Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies.

Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission.

Patterns of child mortality in rural area of Burkina Faso: evidence from the Nanoro health and demographic surveillance system (HDSS).

BACKGROUND: Half of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but patterns and potential drivers of heterogeneity in child mortality in the district had not been studied. Similar studies in other districts indicated proximity to health facilities as a risk factor, usually without distinction between facility types. METHODS: Using Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and proximity to inpatient and outpatient health facilities, seasonality of death, age group, and standard demographic risk factors. RESULTS: Living in homes 40-60 min and > 60 min travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13-2.06) and 1.74 (95% CI: 1.27-2.40) greater hazard of under-5 mortality, respectively, than living in homes < 20 min from an inpatient facility. No such association was found for outpatient facilities. The wet season (July-November) was associated with 1.28 (95% CI: 1.07, 1.53) higher under-5 mortality than the dry season (December-June), likely reflecting the malaria season. CONCLUSIONS: Our results emphasize the importance of geographical proximity to health care, distinguish between inpatient and outpatient facilities, and also show a seasonal effect, probably driven by malaria.

Modeling the impact of Plasmodium falciparum sexual stage immunity on the composition and dynamics of the human infectious reservoir for malaria in natural settings.

Malaria transmission remains high in Sub-Saharan Africa despite large-scale implementation of malaria control interventions. A comprehensive understanding of the transmissibility of infections to mosquitoes may guide the design of more effective transmission reducing strategies. The impact of P. falciparum sexual stage immunity on the infectious reservoir for malaria has never been studied in natural settings. Repeated measurements were carried out at start-wet, peak-wet and dry season, and provided data on antibody responses against gametocyte/gamete antigens Pfs48/45 and Pfs230 as anti-gametocyte immunity. Data on high and low-density infections and their infectiousness to anopheline mosquitoes were obtained using quantitative molecular methods and mosquito feeding assays, respectively. An event-driven model for P. falciparum sexual stage immunity was developed and fit to data using an agent based malaria model infrastructure. We found that Pfs48/45 and Pfs230 antibody densities increased with increasing concurrent gametocyte densities; associated with 55-70% reduction in oocyst intensity and achieved up to 44% reduction in proportions of infected mosquitoes. We showed that P. falciparum sexual stage immunity significantly reduces transmission of microscopic (p < 0.001) but not submicroscopic (p = 0.937) gametocyte infections to mosquitoes and that incorporating sexual stage immunity into mathematical models had a considerable impact on the contribution of different age groups to the infectious reservoir of malaria. Human antibody responses to gametocyte antigens are likely to be dependent on recent and concurrent high-density gametocyte exposure and have a pronounced impact on the likelihood of onward transmission of microscopic gametocyte densities compared to low density infections. Our mathematical simulations indicate that anti-gametocyte immunity is an important factor for predicting and understanding the composition and dynamics of the human infectious reservoir for malaria.

A microplanning model to improve door-to-door health service delivery: the case of Seasonal Malaria Chemoprevention in Sub-Saharan African villages.

BACKGROUND: Malaria incidence has plateaued in Sub-Saharan Africa despite Seasonal Malaria Chemoprevention's (SMC) introduction. Community health workers (CHW) use a door-to-door delivery strategy to treat children with SMC drugs, but for SMC to be as effective as in clinical trials, coverage must be high over successive seasons. METHODS: We developed and used a microplanning model that utilizes population raster to estimate population size, generates optimal households visit itinerary, and quantifies SMC coverage based on CHWs' time investment for treatment and walking. CHWs' performance under current SMC deployment mode was assessed using CHWs' tracking data and compared to microplanning in villages with varying demographics and geographies. RESULTS: Estimates showed that microplanning significantly reduces CHWs' walking distance by 25%, increases the number of visited households by 36% (p < 0.001) and increases SMC coverage by 21% from 37.3% under current SMC deployment mode up to 58.3% under microplanning (p < 0.001). Optimal visit itinerary alone increased SMC coverage up to 100% in small villages whereas in larger or hard-to-reach villages, filling the gap additionally needed an optimization of the CHW ratio. CONCLUSION: We estimate that for a pair of CHWs, the daily optimal number of visited children (assuming 8.5mn spent per child) and walking distance should not exceed 45 (95% CI 27-62) and 5 km (95% CI 3.2-6.2) respectively. Our work contributes to extend SMC coverage by 21-63% and may have broader applicability for other community health programs.

