Assessing the stability of polio eradication after the withdrawal of oral polio vaccine.

The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist in which OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multi-scale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine (IPV) is sufficient to prevent outbreaks in low transmission rate settings and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication.

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.

Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics.

The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings.

Correction to: Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

The original article [1] did not contain comprehensive information regarding two authors' affiliations that may be considered a potential competing interest.

Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

BACKGROUND: Gold mines represent a potential hotspot for Mycobacterium tuberculosis (Mtb) transmission and may be exacerbating the tuberculosis (TB) epidemic in South Africa. However, the presence of multiple factors complicates estimation of the mining contribution to the TB burden in South Africa. METHODS: We developed two models of TB in South Africa, a static risk model and an individual-based model that accounts for longer-term trends. Both models account for four populations - mine workers, peri-mining residents, labor-sending residents, and other residents of South Africa - including the size and prevalence of latent TB infection, active TB, and HIV of each population and mixing between populations. We calibrated to mine- and country-level data and used the static model to estimate force of infection (FOI) and new infections attributable to local residents in each community compared to other residents. Using the individual-based model, we simulated a counterfactual scenario to estimate the fraction of overall TB incidence in South Africa attributable to recent transmission in mines. RESULTS: We estimated that the majority of FOI in each community is attributable to local residents: 93.9% (95% confidence interval 92.4-95.1%), 91.5% (91.4-91.5%), and 94.7% (94.7-94.7%) in gold mining, peri-mining, and labor-sending communities, respectively. Assuming a higher rate of Mtb transmission in mines, 4.1% (2.6-5.8%), 5.0% (4.5-5.5%), and 9.0% (8.8-9.1%) of new infections in South Africa are attributable to gold mine workers, peri-mining residents, and labor-sending residents, respectively. Therefore, mine workers with TB disease, who constitute ~ 2.5% of the prevalent TB cases in South Africa, contribute 1.62 (1.04-2.30) times as many new infections as TB cases in South Africa on average. By modeling TB on a longer time scale, we estimate 63.0% (58.5-67.7%) of incident TB disease in gold mining communities to be attributable to recent transmission, of which 92.5% (92.1-92.9%) is attributable to local transmission. CONCLUSIONS: Gold mine workers are estimated to contribute a disproportionately large number of Mtb infections in South Africa on a per-capita basis. However, mine workers contribute only a small fraction of overall Mtb infections in South Africa. Our results suggest that curtailing transmission in mines may have limited impact at the country level, despite potentially significant impact at the mining level.

Modeling malaria genomics reveals transmission decline and rebound in Senegal.

To study the effects of malaria-control interventions on parasite population genomics, we examined a set of 1,007 samples of the malaria parasite Plasmodium falciparum collected in Thiès, Senegal between 2006 and 2013. The parasite samples were genotyped using a molecular barcode of 24 SNPs. About 35% of the samples grouped into subsets with identical barcodes, varying in size by year and sometimes persisting across years. The barcodes also formed networks of related groups. Analysis of 164 completely sequenced parasites revealed extensive sharing of genomic regions. In at least two cases we found first-generation recombinant offspring of parents whose genomes are similar or identical to genomes also present in the sample. An epidemiological model that tracks parasite genotypes can reproduce the observed pattern of barcode subsets. Quantification of likelihoods in the model strongly suggests a reduction of transmission from 2006-2010 with a significant rebound in 2012-2013. The reduced transmission and rebound were confirmed directly by incidence data from Thiès. These findings imply that intensive intervention to control malaria results in rapid and dramatic changes in parasite population genomics. The results also suggest that genomics combined with epidemiological modeling may afford prompt, continuous, and cost-effective tracking of progress toward malaria elimination.

Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models.

BACKGROUND: The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. METHODS: We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose. FINDINGS: In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels. INTERPRETATION: We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. FUNDING: PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.

Optimal Population-Level Infection Detection Strategies for Malaria Control and Elimination in a Spatial Model of Malaria Transmission.

