Mathematical Modeling of Malaria Infection with Innate and Adaptive Immunity in Individuals and Agent-Based Communities

Background: Agent-based modeling of Plasmodium falciparum infection offers an attractive alternative to the conventional Ross-Macdonald methodology, as it allows simulation of heterogeneous communities subjected to realistic transmission (inoculation patterns). Methodology/Principal Findings: We developed a new, agent based model that accounts for the essential in-host processes: parasite replication and its regulation by innate and adaptive immunity. The model also incorporates a simplified version of antigenic variation by Plasmodium falciparum. We calibrated the model using data from malaria-therapy (MT) studies, and developed a novel calibration procedure that accounts for a deterministic and a pseudo-random component in the observed parasite density patterns. Using the parasite density patterns of 122 MT patients, we generated a large number of calibrated parameters. The resulting data set served as a basis for constructing and simulating heterogeneous agent-based (AB) communities of MT-like hosts. We conducted several numerical experiments subjecting AB communities to realistic inoculation patterns reported from previous field studies, and compared the model output to the observed malaria prevalence in the field. There was overall consistency, supporting the potential of this agent-based methodology to represent transmission in realistic communities. Conclusions/Significance: Our approach represents a novel, convenient and versatile method to model Plasmodiu

Evaluation of alternative mosquito sampling methods for malaria vectors in Lowland South - East Zambia.

Sampling malaria vectors and measuring their biting density is of paramount importance for entomological surveys of malaria transmission. Human landing catch (HLC) has been traditionally regarded as a gold standard method for surveying human exposure to mosquito bites. However, due to the risk of human participant exposure to mosquito-borne parasites and viruses, a variety of alternative, exposure-free trapping methods were compared in lowland, south-east Zambia. Centres for Disease Control and Prevention miniature light trap (CDC-LT), Ifakara Tent Trap model C (ITT-C), resting boxes (RB) and window exit traps (WET) were all compared with HLC using a 3 × 3 Latin Squares design replicated in 4 blocks of 3 houses with long lasting insecticidal nets, half of which were also sprayed with a residual deltamethrin formulation, which was repeated for 10 rounds of 3 nights of rotation each during both the dry and wet seasons. The mean catches of HLC indoor, HLC outdoor, CDC-LT, ITT-C, WET, RB indoor and RB outdoor, were 1.687, 1.004, 3.267, 0.088, 0.004, 0.000 and 0.008 for Anopheles quadriannulatus Theobald respectively, and 7.287, 6.784, 10.958, 5.875, 0.296, 0.158 and 0.458, for An. funestus Giles, respectively. Indoor CDC-LT was more efficient in sampling An. quadriannulatus and An. funestus than HLC indoor (Relative rate [95% Confidence Interval] = 1.873 [1.653, 2.122] and 1.532 [1.441, 1.628], respectively, P < 0.001 for both). ITT-C was the only other alternative which had comparable sensitivity (RR = 0.821 [0.765, 0.881], P < 0.001), relative to HLC indoor other than CDC-LT for sampling An. funestus. While the two most sensitive exposure-free techniques primarily capture host-seeking mosquitoes, both have substantial disadvantages for routine community-based surveillance applications: the CDC-LT requires regular recharging of batteries while the bulkiness of ITT-C makes it difficult to move between sampling locations. RB placed indoors or outdoors and WET had consistently poor sensitivity so it may be useful to evaluate additional alternative methods, such as pyrethrum spray catches and back packer aspirators, for catching resting mosquitoes

Model variations in predicting incidence of Plasmodium falciparum malaria using 1998-2007 morbidity and meteorological data from south Ethiopia

