to the delivery of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) through community health workers (CHWs) in four sub-Saharan African countries: the Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria. The study aimed to understand the factors that influence the anticipated acceptability of this intervention. A total of 216 in-depth interviews and 62 focus group discussions were carried out in the four country sites with pregnant women, women of reproductive age, community leaders, pregnant women's relatives, CHWs, formal and informal health providers. Grounded theory guided the study design and data collection, and content and thematic analysis was performed through a comparative lens. This paper focuses on one crosscutting theme: trust-building. Two mechanisms that underpin communities' trust in delivery of IPTp via CHWs were identified: 'perceived competence' and 'community and healthcare system integration'. Communities' perception of CHWs' competence shapes their trust in them, which suggests that CHWs' credentials should be made public and that specialised training in maternal health is required for them. Integration depends on the promotion of socially embedded practices and the involvement of formal healthcare systems in CHWs' work.

Background: Global malaria mortality estimates are hindered by the low reliability of the verbal autopsy (VA) and the clinical records, the most common sources of information used to estimate malaria-specific mortality. We aimed to determine the accuracy of these tools, as well as of the minimally invasive autopsy (MIA), a needle-based postmortem sampling method, to identify malaria-specific mortality in a large series of deceased patients from Mozambique, using complete autopsy as the gold standard., Methods: Observational study that included 264 deaths, occurring at a tertiary level hospital in Mozambique, from 1 November 2013 to 31 March 2015 (17 months-long period). Clinical data were abstracted, a computer coded VA was completed using the clinical data as source of information, and an MIA followed by a complete autopsy were performed. Screening for malaria infection was conducted postmortem to all participants using molecular and histological techniques (PCR and immunohistochemistry)., Findings: Malaria infection was considered the cause of death in 6/264 (2.3%) cases: 2/54 children (3.7%, both less than 5 years old) and 4/57 (7.0%) maternal deaths. The sensitivity and specificity of the VA, the clinical data and the MIA to identify malaria-specific deaths were 33.3% and 96.1%, 66.7% and 96.1%, and 100% and 100%, respectively. In addition, malaria was identified as a possible contributor in 14 additional patients who died of other diseases. These cases were also accurately identified by the MIA (sensitivity 82.4%, specificity 100%)., Interpretation: The high sensitivity and specificity of the MIA in identifying malaria may help to improve current estimates of malaria-specific mortality in endemic areas., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is a key malaria prevention strategy in areas with moderate to high transmission. As part of the TIPTOP (Transforming IPT for Optimal Pregnancy) project, baseline information about IPTp coverage was collected in eight districts from four sub-Saharan countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria., Methods: Cross-sectional household surveys were conducted using a multistage cluster sampling design to estimate the coverage of IPTp and antenatal care attendance. Eligible participants were women of reproductive age who had ended a pregnancy in the 12 months preceding the interview and who had resided in the selected household during at least the past 4 months of pregnancy. Coverage was calculated using percentages and 95% confidence intervals., Results: A total of 3911 women were interviewed from March to October 2018. Coverage of at least three doses of IPTp (IPTp3+) was 22% and 24% in DRC project districts; 23% and 12% in Madagascar districts; 11% and 16% in Nigeria local government areas; and 63% and 34% in Mozambique districts. In DRC, Madagascar and Nigeria, more than two-thirds of women attending at least four antenatal care visits during pregnancy received less than three doses of IPTp., Conclusions: The IPTp3+ uptake in the survey districts was far from the universal coverage. However, one of the study districts in Mozambique showed a much higher coverage of IPTp3+ than the other areas, which was also higher than the 2018 average national coverage of 41%. The reasons for the high IPTp3+ coverage in this Mozambican district are unclear and require further study., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses., Methods: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer., Results: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2., Conclusions: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children., Competing Interests: Declaration of Competing Interests The authors declare that they have no competing interests., (Copyright © 2021 The British Infection Association. All rights reserved.)

Anemia is a common condition in HIV-infected children; however, its pathophysiology and the contribution of frequent causes of anemia such as iron deficiency (ID) and malaria are poorly understood. We carried out an ancillary study on the effect of HIV on anemia as part of a case-control study on risk factors of anemia among Mozambican children aged 1-59 months with documented HIV status. Of them, 390 children were admitted to the hospital with anemia (hemoglobin [Hb] < 11 g/dL), whereas 272 children without anemia (Hb ≥ 11 g/dL) were recruited in the community. We assessed differences by HIV status in the presentation of anemia etiological factors and the effect of HIV infection on the association of each factor with anemia. Among the 99 HIV-infected and 563 uninfected children included, HIV-infected anemic children had an increased risk of undernutrition (P < 0.0001), Epstein-Barr virus infection (P < 0.0001), bacteremia (P = 0.0060), a decreased risk of malaria (P < 0.0001), and a similar risk of ID (P = 0.7371) compared with anemic-uninfected children. HIV-infected children were significantly less likely to have anemia associated with Plasmodium falciparum hyperparasitemia (P = 0.0444) and had a lower prevalence of parasitemia in the bone marrow (BM) (P < 0.0001) than anemic-uninfected children. Levels of BM erythropoiesis and dyserythropoiesis were comparable between groups. These findings suggest that the pathophysiology of anemia among HIV-infected malaria-exposed children is not related to HIV-specific effects. For unclear reasons, HIV-infected children had reduced risk of malaria infection, whereas ID prevalence was comparable in HIV-infected and uninfected children, suggesting that iron supplementation recommendations should not be different in HIV-infected children.

