Establishing the extent of malaria transmission and challenges facing pre-elimination in the Republic of Djibouti.

BACKGROUND: Countries aiming for malaria elimination require a detailed understanding of the current intensity of malaria transmission within their national borders. National household sample surveys are now being used to define infection prevalence but these are less efficient in areas of exceptionally low endemicity. Here we present the results of a national malaria indicator survey in the Republic of Djibouti, the first in sub-Saharan Africa to combine parasitological and serological markers of malaria, to evaluate the extent of transmission in the country and explore the potential for elimination. METHODS: A national cross-sectional household survey was undertaken from December 2008 to January 2009. A finger prick blood sample was taken from randomly selected participants of all ages to examine for parasitaemia using rapid diagnostic tests (RDTs) and confirmed using Polymerase Chain Reaction (PCR). Blood spots were also collected on filter paper and subsequently used to evaluate the presence of serological markers (combined AMA-1 and MSP-119) of Plasmodium falciparum exposure. Multivariate regression analysis was used to determine the risk factors for P. falciparum infection and/or exposure. The Getis-Ord G-statistic was used to assess spatial heterogeneity of combined infections and serological markers. RESULTS: A total of 7151 individuals were tested using RDTs of which only 42 (0.5%) were positive for P. falciparum infections and confirmed by PCR. Filter paper blood spots were collected for 5605 individuals. Of these 4769 showed concordant optical density results and were retained in subsequent analysis. Overall P. falciparum sero-prevalence was 9.9% (517/4769) for all ages; 6.9% (46/649) in children under the age of five years; and 14.2% (76/510) in the oldest age group (≥50 years). The combined infection and/or antibody prevalence was 10.5% (550/4769) and varied from 8.1% to 14.1% but overall regional differences were not statistically significant (χ2=33.98, p=0.3144). Increasing age (p<0.001) and decreasing household wealth status (p<0.001) were significantly associated with increasing combined P. falciparum infection and/or antibody prevalence. Significant P. falciparum hot spots were observed in Dikhil region. CONCLUSION: Malaria transmission in the Republic of Djibouti is very low across all regions with evidence of micro-epidemiological heterogeneity and limited recent transmission. It would seem that the Republic of Djibouti has a biologically feasible set of pre-conditions for elimination, however, the operational feasibility and the potential risks to elimination posed by P. vivax and human population movement across the sub-region remain to be properly established

Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines

Acquisition of Growth-Inhibitory Antibodies against Blood-Stage Plasmodium falciparum

Background: Antibodies that inhibit the growth of blood-stage Plasmodium falciparum may play an important role in acquired and vaccine-induced immunity in humans. However, the acquisition and activity of these antibodies is not well understood. Methods: We tested dialysed serum and purified immunoglobulins from Kenyan children and adults for inhibition of P. falciparum blood-stage growth in vitro using different parasite lines. Serum antibodies were measured by ELISA to bloodstage parasite antigens, extracted from P. falciparum schizonts, and to recombinant merozoite surface protein 1 (42 kDa Cterminal fragment, MSP1-42). Results: Antibodies to blood-stage antigens present in schizont protein extract and to recombinant MSP1-42 significantly increased with age and were highly correlated. In contrast, growth-inhibitory activity was not strongly associated with age and tended to decline marginally with increasing age and exposure, with young children demonstrating the highest inhibitory activity. Comparison of growth-inhibitory activity among samples collected from the same population at different time points suggested that malaria transmission intensity influenced the level of growth-inhibitory antibodies. Antibodies to recombinant MSP1-42 were not associated with growth inhibition and high immunoglobulin G levels were poorly predictive of inhibitory activity. The level of inhibitory activity against different isolates varied. Conclusions: Children can acquire growth-inhibitory antibodies at a young age, but once they are acquired they do not appear to be boosted by on-going exposure. Inhibitory antibodies may play a role in protection from early childhood malaria

Prevalence of antibodies to AMA1 or specific epitopes by age group in the Chonyi cohort.

<p>Antibodies to recombinant AMA1 protein were tested by standard ELISA. Antibodies to specific AMA1 epitopes were measured by assessing the ability of human serum antibodies to inhibit the binding of monoclonal antibodies 1F9 and 2C5 in competition ELISA. (<b>A</b>) IgG to recombinant AMA1 (P&lt;0.001), (<b>B</b>) inhibition of binding of mAb 1F9 epitope (P&lt;0.001), (<b>C</b>) inhibition of binding of mAb 2C5 (P = 0.028). P values were calculated using the Chi square test for trend excluding age 0 (&lt;1) years. Data represent the proportion of individuals with detectable IgG binding or inhibitory activity and error bars indicate 95% CI.</p

Combined antibody responses to AMA1 and the risk of clinical malaria in the Chonyi cohort.

<p>Notes.</p>1<p>Children were classified as high and low responders for antibodies based on being above or below the median level for the cohort. Analysis compared children who were high responders to both antigens versus those who were low responders to both.</p>2<p>Multivariable Cox proportional hazards adjusted for age.</p>3<p>Hazard ratios show the risk of <i>P. falciparum</i> malaria over a 6 month follow-up period.</p

Association between antibody responses and risk of clinical malaria in the Chonyi cohort.

<p>Notes.</p>1<p>Children were classified as high and low responders for antibodies based on being above or below the median level for the cohort.</p>2<p>Multivariable Cox proportional hazards adjusted for age.</p>3<p>Hazard ratios show the risk of <i>P. falciparum</i> malaria over a 6 month follow-up period comparing children who were high or low antibody responders to each antigen or epitope.</p>4<p>Parasitemia detected by light microscopy.</p

Levels of inhibition of 1F9-binding by human antibodies according to age group and infection status in the Ngerenya cohort.

<p>Values show the level of inhibition of 1F9 mAb binding to AMA1 by human serum antibodies, stratified by infection status at the time of sample collection and grouped according to age. Boxes indicate median and interquartile range, and whiskers represent 95% CI. Positive 1F9 inhibition was defined as inhibition of 1F9 binding&gt;(mean +2 standard deviations of negative controls = 6.19%). Differences in the level of anti-1F9 activity among age groups was significant amongst aparasitemic individuals (P = 0.020, Kruskal Wallis test), but not amongst parasitemic individuals. The median level of anti-1F9 activity was lower amongst aparasitemic compared to parasitemic individuals (median inhibition [IQR] −0.1% [−2.8–1.7] vs 4.3% [−1.0–13.2], P = 0.002, Mann Whitney U test).</p

Optimierung der Zwischenkuehlung und der Zwischenerhitzung beim Gasturbinenprozess

In der vorliegenden Arbeit soll untersucht werden, in welcher Weise sich der thermische Wirkungsgrad des Gasturbinen-Prozesses durch Zwischenkuehlung, Zwischenerhitzung bzw. Zwischenkuehlung und Zwischenerhitzung verbessern laesst. Dabei sollen in erster Linie die Druckverhaeltnisse von ND-Verdichter bzw. HD-Turbine bestimmt werden, bei denen Zwischenkuehlung und Zwischenerhitzung vorgenommen werden sollen, um eine optimale Verbesserung des thermischen Wirkungsgrades zu erreichen. Die numerische Durchrechnung soll mit den Stoffwerten des realen Gases durchgefuehrt werden. Die numerischen Ergebnisse zeigen, dass die Zwischenkuehlung im Verdichter einen weit groesseren Einfluss auf den thermischen Wirkungsgrad hat als die Zwischenerhitzung in der Turbine. Letztere ist aber bei Gasturbinen fuer den Kombibetrieb von Vorteil, erreicht man doch die fuer die Dampferzeugung notwendigen Abgastemperaturen der Gasturbine schon bei relativ niedrigen Turbineneintrittstemperaturen, so dass die NO_x-Emission der Gasturbinen-Brennkammer gering bleibt. Als Ergebnis der Untersuchung kann gelten, dass Gasturbinen im Solobetrieb mit Zwischenkuehlung und im Kombibetrieb mit Zwischenerhitzung ausgefuehrt werden sollten. (orig.)The author investigated how the thermal efficiency of the gas turbine process can be improved by intermediate cooling, intermediate heating, or combined intermediate cooling and heating. The focus was on the pressure ratios of low-pressure compressors and high-pressure turbines. The numeric calculations were carried out using real gas characteristics. The findings suggest that intermediate coling inside the compressor has much more influence on the thermal efficiency than intermediate heating inside the turbine. However, the latter is advantageous in the case of gas turbines for combined cycle operation, as the off-gas temperatures required for steam generation are reached even at relatively low turbine inlet temperatures, so that NOx emissions of the gas turbine combustion chamber will be low. It is recommended that solitary gas turbines should be operated with intermediate cooling and gas turbines in combined cycle operation with intermediate heating.SIGLEAvailable from TIB Hannover: DtF QN1(91,58) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Iron Deficiency Is Associated With Reduced Levels of Plasmodium falciparum-specific Antibodies in African Children.

BACKGROUND: Iron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria. METHODS: The study included 1794 Kenyan and Ugandan children aged 0-7 years. We measured biomarkers of iron and inflammation, and antibodies to P. falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies. RESULTS: The overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, sex, study site, inflammation, and P. falciparum parasitemia (adjusted mean difference on a log-transformed scale (β) -0.46; 95 confidence interval [CI], -.66, -.25 P < .0001; β -0.33; 95 CI, -.50, -.16 P < .0001, respectively). Additional covariates for malaria exposure index, previous malaria episodes, and time since last malaria episode were available for individual cohorts. Meta-analysis was used to allow for these adjustments giving β -0.34; -0.52, -0.16 for anti-AMA-1 antibodies and β -0.26; -0.41, -0.11 for anti-MSP-1 antibodies. Low transferrin saturation was similarly associated with reduced anti-AMA-1 antibody levels. Lower AMA-1 and MSP-1-specific antibody levels persisted over time in iron-deficient children. CONCLUSIONS: Reduced levels of P. falciparum-specific antibodies in iron-deficient children might reflect impaired acquisition of immunity to malaria and/or reduced malaria exposure. Strategies to prevent and treat ID may influence antibody responses to malaria for children living in sub-Saharan Africa