Dynamics of the Human Infectious Reservoir for Malaria Determined by Mosquito Feeding Assays and Ultrasensitive Malaria Diagnosis in Burkina Faso.

BACKGROUND: Plasmodium falciparum gametocytes are essential for malaria transmission. Malaria control measures that aim at reducing transmission require an accurate characterization of the human infectious reservoir. METHODS: We longitudinally determined human infectiousness to mosquitoes and P. falciparum carriage by an ultrasensitive RNA-based diagnostics in 130 randomly selected inhabitants of an endemic area. RESULTS: At least 1 mosquito was infected by 32.6% (100 of 307) of the blood samples; in total, 7.6% of mosquitoes (916 of 12 079) were infected. The proportion of infectious individuals and infected mosquitoes were negatively associated with age and positively with asexual parasites (P < .001). Human infectiousness was higher at the start of the wet season and subsequently declined at the peak of the wet season (adjusted odds ratio, 0.52; P = .06) and in the dry season (0.23; P < .001). Overall, microscopy-negative individuals were responsible for 28.7% of infectious individuals (25 of 87) and 17.0% of mosquito infections (145 of 855). CONCLUSIONS: Our study reveals that the infectious reservoir peaks at the start of the wet season, with prominent roles for infections in children and submicroscopic infections. These findings have important consequences for strategies and the timing of interventions, which need to include submicroscopic infections and be implemented in the dry season.

Key traveller groups of relevance to spatial malaria transmission: a survey of movement patterns in four sub-Saharan African countries.

BACKGROUND: As malaria prevalence declines in many parts of the world due to widescale control efforts and as drug-resistant parasites begin to emerge, a quantitative understanding of human movement is becoming increasingly relevant to malaria control. However, despite its importance, significant knowledge gaps remain regarding human movement, particularly in sub-Saharan Africa. METHODS: A quantitative survey of human movement patterns was conducted in four countries in sub-Saharan Africa: Mali, Burkina Faso, Zambia, and Tanzania, with three to five survey locations chosen in each country. Questions were included on demographic and trip details, malaria risk behaviour, children accompanying travellers, and mobile phone usage to enable phone signal data to be better correlated with movement. A total of 4352 individuals were interviewed and 6411 trips recorded. RESULTS: A cluster analysis of trips highlighted two distinct traveller groups of relevance to malaria transmission: women travelling with children (in all four countries) and youth workers (in Mali). Women travelling with children were more likely to travel to areas of relatively high malaria prevalence in Mali (OR = 4.46, 95% CI = 3.42-5.83), Burkina Faso (OR = 1.58, 95% CI = 1.23-1.58), Zambia (OR = 1.50, 95% CI = 1.20-1.89), and Tanzania (OR = 2.28, 95% CI = 1.71-3.05) compared to other travellers. They were also more likely to own bed nets in Burkina Faso (OR = 1.77, 95% CI = 1.25-2.53) and Zambia (OR = 1.74, 95% CI = 1.34 2.27), and less likely to own a mobile phone in Mali (OR = 0.50, 95% CI = 0.39-0.65), Burkina Faso (OR = 0.39, 95% CI = 0.30-0.52), and Zambia (OR = 0.60, 95% CI = 0.47-0.76). Malian youth workers were more likely to travel to areas of relatively high malaria prevalence (OR = 23, 95% CI = 17-31) and for longer durations (mean of 70 days cf 21 days, p < 0.001) compared to other travellers. CONCLUSIONS: Women travelling with children were a remarkably consistent traveller group across all four countries surveyed. They are expected to contribute greatly towards spatial malaria transmission because the children they travel with tend to have high parasite prevalence. Youth workers were a significant traveller group in Mali and are expected to contribute greatly to spatial malaria transmission because their movements correlate with seasonal rains and hence peak mosquito densities. Interventions aimed at interrupting spatial transmission of parasites should consider these traveller groups.

Improving statistical inference on pathogen densities estimated by quantitative molecular methods: malaria gametocytaemia as a case study.