Objectives: This retrospective analysis performed in Manhiça, Southern Mozambique, aimed to describe the frequency of post-malarial anemia (measured as a decrease of hematocrit ≥10%) and the need for blood transfusions in children with severe malaria treated with intravenous quinine or parenteral artesunate., Methods: All children <15 years admitted with a parasitologically-confirmed diagnosis of malaria from 1 st January 2003 to 31 st December 2017, alive at hospital discharge, and with at least one measurement of hematocrit within 28 days after hospital discharge, detected by passive case detection, were included., Results: The overall prevalence of post-malarial anemia observed in the study was 23.13%, with an estimated incidence rate of 288.84 episodes/1,000 children-month at risk in the follow-up period (28 days after discharge). There were no differences between treatment groups, although the study showed a higher association between blood transfusions and artesunate treatment., Conclusions: In this setting, children with severe malaria frequently present a meaningful decrease of hematocrit (>=10%) in the first weeks after their episode, sometimes requiring blood transfusions. Because of the high underlying prevalence of anemia in malaria-endemic settings, all children with severe malaria need to be actively followed up, irrespective of the treatment received., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The immune status of women changes during and after pregnancy, differs between blood compartments at delivery and is affected by environmental factors particularly in tropical areas endemic for multiple infections. We quantified the plasma concentration of a set of thirty-one T H 1, T H 2, T H 17 and regulatory cytokines, pro-inflammatory and anti-inflammatory cytokines and chemokines, and growth factors (altogether biomarkers), in a cohort of 540 pregnant women from five malaria-endemic tropical countries. Samples were collected at recruitment (first antenatal visit), delivery (periphery, cord and placenta) and postpartum, allowing a longitudinal analysis. We found the lowest concentration of biomarkers at recruitment and the highest at postpartum, with few exceptions. Among them, IL-6, HGF and TGF-β had the highest levels at delivery, and even higher concentrations in the placenta compared to peripheral blood. Placental concentrations were generally higher than peripheral, except for eotaxin that was lower. We also compared plasma biomarker concentrations between the tropical cohort and a control group from Spain at delivery, presenting overall higher biomarker levels the tropical cohort, particularly pro-inflammatory cytokines and growth factors. Only IL-6 presented lower levels in the tropical group. Moreover, a principal component analysis of biomarker concentrations at delivery showed that women from Spain grouped more homogenously, and that IL-6 and IL-8 clustered together in the tropical cohort but not in the Spanish one. Plasma cytokine concentrations correlated with Plasmodium antibody levels at postpartum but not during pregnancy. This basal profiling of immune mediators over gestation and in different compartments at delivery is important to subsequently understand response to infections and clinical outcomes in mothers and infants in tropical areas., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Women attending antenatal care (ANC) are a generally healthy, easy-access population, contributing valuable data for infectious disease surveillance at the community level. ANC-based malaria surveillance would provide a routine measure of the malaria burden in pregnancy, which countries lack, whilst potentially improving pregnancy outcomes. It could also offer contemporary information on temporal trends and the geographic distribution of malaria burden as well as intervention coverage in the population to guide resource allocation and to assess progress towards elimination. Here, we review the factors underlying the relationship between Plasmodium falciparum in pregnancy and in the community, and outline strengths and limitations of an ANC-based surveillance in sub-Saharan Africa, its potential role within wider malaria surveillance systems, and subsequent programmatic applications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mozambique has historically been one of the countries with the highest malaria burden in the world. Starting in the 1960s, malaria control efforts were intensified in the southern region of the country, especially in Maputo city and Maputo province, to aid regional initiatives aimed to eliminate malaria in South Africa and eSwatini. Despite significant reductions in malaria prevalence, elimination was never achieved. Following the World Health Organization's renewed vision of a malaria-free-world, and considering the achievements from the past, the Mozambican National Malaria Control Programme (NMCP) embarked on the development and implementation of a strategic plan to accelerate from malaria control to malaria elimination in southern Mozambique. An initial partnership, supported by the Bill and Melinda Gates Foundation and the La Caixa Foundation, led to the creation of the Mozambican Alliance Towards the Elimination of Malaria (MALTEM) and the Malaria Technical and Advisory Committee (MTAC) to promote national ownership and partner coordination to work towards the goal of malaria elimination in local and cross-border initiatives. Surveillance systems to generate epidemiological and entomological intelligence to inform the malaria control strategies were strengthened, and an impact and feasibility assessment of various interventions aimed to interrupt malaria transmission were conducted in Magude district (Maputo Province) through the "Magude Project". The primary aim of this project was to generate evidence to inform malaria elimination strategies for southern Mozambique. The goal of malaria elimination in areas of low transmission intensity is now included in the national malaria strategic plan for 2017-22 and the NMCP and its partners have started to work towards this goal while evidence continues to be generated to move the national elimination agenda forward.

