Contribution of malaria and sickle cell disease to anaemia among children aged 6-59 months in Nigeria: a cross-sectional study using data from the 2018 Demographic and Health Survey.

OBJECTIVES: To estimate the fraction of anaemia attributable to malaria and sickle cell disease (SCD) among children aged 6-59 months in Nigeria. DESIGN: Cross-sectional analysis of data from Nigeria's 2018 Demographic and Health Survey (DHS). SETTING: Nigeria. PARTICIPANTS: 11 536 children aged 6-59 months from randomly selected households were eligible for participation, of whom 11 142 had complete and valid biomarker data required for this analysis. Maternal education data were available from 10 305 of these children. PRIMARY OUTCOME MEASURE: Haemoglobin concentration. RESULTS: We found that 70.6% (95% CI: 62.7% to 78.5%) of severe anaemia was attributable to malaria compared with 12.4% (95% CI: 11.1% to 13.7%) of mild-to-severe and 29.6% (95% CI: 29.6% to 31.8%) of moderate-to-severe anaemia and that SCD contributed 0.6% (95% CI: 0.4% to 0.9%), 1.3% (95% CI: 1.0% to 1.7%) and 10.6% (95% CI: 6.7% to 14.9%) mild-to-severe, moderate-to-severe and severe anaemia, respectively. Sickle trait was protective against anaemia and was associated with higher haemoglobin concentration compared with children with normal haemoglobin (HbAA) among malaria-positive but not malaria-negative children. CONCLUSIONS: This approach used offers a new tool to estimate the contribution of malaria to anaemia in many settings using widely available DHS data. The fraction of anaemia among young children in Nigeria attributable to malaria and SCD is higher at more severe levels of anaemia. Prevention of malaria and SCD and timely treatment of affected individuals would reduce cases of severe anaemia.

Potential Impacts of Mass Nutritional Supplementation on Measles Dynamics: A Simulation Study.

The bidirectional interaction between undernutrition and infection can be devastating to child health. Nutritional deficiencies impair immunity and increase susceptibility to infection. Simultaneously, infections compound undernutrition by increasing metabolic demand and impairing nutrient absorption. Treatment of acute malnutrition (wasting) can reverse some of its deleterious effects and reduce susceptibility to infectious diseases. Nutrition-specific approaches may be packaged with other interventions, including immunization, to support overall child health. To understand how mass nutritional supplementation, treatment of wasting, and vaccination affect the dynamics of a vaccine-preventable infection, we developed a population-level, compartmental model of measles transmission stratified by age and nutrition status. We simulated a range of scenarios to assess the potential reductions in measles infection and mortality associated with targeted therapeutic feeding for children who are wasted and with a mass supplementation intervention. Nutrition interventions were assumed to increase engagement with the health sector, leading to increased vaccination rates. We found that the combination of wasting treatment and mass supplementation coverage followed by an increase in vaccination coverage of non-wasted children from a baseline of 75% to 85%, leads to 34% to 57% and 65% to 77% reduction in measles infection and mortality and 56% to 60% reduction in overall mortality among wasted children, compared with the wasting treatment alone. Our work highlights the synergistic benefits that may be achieved by leveraging mass nutritional supplementation as a touch point with the health system to increase rates of vaccination and improve child survival beyond what would be expected from the additive benefits of each intervention.

Linked surveillance and genetic data uncovers programmatically relevant geographic scale of Guinea worm transmission in Chad.