Background: Malaria transmission is complex and is believed to be associated with local climate changes. However, simple attempts to extrapolate malaria incidence rates from averaged regional meteorological conditions have proven unsuccessful. Therefore, the objective of this study was to determine if variations in specific meteorological factors are able to consistently predict P. falciparum malaria incidence at different locations in south Ethiopia. Methods: Retrospective data from 42 locations were collected including P. falciparum malaria incidence for the period of 1998-2007 and meteorological variables such as monthly rainfall (all locations), temperature (17 locations), and relative humidity (three locations). Thirty-five data sets qualified for the analysis. Ljung-Box Q statistics was used for model diagnosis, and R squared or stationary R squared was taken as goodness of fit measure. Time series modelling was carried out using Transfer Function (TF) models and univariate auto-regressive integrated moving average (ARIMA) when there was no significant predictor meteorological variable. Results: Of 35 models, five were discarded because of the significant value of Ljung-Box Q statistics. Past P. falciparum malaria incidence alone (17 locations) or when coupled with meteorological variables (four locations) was able to predict P. falciparum malaria incidence within statistical significance. All seasonal AIRMA orders were from locations at altitudes above 1742 m. Monthly rainfall, minimum and maximum temperature was able to predict incidence at four, five and two locations, respectively. In contrast, relative humidity was not able to predict P. falciparum malaria incidence. The R squared values for the models ranged from 16% to 97%, with the exception of one model which had a negative value. Models with seasonal ARIMA orders were found to perform better. However, the models for predicting P. falciparum malaria incidence varied from location to location, and among lagged effects, data transformation forms, ARIMA and TF orders. Conclusions: This study describes P. falciparum malaria incidence models linked with meteorological data. Variability in the models was principally attributed to regional differences, and a single model was not found that fits all locations. Past P. falciparum malaria incidence appeared to be a superior predictor than meteorology. Future efforts in malaria modelling may benefit from inclusion of non-meteorological factors

The plasticity of Plasmodium falciparum gametocytaemia in relation to age in Burkina Faso

BACKGROUND: Malaria transmission depends on the presence of gametocytes in the peripheral blood. In this study, the age-dependency of gametocytaemia was examined by microscopy and molecular tools. METHODS: A total of 5,383 blood samples from individuals of all ages were collected over six cross sectional surveys in Burkina Faso. One cross-sectional study used quantitative nucleic acid sequence based amplification (QT-NASBA) for parasite quantification (n = 412). The proportion of infections with concurrent gametocytaemia and median proportion of gametocytes among all parasites were calculated. RESULTS: Asexual parasite prevalence and gametocyte prevalence decreased with age. Gametocytes made up 1.8% of the total parasite population detected by microscopy in the youngest age group. This proportion gradually increased to 18.2% in adults (p < 0.001). Similarly, gametocytes made up 0.2% of the total parasite population detected by QT-NASBA in the youngest age group, increasing to 5.7% in adults (p < 0.001). This age pattern in gametocytaemia was also evident in the proportion of gametocyte positive slides without concomitant asexual parasites which increased from 13.4% (17/127) in children to 45.6% (52/114) in adults (OR 1.55, 95% CI 1.38-1.74, p < 0.001). CONCLUSIONS: The findings of this study suggest that although gametocytes are most commonly detected in children, the proportion of asexual parasites that is committed to develop into gametocytes may increase with age. These findings underscore the importance of adults for the human infectious reservoir for malaria

Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs

BACKGROUND: There is renewed acknowledgement that targeting gametocytes is essential for malaria control and elimination efforts. Simple mathematical models were fitted to data from clinical trials in order to determine the mean gametocyte circulation time and duration of gametocyte carriage in treated malaria patients. METHODS: Data were used from clinical trials from East Africa. The first trial compared non-artemisinin combination therapy (non-ACT: sulphadoxine-pyrimethamine (SP) plus amodiaquine) and artemisinin-based combination therapy (ACT: SP plus artesunate (AS) or artemether-lumefantrine). The second trial compared ACT (SP+AS) with ACT in combination with a single dose of primaquine (ACT-PQ: SP+AS+PQ). Mature gametocytes were quantified in peripheral blood samples by nucleic acid sequence based amplification. A simple deterministic compartmental model was fitted to gametocyte densities to estimate the circulation time per gametocyte; a similar model was fitted to gametocyte prevalences to estimate the duration of gametocyte carriage after efficacious treatment. RESULTS: The mean circulation time of gametocytes was 4.6-6.5 days. After non-ACT treatment, patients were estimated to carry gametocytes for an average of 55 days (95% CI 28.7 - 107.7). ACT reduced the duration of gametocyte carriage fourfold to 13.4 days (95% CI 10.2-17.5). Addition of PQ to ACT resulted in a further fourfold reduction of the duration of gametocyte carriage. CONCLUSIONS: These findings confirm previous estimates of the circulation time of gametocytes, but indicate a much longer duration of (low density) gametocyte carriage after apparently successful clearance of asexual parasites. ACT shortened the period of gametocyte carriage considerably, and had the most pronounced effect on mature gametocytes when combined with PQ