Background: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine., Objectives: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials., Selection Criteria: Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen., Data Collection and Analysis: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting., Main Results: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I 2 statistic = 0%; moderate-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; moderate-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; moderate-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence)., Authors' Conclusions: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.

Malaria in pregnancy threatens birth outcomes and the health of women and their newborns. This is also the case in low transmission areas, such as Colombia, where Plasmodium vivax is the dominant parasite species. Within the Colombian health system, which underwent major reforms in the 90s, malaria treatment is provided free of charge to patients. However, patients still incur costs, such as transportation and value of time lost due to the disease. We estimated such costs among 40 pregnant women with clinical malaria (30% Plasmodium falciparum, 70% Plasmodium vivax) in the municipality of Tierralta, Northern Colombia. In a cross-sectional study, women were interviewed after an outpatient or inpatient laboratory confirmed malaria episode. Women were asked to report all types of cost incurred before (including prevention), during and immediately after the contact with the health facility. Median total cost was over 16US$ for an outpatient visit, rising to nearly 30US$ if other treatments were sought before reaching the health facility. Median total inpatient cost was 26US$ or 54US$ depending on whether costs incurred prior to admission were excluded or included. For both outpatients and inpatients, direct costs were largely due to transportation and indirect costs constituted the largest share of total costs. Estimated costs are likely to represent only one of the constraints that women face when seeking treatment in an area characterized, at the time of the study, by armed conflict, displacement, and high vulnerability of indigenous women, the group at highest risk of malaria. Importantly, the Colombian peace process, which culminated with the cease-fire in August 2016, may have a positive impact on achieving universal access to healthcare in conflict areas. The current study can inform malaria elimination initiatives in Colombia.

Raquel Gonzalez and colleagues highlight an urgent need to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis.

Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied.

Background: Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants. We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes., Methods and Findings: In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age. Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age. No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP. Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed. Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups. Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group. Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%)., Conclusions: No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes. The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared to those in the SP group may deserve further studies., Trial Registration: ClinicalTrials.gov NCT00811421.

Background: Anaemia is an increasingly recognized health problem in Africa, particularly in infants and pregnant women. Although malaria is known to be the main risk factor of anaemia in both groups, the consequences of maternal factors, particularly malaria in pregnancy (MiP), on infant haemoglobin (Hb) concentrations during the first months of life are still unclear., Methods: We followed-up a cohort of 1005 Beninese pregnant women from the beginning of pregnancy until delivery. A subsample composed of the first 400 offspring of these women were selected at birth and followed until the first year of life. Placental histology and blood smear at 1st clinical antenatal visit (ANC), 2nd ANC and delivery were used to assess malaria during pregnancy. Infant Hb concentrations were measured at birth, 6, 9 and 12 months of age. A mixed multi-level model was used to assess the association between MiP and infant Hb variations during the first 12 months of life., Results: Placental malaria (difference mean [dm] = - 2.8 g/L, 95% CI [-5.3, -0.3], P = 0.03) and maternal peripheral parasitaemia at delivery (dm = - 4.6 g/L, 95% CI [-7.9, -1.3], P = 0.007) were the main maternal factors significantly associated with infant Hb concentrations during the first year of life. Poor maternal nutritional status and malaria infection during infancy were also significantly associated with a decrease in infant Hb., Conclusion: Antimalarial control and nutritional interventions before and during pregnancy should be reinforced to reduce specifically the incidence of infant anaemia, particularly in Sub-Saharan countries.

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy., Methods: The cost-effectiveness of 2-dose IPTp-mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken., Results: For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$ (95%CI 230.99; 244.57), depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet., Conclusions: Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price., Trials Registration: ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440.

