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1.
David Courtin Mayke Oesterholt Harm Huismans Kwadwo Kusi Jacqueline Milet Cyril Badaut Oumar Gaye Will Roeffen Edmond J. Remarque Robert Sauerwein André Garcia Adrian J. F. Luty 《PloS one》2009,4(10)
Background
Antibodies, particularly cytophilic IgG subclasses, with specificity for asexual blood stage antigens of Plasmodium falciparum, are thought to play an important role in acquired immunity to malaria. Evaluating such responses in longitudinal sero-epidemiological field studies, allied to increasing knowledge of the immunological mechanisms associated with anti-malarial protection, will help in the development of malaria vaccines.Methods and Findings
We conducted a 1-year follow-up study of 305 Senegalese children and identified those resistant or susceptible to malaria. In retrospective analyses we then compared post-follow-up IgG responses to six asexual-stage candidate malaria vaccine antigens in groups of individuals with clearly defined clinical and parasitological histories of infection with P. falciparum. In age-adjusted analyses, children resistant to malaria as well as to high-density parasitemia, had significantly higher IgG1 responses to GLURP and IgG3 responses to MSP2 than their susceptible counterparts. Among those resistant to malaria, high anti-MSP1 IgG1 levels were associated with protection against high-density parasitemia. To assess functional attributes, we used an in vitro parasite growth inhibition assay with purified IgG. Samples from individuals with high levels of IgG directed to MSP1, MSP2 and AMA1 gave the strongest parasite growth inhibition, but a marked age-related decline was observed in these effects.Conclusion
Our data are consistent with the idea that protection against P. falciparum malaria in children depends on acquisition of a constellation of appropriate, functionally active IgG subclass responses directed to multiple asexual stage antigens. Our results suggest at least two distinct mechanisms via which antibodies may exert protective effects. Although declining with age, the growth inhibitory effects of purified IgG measurable in vitro reflected levels of anti-AMA1, -MSP1 and -MSP2, but not of anti-GLURP IgG. The latter could act on parasite growth via indirect parasiticidal pathways. 相似文献2.
Background
MSP3 has been shown to induce protection against malaria in African children. The characterization of a family of Plasmodium falciparum merozoite surface protein 3 (MSP3) antigens sharing a similar structural organization, simultaneously expressed on the merozoite surface and targeted by a cross-reactive network of protective antibodies, is intriguing and offers new perspectives for the development of subunit vaccines against malaria.Methods
Eight recombinant polyproteins containing carefully selected regions of this family covalently linked in different combinations were all efficiently produced in Escherichia coli. The polyproteins consisted of one monovalent, one bivalent, one trivalent, two tetravalents, one hexavalent construct, and two tetravalents incorporating coiled-coil repeats regions from LSA3 and p27 vaccine candidates.Results
All eight polyproteins induced a strong and homogeneous antibody response in mice of three distinct genotypes, with a dominance of cytophilic IgG subclasses, lasting up to six months after the last immunization. Vaccine-induced antibodies exerted a strong monocyte-mediated in vitro inhibition of P. falciparum growth. Naturally acquired antibodies from individuals living in an endemic area of Senegal recognized the polyproteins with a reactivity mainly constituted of cytophilic IgG subclasses.Conclusions
Combination of genetically conserved and antigenically related MSP3 proteins provides promising subunit vaccine constructs, with improved features as compared to the first generation construct employed in clinical trials (MSP3-LSP). These multivalent MSP3 vaccine constructs expand the epitope display of MSP3 family proteins, and lead to the efficient induction of a wider range of antibody subclasses, even in genetically different mice. These findings are promising for future immunization of genetically diverse human populations. 相似文献3.
Background
One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. However, published evidence of the protective effect of these antibodies is conflicting.Methods and Findings
We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-142 and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-119 (responders versus nonresponders, 54%, 95% confidence interval [CI] [33%–68%] and 18% [4%–30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2FC27 0.82, 95% CI 0.62–1.08, p = 0.16 and MSP-23D7 0.92, 95% CI 0.75–1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens.Conclusions
These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors'' Summary 相似文献4.