Mass campaigns with antimalarial drugs are potentially a powerful tool for local elimination of malaria, yet current diagnostic technologies are insufficiently sensitive to identify all individuals who harbor infections. At the same time, overtreatment of uninfected individuals increases the risk of accelerating emergence of drug resistance and losing community acceptance. Local heterogeneity in transmission intensity may allow campaign strategies that respond to index cases to successfully target subpatent infections while simultaneously limiting overtreatment. While selective targeting of hotspots of transmission has been proposed as a strategy for malaria control, such targeting has not been tested in the context of malaria elimination. Using household locations, demographics, and prevalence data from a survey of four health facility catchment areas in southern Zambia and an agent-based model of malaria transmission and immunity acquisition, a transmission intensity was fit to each household based on neighborhood age-dependent malaria prevalence. A set of individual infection trajectories was constructed for every household in each catchment area, accounting for heterogeneous exposure and immunity. Various campaign strategies-mass drug administration, mass screen and treat, focal mass drug administration, snowball reactive case detection, pooled sampling, and a hypothetical serological diagnostic-were simulated and evaluated for performance at finding infections, minimizing overtreatment, reducing clinical case counts, and interrupting transmission. For malaria control, presumptive treatment leads to substantial overtreatment without additional morbidity reduction under all but the highest transmission conditions. Compared with untargeted approaches, selective targeting of hotspots with drug campaigns is an ineffective tool for elimination due to limited sensitivity of available field diagnostics. Serological diagnosis is potentially an effective tool for malaria elimination but requires higher coverage to achieve similar results to mass distribution of presumptive treatment.

Malaria Elimination Campaigns in the Lake Kariba Region of Zambia: A Spatial Dynamical Model.

As more regions approach malaria elimination, understanding how different interventions interact to reduce transmission becomes critical. The Lake Kariba area of Southern Province, Zambia, is part of a multi-country elimination effort and presents a particular challenge as it is an interconnected region of variable transmission intensities. In 2012-13, six rounds of mass test-and-treat drug campaigns were carried out in the Lake Kariba region. A spatial dynamical model of malaria transmission in the Lake Kariba area, with transmission and climate modeled at the village scale, was calibrated to the 2012-13 prevalence survey data, with case management rates, insecticide-treated net usage, and drug campaign coverage informed by surveillance. The model captured the spatio-temporal trends of decline and rebound in malaria prevalence in 2012-13 at the village scale. Various interventions implemented between 2016-22 were simulated to compare their effects on reducing regional transmission and achieving and maintaining elimination through 2030. Simulations predict that elimination requires sustaining high coverage with vector control over several years. When vector control measures are well-implemented, targeted mass drug campaigns in high-burden areas further increase the likelihood of elimination, although drug campaigns cannot compensate for insufficient vector control. If infections are regularly imported from outside the region into highly receptive areas, vector control must be maintained within the region until importations cease. Elimination in the Lake Kariba region is possible, although human movement both within and from outside the region risk damaging the success of elimination programs.

Effectiveness of reactive case detection for malaria elimination in three archetypical transmission settings: a modelling study.

