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101.
102.
Mahamadou S. Sissoko Lotus L. van den Hoogen Yacouba Samake Amadou Tapily Adama Z. Diarra Maimouna Coulibaly Madama Bouare Jean Gaudart Philip Knight Robert W. Sauerwein Willem Takken Teun Bousema Ogobara K. Doumbo 《The American journal of tropical medicine and hygiene》2015,93(4):790-797
Heterogeneity in malaria exposure is most readily recognized in areas with low-transmission patterns. By comparison, little research has been done on spatial patterns in malaria exposure in high-endemic settings. We determined the spatial clustering of clinical malaria incidence, asymptomatic parasite carriage, and Anopheles density in two villages in Mali exposed to low- and mesoendemic-malaria transmission. In the two study areas that were < 1 km2 in size, we observed evidence for spatial clustering of Anopheles densities or malaria parasite carriage during the dry season. Anopheles density and malaria prevalence appeared associated in some of our detected hotspots. However, many households with high parasite prevalence or high Anopheles densities were located outside the identified hotspots. Our findings indicate that within small villages exposed to low- or mesoendemic-malaria transmission, spatial patterns in mosquito densities and parasite carriage are best detected in the dry season. Considering the high prevalence of parasite carriage outside detected hotspots, the suitability of the area for targeting control efforts to households or areas of more intense malaria transmission may be limited. 相似文献
103.
Jason A. Bailey Jozelyn Pablo Amadou Niangaly Mark A. Travassos Amed Ouattara Drissa Coulibaly Matthew B. Laurens Shannon L. Takala-Harrison Kirsten E. Lyke Jeff Skinner Andrea A. Berry Algis Jasinskas Rie Nakajima-Sasaki Bourema Kouriba Mahamadou A. Thera Philip L. Felgner Ogobara K. Doumbo Christopher V. Plowe 《The American journal of tropical medicine and hygiene》2015,92(1):9-12
Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP119, n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy.Plasmodium falciparum uses antigenic variation to evade host immunity, including vaccine-induced immunity.1,2 The protective immunity against P. falciparum malaria disease that is acquired after years of exposure is believed to reflect, in part, the gradual acquisition of allele-specific immune responses against a repertoire of parasite antigens, and, importantly, against diverse variants of these antigens.3 Apical membrane antigen 1 (AMA1) and merozoite surface protein 1 (MSP1) are immunogenic parasite surface antigens considered vital for erythrocyte attachment and invasion. Antibodies against these proteins are associated with protection against malaria, and several subunit AMA1 and MSP1 vaccines have been developed and tested.1,4–6 Both AMA1 and MSP119, the C-terminus portion of the MSP1 protein used in subunit vaccines, are highly variable, with sequence diversity encoded by single nucleotide polymorphisms.7,8 The highest prevalence of any one of the 440 AMA1 haplotypes observed from sequencing the ama1 gene among more than 1,400 field infections diagnosed during prospective incidence studies and vaccine trials was less than 4%.1,8,9Although less extreme, MSP119 also has substantial diversity, with 17 haplotypes detected among more than 1,300 infections.7 Because vaccines that include dozens or hundreds of antigen variants are not feasible, malaria vaccine development would be aided by the identification of a manageable number of serodominant, cross-protective haplotypes among AMA1 and MSP119 variants. Developing such strain-transcending vaccines is hindered by the limited availability of diverse parasite antigens and the low throughput of standard assays such as enzyme-linked immunosorbent assay for measuring antibody responses.Protein microarrays offer the possibility of overcoming these obstacles to enable high throughput evaluations of seroreactivity to large numbers of antigen variants. Plasmodium falciparum proteins expressed in a cell-free Escherichia coli translation system and spotted onto microarrays are recognized by serum antibodies of persons exposed to malaria.10–12 To date, this platform has been used to measure seroreactivity to large numbers of proteins derived from the genome of the P. falciparum reference