BACKGROUND: Guinea worm (Dracunculus medinensis) was detected in Chad in 2010 after a supposed ten-year absence, posing a challenge to the global eradication effort. Initiation of a village-based surveillance system in 2012 revealed a substantial number of dogs infected with Guinea worm, raising questions about paratenic hosts and cross-species transmission. METHODOLOGY/PRINCIPAL FINDINGS: We coupled genomic and surveillance case data from 2012-2018 to investigate the modes of transmission between dog and human hosts and the geographic connectivity of worms. Eighty-six variants across four genes in the mitochondrial genome identified 41 genetically distinct worm genotypes. Spatiotemporal modeling revealed worms with the same genotype ('genetically identical') were within a median range of 18.6 kilometers of each other, but largely within approximately 50 kilometers. Genetically identical worms varied in their degree of spatial clustering, suggesting there may be different factors that favor or constrain transmission. Each worm was surrounded by five to ten genetically distinct worms within a 50 kilometer radius. As expected, we observed a change in the genetic similarity distribution between pairs of worms using variants across the complete mitochondrial genome in an independent population. CONCLUSIONS/SIGNIFICANCE: In the largest study linking genetic and surveillance data to date of Guinea worm cases in Chad, we show genetic identity and modeling can facilitate the understanding of local transmission. The co-occurrence of genetically non-identical worms in quantitatively identified transmission ranges highlights the necessity for genomic tools to link cases. The improved discrimination between pairs of worms from variants identified across the complete mitochondrial genome suggests that expanding the number of genomic markers could link cases at a finer scale. These results suggest that scaling up genomic surveillance for Guinea worm may provide additional value for programmatic decision-making critical for monitoring cases and intervention efficacy to achieve elimination.

Disease Surveillance Investments and Administration: Limits to Information Value in Pakistan Polio Eradication.

In Pakistan, annual poliovirus investment decisions drive quantities of supplemental immunization campaigns districts receive. In this article, we assess whether increased spending on poliovirus surveillance is associated with greater likelihood of correctly identifying districts at high risk of polio with assignment of an elevated "risk ranking." We reviewed programmatic documents from Pakistan for the period from 2012-2017, recording whether districts had been classified as "high risk" or "low risk" in each year. Through document review, we developed a decision tree to describe the ranking decisions. Then, integrating data from the World Health Organization and Global Polio Eradication Initiative, we constructed a Bayesian decision network reflecting investments in polio surveillance and immunization campaigns, surveillance metrics, disease incidence, immunization rates, and occurrence of polio cases. We test these factors for statistical association with the outcome of interest-a change in risk rank between the beginning and the end of the one-year time period. We simulate different spending scenarios and predict their impact on district risk ranking in future time periods. We find that per district spending increases are associated with increased identification of cases of acute flaccid paralysis (AFP). However, the low specificity of AFP investment and the largely invariant ranking of district risk means that even large increases in surveillance spending are unlikely to promote major changes in risk rankings at the current stage of the Pakistan polio eradication campaign.

Optimization of frequency and targeting of measles supplemental immunization activities in Nigeria: A cost-effectiveness analysis.

BACKGROUND: Measles causes significant childhood morbidity in Nigeria. Routine immunization (RI) coverage is around 40% country-wide, with very high levels of spatial heterogeneity (3-86%), with supplemental immunization activities (SIAs) at 2-year or 3-year intervals. We investigated cost savings and burden reduction that could be achieved by adjusting the inter-campaign interval by region. METHODS: We modeled 81 scenarios; permuting SIA calendars of every one, two, or three years in each of four regions of Nigeria (North-west, North-central, North-east, and South). We used an agent-based disease transmission model to estimate the number of measles cases and ingredients-based cost models to estimate RI and SIA costs for each scenario over a 10 year period. RESULTS: Decreasing SIAs to every three years in the North-central and South (regions of above national-average RI coverage) while increasing to every year in either the North-east or North-west (regions of below national-average RI coverage) would avert measles cases (0.4 or 1.4 million, respectively), and save vaccination costs (save $19.4 or $5.4 million, respectively), compared to a base-case of national SIAs every two years. Decreasing SIA frequency to every three years in the South while increasing to every year in the just the North-west, or in all Northern regions would prevent more cases (2.1 or 5.0 million, respectively), but would increase vaccination costs (add $3.5 million or $34.6 million, respectively), for $1.65 or $6.99 per case averted, respectively. CONCLUSIONS: Our modeling shows how increasing SIA frequency in Northern regions, where RI is low and birth rates are high, while decreasing frequency in the South of Nigeria would reduce the number of measles cases with relatively little or no increase in vaccination costs. A national vaccination strategy that incorporates regional SIA targeting in contexts with a high level of sub-national variation would lead to improved health outcomes and/or lower costs.

Assessing the sensitivity of the polio environmental surveillance system.