Kalifa A. Bojang Paul J. M. Milligan David J. Conway Fatou Sisay-Joof Muminatou Jallow Davis C. Nwakanma Ismaela Abubakr Fanta Njie Brian Greenwood 《PloS one》2010,5(6)
Background
In malaria endemic countries, children who have experienced an episode of severe anaemia are at increased risk of a recurrence of anaemia. There is a need to find ways of protecting these at risk children from malaria and chemoprevention offers a potential way of achieving this objective.Methods
During the 2003 and 2004 malaria transmission seasons, 1200 Gambian children with moderate or severe anaemia (Hb concentration <7 g/dL) were randomised to receive either monthly sulfadoxine-pyrimethamine (SP) or placebo until the end of the malaria transmission season in which they were enrolled, in a double-blind trial. All study subjects were treated with oral iron for 28 days and morbidity was monitored through surveillance at health centres. The primary endpoint was the proportion of children with moderate or severe anaemia at the end of the transmission season. Secondary endpoints included the incidence of clinical episodes of malaria during the surveillance period, outpatient attendances, the prevalence of parasitaemia and splenomegaly, nutritional status at the end of the malaria transmission season and compliance with the treatment regimen.Results
The proportions of children with a Hb concentration of <7 g/dL at the end of the malaria transmission season were similar in the two study groups, 14/464 (3.0%) in children who received at least one dose of SP and 16/471 (3.4%) in those who received placebo, prevalence ratio 0.89 (0.44,1.8) P = 0.742. The protective efficacy of SP against episodes of clinical malaria was 53% (95% CI 37%, 65%). Treatment with SP was safe and well tolerated; no serious adverse events related to SP administration were observed. Mortality following discharge from hospital was low among children who received SP or placebo (6 in the SP group and 9 in the placebo group respectively).Conclusions
Intermittent treatment with SP did not reduce the proportion of previously anaemic children with moderate or severe anaemia at the end of the malaria season, although it prevented malaria. The combination of appropriate antimalarial treatment plus one month of iron supplementation and good access to healthcare during follow-up proved effective in restoring haemoglobin to an acceptable level in the Gambian setting.Trial Registration
ClinicalTrials.gov NCT00131716相似文献5.
Background
Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level.Method and Findings
We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1142 were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual''s malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1142 antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66–0.73), 0.71 (95%CI: 0.69–0.73) and 0.82 (95%CI: 0.80–0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1142 antibody levels provided an AUC of 0.83 (95%CI: 0.79–0.88).Conclusion
We have proposed an approach to estimating the intensity of an individual''s malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria. 相似文献6.
Margaret Kweku Dongmei Liu Martin Adjuik Fred Binka Mahmood Seidu Brian Greenwood Daniel Chandramohan 《PloS one》2008,3(12)
Background
Malaria and anaemia are the leading causes of morbidity and mortality in children in sub-Saharan Africa. We have investigated the effect of intermittent preventive treatment with sulphadoxine-pyrimethamine or artesunate plus amodiaquine on anaemia and malaria in children in an area of intense, prolonged, seasonal malaria transmission in Ghana.Methods
2451 children aged 3–59 months from 30 villages were individually randomised to receive placebo or artesunate plus amodiaquine (AS+AQ) monthly or bimonthly, or sulphadoxine-pyrimethamine (SP) bimonthly over a period of six months. The primary outcome measures were episodes of anaemia (Hb<8.0 g/dl) or malaria detected through passive surveillance.Findings
Monthly artesunate plus amodiaquine reduced the incidence of malaria by 69% (95% CI: 63%, 74%) and anaemia by 45% (95% CI: 25%,60%), bimonthly sulphadoxine-pyrimethamine reduced the incidence of malaria by 24% (95% CI: 14%,33%) and anaemia by 30% (95% CI: 6%, 49%) and bimonthly artesunate plus amodiaquine reduced the incidence of malaria by 17% (95% CI: 6%, 27%) and anaemia by 32% (95% CI: 7%, 50%) compared to placebo. There were no statistically significant reductions in the episodes of all cause or malaria specific hospital admissions in any of the intervention groups compared to the placebo group. There was no significant increase in the incidence of clinical malaria in the post intervention period in children who were >1 year old when they received IPTc compared to the placebo group. However the incidence of malaria in the post intervention period was higher in children who were <1 year old when they received AS+AQ monthly compared to the placebo group.Interpretation
IPTc is safe and efficacious in reducing the burden of malaria in an area of Ghana with a prolonged, intense malaria transmission season.Trial Registration
ClinicalTrials.gov NCT00119132相似文献7.