strain 3D7.10,12–14 To examine antibody responses to diverse variants of highly polymorphic P. falciparum antigens, we amplified, expressed and printed dozens of field-derived variants of AMA1 and MSP119 on a protein microarray.Antigen genes were amplified by polymerase chain reaction from DNA extracted from dried blood spots collected in a cohort study and an AMA1 vaccine trial in Mali, Africa. The resulting amplicons were analyzed by using the BigDye® Terminator v3.1 Cycle Direct Sequencing Kit (Applied Biosciences, Foster City, CA).4,8,15 Sequence contigs were compiled by using Sequencher software (Gene Codes, Ann Arbor, MI).9,16 Sixty of the most prevalent AMA1 ectodomain haplotypes and 10 MSP119 haplotypes were selected for inclusion on the prototype protein microarray. Microarray construction has been described.17Serum samples were obtained from 18 adults 18–55 years of age enrolled in the control arm of a phase 1 trial of an AMA1-based vaccine conducted during 2004–2005 in Bandiagara, Mali.18 Similarly, serum samples were randomly obtained from 24 children 1–6 years of age enrolled in the control arm of a phase 1 trial of an AMA1-based malaria vaccine during 2006–2007 at the same site.6,19 Bandiagara, Mali has high seasonal malaria transmission coinciding with the June–November rainy season, with entomologic inoculation rates of 50–150 infected bites/person/season.8 For each participant, paired serum samples from two time points corresponding to the pre-malaria (May–June) and post-malaria (December–January) seasons were probed in random order to eliminate batch and slide effects.Two microliters of serum from individual participant samples was diluted 1:200 with 10% E. coli lysate in blocking buffer and hybridized onto separate protein arrays overnight. Arrays were stained, washed, and scanned by using a Perkin-Elmer (Waltham, MA) ScanArray Express HT microarray scanner. Probing protocols have been described.10,12,17 Fluorescence was quantified by using the ScanArray Express Suite (Perkin-Elmer). Median fluorescent intensities (MFIs) were calculated by using an adaptive capture feature to account for varying spot size, and the per-spot local background was subtracted.Raw MFIs were asinh-transformed to convert the MFI values to a Gaussian (normal) distribution, and biological variance contributed by seroreactivity to the E. coli components included in the translation protocol was subtracted by taking the average of eight empty vector, translated, negative controls (i.e., the no DNA controls). Residual non-biological variance between slides, batches, and individual arrays was corrected by using robust linear modeling (RLM) with respect to the negative and positive controls.20 Asinh-transformed, RLM-scaled data were reverted to fluorescent intensities by sinh reverse-transformation and plotted on a heat map to show global trends (Figure 1).Open in a separate windowFigure 1.Heat map of seroreactivity to Plasmodium falciparum apical membrane antigen 1 (AMA1) and merozoite surface protein 1–19 (MSP119) variants. Each column represents serum from an individual Malian child or adult, or a malaria-naive North American adult, and each row represents an antigen variant. Gray, black, and red indicate low, moderate and high seroreactivity, respectively, to probed antigens. Four serial dilutions of IgG peptide were printed and probed as positive probing controls and used as a standardization parameter for robust linear model scaling as a measurement of total IgG. MFI = median fluorescent intensity.Parametric statistical hypotheses were tested on asinh-transformed, RLM-scaled data by using BioconductR (http://www.bioconductor.org/index.html, Excel (Microsoft, Redmond, WA), and SAS/STAT software (SAS Institute, Cary, NC). The magnitude of seroreactivity was measured by mean MFI using matched pair Student''s t tests (Antigen Cohort Mean MFI (95% CI) Serorecognition (%, 95% CI) Pre-season Post-season Pre-season Post-season AMA1 Children 296 (226–365) 434 (348–522) 13.1 (5.8–20.4) 18.6 (11.1– 26.1) Adults 1,506 (1,324–1,687) 1,428 (1,271–1,585) 49.3 (37.0–61.6) 53.2 (42.7–63.7) Controls 8.78 (5.22–12.4) – – – MSP119 Children 20.9 (4.40–37.5) 191 (110–273) 2.5 (–0.9 to 5.9) 9.4 (3.5–15.4) Adults 627 (345–909) 940 (474–1,406) 21.1 (11.4–30.9) 18.9 (6.3–31.4) Controls 21.4 (16.8–26.05) – – –