BACKGROUND: The polio environmental surveillance (ES) system has been an incredible tool for advancing polio eradication efforts because of its ability to highlight the spatial and temporal extent of poliovirus circulation. While ES often outperforms, or is more sensitive than AFP surveillance, the sensitivity of the ES system has not been well characterized. Fundamental uncertainty of ES site sensitivity makes it difficult to interpret results from ES, particularly negative results. METHODS AND FINDINGS: To study ES sensitivity, we used data from Afghanistan and Pakistan to examine the probability that each ES site detected the Sabin 1, 2, or 3 components of the oral polio vaccine (OPV) as a function of virus prevalence within the same district (estimated from AFP data). Accounting for virus prevalence is essential for estimating site sensitivity because Sabin detection rates should vary with prevalence-high immediately after supplemental immunization activities (SIAs), but low in subsequent months. We found that most ES sites in Pakistan and Afghanistan are highly sensitive for detecting poliovirus relative to AFP surveillance in the same districts. For example, even when Sabin poliovirus is at low prevalence of ~0.5-3% in AFP surveillance, most ES sites have ~34-50% probability of detecting Sabin. However, there was considerable variation in ES site sensitivity and we flagged several sites for re-evaluation based on low sensitivity rankings and low wild polio virus detection rates. In these areas, adding new sites or modifying collection methods in current sites could improve sensitivity of environmental surveillance. CONCLUSIONS: Relating ES detections to virus prevalence significantly improved our ability to evaluate site sensitivity compared to evaluations based solely on ES detection rates. To extend our approach to new sites and regions, we provide a preliminary framework for relating ES and AFP detection rates, and descriptions of how detection rates might relate to SIAs and natural seasonality.

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.

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.

The risk of type 2 oral polio vaccine use in post-cessation outbreak response.

BACKGROUND: Wild type 2 poliovirus was last observed in 1999. The Sabin-strain oral polio vaccine type 2 (OPV2) was critical to eradication, but it is known to revert to a neurovirulent phenotype, causing vaccine-associated paralytic poliomyelitis. OPV2 is also transmissible and can establish circulating lineages, called circulating vaccine-derived polioviruses (cVDPVs), which can also cause paralytic outbreaks. Thus, in April 2016, OPV2 was removed from immunization activities worldwide. Interrupting transmission of cVDPV2 lineages that survive cessation will require OPV2 in outbreak response, which risks seeding new cVDPVs. This potential cascade of outbreak responses seeding VDPVs, necessitating further outbreak responses, presents a critical risk to the OPV2 cessation effort. METHODS: The EMOD individual-based disease transmission model was used to investigate OPV2 use in outbreak response post-cessation in West African populations. A hypothetical outbreak response in northwest Nigeria is modeled, and a cVDPV2 lineage is considered established if the Sabin strain escapes the response region and continues circulating 9 months post-response. The probability of this event was investigated in a variety of possible scenarios. RESULTS: Under a broad range of scenarios, the probability that widespread OPV2 use in outbreak response (~2 million doses) establishes new cVDPV2 lineages in this model may exceed 50% as soon as 18 months or as late as 4 years post-cessation. CONCLUSIONS: The risk of a cycle in which outbreak responses seed new cVDPV2 lineages suggests that OPV2 use should be managed carefully as time from cessation increases. It is unclear whether this risk can be mitigated in the long term, as mucosal immunity against type 2 poliovirus declines globally. Therefore, current programmatic strategies should aim to minimize the possibility that continued OPV2 use will be necessary in future years: conducting rapid and aggressive outbreak responses where cVDPV2 lineages are discovered, maintaining high-quality surveillance in all high-risk settings, strengthening the use of the inactivated polio vaccine as a booster in the OPV2-exposed and in routine immunization, and gaining access to currently inaccessible areas of the world to conduct surveillance.

Spatial model for risk prediction and sub-national prioritization to aid poliovirus eradication in Pakistan.

