John Lusingu

IT University of Copenhagen, København, Capital Region, Denmark

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Publications (62)566.88 Total impact

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    ABSTRACT: Severe malaria syndromes are precipitated by Plasmodium falciparum parasites binding to endothelial receptors on the vascular lining. This binding is mediated by members of the highly variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We have previously identified a subset of PfEMP1 associated with severe malaria and found that the receptor for these PfEMP1 variants is Endothelial Protein C Receptor (EPCR). The binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDR) of the subtypes α1.1 and α1.4-8 In this study, we investigated the acquisition of anti-CIDR antibodies using plasma samples collected in four study villages with different malaria transmission intensities in north-eastern Tanzania during a period with a decline in malaria transmission. We show that individuals exposed to high levels of malaria transmission acquire antibodies to EPCR-binding CIDR domains early in life and that these antibodies are acquired more rapidly than antibodies to other CIDR domains. The rate by which antibodies to EPCR-binding CIDR domains are acquired in endemic population is determined by the malaria transmission intensity and on a population level the antibodies are rapidly lost if transmission is interrupted. This indicates that a sustained exposure is required to maintain the production of the antibodies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and immunity 05/2015; DOI:10.1128/IAI.00271-15 · 4.16 Impact Factor
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    ABSTRACT: Summary Background The effi cacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the fi nal results from the same trial, including the effi cacy of a booster dose. Methods From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at fi rst vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modifi ed intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this fi nal analysis, we present data for the effi cacy of the booster on the occurrence of malaria. Vaccine effi cacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. Findings 8922 children and 6537 young infants were included in the modifi ed intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39–50) and young infants for 38 months (34–41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case defi nition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8–40·5) and 7396 occurred in the R3C group (28·3%, 23·3–32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, –23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case defi nition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9–31·5) and 5444 occurred in the R3C group (18·3%, 11·7–24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI –9·4 to 37·5) and 104 in the R3C group (10·3%, –17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387–2186) in the R3R group and 1363 per 1000 children (995–1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose. Effi cacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other eff ective control measures, especially in areas of high transmission.
    The Lancet 04/2015; 385:1581. · 45.22 Impact Factor
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    ABSTRACT: We aimed to determine the current prevalence of four P. falciparum candidate artemisinin resistance biomarkers L263E, E431K, A623E, and S769N in the pfatpase6 gene in a high transmission area in Tanzania in a retrospective cross sectional study using 154 archived samples collected from three previous malaria studies in 2010, 2011 and 2013. Mutations in pfatpase6 gene were detected in parasite DNA isolated from Dried Blood Spots by using PCR-RFLP. We observed overall allelic frequencies for L263E, E431K, A623E, and S769N to be 5.8% (9/154), 16.2% (25/154), 0.0% (0/154), and 3.9% (6/154). The L263E mutation was not detected in 2010 but occurred at 3.9% and 2.6% in 2011 and 2013 respectively. The L263E mutation showed a significant change of frequency between 2010 and 2011, but not between 2011 and 2013 (íµí±ƒ < 0.05). Frequency of E431K was highest of all without any clear trend whereas S769N increased from 2.2% in 2010 to 3.6% in 2011 and 5.1% in 2013. A623E mutation was not detected. The worrisome detection and the increase in the frequency of S769N and other mutations calls for urgent assessment of temporal changes of known artemisinin biomarkers in association with in vivo ACT efficacy.
    Malaria Research and Treatment 01/2015; 2015(1):7. DOI:10.1155/2015/279028
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    ABSTRACT: The PfEMP1 family of surface proteins is central for Plasmodium falciparum virulence and must retain the ability to bind to host receptors while also diversifying to aid immune evasion. The interaction between CIDRα1 domains of PfEMP1 and endothelial protein C receptor (EPCR) is associated with severe childhood malaria. We combine crystal structures of CIDRα1:EPCR complexes with analysis of 885 CIDRα1 sequences, showing that the EPCR-binding surfaces of CIDRα1 domains are conserved in shape and bonding potential, despite dramatic sequence diversity. Additionally, these domains mimic features of the natural EPCR ligand and can block this ligand interaction. Using peptides corresponding to the EPCR-binding region, antibodies can be purified from individuals in malaria-endemic regions that block EPCR binding of diverse CIDRα1 variants. This highlights the extent to which such a surface protein family can diversify while maintaining ligand-binding capacity and identifies features that should be mimicked in immunogens to prevent EPCR binding. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Host & Microbe 12/2014; 17(1). DOI:10.1016/j.chom.2014.11.007 · 12.19 Impact Factor