BACKGROUND: Reactive case detection could be a powerful tool in malaria elimination, as it selectively targets transmission pockets. However, field operations have yet to demonstrate under which conditions, if any, reactive case detection is best poised to push a region to elimination. This study uses mathematical modelling to assess how baseline transmission intensity and local interconnectedness affect the impact of reactive activities in the context of other possible intervention packages. METHODS: Communities in Southern Province, Zambia, where elimination operations are currently underway, were used as representatives of three archetypes of malaria transmission: low-transmission, high household density; high-transmission, low household density; and high-transmission, high household density. Transmission at the spatially-connected household level was simulated with a dynamical model of malaria transmission, and local variation in vectorial capacity and intervention coverage were parameterized according to data collected from the area. Various potential intervention packages were imposed on each of the archetypical settings and the resulting likelihoods of elimination by the end of 2020 were compared. RESULTS: Simulations predict that success of elimination campaigns in both low- and high-transmission areas is strongly dependent on stemming the flow of imported infections, underscoring the need for regional-scale strategies capable of reducing transmission concurrently across many connected areas. In historically low-transmission areas, treatment of clinical malaria should form the cornerstone of elimination operations, as most malaria infections in these areas are symptomatic and onward transmission would be mitigated through health system strengthening; reactive case detection has minimal impact in these settings. In historically high-transmission areas, vector control and case management are crucial for limiting outbreak size, and the asymptomatic reservoir must be addressed through reactive case detection or mass drug campaigns. CONCLUSIONS: Reactive case detection is recommended only for settings where transmission has recently been reduced rather than all low-transmission settings. This is demonstrated in a modelling framework with strong out-of-sample accuracy across a range of transmission settings while including methodologies for understanding the most resource-effective allocations of health workers. This approach generalizes to providing a platform for planning rational scale-up of health systems based on locally-optimized impact according to simplified stratification.

Mapping multiple components of malaria risk for improved targeting of elimination interventions.

There is a long history of considering the constituent components of malaria risk and the malaria transmission cycle via the use of mathematical models, yet strategic planning in endemic countries tends not to take full advantage of available disease intelligence to tailor interventions. National malaria programmes typically make operational decisions about where to implement vector control and surveillance activities based upon simple categorizations of annual parasite incidence. With technological advances, an enormous opportunity exists to better target specific malaria interventions to the places where they will have greatest impact by mapping and evaluating metrics related to a variety of risk components, each of which describes a different facet of the transmission cycle. Here, these components and their implications for operational decision-making are reviewed. For each component, related mappable malaria metrics are also described which may be measured and evaluated by malaria programmes seeking to better understand the determinants of malaria risk. Implementing tailored programmes based on knowledge of the heterogeneous distribution of the drivers of malaria transmission rather than only consideration of traditional metrics such as case incidence has the potential to result in substantial improvements in decision-making. As programmes improve their ability to prioritize their available tools to the places where evidence suggests they will be most effective, elimination aspirations may become increasingly feasible.

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.

A computational lens for sexual-stage transmission, reproduction, fitness and kinetics in Plasmodium falciparum.

BACKGROUND: The burden of falciparum malaria remains unacceptably high in much of sub-Saharan Africa and massive efforts are underway to eliminate the parasite. While symptoms of malaria are caused by asexual reproduction of the parasite, transmission to new human hosts relies entirely on male and female sexual-stage parasites, known as gametocytes. Successful transmission can be observed at very low gametocyte densities, which raises the question of whether transmission-enhancing mechanisms exist in the human host, the mosquito, or both. METHODS: A new computational model was developed to investigate the probability of fertilization over a range of overdispersion parameters and male gamete exploration rates. Simulations were used to fit a likelihood surface for data on rates of mosquito infection across a wide range of host gametocyte densities. RESULTS: The best fit simultaneously requires very strong overdispersion and faster gamete exploration than is possible with random swimming in order to explain typical prevalence levels in mosquitoes. Gametocyte overdispersion or clustering in the human host and faster gamete exploration of the mosquito blood meal are highly probably given these results. CONCLUSIONS: Density-dependent gametocyte clustering in the human host, and non-random searching (e.g., chemotaxis) in the mosquito are probable. Future work should aim to discover these mechanisms, as disrupting parasite development in the mosquito will play a critical role in eliminating malaria.

Tuberculosis control strategies to reach the 2035 global targets in China: the role of changing demographics and reactivation disease.