Pregnancy triggers immunological changes aimed to tolerate the fetus. However, it has not been properly addressed whether similar changes occur in tropical areas with high infection pressure and whether these changes render women more susceptible to infectious diseases. We compared the frequencies of T cell subsets, including regulatory T cells, in pregnant and nonpregnant women from Papua New Guinea, a high malaria transmission area, and from Spain, a malaria-free country. We also assessed the relationship among these cellular subsets, malaria infection, and delivery outcomes. CD4(+)FOXP3(+)CD127(low) T cells (Tregs) were decreased in pregnant women in both countries but were not associated with malaria infection or poor delivery outcomes. An expansion of IFN-γ-producing cells and intracytoplasmic IFN-γ levels was found in pregnant compared with nonpregnant women only in Papua New Guinea. Increased CD4(+)IL-10(+)IFN-γ(+) frequencies and Treg-IFN-γ production were found in women with current Plasmodium falciparum infection. Higher CD4(+)IL-10(-)IFN-γ(+) T cells frequencies and production of proinflammatory cytokines (including TNF and IL-2) at recruitment (first antenatal visit) had a protective association with birth weight and future (delivery) P. falciparum infection, respectively. Higher intracellular IL-10 levels in T cells had a protective association with future P. falciparum infection and hemoglobin levels at delivery. The protective associations were found also with nonmalaria-specific T cell responses. Treg frequencies positively correlated with plasma eotaxin concentrations, but this subset did not express eotaxin receptor CCR3. Thus, an activated immune system during pregnancy might contribute to protection against malaria during pregnancy and poor delivery outcomes., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs)., Methods and Findings: A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p=0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p=0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p=0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p=0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p=0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis., Conclusions: An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs., Trial Registration: ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary.

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women., Methods and Findings: A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86-1.22; p=0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51-0.96]; p=0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85-0.99]; p=0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52-0.88]; p=0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78-0.95]; p=0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment., Conclusions: Women taking MQ IPTp (15 mg/kg) in the context of long lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy., Trial Registration: ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001429343 Please see later in the article for the Editors' Summary.

Pregnancy triggers immunological changes aimed to tolerate the fetus, but its impact on B lymphocytes is poorly understood. In addition, exposure to the Plasmodium parasite is associated with altered distribution of peripheral memory B cell (MBC) subsets. To study the combined impact of high malaria exposure and pregnancy in B cell subpopulations, we analyzed PBMCs from pregnant and nonpregnant individuals from a malaria-nonendemic country (Spain) and from a high malaria-endemic country (Papua New Guinea). In the malaria-naive cohorts, pregnancy was associated with a significant expansion of all switched (IgD(-)) MBC and a decrease of naive B cells. Malaria-exposed women had more atypical MBC and fewer marginal zone-like MBC, and their levels correlated with both Plasmodium vivax- and Plasmodium falciparum-specific plasma IgG levels. Classical but not atypical MBC were increased in P. falciparum infections. Moreover, active atypical MBC positively correlated with proinflammatory cytokine plasma concentrations and had lower surface IgG levels than the average. Decreased plasma eotaxin (CCL11) levels were associated with pregnancy and malaria exposure and also correlated with B cell subset frequencies. Additionally, active atypical and active classical MBC expressed higher levels of eotaxin receptor CCR3 than the other B cell subsets, suggesting a chemotactic effect of eotaxin on these B cell subsets. These findings are important to understand immunity to infections like malaria that result in negative outcomes for both the mother and the newborn and may have important implications on vaccine development., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Background: Control of malaria in pregnant women is still a major challenge as it constitutes an important cause of maternal and neonatal mortality. Mefloquine (MQ) has been used for malaria chemoprophylaxis in non-immune travellers for several decades and it constitutes a potential candidate for intermittent preventive treatment in pregnant women (IPTp)., Methods: The safety of MQ, including its safety in pregnancy, is controversial and a continuing subject of debate. Published studies which evaluated the use of MQ for malaria prevention or treatment in pregnant women and which reported data on drug tolerability and/or pregnancy outcomes have been reviewed systematically., Results: Eighteen articles fitted the inclusion criteria, only one study was double-blind and placebo controlled. No differences were found in the risk of adverse pregnancy outcomes in women exposed to MQ compared to those exposed to other anti-malarials or to the general population. MQ combined with artesunate seems to be better tolerated than standard quinine therapy for treatment of non-severe falciparum malaria, but a MQ loading dose (10 mg/kg) is associated with more dizziness compared with placebo. When used for IPTp, MQ (15 mg/kg) may have more side effects than sulphadoxine- pyrimethamine., Conclusions: In the published literature there are no indications that MQ use during pregnancy carries an increased risk for the foetus. Ideally, the use of MQ to prevent malaria should be based on a risk-benefit analysis of adverse effects against the risk of acquiring the infection. For this purpose double-blinded randomized controlled trials in African pregnant women are much needed.