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    ABSTRACT: Although the burden of malaria in many parts of Tanzania has declined, the proportion of children with fever has not changed. This situation underscores the need to explore the possible causes of febrile episodes in patients presenting with symptoms at the Korogwe District Hospital (KDH).
    PLoS ONE 08/2014; 9(8):e104197. DOI:10.1371/journal.pone.0104197 · 3.53 Impact Factor
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    ABSTRACT: Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using samples collected during 2004-2008, we investigated the evolutionary origin of the A581G mutation by characterizing microsatellite diversity flanking Pfdhps triple-mutant (437G+540E+581G) alleles from 3 locations in eastern Africa and comparing it with double-mutant (437G+540E) alleles from the same area. In Ethiopia, both alleles derived from 1 lineage that was distinct from those in Uganda and Tanzania. Uganda and Tanzania triple mutants derived from the previously characterized southeastern Africa double-mutant lineage. The A581G mutation has occurred multiple times on local Pfdhps double-mutant backgrounds; however, a novel microsatellite allele incorporated into the Tanzania lineage since 2004 illustrates the local expansion of emergent triple-mutant lineages.
    Emerging infectious diseases 08/2014; 20(8):1280-6. DOI:10.3201/eid2008.131897 · 7.33 Impact Factor
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    ABSTRACT: Abstract Background:A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. Methods and Findings:6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p,0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Postvaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residualsp,0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from21 to 49, respectively; corresponding ranges among infants were210 to 1,402 and213 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively. Conclusions:RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa. Trial registration:http://www.ClinicalTrials.gov NCT00866619 Please see later in the article for the Editors’ Summary
    PLoS Medicine 07/2014; 11(7). DOI:10.1371/journal.pmed.1001685 · 14.00 Impact Factor
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    ABSTRACT: Background The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria.Methods Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.ResultsVaccine-induced anti-CSP antibody titres were significantly associated with age (P¿=¿0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P¿=¿0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P¿=¿0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR)¿=¿20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR¿=¿20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.Conclusions Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
    BMC Medicine 07/2014; 12(1):117. DOI:10.1186/PREACCEPT-5212460251240508 · 7.28 Impact Factor
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    ABSTRACT: Background The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS,S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. Methods Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated. Results Polyclonal anti-CS IgG preparations from RTS,S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation. Conclusions This study does not support the concept that anti-CS antibodies induced by the RTS,S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding.
    Malaria Journal 07/2014; 13(1):263. DOI:10.1186/1475-2875-13-263 · 3.49 Impact Factor
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    ABSTRACT: Community perception in biomedical research remains critical in Africa with many participants being driven by different motives. The objective of this study was to explore the perceived motives for women or females guardians to volunteer for their children to participate in biomedical research and to explore experiences and challenges faced by Community Owned Resource Persons (CORPs) when mobilizing community members to participate in biomedical research. This cross sectional study was conducted in Korogwe district, in north-eastern Tanzania. Qualitative methods combining random and purposive sampling techniques were used for data collection. A randomly selected sample using random table method from the existing list of households in the ward office was used to select participants for Focus Group Discussions (FGDs). A purposive sampling technique was used for In-Depth Interviews (IDIs) with CORPs. Thematic framework analysis was used to analyze the data. Need for better health services, availability of qualified clinicians, and better access to services provided at the research points were reported as main motives for community members to participate in biomedical research. With regard to experience and challenges faced by CORPs, the main reasons for mothers and guardians not participating in biomedical research were linked to misconception of the malariometric surveys, negative perception of the validity and sensitivity of rapid diagnostic tests, fear of knowing Human Immunodeficiency Virus Infection (HIV) /Acquired Immune Deficiency Syndrome (HIV/AIDS) sero status, and lack of trust for the medical information provided by the CORPs. Challenges reported by CORPs included lack ofawareness of malariometric surveys among participants, time consumption in mobilization of the community, difficulties in identifying individual results, and family responsibilities. This study has shown that majority of community members had positive perceptions of the about malariometric surveys services provided. The availability of free health services was the major determining factor for community members' participation in malariometric surveys. CORPs are instrumental in mobilizing community members participation during malariometric surveys, despite their experiences and the challenges they face.
    BMC Public Health 04/2014; 14(1):385. DOI:10.1186/1471-2458-14-385 · 2.32 Impact Factor
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    ABSTRACT: Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008-October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birthweights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.