Kalifa Bojang Francis Akor Ousman Bittaye David Conway Christian Bottomley Paul Milligan Brian Greenwood 《PloS one》2010,5(6)
Background
Results from trials of intermittent preventive treatment (IPT) in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP) given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ) and dihydroartemisinin (DHA) plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission.Methods
During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ), SP plus piperaquine (PQ) or dihydroartemisinin (DHA) plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season.Results
All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22), 0.06 (95% CI: 0.022, 0.16) and 0.06 (95% CI: 0.02, 0.15) respectively. The incidence of malaria in the control group was 0.79 cases per child year (0.58, 1.08).Conclusion
All the three regimens of IPT in children were safe and highly efficaciousTrial Registration
ClinicalTrials.gov NCT00561899相似文献8.
Frances Ibison Ally Olotu Daniel M. Muema Jedida Mwacharo Eric Ohuma Domtila Kimani Kevin Marsh Philip Bejon Francis M. Ndungu 《PloS one》2012,7(12)
Background
Although antibodies are critical for immunity to malaria, their functional attributes that determine protection remain unclear. We tested for associations between antibody avidities to Plasmodium falciparum (Pf) antigens and age, asymptomatic parasitaemia, malaria exposure index (a distance weighted local malaria prevalence) and immunity to febrile malaria during 10-months of prospective follow up.Methods
Cross-sectional antibody levels and avidities to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 142 (MSP1) and Merozoite Surface Protein 3 (MSP3) were measured by Enzyme Linked Immunosorbent Assay in 275 children, who had experienced at least one episode of clinical malaria by the time of this study, as determined by active weekly surveillance.Results
Antibody levels to AMA1, MSP1 and MSP3 increased with age. Anti-AMA1 and MSP1 antibody avidities were (respectively) positively and negatively associated with age, while anti-MSP3 antibody avidities did not change. Antibody levels to all three antigens were elevated in the presence of asymptomatic parasitaemia, but their associated avidities were not. Unlike antibody levels, antibody avidities to the three-merozoite antigens did not increase with exposure to Pf malaria. There were no consistent prospective associations between antibody avidities and malaria episodes.Conclusion
We found no evidence that antibody avidities to Pf-merozoite antigens are associated with either exposure or immunity to malaria. 相似文献9.
Tamsir O. Diallo Franck Remoue Lobna Gaayeb Anne-Marie Schacht Nicole Charrier Dick De Clerck Jean-Pierre Dompnier Sophie Pillet Olivier Garraud Abdoulaye A. N'Diaye Gilles Riveau 《PloS one》2010,5(9)
Background
Malaria and schistosomiasis coinfection frequently occurs in tropical countries. This study evaluates the influence of Schistosoma haematobium infection on specific antibody responses and cytokine production to recombinant merozoite surface protein-1-19 (MSP1-19) and schizont extract of Plasmodium falciparum in malaria-infected children.Methodology
Specific IgG1 to MSP1-19, as well as IgG1 and IgG3 to schizont extract were significantly increased in coinfected children compared to P. falciparum mono-infected children. Stimulation with MSP1-19 lead to a specific production of both interleukin-10 (IL-10) and interferon-γ (IFN-γ), whereas the stimulation with schizont extract produced an IL-10 response only in the coinfected group.Conclusions
Our study suggests that schistosomiasis coinfection favours anti-malarial protective antibody responses, which could be associated with the regulation of IL-10 and IFN-γ production and seems to be antigen-dependent. This study demonstrates the importance of infectious status of the population in the evaluation of acquired immunity against malaria and highlights the consequences of a multiple infection environment during clinical trials of anti-malaria vaccine candidates. 相似文献10.