BACKGROUND: Pakistan is one of only three countries where poliovirus circulation remains endemic. For the Pakistan Polio Eradication Program, identifying high risk districts is essential to target interventions and allocate limited resources. METHODS: Using a hierarchical Bayesian framework we developed a spatial Poisson hurdle model to jointly model the probability of one or more paralytic polio cases, and the number of cases that would be detected in the event of an outbreak. Rates of underimmunization, routine immunization, and population immunity, as well as seasonality and a history of cases were used to project future risk of cases. RESULTS: The expected number of cases in each district in a 6-month period was predicted using indicators from the previous 6-months and the estimated coefficients from the model. The model achieves an average of 90% predictive accuracy as measured by area under the receiver operating characteristic (ROC) curve, for the past 3 years of cases. CONCLUSIONS: The risk of poliovirus has decreased dramatically in many of the key reservoir areas in Pakistan. The results of this model have been used to prioritize sub-national areas in Pakistan to receive additional immunization activities, additional monitoring, or other special interventions.

Evaluating cessation of the type 2 oral polio vaccine by modeling pre- and post-cessation detection rates.

The globally synchronized removal of the attenuated Sabin type 2 strain from the oral polio vaccine (OPV) in April 2016 marked a major change in polio vaccination policy. This change will provide a significant reduction in the burden of vaccine-associated paralytic polio (VAPP), but may increase the risk of circulating vaccine-derived poliovirus (cVDPV2) outbreaks during the transition period. This risk can be monitored by tracking the disappearance of Sabin-like type 2 (SL2) using data from the polio surveillance system. We studied SL2 prevalence in 17 countries in Africa and Asia, from 2010 to 2016 using acute flaccid paralysis surveillance data. We modeled the peak and decay of SL2 prevalence following mass vaccination events using a beta-binomial model for the detection rate, and a Ricker function for the temporal dependence. We found type 2 circulated the longest of all serotypes after a vaccination campaign, but that SL2 prevalence returned to baseline levels in approximately 50days. Post-cessation model predictions identified 19 anomalous SL2 detections outside of model predictions in Afghanistan, India, Nigeria, Pakistan, and western Africa. Our models established benchmarks for the duration of SL2 detection after OPV2 cessation. As predicted, SL2 detection rates have plummeted, except in Nigeria where OPV2 use continued for some time in response to recent cVDPV2 detections. However, the anomalous SL2 detections suggest specific areas that merit enhanced monitoring for signs of cVDPV2 outbreaks.

A spatial model of Wild Poliovirus Type 1 in Kano State, Nigeria: calibration and assessment of elimination probability.

BACKGROUND: Since the launch of the Global Polio Eradication Initiative, all but three countries (Nigeria, Pakistan, and Afghanistan) have apparently interrupted all wild poliovirus (WPV) transmission, and only one of three wild serotypes has been reported globally since 2012. Countrywide supplemental immunization campaigns in Nigeria produced dramatic reduction in WPV Type 1 paralysis cases since 2010 compared to the 2000's, and WPV1 has not been observed in Nigeria since July 24, 2014. This article presents the development and calibration of a spatial metapopulation model of wild poliovirus Type 1 transmission in Kano State, Nigeria, which was the location of the most recent WPV1 case and 5 out of 6 of the reported WPV1 paralytic cases in Nigeria in 2014. METHODS: The model is calibrated to data on the case counts and age at onset of paralysis from 2003-2009. The features of the data drive model development from a simple susceptible-exposed-infective-recovered (SEIR) model to a spatial metapopulation model featuring seasonal forcing and age-dependent transmission. The calibrated parameter space is then resampled, projected forward, and compared to more recent case counts to estimate the probability that Type 1 poliovirus has been eliminated in Kano state. RESULTS: The model indicates a 91 % probability that Type 1 poliovirus has been eliminated from Kano state as of October 2015. This probability rises to >99 % if no WPV1 paralysis cases are detected for another year. The other states in Nigeria have experienced even longer case-free periods (the only other state with a WPV1 case was Yobe, on April 19, 2014), and Nigeria is the last remaining country in Africa to experience endemic WPV1 transmission, so these results can be interpreted as an upper bound on the probability that WPV1 transmission is currently interrupted continent-wide. CONCLUSIONS: While the results indicate optimism that WPV1 transmission has been interrupted in Kano state, the model also assumes that frequent SIAs with high coverage continue to take place in Kano state through the end of the certification period. We conclude that though WPV1 appears to be on the brink of continent-wide elimination (WHO officially removed Nigeria from the list of polio-endemic countries on September 25, 2015), it is important for the polio program to maintain vigilance in surveillance and vaccination activities to prevent WPV1 resurgence through the WHO's 3-year eradication certification period.

