Serology describes a profile of declining malaria transmission in Farafenni, The Gambia

BACKGROUND: Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes. METHODS: Data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011 were compiled. Antibody responses to MSP-119 were measured in samples from all surveys, data were normalized and expressed as seroprevalence and seroconversion rates (SCR) using different mathematical models. RESULTS: Results showed declines in serological metrics with seroprevalence in children aged one to 5 years dropping from 19 % (95 % CI 15-23 %) in 1988 to 1 % (0-2 %) in 2011 (p value for trend in proportions < 0.001) and the SCR dropping from 0.069 year(-1) (0.059-0.080) to 0.022 year(-1) (0.017-0.028; p = 0.004). The serological data were consistent with previously described drops in both parasite prevalence in children aged 1-5 years (62 %, 57-66 %, in 1988 to 2 %, 0-4 %, in 2011; p < 0.001), and all-cause under five mortality rates (37 per 1000 person-years, 34-41, in 1990 to 17, 15-19, in 2006; p = 0.059). CONCLUSIONS: This analysis shows accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses. Demonstrating congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring and evaluation of malaria transmission

Serological Markers Suggest Heterogeneity of Effectiveness of Malaria Control Interventions on Bioko Island, Equatorial Guinea

BACKGROUND: In order to control and eliminate malaria, areas of on-going transmission need to be identified and targeted for malaria control interventions. Immediately following intense interventions, malaria transmission can become more heterogeneous if interventions are more successful in some areas than others. Bioko Island, Equatorial Guinea, has been subject to comprehensive malaria control interventions since 2004. This has resulted in substantial reductions in the parasite burden, although this drop has not been uniform across the island. METHODS/PRINCIPAL FINDINGS: In 2008, filter paper blood samples were collected from 7387 people in a cross-sectional study incorporating 18 sentinel sites across Bioko, Equatorial Guinea. Antibodies were measured to P. falciparum Apical Membrane Antigen-1 (AMA-1) by Enzyme Linked Immunosorbent Assay (ELISA). Age-specific seropositivity rates were used to estimate seroconversion rates (SCR). Analysis indicated there had been at least a 60% decline in SCR in four out of five regions on the island. Changes in SCR showed a high degree of congruence with changes in parasite rate (PR) and with regional reductions in all cause child mortality. The mean age adjusted concentration of anti-AMA-1 antibodies was mapped to identify areas where individual antibody responses were higher than expected. This approach confirmed the North West of the island as a major focus of continuing infection and an area where control interventions need to be concentrated or re-evaluated. CONCLUSION/INTERPRETATION: Both SCR and PR revealed heterogeneity in malaria transmission and demonstrated the variable effectiveness of malaria control measures. This work confirms the utility of serological analysis as an adjunct measure for monitoring transmission. Age-specific seroprevalence based evidence of changes in transmission over time will be of particular value when no baseline data are available. Importantly, SCR data provide additional evidence to link malaria control activities to contemporaneous reductions in all-cause child mortality

Serologically defined variations in malaria endemicity in Pará state, Brazil

BACKGROUND: Measurement of malaria endemicity is typically based on vector or parasite measures. A complementary approach is the detection of parasite specific IgG antibodies. We determined the antibody levels and seroconversion rates to both P. vivax and P. falciparum merozoite antigens in individuals living in areas of varying P. vivax endemicity in Pará state, Brazilian Amazon region. METHODOLOGY/PRINCIPAL FINDINGS: The prevalence of antibodies to recombinant antigens from P. vivax and P. falciparum was determined in 1,330 individuals. Cross sectional surveys were conducted in the north of Brazil in Anajás, Belém, Goianésia do Pará, Jacareacanga, Itaituba, Trairão, all in the Pará state, and Sucuriju, a free-malaria site in the neighboring state Amapá. Seroprevalence to any P. vivax antigens (MSP1 or AMA-1) was 52.5%, whereas 24.7% of the individuals were seropositive to any P. falciparum antigens (MSP1 or AMA-1). For P. vivax antigens, the seroconversion rates (SCR) ranged from 0.005 (Sucuriju) to 0.201 (Goianésia do Pará), and are strongly correlated to the corresponding Annual Parasite Index (API). We detected two sites with distinct characteristics: Goianésia do Pará where seroprevalence curve does not change with age, and Sucuriju where seroprevalence curve is better described by a model with two SCRs compatible with a decrease in force of infection occurred 14 years ago (from 0.069 to 0.005). For P. falciparum antigens, current SCR estimates varied from 0.002 (Belém) to 0.018 (Goianésia do Pará). We also detected a putative decrease in disease transmission occurred ∼29 years ago in Anajás, Goianésia do Pará, Itaituba, Jacareacanga, and Trairão. CONCLUSIONS: We observed heterogeneity of serological indices across study sites with different endemicity levels and temporal changes in the force of infection in some of the sites. Our study provides further evidence that serology can be used to measure and monitor transmission of both major species of malaria parasite

Estimating malaria transmission intensity from Plasmodium falciparum serological data using antibody density models.