Dicko A Barry A Dicko M Diallo AI Tembine I Dicko Y Dara N Sidibe Y Santara G Conaré T Chandramohan D Cousens S Milligan PJ Diallo DA Doumbo OK Greenwood B 《PloS one》2011,6(8):e23390
Background
Intermittent preventive treatment of malaria in children (IPTc) is a promising strategy for malaria control. A study conducted in Mali in 2008 showed that administration of three courses of IPTc with sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals reduced clinical malaria, severe malaria and malaria infection by >80% in children under 5 years of age. Here we report the results of a follow-on study undertaken to establish whether children who had received IPTc would be at increased risk of malaria during the subsequent malaria transmission season.Methods
Morbidity from malaria and the prevalence of malaria parasitaemia and anaemia were measured in children who had previously received IPTc with SP and AQ using similar surveillance methods to those employed during the previous intervention period.Results
1396 of 1508 children (93%) who had previously received IPTc and 1406 of 1508 children (93%) who had previously received placebos were followed up during the high malaria transmission season of the year following the intervention. Incidence rates of clinical malaria during the post-intervention transmission season (July –November 2009) were 1.87 (95% CI 1.76 –1.99) and 1.73 (95% CI; 1.62–1.85) episodes per child year in the previous intervention and placebo groups respectively; incidence rate ratio (IRR) 1.09 (95% CI 0.99 –1.21) (P = 0.08). The prevalence of malaria infection was similar in the two groups, 7.4% versus 7.5%, prevalence ratio (PR) of 0.99 (95% CI 0.73–1.33) (P = 0.95). At the end of post-intervention malaria transmission season, the prevalence of anaemia, defined as a haemoglobin concentration<11g/dL, was similar in the two groups (56.2% versus 55.6%; PR = 1.01 [95% CI 0.91 – 1.12]) (P = 0.84).Conclusion
IPTc with SP+AQ was not associated with an increase in incidence of malaria episodes, prevalence of malaria infection or anaemia in the subsequent malaria transmission season.Trial Registration
ClinicalTrials.gov NCT00738946相似文献11.
Sodiomon B. Sirima Alfred B. Tiono Alphonse Ouédraogo Amidou Diarra André Lin Ouédraogo Jean Baptiste Yaro Espérance Ouédraogo Adama Gansané Edith C. Bougouma Amadou T. Konaté Youssouf Kaboré Abdoulaye Traoré Chilengi Roma Issiaka Soulama Adrian J. F. Luty Simon Cousens Issa Nébié 《PloS one》2009,4(10)
Background
A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult volunteers in Burkina Faso confirmed that the vaccine was safe.The aim of this study was to assess the safety and immunogenicity of this vaccine candidate in children aged 12–24 months living in malaria endemic area of Burkina Faso.Methods
The study was a double-blind, randomized, controlled, dose escalation phase Ib trial, designed to assess the safety, reactogenicity and immunogenicity of three doses of either 15 or 30 µg of MSP3-LSP adsorbed on aluminum hydroxide in 45 children 12 to 24 months of age randomized into three equal groups. Each group received 3 vaccine doses (on days 0, 28 and 56) of either 15 µg of MSP3-LSP, 30 µg of MSP3-LSP or of the Engerix B hepatitis B vaccine. Children were visited at home daily for the 6 days following each vaccination to solicit symptoms which might be related to vaccination. Serious adverse events occurring during the study period (1 year) were recorded. Antibody responses to MSP3-LSP were measured on days 0, 28, 56 and 84.Results
All 45 enrolled children received three MSP3 vaccine doses. No serious adverse events were reported. Most of the adverse events reported were mild to moderate in severity. The only reported local symptoms with grade 3 severity were swelling and induration, with an apparently dose related response. All grade 3 adverse events resolved without any sequelae. Both MSP3 doses regimens were able to elicit high levels of anti-MSP3 specific IgG1 and IgG3 antibodies in the volunteers with very little or no increase in IgG2, IgG4 and IgM classes: i.e. vaccination induced predominantly the isotypes involved in the monocyte-dependent mechanism of P. falciparum parasite-killing.Conclusion
Our results support the promise of MSP3-LSP as a malaria vaccine candidate, both in terms of tolerability and of immunogenicity. Further assessment of the efficacy of this vaccine is recommended.Trial Registration
ClinicalTrials.gov NCT00452088相似文献12.