BACKGROUND: Quantitative molecular methods (QMMs) such as quantitative real-time polymerase chain reaction (q-PCR), reverse-transcriptase PCR (qRT-PCR) and quantitative nucleic acid sequence-based amplification (QT-NASBA) are increasingly used to estimate pathogen density in a variety of clinical and epidemiological contexts. These methods are often classified as semi-quantitative, yet estimates of reliability or sensitivity are seldom reported. Here, a statistical framework is developed for assessing the reliability (uncertainty) of pathogen densities estimated using QMMs and the associated diagnostic sensitivity. The method is illustrated with quantification of Plasmodium falciparum gametocytaemia by QT-NASBA. RESULTS: The reliability of pathogen (e.g. gametocyte) densities, and the accompanying diagnostic sensitivity, estimated by two contrasting statistical calibration techniques, are compared; a traditional method and a mixed model Bayesian approach. The latter accounts for statistical dependence of QMM assays run under identical laboratory protocols and permits structural modelling of experimental measurements, allowing precision to vary with pathogen density. Traditional calibration cannot account for inter-assay variability arising from imperfect QMMs and generates estimates of pathogen density that have poor reliability, are variable among assays and inaccurately reflect diagnostic sensitivity. The Bayesian mixed model approach assimilates information from replica QMM assays, improving reliability and inter-assay homogeneity, providing an accurate appraisal of quantitative and diagnostic performance. CONCLUSIONS: Bayesian mixed model statistical calibration supersedes traditional techniques in the context of QMM-derived estimates of pathogen density, offering the potential to improve substantially the depth and quality of clinical and epidemiological inference for a wide variety of pathogens.

Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial.

BACKGROUND: Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans. METHODS: In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates. RESULTS: The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07-1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment. CONCLUSIONS: We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes. CLINICAL TRIALS REGISTRATION: NCT0160325.

Characterization of the infectious reservoir of malaria with an agent-based model calibrated to age-stratified parasite densities and infectiousness.

BACKGROUND: Elimination of malaria can only be achieved through removal of all vectors or complete depletion of the infectious reservoir in humans. Mechanistic models can be built to synthesize diverse observations from the field collected under a variety of conditions and subsequently used to query the infectious reservoir in great detail. METHODS: The EMOD model of malaria transmission was calibrated to prevalence, incidence, asexual parasite density, gametocyte density, infection duration, and infectiousness data from nine study sites. The infectious reservoir was characterized by age and parasite detectability with diagnostics of varying sensitivity over a range of transmission intensities with and without case management and vector control. Mass screen-and-treat drug campaigns were tested for likelihood of achieving elimination. RESULTS: The composition of the infectious reservoir is similar over a range of transmission intensities, and higher intensity settings are biased towards infections in children. Recent ramp-ups in case management and use of insecticide-treated bed nets (ITNs) reduce the infectious reservoir and shift the composition towards sub-microscopic infections. Mass campaigns with anti-malarial drugs are highly effective at interrupting transmission if deployed shortly after ITN campaigns. CONCLUSIONS: Low-density infections comprise a substantial portion of the infectious reservoir. Proper timing of vector control, seasonal variation in transmission intensity and mass drug campaigns allows lingering population immunity to help drive a region towards elimination.

Has the Gratuité policy reduced inequities in geographic access to antenatal care in Burkina Faso? Evidence from facility-based data from 2014 to 2022.

Background: Evidence shows that user fee exemption policies improve the use of maternal, newborn, and child health (MNCH) services. However, addressing the cost of care is only one barrier to accessing MNCH services. Poor geographic accessibility relating to distance is another. Our objective in this study was to assess the effect of a user fee exemption policy in Burkina Faso (Gratuité) on antenatal care (ANC) use, considering distance to health facilities. Methods: We conducted a cross-sectional study with sub-analysis by intervention period to compare utilization of ANC services (outcome of interest) in pregnant women who used the service in the context of the Gratuité user fee exemption policy and those who did not, in Manga district, Burkina Faso. Dependent variables included were socio-demographic characteristics, obstetric history, and distance to the lower-level health facility (known as Centre de Santé et Promotion Sociale) in which care was sort. Univariate, bivariate, and multivariate analyses were performed across the entire population, within those who used ANC before the policy and after its inception. Results: For women who used services before the Gratuité policy was introduced, those living 5-9 km were almost twice (OR = 1.94; 95% CI: 1.17-3.21) more likely to have their first ANC visit (ANC1) in the first trimester compared to those living <5 km of the nearest health facility. After the policy was introduced, women living 5-9 km and >10 km from the nearest facility were almost twice (OR = 1.86; 95% CI: 1.14-3.05) and over twice (OR = 2.04; 95% CI: 1.20-3.48) more likely respectively to use ANC1 in the first trimester compared to those living within 5 km of the nearest health facility. Also, women living over 10 km from the nearest facility were 1.29 times (OR = 1.29; 95% CI: 1.00-1.66) more likely to have 4+ ANC than those living less than 5 km from the nearest health facility. Conclusions: Insofar as the financial barrier to ANC has been lifted and the geographical barrier reduced for the populations that live farther away from services through the Gratuité policy, then the Burkinabé government must make efforts to sustain the policy and ensure that benefits of the policy reach the targeted and its gains maximized.