Background: Intermittent Preventive Treatment (IPTp) and insecticide treated nets (ITNs) are recommended malaria in pregnancy preventive interventions in sub-Saharan Africa. Despite their cost-effectiveness and seemingly straight-forward delivery mechanism, their uptake remains low. We aimed at describing perceptions of pregnant women regarding malaria and the recommended prevention interventions to understand barriers to uptake and help to improve their effectiveness., Methods and Findings: We used mixed methods to collect data among 85 pregnant women from a rural area of Southern Mozambique. Information was obtained through observations, in-depth interviews, and focused ethnographic exercises (Free-listing and Pairwise comparisons). Thematic analysis was performed on qualitative data. Data from focused ethnographic exercises were summarized into frequency distribution tables and matrices. Malaria was not viewed as a threat to pregnancy. Participants were not fully aware of malaria- associated adverse maternal and birth outcomes. ITNs were the most preferred and used malaria preventive intervention, while IPTp fell between second and third. Indoor Residual Spraying (IRS) was the least preferred intervention., Conclusions: Low awareness of the risks and adverse consequences of malaria in pregnancy did not seem to affect acceptability or uptake to the different malaria preventive interventions in the same manner. Perceived convenience, the delivery approach, and type of provider were the key factors. Pregnant women, through antenatal care (ANC) services, can be the vehicles of ITN distribution in the communities to maximise overall ITN coverage. There is a need to improve knowledge about neonatal health and malaria to improve uptake of interventions delivered through channels other than the health facility.

Introduction: Malaria continues to represent a huge global health burden on the most vulnerable populations. The Intermittent Preventive Treatment (IPT) strategy has been shown to be an efficacious intervention in preventing most of the deleterious effects of malaria in pregnant women and infants. Yet, the effectiveness of the IPT strategy may be impaired by the increasing resistance to sulfadoxine-pyrimethamine (SP), and the scarcity of alternative antimalarial drugs., Areas Covered: This review examines all the available information on IPT, in an aim to provide the scientific community with a framework to understand the benefits and limitations of this malaria control strategy. It includes the understanding of the historical background of the IPT strategy, the drug's mechanisms of actions, updated information on current available evidence, the implications of drug resistance and choice of alternative drugs, and a comprehensive discussion on the perspectives of IPT for malaria control in pregnant women and infants., Expert Opinion: IPT in pregnancy and infants is a cost-effective strategy that can contribute significantly to the control of malaria in endemic areas. Monitoring its effectiveness will allow tracking of progress, evaluation of the adequacy of currently used drugs and will highlight the eventual need for new therapies or alternative interventions.

Background: Severe malaria is difficult to differentiate from other forms of malaria or other infections with similar symptoms. Any parameter associated to malaria-attributable severe disease could help to improve severe malaria diagnosis., Methodology: This study assessed the relation between erythropoietin (EPO) and malaria-attributable severe disease in an area of Mozambique with moderate malaria transmission. 211 children <5 years, recruited at Manhiça District Hospital or in the surrounding villages, were included in one of the following groups: severe malaria (SM, n = 44), hospital malaria without severity (HM, n = 49), uncomplicated malaria (UM, n = 47), invasive bacterial infection without malaria parasites (IBI, n = 39) and healthy community controls (C, n = 32). Malaria was diagnosed by microscopy and IBI by blood/cerebrospinal fluid culture., Principal Findings: Mean EPO concentration in the control group was 20.95 U/l (SD = 2.96 U/l). Values in this group were lower when compared to each of the clinical groups (p = 0.026 C versus UM, p<0.001 C vs HM, p<0.001 C vs SM and p<0.001 C vs IBI). In the 3 malaria groups, values increased with severity [mean = 40.82 U/l (SD = 4.07 U/l), 125.91 U/l (SD = 4.99U/l) and 320.87 U/l (SD = 5.91U/l) for UM, HM and SM, respectively, p<0.001]. The IBI group [mean = 101.75 U/l (SD = 4.12 U/l)] presented lower values than the SM one (p = 0.002). In spite of the differences, values overlapped between study groups and EPO levels were only associated to hemoglobin. Hemoglobin means of the clinical groups were 93.98 g/dl (SD = 14.77 g/dl) for UM, 75.96 g/dl (SD = 16.48 g/dl) for HM, 64.34 g/dl (SD = 22.99 g/dl) for SM and 75.67 g/dl (SD = 16.58 g/dl) for IBI., Conclusions: Although EPO levels increase according to malaria severity and are higher in severe malaria than in bacteremia, the utility of EPO to distinguish malaria-attributable severe disease is limited due to the overlap of values between the study groups and the main role of hemoglobin in the expression of EPO.