Kazutoyo Miura Mahamadou Diakite Ababacar Diouf Saibou Doumbia Drissa Konate Abdoul S. Keita Samuel E. Moretz Gregory Tullo Hong Zhou Tatiana M. Lopera-Mesa Jennifer M. Anderson Rick M. Fairhurst Carole A. Long 《PloS one》2013,8(3)
Heterozygous hemoglobin (Hb) AS (sickle-cell trait) and HbAC are hypothesized to protect against Plasmodium falciparum malaria in part by enhancing naturally-acquired immunity to this disease. To investigate this hypothesis, we compared antibody levels to four merozoite antigens from the P. falciparum 3D7 clone (apical membrane antigen 1, AMA1-3D7; merozoite surface protein 1, MSP1-3D7; 175 kDa erythrocyte-binding antigen, EBA175-3D7; and merozoite surface protein 2, MSP2-3D7) in a cohort of 103 HbAA, 73 HbAS and 30 HbAC children aged 3 to 11 years in a malaria-endemic area of Mali. In the 2009 transmission season we found that HbAS, but not HbAC, significantly reduced the risk of malaria compared to HbAA. IgG levels to MSP1 and MSP2 at the start of this transmission season inversely correlated with malaria incidence after adjusting for age and Hb type. However, HbAS children had significantly lower IgG levels to EBA175 and MSP2 compared to HbAA children. On the other hand, HbAC children had similar IgG levels to all four antigens. The parasite growth-inhibitory activity of purified IgG samples did not differ significantly by Hb type. Changes in antigen-specific IgG levels during the 2009 transmission and 2010 dry seasons also did not differ by Hb type, and none of these IgG levels dropped significantly during the dry season. These data suggest that sickle-cell trait does not reduce the risk of malaria by enhancing the acquisition of IgG responses to merozoite antigens. 相似文献
13.
Badara Cisse Matthew Cairns Ernest Faye Ousmane NDiaye Babacar Faye Cecile Cames Yue Cheng Maguette NDiaye Aminata Collé L? Kirsten Simondon Jean-Francois Trape Oumar Faye Jean Louis NDiaye Oumar Gaye Brian Greenwood Paul Milligan 《PloS one》2009,4(9)
Background
The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal.Methods
Treatments were delivered to children 3–59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events.Results
1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/µL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI −2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI −1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season.Conclusions
Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites.Trial Registration
ClinicalTrials.gov NCT00529620相似文献14.
Wilson DW Fowkes FJ Gilson PR Elliott SR Tavul L Michon P Dabod E Siba PM Mueller I Crabb BS Beeson JG 《PloS one》2011,6(11):e27705
Background
Antibodies targeting blood stage antigens are important in protection against malaria, but the key targets and mechanisms of immunity are not well understood. Merozoite surface protein 1 (MSP1) is an abundant and essential protein. The C-terminal 19 kDa region (MSP1-19) is regarded as a promising vaccine candidate and may also be an important target of immunity.Methodology/Findings
Growth inhibitory antibodies against asexual-stage parasites and IgG to recombinant MSP1-19 were measured in plasma samples from a longitudinal cohort of 206 children in Papua New Guinea. Differential inhibition by samples of mutant P. falciparum lines that expressed either the P. falciparum or P. chabaudi form of MSP1-19 were used to quantify MSP1-19 specific growth-inhibitory antibodies. The great majority of children had detectable IgG to MSP1-19, and high levels of IgG were significantly associated with a reduced risk of symptomatic P. falciparum malaria during the 6-month follow-up period. However, there was little evidence of PfMSP1-19 specific growth inhibition by plasma samples from children. Similar results were found when testing non-dialysed or dialysed plasma, or purified antibodies, or when measuring growth inhibition in flow cytometry or microscopy-based assays. Rabbit antisera generated by immunization with recombinant MSP1-19 demonstrated strong MSP1-19 specific growth-inhibitory activity, which appeared to be due to much higher antibody levels than human samples; antibody avidity was similar between rabbit antisera and human plasma.Conclusions/Significance
These data suggest that MSP1-19 is not a major target of growth inhibitory antibodies and that the protective effects of antibodies to MSP1-19 are not due to growth inhibitory activity, but may instead be mediated by other mechanisms. Alternatively, antibodies to MSP1-19 may act as a marker of protective immunity. 相似文献15.