BACKGROUND: In the last 20 years, China ramped up a DOTS (directly observed treatment, short-course)-based tuberculosis (TB) control program with 80% population coverage, achieving the 2015 Millennium Development Goal of a 50% reduction in TB prevalence and mortality. Recently, the World Health Organization developed the End TB Strategy, with an overall goal of a 90% reduction in TB incidence and a 95% reduction in TB deaths from 2015-2035. As the TB burden shifts to older individuals and China's overall population ages, it is unclear if maintaining the current DOTS strategy will be sufficient for China to reach the global targets. METHODS: We developed an individual-based computational model of TB transmission, implementing realistic age demographics and fitting to country-level data of age-dependent prevalence over time. We explored the trajectory of TB burden if the DOTS strategy is maintained or if new interventions are introduced using currently available and soon-to-be-available tools. These interventions include increasing population coverage of DOTS, reducing time to treatment, increasing treatment success, and active case finding among elders > 65 years old. We also considered preventative therapy in latently infected elders, a strategy limited by resource constraints and the risk of adverse events. RESULTS: Maintenance of the DOTS strategy reduces TB incidence and mortality by 42% (95% credible interval, 27-59%) and 41% (5-64%), respectively, between 2015 and 2035. A combination of all feasible interventions nears the 2035 mortality target, reducing TB incidence and mortality by 59% (50-76%) and 83% (73-94%). Addition of preventative therapy for elders would enable China to nearly reach both the incidence and mortality targets, reducing incidence and mortality by 84% (78-93%) and 92% (86-98%). CONCLUSIONS: The current decline in incidence is driven by two factors: maintaining a low level of new infections in young individuals and the aging out of older latently infected individuals who contribute incidence due to reactivation disease. While further reducing the level of new infections has a modest effect on burden, interventions that limit reactivation have a greater impact on TB burden. Tools that make preventative therapy more feasible on a large scale and in elders will help China achieve the global targets.

Calibration of an intrahost malaria model and parameter ensemble evaluation of a pre-erythrocytic vaccine.

BACKGROUND: A pre-erythrocytic vaccine could provide a useful tool for burden reduction and eventual eradication of malaria. Mathematical malaria models provide a mechanism for evaluating the effective burden reduction across a range of transmission conditions where such a vaccine might be deployed. METHODS: The EMOD model is an individual-based model of malaria transmission dynamics, including vector lifecycles and species-specific behaviour, coupled to a mechanistic intrahost model of malaria parasite and host immune system dynamics. The present work describes the extension of the EMOD model to include diagnoses of severe malaria and iterative calibration of the immune system parameters and parasite antigenic variation to age-stratified prevalence, incidence and severe disease incidence data obtained from multiple regions with broadly varying transmission conditions in Africa. An ensemble of calibrated model parameter sets is then employed to evaluate the potential impact of routine immunization with a pre-erythrocytic vaccine. RESULTS: The reduction in severe malaria burden exhibits a broad peak at moderate transmission conditions. Under sufficiently intense transmission, a vaccine that reduces but does not eliminate the probability of acquisition from a single challenge bite may delay infections but produces minimal or no net reduction. Conversely, under sufficiently weak transmission conditions, a vaccine can provide a high fractional reduction but avert a relatively low absolute number of cases due to low baseline burden. CONCLUSIONS: Roll-out of routine immunization with pre-erythrocytic malaria vaccines can provide substantial burden reduction across a range of transmission conditions typical to many regions in Africa.

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.

Mass campaigns with antimalarial drugs: a modelling comparison of artemether-lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination.