Background: Malaria in pregnancy is a public health problem for endemic countries. Economic evaluations of malaria preventive strategies in pregnancy are needed to guide health policies., Methods and Findings: This analysis was carried out in the context of a trial of malaria intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP), where both intervention groups received an insecticide treated net through the antenatal clinic (ANC) in Mozambique. The cost-effectiveness of IPTp-SP on maternal clinical malaria and neonatal survival was estimated. Correlation and threshold analyses were undertaken to assess the main factors affecting the economic outcomes and the cut-off values beyond which the intervention is no longer cost-effective. In 2007 US$, the incremental cost-effectiveness ratio (ICER) for maternal malaria was 41.46 US$ (95% CI 20.5, 96.7) per disability-adjusted life-year (DALY) averted. The ICER per DALY averted due to the reduction in neonatal mortality was 1.08 US$ (95% CI 0.43, 3.48). The ICER including both the effect on the mother and on the newborn was 1.02 US$ (95% CI 0.42, 3.21) per DALY averted. Efficacy was the main factor affecting the economic evaluation of IPTp-SP. The intervention remained cost-effective with an increase in drug cost per dose up to 11 times in the case of maternal malaria and 183 times in the case of neonatal mortality., Conclusions: IPTp-SP was highly cost-effective for both prevention of maternal malaria and reduction of neonatal mortality in Mozambique. These findings are likely to hold for other settings where IPTp-SP is implemented through ANC visits. The intervention remained cost-effective even with a significant increase in drug and other intervention costs. Improvements in the protective efficacy of the intervention would increase its cost-effectiveness. Provision of IPTp with a more effective, although more expensive drug than SP may still remain a cost-effective public health measure to prevent malaria in pregnancy., Trial Registration: ClinicalTrials.gov NCT00209781.

Background: Intermittent preventive treatment in infants (IPTi) has been shown to decrease clinical malaria by approximately 30% in the first year of life and is a promising malaria control strategy for Sub-Saharan Africa which can be delivered alongside the Expanded Programme on Immunisation (EPI). To date, there have been limited data on the cost-effectiveness of this strategy using sulfadoxine pyrimethamine (SP) and no published data on cost-effectiveness using other antimalarials., Methods: We analysed data from 5 countries in sub-Saharan Africa using a total of 5 different IPTi drug regimens; SP, mefloquine (MQ), 3 days of chlorproguanil-dapsone (CD), SP plus 3 days of artesunate (SP-AS3) and 3 days of amodiaquine-artesunate (AQ3-AS3).The cost per malaria episode averted and cost per Disability-Adjusted Life-Year (DALY) averted were modeled using both trial specific protective efficacy (PE) for all IPTi drugs and a pooled PE for IPTi with SP, malaria incidence, an estimated malaria case fatality rate of 1.57%, IPTi delivery costs and country specific provider and household malaria treatment costs., Findings: In sites where IPTi had a significant effect on reducing malaria, the cost per episode averted for IPTi-SP was very low, USD 1.36-4.03 based on trial specific data and USD 0.68-2.27 based on the pooled analysis. For IPTi using alternative antimalarials, the lowest cost per case averted was for AQ3-AS3 in western Kenya (USD 4.62) and the highest was for MQ in Korowge, Tanzania (USD 18.56). Where efficacious, based only on intervention costs, IPTi was shown to be cost effective in all the sites and highly cost-effective in all but one of the sites, ranging from USD 2.90 (Ifakara, Tanzania with SP) to USD 39.63 (Korogwe, Tanzania with MQ) per DALY averted. In addition, IPTi reduced health system costs and showed significant savings to households from malaria cases averted. A threshold analysis showed that there is room for the IPTi-efficacy to fall and still remain highly cost effective in all sites where IPTi had a statistically significant effect on clinical malaria., Conclusions: IPTi delivered alongside the EPI is a highly cost effective intervention against clinical malaria with a range of drugs in a range of malaria transmission settings. Where IPTi did not have a statistically significant impact on malaria, generally in low transmission sites, it was not cost effective.

Importance of the Field: Malaria infection during pregnancy is a major public health problem worldwide, with 50 million pregnancies exposed to the infection every year. Approximately 25,000 maternal deaths and between 75,000 and 200,000 infant deaths could be prevented each year by effective malaria control in pregnancy. Antimalarial drug treatment and prevention has been hampered by the appearance of drug resistance, which has been a particular problem in pregnancy due to the inherent safety issues., Areas Covered in This Review: New antimalarial drugs and combinations are being studied but there is not yet sufficient information on their efficacy or, more importantly, on their safety in pregnancy. This article provides an overview of the relevance of the topic and reviews the current antimalarial drugs recommended for pregnancy, as well as the guidelines for both treatment and prevention in women living in endemic areas and for travellers., What the Reader Will Gain: Updated information on the drugs currently used for malaria treatment and prevention in pregnancy, including new drugs under development, is provided. The gaps on efficacy and safety information for use during pregnancy are also discussed., Take Home Message: Prevention and case management of malaria during pregnancy is based on risk-benefit criteria and poses one of the greatest challenges to current malaria control.

Background: In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association., Methods: In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP., Findings: There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136). There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041). Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039). IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%); p = 0.024]., Conclusions: Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health., Trial Registration: ClinicalTrials.gov NCT00209781.