Christian Roussilhon Philippe Brasseur Patrice Agnamey Jean-Louis Pérignon Pierre Druilhe 《PloS one》2010,5(2)
Background
Former studies have pointed to a monocyte-dependant effect of antibodies in protection against malaria and thereby to cytophilic antibodies IgG1 and IgG3, which trigger monocyte receptors. Field investigations have further documented that a switch from non-cytophilic to cytophilic classes of antimalarial antibodies was associated with protection. The hypothesis that the non-cytophilic isotype imbalance could be related to concomittant helminthic infections was supported by several interventions and case-control studies.Methods and Findings
We investigated here the hypothesis that the delayed acquisition of immunity to malaria could be related to a worm-induced Th2 drive on antimalarial immune responses. IgG1 to IgG4 responses against 6 different parasite-derived antigens were analyzed in sera from 203 Senegalese children, half carrying intestinal worms, presenting 421 clinical malaria attacks over 51 months. Results show a significant correlation between the occurrence of malaria attacks, worm carriage (particularly that of hookworms) and a decrease in cytophilic IgG1 and IgG3 responses and an increase in non-cytophilic IgG4 response to the merozoite stage protein 3 (MSP3) vaccine candidate.Conclusion
The results confirm the association with protection of anti-MSP3 cytophilic responses, confirm in one additional setting that worms increase malaria morbidity and show a Th2 worm-driven pattern of anti-malarial immune responses. They document why large anthelminthic mass treatments may be worth being assessed as malaria control policies. 相似文献16.
Gemma Moncunill Alfredo Mayor Alfons Jiménez Augusto Nhabomba Núria Casas-Vila Laura Puyol Joseph J. Campo Maria Nelia Manaca Ruth Aguilar María-Jesús Pinazo Mercè Almirall Cristina Soler José Mu?oz Azucena Bardají Evelina Angov Sheetij Dutta Chetan E. Chitnis Pedro L. Alonso Joaquim Gascón Carlota Doba?o 《PloS one》2013,8(8)
Background
Malaria immunity is commonly believed to wane in the absence of Plasmodium falciparum exposure, based on limited epidemiological data and short-lived antibody responses in some longitudinal studies in endemic areas.Methods
A cross-sectional study was conducted among sub-Saharan African adults residing in Spain for 1 up to 38 years (immigrants) with clinical malaria (n=55) or without malaria (n=37), naïve adults (travelers) with a first clinical malaria episode (n=20) and life-long malaria exposed adults from Mozambique (semi-immune adults) without malaria (n=27) or with clinical malaria (n=50). Blood samples were collected and IgG levels against the erythrocytic antigens AMA-1 and MSP-142 (3D7 and FVO strains), EBA-175 and DBL-α were determined by Luminex. IgG levels against antigens on the surface of infected erythrocytes (IEs) were measured by flow cytometry.Results
Immigrants without malaria had lower IgG levels than healthy semi-immune adults regardless of the antigen tested (P≤0.026), but no correlation was found between IgG levels and time since migration. Upon reinfection, immigrants with malaria had higher levels of IgG against all antigens than immigrants without malaria. However, the magnitude of the response compared to semi-immune adults with malaria depended on the antigen tested. Thus, immigrants had higher IgG levels against AMA-1 and MSP-142 (P≤0.015), similar levels against EBA-175 and DBL-α, and lower levels against IEs (P≤0.016). Immigrants had higher IgG levels against all antigens tested compared to travelers (P≤0.001), both with malaria.Conclusions
Upon cessation of malaria exposure, IgG responses to malaria-specific antigens were maintained to a large extent, although the conservation and the magnitude of the recall response depended on the nature of the antigen. Studies on immigrant populations can shed light on the factors that determine the duration of malaria specific antibody responses and its effect on protection, with important implications for future vaccine design and public health control measures. 相似文献17.