    Emerging Infectious Diseases 09/2013; 19(9). DOI:10.3201/eid1909.130133 · 7.33 Impact Factor
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    ABSTRACT: National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010.
    The Lancet Global Health 07/2013; 1(1):e26-e36. DOI:10.1016/S2214-109X(13)70006-8 · 10.04 Impact Factor
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    ABSTRACT: Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.
    Nature 06/2013; DOI:10.1038/nature12216 · 42.35 Impact Factor
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    ABSTRACT: BACKGROUND: Studies conducted thus far have demonstrated that the malaria vaccine (RTS,S) has a promising safety profile. Within the context of planning for future vaccine trials and for the purpose of building on previous research that has been undertaken in sub-Saharan Africa with regard to community perceptions about clinical studies, this research aimed to explore the community perceptions on the secondary health benefits established by the malaria vaccine trials (RTS,S Phase 2 and Phase 3) at the Korogwe site in Tanzania. METHODS: An exploratory qualitative study design was used. Participants were recruited from the Korogwe site. Sampling techniques were purposive and random. A total of five focus group discussions and six in-depth interviews were conducted. Interview guides with open-ended questions were employed to collect data. Male and female parents whose infants participated and those whose infants did not participate in the trials, health workers and community leaders were interviewed. Thematic analysis framework was used to analyse the data. RESULTS: The activities of a malaria vaccine project appeared to be well known to the community. Respondents had largely positive views towards the secondary health benefits which have been established by malaria vaccine trials. The project has led to a massive investment in health care infrastructure and an improvement in health care services across the study areas. The project was perceived by the community to have established major secondary health benefits. Misconceptions amongst respondents, especially with regard to blood samples, were also observed in this study. CONCLUSION: Despite some misconceptions with regard to the conduct of malaria vaccine trials, especially on blood sampling, generally this study observed that most participants were positive about the secondary health benefits brought about by the malaria vaccine trials in Korogwe.
    Malaria Journal 05/2013; 12(1):157. DOI:10.1186/1475-2875-12-157 · 3.49 Impact Factor
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    ABSTRACT: BACKGROUND: The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data. METHODS: We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2-10 years (PrP2-10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. FINDINGS: Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP2-10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2-10 20%) it was 41% (21 to 57), and at high transmission (PrP2-10 70%) the efficacy was 4% (-10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)-eg, at low transmission (PrP2-10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (-38 to 38) after 3 years. INTERPRETATION: Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination. FUNDING: Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust.
    The Lancet Infectious Diseases 02/2013; 13(4). DOI:10.1016/S1473-3099(13)70005-7 · 19.45 Impact Factor
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    ABSTRACT: Pregnancy associated malaria is associated with decreased birth weight, but in-utero evaluation of fetal growth alterations is rarely performed. The objective of this study was to investigate malaria induced changes in fetal growth during the 3(rd) trimester using trans-abdominal ultrasound. An observational study of 876 pregnant women (398 primi- and secundigravidae and 478 multigravidae) was conducted in Tanzania. Fetal growth was monitored with ultrasound and screening for malaria was performed regularly. Birth weight and fetal weight were converted to z-scores, and fetal growth evaluated as fetal weight gain from the 26th week of pregnancy. Malaria infection only affected birth weight and fetal growth among primi- and secundigravid women. Forty-eight of the 398 primi- and secundigravid women had malaria during pregnancy causing a reduction in the newborns z-score of -0.50 (95% CI: -0.86, -0.13, P = 0.008, multiple linear regression). Fifty-eight percent (28/48) of the primi- and secundigravidae had malaria in the first half of pregnancy, but an effect on fetal growth was observed in the 3(rd) trimester with an OR of 4.89 for the fetal growth rate belonging to the lowest 25% in the population (95%CI: 2.03-11.79, P<0.001, multiple logistic regression). At an individual level, among the primi- and secundigravidae, 27% experienced alterations of fetal growth immediately after exposure but only for a short interval, 27% only late in pregnancy, 16.2% persistently from exposure until the end of pregnancy, and 29.7% had no alterations of fetal growth. The effect of malaria infections was observed during the 3(rd) trimester, despite infections occurring much earlier in pregnancy, and different mechanisms might operate leading to different patterns of growth alterations. This study highlights the need for protection against malaria throughout pregnancy and the recognition that observed changes in fetal growth might be a consequence of an infection much earlier in pregnancy.