Background: Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children., Methodology/principal Findings: The non-inferiority of DHA-PQP versus artemether-lumefantrine (AL) in children 6-59 months old with uncomplicated P. falciparum malaria was tested in five African countries (Burkina Faso, Kenya, Mozambique, Uganda and Zambia). Patients were randomised (2:1) to receive either DHA-PQP or AL. Non-inferiority was assessed using a margin of -5% for the lower limit of the one-sided 97.5% confidence interval on the treatment difference (DHA-PQP vs. AL) of the day 28 polymerase chain reaction (PCR) corrected cure rate. Efficacy analysis was performed in several populations, and two of them are presented here: intention-to-treat (ITT) and enlarged per-protocol (ePP). 1553 children were randomised, 1039 receiving DHA-PQP and 514 AL. The PCR-corrected day 28 cure rate was 90.4% (ITT) and 94.7% (ePP) in the DHA-PQP group, and 90.0% (ITT) and 95.3% (ePP) in the AL group. The lower limits of the one-sided 97.5% CI of the difference between the two treatments were -2.80% and -2.96%, in the ITT and ePP populations, respectively. In the ITT population, the Kaplan-Meier estimate of the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%-15.76%) for DHA-PQP vs 24.00% (95% CI: 20.11%-27.88%) for AL (p<0.0001)., Conclusions/significance: DHA-PQP is as efficacious as AL in treating uncomplicated malaria in African children from different endemicity settings, and shows a comparable safety profile. The occurrence of new infections within the 42-day follow up was significantly lower in the DHA-PQP group, indicating a longer post-treatment prophylactic effect., Trial Registration: Controlled-trials.com ISRCTN16263443.

Objectives: To describe the prevalence, aetiology and prognostic implications of coexisting invasive bacterial disease in children admitted with severe malaria in a rural Mozambican Hospital., Methods: Retrospective study of data systematically collected from June 2003 to May 2007 in a rural Mozambican hospital, from all children younger than 5 years admitted with severe malaria., Results: Seven thousand and forty-three children were admitted with a diagnosis of malaria. 25.2% fulfilled the criteria for severe malaria. 5.4% of the children with severe malaria and valid blood culture results had a concomitant bacteraemia. Case fatality rates of severe malaria cases rose steeply when bacteraemia was also present (from 4.0% to 22.0%, P < 0.0001), and bacteraemia was an independent risk factor for death among severe malaria patients (adjusted OR 6.2, 95% CI 2.8-13.7, P = 0.0001). Streptococcus pneumoniae, Gram-negative bacteria, Staphilococcus aureus and non-typhoid Salmonella (NTS) were the most frequently isolated microorganisms among severe malaria cases. Their frequency and associated case fatality rates (CFR) varied according to age and to syndromic presentation. Streptococcus pneumoniae had a relatively low CFR, but was consistently associated with severe malaria syndromes, or anaemia severity groups. No clear-cut relationship between malarial anaemia and NTS bacteraemia was found., Conclusions: The coexistence of malaria and invasive bacterial infections is a frequent and life-threatening condition in many endemic African settings. In Mozambique, S. pneumoniae is the leading pathogen in this interaction, possibly as a consequence of the high HIV prevalence in the area. Measures directed at reducing the burden of both those infections are urgently needed to reduce child mortality in Africa.

Background: A key to making insecticide-treated nets (ITNs) a long-term, sustainable solution to the spread of malaria is understanding what drives their purchase and use. Few studies have analysed the determinants of demand for bed nets for malaria prevention at the household level, and in particular, how demand for nets compares with demand for other mosquito prevention methods., Methods: This study uses a household survey to assess the determinants of demand for bed nets in an area of endemic malaria transmission in rural, southern Mozambique. The study looks at willingness to pay (WTP) for bed nets, net ownership, usage, and past purchase behaviour, alongside expenditure and frequency of use of alternate methods for malaria prevention., Results: While overall net ownership in the sample is low, the evidence fails to suggest that poorer households are less likely to own bed nets, when controlling for covariates, nor does the likelihood of receiving a free net depend on socioeconomic status (SES). Formal schooling and market knowledge seem to indicate higher average willingness to pay, while use of alternate methods for malaria prevention, and receipt of Indoor Residual Spraying (IRS) are found to decrease demand for bed nets., Conclusion: For long-term sustainability of ITNs to be realized, results suggest that either full or partial subsidies may be necessary in some contexts to encourage households to obtain and use nets. Given the possible substitution effects of combined malaria control interventions, and the danger of not taking into consideration household preferences for malaria prevention, successful malaria control campaigns should invest a portion of their funds towards educating recipients of IRS and users of other preventive methods on the importance of net use even in the absence of mosquitoes.