Konaté AT Yaro JB Ouédraogo AZ Diarra A Gansané A Soulama I Kangoyé DT Kaboré Y Ouédraogo E Ouédraogo A Tiono AB Ouédraogo IN Chandramohan D Cousens S Milligan PJ Sirima SB Greenwood BM Diallo DA 《PloS one》2011,6(8):e23391
Background
Interventions that reduce exposure to malaria infection may lead to delayed malaria morbidity and mortality. We investigated whether intermittent preventive treatment of malaria in children (IPTc) was associated with an increase in the incidence of malaria after cessation of the intervention.Methods
An individually randomised, trial of IPTc, comparing three courses of sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) with placebos was implemented in children aged 3–59 months during the 2008 malaria transmission season in Burkina Faso. All children in the trial were given a long lasting insecticide treated net; 1509 children received SP+AQ and 1505 received placebos. Passive surveillance for malaria was maintained until the end of the subsequent malaria transmission season in 2009, and active surveillance for malaria infection, anaemia and malnutrition was conducted.Results
On thousand, four hundred and sixteen children (93.8%) and 1399 children (93.0%) initially enrolled in the intervention and control arms of the trial respectively were followed during the 2009 malaria transmission season. During the period July 2009 to November 2009, incidence rates of clinical malaria were 3.84 (95%CI; 3.67–4.02) and 3.45 (95%CI; 3.29–3.62) episodes per child during the follow up period in children who had previously received IPT or placebos, indicating a small increase in risk for children in the former intervention arm (IRR = 1.12; 95%CI 1.04–1.20) (P = 0.003). Children who had received SP+AQ had a lower prevalence of malaria infection (adjusted PR: 0.88 95%CI: 0.79–0.98) (P = 0.04) but they had a higher parasite density (P = 0.001) if they were infected. There was no evidence that the risks of moderately severe anaemia (Hb<8 g/dL), wasting, stunting, or of being underweight in children differed between treatment arms.Conclusion
IPT with SP+AQ was associated with a small increase in the incidence of clinical malaria in the subsequent malaria transmission season.Trial Registration
ClinicalTrials.gov NCT00738946相似文献18.
Indu Malhotra Arlene Dent Peter Mungai Alex Wamachi John H. Ouma David L. Narum Eric Muchiri Daniel J. Tisch Christopher L. King 《PLoS medicine》2009,6(7)
Background
Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child''s susceptibility to subsequent malaria infections.Methods and Findings
We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFNγ, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFNγ, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf−, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10–2.43; p = 0.024) and 1.34 (95% CI 0.95–1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95%CI 0.97–2.07, p = 0.074) and 1.39 (95%CI 0.99–2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFNγ and/or IL-2 production (p<0.001) and higher IL-10 release (p<0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage–specific IgG antibody levels were similar among the three groups.Conclusions
These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas. Please see later in the article for Editors'' Summary 相似文献19.
Wilson AL;IPTc Taskforce 《PloS one》2011,6(2):e16976
Background
Intermittent preventive treatment of malaria in children less than five years of age (IPTc) has been investigated as a measure to control the burden of malaria in the Sahel and sub-Sahelian areas of Africa where malaria transmission is markedly seasonal.Methods and Findings
IPTc studies were identified using a systematic literature search. Meta-analysis was used to assess the protective efficacy of IPTc against clinical episodes of falciparum malaria. The impact of IPTc on all-cause mortality, hospital admissions, severe malaria and the prevalence of parasitaemia and anaemia was investigated. Three aspects of safety were also assessed: adverse reactions to study drugs, development of drug resistance and loss of immunity to malaria. Twelve IPTc studies were identified: seven controlled and five non-controlled trials. Controlled studies demonstrated protective efficacies against clinical malaria of between 31% and 93% and meta-analysis gave an overall protective efficacy of monthly administered IPTc of 82% (95%CI 75%–87%) during the malaria transmission season. Pooling results from twelve studies demonstrated a protective effect of IPTc against all-cause mortality of 57% (95%CI 24%–76%) during the malaria transmission season. No serious adverse events attributable to the drugs used for IPTc were observed in any of the studies. Data from three studies that followed children during the malaria transmission season in the year following IPTc administration showed evidence of a slight increase in the incidence of clinical malaria compared to children who had not received IPTc.Conclusions
IPTc is a safe method of malaria control that has the potential to avert a significant proportion of clinical malaria episodes in areas with markedly seasonal malaria transmission and also appears to have a substantial protective effect against all-cause mortality. These findings indicate that IPTc is a potentially valuable tool that can contribute to the control of malaria in areas with markedly seasonal transmission. 相似文献20.
Ebako N. Takem Muna Affara Alfred Amambua-Ngwa Joseph Okebe Serign J. Ceesay Musa Jawara Eniyou Oriero Davis Nwakanma Margaret Pinder Caitlin Clifford Makie Taal Momodou Sowe Penda Suso Alphonse Mendy Amicoleh Mbaye Chris Drakeley Umberto D'Alessandro 《PloS one》2013,8(6)