A cluster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrupt malaria transmission in a low endemic area in Tanzania

Contains fulltext : 96570.pdf (publisher's version ) (Open Access)BACKGROUND: Effective mass drug administration (MDA) with anti-malarial drugs can clear the human infectious reservoir for malaria and thereby interrupt malaria transmission. The likelihood of success of MDA depends on the intensity and seasonality of malaria transmission, the efficacy of the intervention in rapidly clearing all malaria parasite stages and the degree to which symptomatic and asymptomatic parasite carriers participate in the intervention. The impact of MDA with the gametocytocidal drug combination sulphadoxine-pyrimethamine (SP) plus artesunate (AS) plus primaquine (PQ, single dose 0.75 mg/kg) on malaria transmission was determined in an area of very low and seasonal malaria transmission in northern Tanzania. METHODS: In a cluster-randomized trial in four villages in Lower Moshi, Tanzania, eight clusters (1,110 individuals; cluster size 47- 209) were randomized to observed treatment with SP+AS+PQ and eight clusters (2,347 individuals, cluster size 55- 737) to treatment with placebo over three days. Intervention and control clusters were 1 km apart; households that were located between clusters were treated as buffer zones where all individuals received SP+AS+PQ but were not selected for the evaluation. Passive case detection was done for the entire cohort and active case detection in 149 children aged 1-10 year from the intervention arm and 143 from the control arm. Four cross-sectional surveys assessed parasite carriage by microscopy and molecular methods during a five-month follow-up period. RESULTS: The coverage rate in the intervention arm was 93.0% (1,117/1,201). Parasite prevalence by molecular detection methods was 2.2-2.7% prior to the intervention and undetectable during follow-up in both the control and intervention clusters. None of the slides collected during cross-sectional surveys had microscopically detectable parasite densities. Three clinical malaria episodes occurred in the intervention (n = 1) and control clusters (n = 2). CONCLUSIONS: This study illustrates the possibility to achieve high coverage with a three-day intervention but also the difficulty in defining suitable outcome measures to evaluate interventions in areas of very low malaria transmission intensity. The decline in transmission intensity prior to the intervention made it impossible to assess the impact of MDA in the chosen study setting. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00509015

Marked variation in MSP-119 antibody responses to malaria in western Kenyan highlands

<p>Abstract</p> <p>Background</p> <p>Assessment of malaria endemicity at different altitudes and transmission intensities, in the era of dwindling vector densities in the highlands, will provide valuable information for malaria control and surveillance. Measurement of serum anti-malarial antibodies is a useful marker of malaria exposure that indicates long-term transmission potential. We studied the serologic evidence of malaria endemicity at two highland sites along a transmission intensity cline. An improved understanding of the micro-geographic variation in malaria exposure in the highland ecosystems will be relevant in planning effective malaria control.</p> <p>Methods</p> <p>Total IgG levels to <it>Plasmodium falciparum </it>MSP-1₁₉were measured in an age-stratified cohort (< 5, 5-14 and ≥ 15 years) in 795 participants from an uphill and valley bottom residents during low and high malaria transmission seasons. Antibody prevalence and level was compared between different localities. Regression analysis was performed to examine the association between antibody prevalence and parasite prevalence. Age-specific MSP-1₁₉seroprevalence data was fitted to a simple reversible catalytic model to investigate the relationship between parasite exposure and age.</p> <p>Results</p> <p>Higher MSP-1₁₉seroprevalence and density were observed in the valley residents than in the uphill dwellers. Adults (> 15 years) recorded high and stable immune response in spite of changing seasons. Lower responses were observed in children (≤ 15 years), which, fluctuated with changing seasons particularly in the valley residents. In the uphill population, annual seroconversion rate (SCR) was 8.3% and reversion rate was 3.0%, with seroprevalence reaching a plateau of 73.3% by age of 20. Contrary, in the valley bottom population, the annual SCR was 35.8% and the annual seroreversion rate was 3.5%, and seroprevalence in the population had reached 91.2% by age 10.</p> <p>Conclusion</p> <p>The study reveals the micro-geographic variation in malaria endemicity in the highland eco-system; this validates the usefulness of sero-epidemiological tools in assessing malaria endemicity in the era of decreasing sensitivity of conventional tools.</p