Background: Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets (ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of their combined use., Methods: 1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC) visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess the safety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight., Findings: Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence at delivery (RR, 0.92 [95% CI, 0.79-1.08]), low birth weight (RR, 0.99 [95% CI, 0.70-1.39]), or overall placental infection (p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40-61.20]; p = 0.020) in the incidence of clinical malaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p<0.001), and of actively infected placentas (7.04% vs 13.60%) (p = 0.002). There was a reduction in severe anaemia at delivery of borderline statistical significance (p = 0.055). These effects were not modified by gravidity or HIV status. Reported ITN's use was more than 90% in both groups., Conclusions: Two-dose SP was associated with a reduction in some indicators, but these were not translated to significant improvement in other maternal or birth outcomes. The use of ITNs during pregnancy may reduce the need to administer IPTp. ITNs should be part of the ANC package in sub-Saharan Africa., Trial Registration: ClinicalTrials.gov NCT00209781.

Background: There is a widespread notion, based on limited information, that in areas of stable malaria transmission most pregnant women with Plasmodium falciparum infection are asymptomatic. This study aim to characterize the clinical presentation of malaria in African pregnant women and to evaluate the adequacy of case management based on clinical complaints., Methods: A hospital-based descriptive study between August 2003 and November 2005 was conducted at the maternity clinic of a rural hospital in Mozambique. All women attending the maternity clinic were invited to participate. A total of 2,330 women made 3,437 eligible visits, 3129 were analysed, the remainder were excluded because diagnostic results were unavailable or they were repeat visits. Women gave a standardized clinical history and had a medical exam. Malaria parasitaemia and haematocrit in capillary blood was determined for all women with signs or symptoms compatible with malaria including: presence and history of fever, arthromyalgias, headache, history of convulsions and pallor. Outcome measure was association of malaria symptoms or signs with positive blood slide for malaria parasitaemia., Results: In 77.4% of visits pregnant women had symptoms suggestive of malaria; 23% (708/3129) were in the first trimester. Malaria parasitaemia was confirmed in 26.9% (842/3129) of visits. Headache, arthromyalgias and history of fever were the most common symptoms (86.5%, 74.8% and 65.4%) presented, but their positive predictive values for malaria parasitaemia were low [28% (27-30), 29% (28-31), and 33% (31-35), respectively]., Conclusion: Symptoms suggestive of malaria were very frequent among pregnant women attending a rural maternity clinic in an area of stable malaria transmission. However, less than a third of them were parasitaemic. In the absence of microscopy or rapid diagnostic tests, a large proportion of women, including those in the first trimester of gestation, would be unnecessarily receiving antimalarial drugs, often those with unknown safety profiles for pregnancy. Accessibility to malaria diagnostic tools needs to be improved for pregnant women and drugs with a safety profile in all gestational ages are urgently needed.

BackgroundArtesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.MethodsIndividual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.ResultsForty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P

Chronic immune activation from persistent malaria infections can induce immunophenotypic changes associated with T-cell exhaustion. However, associations between T and B cells during chronic exposure remain undefined. We analyzed peripheral blood mononuclear cells from malaria-exposed pregnant women from Papua New Guinea and Spanish malaria-naïve individuals using flow cytometry to profile T-cell exhaustion markers phenotypically. T-cell lineage (CD3, CD4, and CD8), inhibitory (PD1, TIM3, LAG3, CTLA4, and 2B4), and senescence (CD28-) markers were assessed. Dimensionality reduction methods revealed increased PD1, TIM3, and LAG3 expression in malaria-exposed individuals. Manual gating confirmed significantly higher frequencies of PD1+CD4+ and CD4+, CD8+, and double-negative (DN) T cells expressing TIM3 in malaria-exposed individuals. Increased frequencies of T cells co-expressing multiple markers were also found in malaria-exposed individuals. T-cell data were analyzed with B-cell populations from a previous study where we reported an alteration of B-cell subsets, including increased frequencies of atypical memory B cells (aMBC) and reduction in marginal zone (MZ-like) B cells during malaria exposure. Frequencies of aMBC subsets and MZ-like B cells expressing CD95+ had significant positive correlations with CD28+PD1+TIM3+CD4+ and DN T cells and CD28+TIM3+2B4+CD8+ T cells. Frequencies of aMBC, known to associate with malaria anemia, were inversely correlated with hemoglobin levels in malaria-exposed women. Similarly, inverse correlations with hemoglobin levels were found for TIM3+CD8+ and CD28+PD1+TIM3+CD4+ T cells. Our findings provide further insights into the effects of chronic malaria exposure on circulating B- and T-cell populations, which could impact immunity and responses to vaccination. Chronic malaria exposure is associated with increased frequencies of T cells with inhibitory markers and expanded atypical memory B cells, which were found to positively correlate with each other. T cells with inhibitory markers and atypical memory B cells had positive correlations with malaria antibodies and negative correlations with hemoglobin levels in the chronically exposed individuals. T-cell subsets with inhibitory markers and B-cell subsets were able to distinguish malaria exposed versus non-exposed individuals using dimensionality reduction analysis. Graphical Abstract [ABSTRACT FROM AUTHOR]