BACKGROUND: Antimalarial drugs are a powerful tool for malaria control and elimination. Artemisinin-based combination therapies (ACTs) can reduce transmission when widely distributed in a campaign setting. Modelling mass antimalarial campaigns can elucidate how to most effectively deploy drug-based interventions and quantitatively compare the effects of cure, prophylaxis, and transmission-blocking in suppressing parasite prevalence. METHODS: A previously established agent-based model that includes innate and adaptive immunity was used to simulate malaria infections and transmission. Pharmacokinetics of artemether, lumefantrine, dihydroartemisinin, piperaquine, and primaquine were modelled with a double-exponential distribution-elimination model including weight-dependent parameters and age-dependent dosing. Drug killing of asexual parasites and gametocytes was calibrated to clinical data. Mass distribution of ACTs and primaquine was simulated with seasonal mosquito dynamics at a range of transmission intensities. RESULTS: A single mass campaign with antimalarial drugs is insufficient to permanently reduce malaria prevalence when transmission is high. Current diagnostics are insufficiently sensitive to accurately identify asymptomatic infections, and mass-screen-and-treat campaigns are much less efficacious than mass drug administrations. Improving campaign coverage leads to decreased prevalence one month after the end of the campaign, while increasing compliance lengthens the duration of protection against reinfection. Use of a long-lasting prophylactic as part of a mass drug administration regimen confers the most benefit under conditions of high transmission and moderately high coverage. Addition of primaquine can reduce prevalence but exerts its largest effect when coupled with a long-lasting prophylactic. CONCLUSIONS: Mass administration of antimalarial drugs can be a powerful tool to reduce prevalence for a few months post-campaign. A slow-decaying prophylactic administered with a parasite-clearing drug offers strong protection against reinfection, especially in highly endemic areas. Transmission-blocking drugs have only limited effects unless administered with a prophylactic under very high coverage.

Predictive spatial risk model of poliovirus to aid prioritization and hasten eradication in Nigeria.

BACKGROUND: One of the challenges facing the Global Polio Eradication Initiative is efficiently directing limited resources, such as specially trained personnel, community outreach activities, and satellite vaccinator tracking, to the most at-risk areas to maximize the impact of interventions. A validated predictive model of wild poliovirus circulation would greatly inform prioritization efforts by accurately forecasting areas at greatest risk, thus enabling the greatest effect of program interventions. METHODS: Using Nigerian acute flaccid paralysis surveillance data from 2004-2013, we developed a spatial hierarchical Poisson hurdle model fitted within a Bayesian framework to study historical polio caseload patterns and forecast future circulation of type 1 and 3 wild poliovirus within districts in Nigeria. A Bayesian temporal smoothing model was applied to address data sparsity underlying estimates of covariates at the district level. RESULTS: We find that calculated vaccine-derived population immunity is significantly negatively associated with the probability and number of wild poliovirus case(s) within a district. Recent case information is significantly positively associated with probability of a case, but not the number of cases. We used lagged indicators and coefficients from the fitted models to forecast reported cases in the subsequent six-month periods. Over the past three years, the average predictive ability is 86 ± 2% and 85 ± 4% for wild poliovirus type 1 and 3, respectively. Interestingly, the predictive accuracy of historical transmission patterns alone is equivalent (86 ± 2% and 84 ± 4% for type 1 and 3, respectively). We calculate uncertainty in risk ranking to inform assessments of changes in rank between time periods. CONCLUSIONS: The model developed in this study successfully predicts districts at risk for future wild poliovirus cases in Nigeria. The highest predicted district risk was 12.8 WPV1 cases in 2006, while the lowest district risk was 0.001 WPV1 cases in 2013. Model results have been used to direct the allocation of many different interventions, including political and religious advocacy visits. This modeling approach could be applied to other vaccine preventable diseases for use in other control and elimination programs.

Fun with maths: exploring implications of mathematical models for malaria eradication.

Mathematical analyses and modelling have an important role informing malaria eradication strategies. Simple mathematical approaches can answer many questions, but it is important to investigate their assumptions and to test whether simple assumptions affect the results. In this note, four examples demonstrate both the effects of model structures and assumptions and also the benefits of using a diversity of model approaches. These examples include the time to eradication, the impact of vaccine efficacy and coverage, drug programs and the effects of duration of infections and delays to treatment, and the influence of seasonality and migration coupling on disease fadeout. An excessively simple structure can miss key results, but simple mathematical approaches can still achieve key results for eradication strategy and define areas for investigation by more complex models.