Population, behavioural and environmental drivers of malaria prevalence in the Democratic Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Malaria is highly endemic in the Democratic Republic of Congo (DRC), but the limits and intensity of transmission within the country are unknown. It is important to discern these patterns as well as the drivers which may underlie them in order for effective prevention measures to be carried out.</p> <p>Methods</p> <p>By applying high-throughput PCR analyses on leftover dried blood spots from the 2007 Demographic and Health Survey (DHS) for the DRC, prevalence estimates were generated and ecological drivers of malaria were explored using spatial statistical analyses and multilevel modelling.</p> <p>Results</p> <p>Of the 7,746 respondents, 2268 (29.3%) were parasitaemic; prevalence ranged from 0-82% within geographically-defined survey clusters. Regional variation in these rates was mapped using the inverse-distance weighting spatial interpolation technique. Males were more likely to be parasitaemic than older people or females (p < 0.0001), while wealthier people were at a lower risk (p < 0.001). Increased community use of bed nets (p = 0.001) and community wealth (p < 0.05) were protective against malaria at the community level but not at the individual level. Paradoxically, the number of battle events since 1994 surrounding one's community was negatively associated with malaria risk (p < 0.0001).</p> <p>Conclusions</p> <p>This research demonstrates the feasibility of using population-based behavioural and molecular surveillance in conjunction with DHS data and geographic methods to study endemic infectious diseases. This study provides the most accurate population-based estimates to date of where illness from malaria occurs in the DRC and what factors contribute to the estimated spatial patterns. This study suggests that spatial information and analyses can enable the DRC government to focus its control efforts against malaria.</p

Malaria vaccines and their potential role in the elimination of malaria

Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely

A Sub-Microscopic Gametocyte Reservoir Can Sustain Malaria Transmission

Novel diagnostic tools, including PCR and high field gradient magnetic fractionation (HFGMF), have improved detection of asexual Plasmodium falciparum parasites and especially infectious gametocytes in human blood. These techniques indicate a significant number of people carry gametocyte densities that fall below the conventional threshold of detection achieved by standard light microscopy (LM).To determine how low-level gametocytemia may affect transmission in present large-scale efforts for P. falciparum control in endemic areas, we developed a refinement of the classical Ross-Macdonald model of malaria transmission by introducing multiple infective compartments to model the potential impact of highly prevalent, low gametocytaemic reservoirs in the population. Models were calibrated using field-based data and several numerical experiments were conducted to assess the effect of high and low gametocytemia on P. falciparum transmission and control. Special consideration was given to the impact of long-lasting insecticide-treated bed nets (LLIN), presently considered the most efficient way to prevent transmission, and particularly LLIN coverage similar to goals targeted by the Roll Back Malaria and Global Fund malaria control campaigns. Our analyses indicate that models which include only moderate-to-high gametocytemia (detectable by LM) predict finite eradication times after LLIN introduction. Models that include a low gametocytemia reservoir (requiring PCR or HFGMF detection) predict much more stable, persistent transmission. Our modeled outcomes result in significantly different estimates for the level and duration of control needed to achieve malaria elimination if submicroscopic gametocytes are included.It will be very important to complement current methods of surveillance with enhanced diagnostic techniques to detect asexual parasites and gametocytes to more accurately plan, monitor and guide malaria control programs aimed at eliminating malaria