Analysis of vaccination campaign effectiveness and population immunity to support and sustain polio elimination in Nigeria.

BACKGROUND: The world is closer than ever to a polio-free Africa. In this end-stage, it is important to ensure high levels of population immunity to prevent polio outbreaks. Here, we introduce a new method of assessing vaccination campaign effectiveness and estimating immunity at the district-level. We demonstrate how this approach can be used to plan the vaccination campaigns prospectively to better manage population immunity in Northern Nigeria. METHODS: Using Nigerian acute flaccid paralysis surveillance data from 2004-2014, we developed a Bayesian hierarchical model of campaign effectiveness and compared it to lot-quality assurance sampling data. We then used reconstructed sero-specific population immunity based on campaign history and compared district estimates of immunity to the occurrence of confirmed poliovirus cases. RESULTS: Estimated campaign effectiveness has improved across northern Nigeria since 2004, with Kano state experiencing an increase of 40 % (95 % CI, 26-54 %) in effectiveness from 2013 to 2014. Immunity to type 1 poliovirus has increased steadily. On the other hand, type 2 immunity was low and variable until the recent use of trivalent oral polio vaccine. We find that immunity estimates are related to the occurrence of both wild and vaccine-derived poliovirus cases and that campaign effectiveness correlates with direct measurements using lot-quality assurance sampling. Future campaign schedules highlight the trade-offs involved with using different vaccine types. CONCLUSIONS: The model in this study provides a novel method for assessing vaccination campaign performance and epidemiologically-relevant estimates of population immunity. Small-area estimates of campaign effectiveness can then be used to evaluate prospective campaign plans. This modeling approach could be applied to other countries as well as other vaccine preventable diseases.

Advancing digital methods in the fight against communicable diseases.

Important advances are being made in the fight against communicable diseases by using new digital tools. While they can be a challenge to deploy at-scale, GPS-enabled smartphones, electronic dashboards and computer models have multiple benefits. They can facilitate program operations, lead to new insights about the disease transmission and support strategic planning. Today, tools such as these are used to vaccinate more children against polio in Nigeria, reduce the malaria burden in Zambia and help predict the spread of the Ebola epidemic in West Africa.

Lot quality assurance sampling to monitor supplemental immunization activity quality: an essential tool for improving performance in polio endemic countries.

Monitoring the quality of supplementary immunization activities (SIAs) is a key tool for polio eradication. Regular monitoring data, however, are often unreliable, showing high coverage levels in virtually all areas, including those with ongoing virus circulation. To address this challenge, lot quality assurance sampling (LQAS) was introduced in 2009 as an additional tool to monitor SIA quality. Now used in 8 countries, LQAS provides a number of programmatic benefits: identifying areas of weak coverage quality with statistical reliability, differentiating areas of varying coverage with greater precision, and allowing for trend analysis of campaign quality. LQAS also accommodates changes to survey format, interpretation thresholds, evaluations of sample size, and data collection through mobile phones to improve timeliness of reporting and allow for visualization of campaign quality. LQAS becomes increasingly important to address remaining gaps in SIA quality and help focus resources on high-risk areas to prevent the continued transmission of wild poliovirus.

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.

An environmental data set for vector-borne disease modeling and epidemiology.

Understanding the environmental conditions of disease transmission is important in the study of vector-borne diseases. Low- and middle-income countries bear a significant portion of the disease burden; but data about weather conditions in those countries can be sparse and difficult to reconstruct. Here, we describe methods to assemble high-resolution gridded time series data sets of air temperature, relative humidity, land temperature, and rainfall for such areas; and we test these methods on the island of Madagascar. Air temperature and relative humidity were constructed using statistical interpolation of weather station measurements; the resulting median 95th percentile absolute errors were 2.75°C and 16.6%. Missing pixels from the MODIS11 remote sensing land temperature product were estimated using Fourier decomposition and time-series analysis; thus providing an alternative to the 8-day and 30-day aggregated products. The RFE 2.0 remote sensing rainfall estimator was characterized by comparing it with multiple interpolated rainfall products, and we observed significant differences in temporal and spatial heterogeneity relevant to vector-borne disease modeling.