    PLoS ONE 01/2013; 8(1):e53794. DOI:10.1371/journal.pone.0053794 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: The ability of Plasmodium falciparum to undergo antigenic variation, by switching expression among protein variants encoded by multigene families, such as var, rif and stevor, is key to the survival of this parasite in the human host. The RIFIN protein family can be divided into A and B types based on the presence or absence of a 25 amino acid motif in the semi-conserved domain. A particular type B RIFIN, PF13_0006, has previously been shown to be strongly transcribed in the asexual and sexual stages of P. falciparum in vitro. METHODS: Antibodies to recombinant PF13_0006 RIFIN were used in immunofluorescence and confocal imaging of 3D7 parasites throughout the asexual reproduction and sexual development to examine the expression of PF13_0006. Furthermore, reactivity to recombinant PF13_0006 was measured in plasma samples collected from individuals from both East and West African endemic areas. RESULTS: The PF13_0006 RIFIN variant appeared expressed by both released merozoites and gametes after emergence. 7.4% and 12.1% of individuals from East and West African endemic areas, respectively, carry plasma antibodies that recognize recombinant PF13_0006, where the antibody responses were more common among older children. CONCLUSIONS: The stage specificity of PF13_0006 suggests that the diversity of RIFIN variants has evolved to provide multiple specialized functions in different stages of the parasite life cycle. These data also suggest that RIFIN variants antigenically similar to PF13_0006 occur in African parasite populations.
    Malaria Journal 12/2012; 11(1):429. DOI:10.1186/1475-2875-11-429 · 3.49 Impact Factor
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    ABSTRACT: Background The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. Methods We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. Results The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, −7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). Conclusions The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.)
    New England Journal of Medicine 12/2012; 367(367):2284-2295. · 54.42 Impact Factor
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    ABSTRACT: Sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous spaces causes inflammation and pathology. Knowledge of the profiles of immune cells associated with the physiopathology of pregnancy-associated malaria (PAM) is scarce. We conducted a longitudinal, prospective study, both in Benin and Tanzania, including ∼1000 pregnant women in each site with systematic follow-up at scheduled antenatal visits until delivery. We used ex vivo flow cytometry to identify peripheral blood mononuclear cell (PBMC) profiles that are associated with PAM and anaemia, determining the phenotypic composition and activation status of PBMC in selected sub-groups with and without PAM both at inclusion and at delivery in a total of 302 women. Both at inclusion and at delivery PAM was associated with significantly increased frequencies both of B cells overall and of activated B cells. Infection-related profiles were otherwise quite distinct at the two different time-points. At inclusion, PAM was associated with anaemia, with an increased frequency of immature monocytes and with a decreased frequency of regulatory T cells (Treg). At delivery, infected women presented with significantly fewer plasmacytoid dendritic cells (DC), more myeloid DC expressing low levels of HLA-DR, and more effector T cells (Teff) compared to uninfected women. Independent associations with an increased risk of anaemia were found for altered antigen-presenting cell frequencies at inclusion, but for an increased frequency of Teff at delivery. Our findings emphasize the prominent role played by B cells during PAM whenever it arises during pregnancy, whilst also revealing signature changes in other circulating cell types that, we conclude, primarily reflect the relative duration of the infections. Thus, the acute, recently-acquired infections present at delivery were marked by changes in DC and Teff frequencies, contrasting with infections at inclusion, considered chronic in nature, that were characterized by an abundance of immature monocytes and a paucity of Treg in PBMC.
    PLoS ONE 12/2012; 7(12):e49621. DOI:10.1371/journal.pone.0049621 · 3.53 Impact Factor
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    ABSTRACT: In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity as well as fetal and neonatal mortality. Erythrocytes infected by these malaria-causing parasites accumulate through adhesive interactions in placental intervillous spaces, thus evading detection in peripheral blood smears. Sequestered infected erythrocytes induce inflammation, offering the possibility of detecting inflammatory mediators in peripheral blood that could act as biomarkers of placental infection. In a longitudinal, prospective study in Tanzania, we quantified a range of different cytokines, chemokines and angiogenic factors in peripheral plasma samples, taken on multiple sequential occasions during pregnancy up to and including delivery, from P. falciparum-infected women and matched uninfected controls. The results show that during healthy, uninfected pregnancies the levels of most of the panel of molecules we measured were largely unchanged except at delivery. In women with P. falciparum, however, both comparative and longitudinal assessments consistently showed that the levels of IL-10 and IP-10 increased significantly whilst that of RANTES decreased significantly, regardless of gestational age at the time the infection was detected. ROC curve analysis indicated that a combination of increased IL-10 and IP-10 levels and decreased RANTES levels might be predictive of P. falciparum infections. In conclusion, our data suggest that host biomarkers in peripheral blood may represent useful diagnostic markers of P. falciparum infection during pregnancy, but placental histology results would need to be included to verify these findings.
    PLoS ONE 11/2012; 7(11):e48763. DOI:10.1371/journal.pone.0048763 · 3.53 Impact Factor

Publication Stats

2k Citations
566.88 Total Impact Points

Institutions

  • 2009–2015
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2004–2015
    • National Institute for Medical Research (NIMR)
      Dār es Salām, Dar es Salaam, Tanzania
  • 2011
    • KEMRI-Wellcome Trust Research Programme
      Kilifi, Kilifi, Kenya