Naturally acquired immune responses to Plasmodium falciparum sexual stage antigens Pfs48/45 and Pfs230 in an area of seasonal transmission.

Acquisition of immunity to Plasmodium falciparum sexual stages is a key determinant for reducing human-mosquito transmission by preventing the fertilization and the development of the parasite in the mosquito midgut. Naturally acquired immunity against sexual stages may therefore form the basis for the development of transmission-blocking vaccines, but studies conducted to date offer little in the way of consistent findings. Here, we describe the acquisition of antigametocyte immune responses in malaria-exposed individuals in Burkina Faso. A total of 719 blood samples were collected in a series of three cross-sectional surveys at the start, peak, and end of the wet season. The seroprevalence of antibodies with specificity for the sexual stage antigens Pfs48/45 and Pfs230 was 2-fold lower (22 to 28%) than that for an asexual blood stage antigen glutamate-rich protein (GLURP) (65%) or for the preerythrocytic stage antigen circumsporozoite protein (CSP) (54%). The youngest children responded at frequencies similar to those for all four antigens but, in contrast with the immune responses to GLURP and CSP that increased with age independently of season and area of residence, there was no evidence for a clear age dependence of responses to Pfs48/45 and Pfs230. Anti-Pfs230 antibodies were most prevalent at the peak of the wet season (P < 0.001). Our findings suggest that naturally acquired immunity against Pfs48/45 and Pfs230 is a function of recent exposure rather than of cumulative exposure to gametocytes.

Seeding COVID-19 across Sub-Saharan Africa: An Analysis of Reported Importation Events across 49 Countries.

The first case of COVID-19 in sub-Saharan Africa (SSA) was reported by Nigeria on February 27, 2020. Whereas case counts in the entire region remain considerably less than those being reported by individual countries in Europe, Asia, and the Americas, variation in preparedness and response capacity as well as in data availability has raised concerns about undetected transmission events in the SSA region. To capture epidemiological details related to early transmission events into and within countries, a line list was developed from publicly available data on institutional websites, situation reports, press releases, and social media accounts. The availability of indicators-gender, age, travel history, date of arrival in country, reporting date of confirmation, and how detected-for each imported case was assessed. We evaluated the relationship between the time to first reported importation and the Global Health Security Index (GHSI) overall score; 13,201 confirmed cases of COVID-19 were reported by 48 countries in SSA during the 54 days following the first known introduction to the region. Of the 2,516 cases for which travel history information was publicly available, 1,129 (44.9%) were considered importation events. Imported cases tended to be male (65.0%), with a median age of 41.0 years (range: 6 weeks-88 years; IQR: 31-54 years). A country's time to report its first importation was not related to the GHSI overall score, after controlling for air traffic. Countries in SSA generally reported with less publicly available detail over time and tended to have greater information on imported than local cases.

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.

Clinical management and mortality among COVID-19 cases in sub-Saharan Africa: A retrospective study from Burkina Faso and simulated case analysis.