BACKGROUND: Serological data are increasingly being used to monitor malaria transmission intensity and have been demonstrated to be particularly useful in areas of low transmission where traditional measures such as EIR and parasite prevalence are limited. The seroconversion rate (SCR) is usually estimated using catalytic models in which the measured antibody levels are used to categorize individuals as seropositive or seronegative. One limitation of this approach is the requirement to impose a fixed cut-off to distinguish seropositive and negative individuals. Furthermore, the continuous variation in antibody levels is ignored thereby potentially reducing the precision of the estimate. METHODS: An age-specific density model which mimics antibody acquisition and loss was developed to make full use of the information provided by serological measures of antibody levels. This was fitted to blood-stage antibody density data from 12 villages at varying transmission intensity in Northern Tanzania to estimate the exposure rate as an alternative measure of transmission intensity. RESULTS: The results show a high correlation between the exposure rate estimates obtained and the estimated SCR obtained from a catalytic model (r = 0.95) and with two derived measures of EIR (r = 0.74 and r = 0.81). Estimates of exposure rate obtained with the density model were also more precise than those derived from catalytic models. CONCLUSION: This approach, if validated across different epidemiological settings, could be a useful alternative framework for quantifying transmission intensity, which makes more complete use of serological data

Health Centre Surveys as a Potential Tool for Monitoring Malaria Epidemiology by Area and over Time

BACKGROUND: Presently, many malaria control programmes use health facility data to evaluate the impact of their interventions. Facility-based malaria data, although useful, have problems with completeness, validity and representativeness and reliance on routinely collected health facility data might undermine demonstration of the magnitude of the impact of the recent scaleups of malaria interventions. To determine whether carefully conducted health centre surveys can be reliable means of monitoring area specific malaria epidemiology, we have compared malaria specific indices obtained from surveys in health centres with indices obtained from cross-sectional surveys conducted in their catchment communities. METHODS: A series of age stratified, seasonal, cross-sectional surveys were conducted during the peak malaria transmission season in 2008 and during the following dry season in 2009 in six ecologically diverse areas in The Gambia. Participants were patients who attended the health centres plus a representative sample from the catchment villages of these health facilities. Parasitaemia, anaemia, attributable proportion of fever and anti-MSP1-(19) antibody seroprevalence were compared in the health facility attendees and community participants. RESULTS: A total of 16,230 subjects completed the study; approximately half participated in the health centre surveys and half in the wet season surveys. Data from both the health centre and community surveys showed that malaria endemicity in The Gambia is now low, heterogeneous and seasonal. In the wet season, parasitaemia, seroprevalence and fever prevalence were higher in subjects seen in the health centres than in the community surveys. Age patterns of parasitaemia, attributable proportions of fever and seroprevalence rates were similar in subjects who participated in the community and health centre surveys. CONCLUSION: Health centre surveys have potential as a surveillance tool for evaluating area specific malaria control activities and for monitoring changes in local malaria epidemiology over time

Detecting Foci of Malaria Transmission with School Surveys: A Pilot Study in the Gambia.

BACKGROUND: In areas of declining malaria transmission such as in The Gambia, the identification of malaria infected individuals becomes increasingly harder. School surveys may be used to identify foci of malaria transmission in the community. METHODS: The survey was carried out in May-June 2011, before the beginning of the malaria transmission season. Thirty two schools in the Upper River Region of The Gambia were selected with probability proportional to size; in each school approximately 100 children were randomly chosen for inclusion in the study. Each child had a finger prick blood sample collected for the determination of antimalarial antibodies by ELISA, malaria infection by microscopy and PCR, and for haemoglobin measurement. In addition, a simple questionnaire on socio-demographic variables and the use of insecticide-treated bed nets was completed. The cut-off for positivity for antimalarial antibodies was obtained using finite mixture models. The clustered nature of the data was taken into account in the analyses. RESULTS: A total of 3,277 children were included in the survey. The mean age was 10 years (SD = 2.7) [range 4-21], with males and females evenly distributed. The prevalence of malaria infection as determined by PCR was 13.6% (426/3124) [95% CI = 12.2-16.3] with marked variation between schools (range 3-25%, p<0.001), while the seroprevalence was 7.8% (234/2994) [95%CI = 6.4-9.8] for MSP119, 11.6% (364/2997) [95%CI = 9.4-14.5] for MSP2, and 20.0% (593/2973) [95% CI = 16.5-23.2) for AMA1. The prevalence of all the three antimalarial antibodies positive was 2.7% (79/2920). CONCLUSIONS: This survey shows that malaria prevalence and seroprevalence before the transmission season were highly heterogeneous

Sero-epidemiological evaluation of changes in Plasmodium falciparum and Plasmodium vivax transmission patterns over the rainy season in Cambodia

<p>Abstract</p> <p>Background</p> <p>In Cambodia, malaria transmission is low and most cases occur in forested areas. Sero-epidemiological techniques can be used to identify both areas of ongoing transmission and high-risk groups to be targeted by control interventions. This study utilizes repeated cross-sectional data to assess the risk of being malaria sero-positive at two consecutive time points during the rainy season and investigates who is most likely to sero-convert over the transmission season.</p> <p>Methods</p> <p>In 2005, two cross-sectional surveys, one in the middle and the other at the end of the malaria transmission season, were carried out in two ecologically distinct regions in Cambodia. Parasitological and serological data were collected in four districts. Antibodies to <it>Plasmodium falciparum </it>Glutamate Rich Protein (GLURP) and <it>Plasmodium vivax </it>Merozoite Surface Protein-1₁₉(MSP-1₁₉) were detected using Enzyme Linked Immunosorbent Assay (ELISA). The force of infection was estimated using a simple catalytic model fitted using maximum likelihood methods. Risks for sero-converting during the rainy season were analysed using the Classification and Regression Tree (CART) method.</p> <p>Results</p> <p>A total of 804 individuals participating in both surveys were analysed. The overall parasite prevalence was low (4.6% and 2.0% for <it>P. falciparum </it>and 7.9% and 6.0% for <it>P. vivax </it>in August and November respectively). <it>P. falciparum </it>force of infection was higher in the eastern region and increased between August and November, whilst <it>P. vivax </it>force of infection was higher in the western region and remained similar in both surveys. In the western region, malaria transmission changed very little across the season (for both species). CART analysis for <it>P. falciparum </it>in the east highlighted age, ethnicity, village of residence and forest work as important predictors for malaria exposure during the rainy season. Adults were more likely to increase their antibody responses to <it>P. falciparum </it>during the transmission season than children, whilst members of the Charay ethnic group demonstrated the largest increases.</p> <p>Discussion</p> <p>In areas of low transmission intensity, such as in Cambodia, the analysis of longitudinal serological data enables a sensitive evaluation of transmission dynamics. Consecutive serological surveys allow an insight into spatio-temporal patterns of malaria transmission. The use of CART enabled multiple interactions to be accounted for simultaneously and permitted risk factors for exposure to be clearly identified.</p

Using serological measures to monitor changes in malaria transmission in Vanuatu

BACKGROUND: With renewed interest in malaria elimination, island environments present unique opportunities to achieve this goal. However, as transmission decreases, monitoring and evaluation programmes need increasingly sensitive tools to assess Plasmodium falciparum and Plasmodium vivax exposure. In 2009, to assess the role of serological markers in evaluating malaria transmission, a cross-sectional seroprevalence study was carried out in Tanna and Aneityum, two of the southernmost islands of the Vanuatu archipelago, areas where malaria transmission has been variably reduced over the past few decades. METHODS: Malaria transmission was assessed using serological markers for exposure to P. falciparum and P. vivax. Filter blood spot papers were collected from 1,249 people from Tanna, and 517 people from Aneityum to assess the prevalence of antibodies to two P. falciparum antigens (MSP-119 and AMA-1) and two P. vivax antigens (MSP-119 and AMA-1). Age-specific prevalence was modelled using a simple catalytic conversion model based on maximum likelihood to generate a community seroconversion rate (SCR). RESULTS: Overall seropositivity in Tanna was 9.4%, 12.4% and 16.6% to P. falciparum MSP-119, AMA-1 and Schizont Extract respectively and 12.6% and 15.0% to P. vivax MSP-119 and AMA-1 respectively. Serological results distinguished between areas of differential dominance of either P. vivax or P. falciparum and analysis of age-stratified results showed a step in seroprevalence occurring approximately 30 years ago on both islands, indicative of a change in transmission intensity at this time. Results from Aneityum suggest that several children may have been exposed to malaria since the 2002 P. vivax epidemic. CONCLUSION: Seroepidemiology can provide key information on malaria transmission for control programmes, when parasite rates are low. As Vanuatu moves closer to malaria elimination, monitoring changes in transmission intensity and identification of residual malaria foci is paramount in order to concentrate intervention efforts

Hot Spot or Not: A Comparison of Spatial Statistical Methods to Predict Prospective Malaria Infections.

Within affected communities, Plasmodium falciparum infections may be skewed in distribution such that single or small clusters of households consistently harbour a disproportionate number of infected individuals throughout the year. Identifying these hotspots of malaria transmission would permit targeting of interventions and a more rapid reduction in malaria burden across the whole community. This study set out to compare different statistical methods of hotspot detection (SaTScan, kernel smoothing, weighted local prevalence) using different indicators (PCR positivity, AMA-1 and MSP-1 antibodies) for prediction of infection the following year. Two full surveys of four villages in Mwanza, Tanzania were completed over consecutive years, 2010-2011. In both surveys, infection was assessed using nested polymerase chain reaction (nPCR). In addition in 2010, serologic markers (AMA-1 and MSP-119 antibodies) of exposure were assessed. Baseline clustering of infection and serological markers were assessed using three geospatial methods: spatial scan statistics, kernel analysis and weighted local prevalence analysis. Methods were compared in their ability to predict infection in the second year of the study using random effects logistic regression models, and comparisons of the area under the receiver operating curve (AUC) for each model. Sensitivity analysis was conducted to explore the effect of varying radius size for the kernel and weighted local prevalence methods and maximum population size for the spatial scan statistic. Guided by AUC values, the kernel method and spatial scan statistics appeared to be more predictive of infection in the following year. Hotspots of PCR-detected infection and seropositivity to AMA-1 were predictive of subsequent infection. For the kernel method, a 1 km window was optimal. Similarly, allowing hotspots to contain up to 50% of the population was a better predictor of infection in the second year using spatial scan statistics than smaller maximum population sizes. Clusters of AMA-1 seroprevalence or parasite prevalence that are predictive of infection a year later can be identified using geospatial models. Kernel smoothing using a 1 km window and spatial scan statistics both provided accurate prediction of future infection

Antibodies elicited in adults by a primary Plasmodium falciparum blood-stage infection recognize different epitopes compared with immune individuals

<p>Abstract</p> <p>Background</p> <p>Asexual stage antibody responses following initial <it>Plasmodium falciparum </it>infections in previously healthy adults may inform vaccine development, yet these have not been as intensively studied as they have in populations from malaria-endemic areas.</p> <p>Methods</p> <p>Serum samples were collected over a six-month period from twenty travellers having returned with falciparum malaria. Fourteen of these were malaria-naïve and six had a past history of one to two episodes of malaria. Antibodies to seven asexual stage <it>P. falciparum </it>antigens were measured by ELISA. Invasion inhibitory antibody responses to the 19kDa fragment of merozoite surface protein 1 (MSP1₁₉) were determined.</p> <p>Results</p> <p>Short-lived antibody responses were found in the majority of the subjects. While MSP1₁₉antibodies were most common, MSP1 block 2 antibodies were significantly less frequent and recognized conserved domains. Antibodies to MSP2 cross-reacted to the dimorphic allelic families and anti-MSP2 isotypes were not IgG3 skewed as shown previously. MSP1₁₉invasion inhibiting antibodies were present in 9/20 patients. A past history of malaria did not influence the frequency of these short-lived, functional antibodies (p = 0.2, 2-tailed Fisher's exact test).</p> <p>Conclusion</p> <p>Adults infected with <it>P. falciparum </it>for the first time, develop relatively short-lived immune responses that, in the case of MSP1₁₉, are functional. Antibodies to the polymorphic antigens studied were particularly directed to allelic family specific, non-repetitive and conserved determinants and were not IgG subclass skewed. These responses are substantially different to those found in malaria immune individuals.</p