BACKGROUND: Absolute numbers of COVID-19 cases and deaths reported to date in the sub-Saharan Africa (SSA) region have been significantly lower than those across the Americas, Asia and Europe. As a result, there has been limited information about the demographic and clinical characteristics of deceased cases in the region, as well as the impacts of different case management strategies. METHODS: Data from deceased cases reported across SSA through 10 May 2020 and from hospitalized cases in Burkina Faso through 15 April 2020 were analyzed. Demographic, epidemiological and clinical information on deceased cases in SSA was derived through a line-list of publicly available information and, for cases in Burkina Faso, from aggregate records at the Centre Hospitalier Universitaire de Tengandogo in Ouagadougou. A synthetic case population was probabilistically derived using distributions of age, sex and underlying conditions from populations of West African countries to assess individual risk factors and treatment effect sizes. Logistic regression analysis was conducted to evaluate the adjusted odds of survival for patients receiving oxygen therapy or convalescent plasma, based on therapeutic effectiveness observed for other respiratory illnesses. RESULTS: Across SSA, deceased cases for which demographic data were available were predominantly male (63/103, 61.2%) and aged >50 years (59/75, 78.7%). In Burkina Faso, specifically, the majority of deceased cases either did not seek care at all or were hospitalized for a single day (59.4%, 19/32). Hypertension and diabetes were often reported as underlying conditions. After adjustment for sex, age and underlying conditions in the synthetic case population, the odds of mortality for cases not receiving oxygen therapy were significantly higher than for those receiving oxygen, such as due to disruptions to standard care (OR 2.07; 95% CI 1.56-2.75). Cases receiving convalescent plasma had 50% reduced odds of mortality than those who did not (95% CI 0.24-0.93). CONCLUSIONS: Investment in sustainable production and maintenance of supplies for oxygen therapy, along with messaging around early and appropriate use for healthcare providers, caregivers and patients could reduce COVID-19 deaths in SSA. Further investigation into convalescent plasma is warranted until data on its effectiveness specifically in treating COVID-19 becomes available. The success of supportive or curative clinical interventions will depend on earlier treatment seeking, such that community engagement and risk communication will be critical components of the response.

The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

Author Correction: The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Seasonal patterns of Plasmodium falciparum gametocyte prevalence and density in a rural population of Burkina Faso.

Gametocytes are the malaria parasite stages that secure the transmission from the human host to the mosquito. The identification of natural parameters that influence gametocyte carriage can contribute to a better understanding of the dynamics of the sexual stage parasites for transmission reducing strategies. A total of 3400 blood slide readings were done during four cross-sectional surveys (2002-2003) including all age groups to determine the effect of season on Plasmodium falciparum gametocytes in a seasonal malaria transmission area of Burkina Faso. Entomological data were collected to determine the malaria transmission intensity in relation to seasons. Transmission intensity was estimated by monthly EIRs, averaging 28 and 32 infective bites/person/month in the wet seasons of 2002 and 2003, respectively. The EIR in the dry seasons was below one infective bite/person/month. The gametocyte prevalence was significantly higher at the start and peak of the wet season compared to the dry season when corrected for asexual parasite density and age. Gametocyte density significantly increased during the wet season after correction for asexual parasite density and age. In this study, season appears to be an independent parameter that determines gametocyte prevalence and density and should be considered to be included in epidemiological studies on malaria transmission.

Mathematical models of human mobility of relevance to malaria transmission in Africa.

As Africa-wide malaria prevalence declines, an understanding of human movement patterns is essential to inform how best to target interventions. We fitted movement models to trip data from surveys conducted at 3-5 sites throughout each of Mali, Burkina Faso, Zambia and Tanzania. Two models were compared in terms of their ability to predict the observed movement patterns - a gravity model, in which movement rates between pairs of locations increase with population size and decrease with distance, and a radiation model, in which travelers are cumulatively "absorbed" as they move outwards from their origin of travel. The gravity model provided a better fit to the data overall and for travel to large populations, while the radiation model provided a better fit for nearby populations. One strength of the data set was that trips could be categorized according to traveler group - namely, women traveling with children in all survey countries and youth workers in Mali. For gravity models fitted to data specific to these groups, youth workers were found to have a higher travel frequency to large population centers, and women traveling with children a lower frequency. These models may help predict the spatial transmission of malaria parasites and inform strategies to control their spread.

Implementation and applications of EMOD, an individual-based multi-disease modeling platform.

Individual-based models provide modularity and structural flexibility necessary for modeling of infectious diseases at the within-host and population levels, but are challenging to implement. Levels of complexity can exceed the capacity and timescales for students and trainees in most academic institutions. Here we describe the process and advantages of a multi-disease framework approach developed with formal software support. The epidemiological modeling software, EMOD, has undergone a decade of software development. It is structured so that a majority of code is shared across disease modeling including malaria, HIV, tuberculosis, dengue, polio and typhoid. In additional to implementation efficiency, the sharing increases code usage and testing. The freely available codebase also includes hundreds of regression tests, scientific feature tests and component tests to help verify functionality and avoid inadvertent changes to functionality during future development. Here we describe the levels of detail, flexible configurability and modularity enabled by EMOD and the role of software development principles and processes in its development.

Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity.

Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes.