Economic optimization of Wolbachia-infected Aedes aegypti release to prevent dengue.

BACKGROUND: Dengue virus, primarily transmitted by the Aedes aegypti mosquito, is a major public health concern affecting ≈3.83 billion people worldwide. Recent releases of Wolbachia-transinfected Ae. aegypti in several cities worldwide have shown that it can reduce dengue transmission. However, these releases are costly, and, to date, no framework has been proposed for determining economically optimal release strategies that account for both costs associated with disease risk and releases. RESULTS: We present a flexible stochastic dynamic programming framework for determining optimal release schedules for Wolbachia-transinfected mosquitoes that balances the cost of dengue infection with the costs of rearing and releasing transinfected mosquitoes. Using an ordinary differential equation model of Wolbachia and dengue in a hypothetical city loosely describing areas at risk of new dengue epidemics, we determined that an all-or-nothing release strategy that quickly brings Wolbachia to fixation is often the optimal solution. Based on this, we examined the optimal facility size, finding that it was inelastic with respect to the mosquito population size, with a 100% increase in population size resulting in a 50-67% increase in optimal facility size. Furthermore, we found that these results are robust to mosquito life-history parameters and are mostly determined by the mosquito population size and the fitness costs associated with Wolbachia. CONCLUSIONS: These results reinforce that Wolbachia-transinfected mosquitoes can reduce the cost of dengue epidemics. Furthermore, they emphasize the importance of determining the size of the target population and fitness costs associated with Wolbachia before releases occur. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Comparison of commercially available, rapid, point-of-care C-reactive protein assays among children with febrile illness in southwestern Uganda.

In Uganda, children with febrile illness are often treated with antibiotics even though most have self-limiting, likely viral, infections. C-reactive protein (CRP) measurement can help identify those who are more likely to have a bacterial infection and therefore need antibiotic treatment. Implementation of a CRP rapid diagnostic test (RDT) at the point-of-care in resource-constrained settings with minimal laboratory infrastructure could reduce unnecessary antibiotic use. In this study, we evaluated the performance of three semi-quantitative CRP RDTs (Actim, BTNX, Duo) against a reference CRP assay requiring an electrically powered analyzer (Afinion). While both tests demonstrated substantial agreement with Afinion, Actim had slightly higher agreement than BTNX. The sensitivity was higher for the BTNX test, whereas the Actim test had a higher specificity, at cut-offs of 40 mg/L and 80 mg/L. At a cut-off of 20 mg/L, Duo demonstrated substantial agreement with the Afinion test as well. Our results demonstrate the reliability of CRP RDTs when compared to a reference standard. CRP RDTs without the need for a laboratory-based analyzer are promising tools for optimizing antibiotic use in low-resource settings.

Evolution of Spatial Risk of Malaria Infection After a Pragmatic Chemoprevention Program in Response to Severe Flooding in Rural Western Uganda.

BACKGROUND: Malaria epidemics result from extreme precipitation and flooding, which are increasing with global climate change. Local adaptation and mitigation strategies will be essential to prevent excess morbidity and mortality. METHODS: We investigated the spatial risk of malaria infection at multiple timepoints after severe flooding in rural western Uganda employing longitudinal household surveys measuring parasite prevalence and leveraging remotely sensed information to inform spatial models of malaria risk in the 3 months after flooding. RESULTS: We identified clusters of malaria risk emerging in areas (1) that showed the greatest changes in Normalized Difference Vegetation Index from pre- to postflood and (2) where residents were displaced for longer periods of time and had lower access to long-lasting insecticidal nets, both of which were associated with a positive malaria rapid diagnostic test result. The disproportionate risk persisted despite a concurrent chemoprevention program that achieved high coverage. CONCLUSIONS: The findings enhance our understanding not only of the spatial evolution of malaria risk after flooding, but also in the context of an effective intervention. The results provide a "proof of concept" for programs aiming to prevent malaria outbreaks after flooding using a combination of interventions. Further study of mitigation strategies-and particularly studies of implementation-is urgently needed.

The effect of governance structures on optimal control of two-patch epidemic models.

Infectious diseases continue to pose a significant threat to the health of humans globally. While the spread of pathogens transcends geographical boundaries, the management of infectious diseases typically occurs within distinct spatial units, determined by geopolitical boundaries. The allocation of management resources within and across regions (the "governance structure") can affect epidemiological outcomes considerably, and policy-makers are often confronted with a choice between applying control measures uniformly or differentially across regions. Here, we investigate the extent to which uniform and non-uniform governance structures affect the costs of an infectious disease outbreak in two-patch systems using an optimal control framework. A uniform policy implements control measures with the same time varying rate functions across both patches, while these measures are allowed to differ between the patches in a non-uniform policy. We compare results from two systems of differential equations representing transmission of cholera and Ebola, respectively, to understand the interplay between transmission mode, governance structure and the optimal control of outbreaks. In our case studies, the governance structure has a meaningful impact on the allocation of resources and burden of cases, although the difference in total costs is minimal. Understanding how governance structure affects both the optimal control functions and epidemiological outcomes is crucial for the effective management of infectious diseases going forward.

Leveraging insect-specific viruses to elucidate mosquito population structure and dynamics.

Several aspects of mosquito ecology that are important for vectored disease transmission and control have been difficult to measure at epidemiologically important scales in the field. In particular, the ability to describe mosquito population structure and movement rates has been hindered by difficulty in quantifying fine-scale genetic variation among populations. The mosquito virome represents a possible avenue for quantifying population structure and movement rates across multiple spatial scales. Mosquito viromes contain a diversity of viruses, including several insect-specific viruses (ISVs) and "core" viruses that have high prevalence across populations. To date, virome studies have focused on viral discovery and have only recently begun examining viral ecology. While nonpathogenic ISVs may be of little public health relevance themselves, they provide a possible route for quantifying mosquito population structure and dynamics. For example, vertically transmitted viruses could behave as a rapidly evolving extension of the host's genome. It should be possible to apply established analytical methods to appropriate viral phylogenies and incidence data to generate novel approaches for estimating mosquito population structure and dispersal over epidemiologically relevant timescales. By studying the virome through the lens of spatial and genomic epidemiology, it may be possible to investigate otherwise cryptic aspects of mosquito ecology. A better understanding of mosquito population structure and dynamics are key for understanding mosquito-borne disease ecology and methods based on ISVs could provide a powerful tool for informing mosquito control programs.

Comparing field-collected versus remotely-sensed variables to model malaria risk in the highlands of western Uganda.

BACKGROUND: Malaria risk is not uniform across relatively small geographic areas, such as within a village. This heterogeneity in risk is associated with factors including demographic characteristics, individual behaviours, home construction, and environmental conditions, the importance of which varies by setting, making prediction difficult. This study attempted to compare the ability of statistical models to predict malaria risk at the household level using either (i) free easily-obtained remotely-sensed data or (ii) results from a resource-intensive household survey. METHODS: The results of a household malaria survey conducted in 3 villages in western Uganda were combined with remotely-sensed environmental data to develop predictive models of two outcomes of interest (1) a positive ultrasensitive rapid diagnostic test (uRDT) and (2) inpatient admission for malaria within the last year. Generalized additive models were fit to each result using factors from the remotely-sensed data, the household survey, or a combination of both. Using a cross-validation approach, each model's ability to predict malaria risk for out-of-sample households (OOS) and villages (OOV) was evaluated. RESULTS: Models fit using only environmental variables provided a better fit and higher OOS predictive power for uRDT result (AIC = 362, AUC = 0.736) and inpatient admission (AIC = 623, AUC = 0.672) compared to models using household variables (uRDT AIC = 376, Admission AIC = 644, uRDT AUC = 0.667, Admission AUC = 0.653). Combining the datasets did not result in a better fit or higher OOS predictive power for uRDT results (AIC = 367, AUC = 0.671), but did for inpatient admission (AIC = 615, AUC = 0.683). Household factors performed best when predicting OOV uRDT results (AUC = 0.596) and inpatient admission (AUC = 0.553), but not much better than a random classifier. CONCLUSIONS: These results suggest that residual malaria risk is driven more by the external environment than home construction within the study area, possibly due to transmission regularly occurring outside of the home. Additionally, they suggest that when predicting malaria risk the benefit may not outweigh the high costs of attaining detailed information on household predictors. Instead, using remotely-sensed data provides an equally effective, cost-efficient alternative.

Evaluation of an open forecasting challenge to assess skill of West Nile virus neuroinvasive disease prediction.

BACKGROUND: West Nile virus (WNV) is the leading cause of mosquito-borne illness in the continental USA. WNV occurrence has high spatiotemporal variation, and current approaches to targeted control of the virus are limited, making forecasting a public health priority. However, little research has been done to compare strengths and weaknesses of WNV disease forecasting approaches on the national scale. We used forecasts submitted to the 2020 WNV Forecasting Challenge, an open challenge organized by the Centers for Disease Control and Prevention, to assess the status of WNV neuroinvasive disease (WNND) prediction and identify avenues for improvement. METHODS: We performed a multi-model comparative assessment of probabilistic forecasts submitted by 15 teams for annual WNND cases in US counties for 2020 and assessed forecast accuracy, calibration, and discriminatory power. In the evaluation, we included forecasts produced by comparison models of varying complexity as benchmarks of forecast performance. We also used regression analysis to identify modeling approaches and contextual factors that were associated with forecast skill. RESULTS: Simple models based on historical WNND cases generally scored better than more complex models and combined higher discriminatory power with better calibration of uncertainty. Forecast skill improved across updated forecast submissions submitted during the 2020 season. Among models using additional data, inclusion of climate or human demographic data was associated with higher skill, while inclusion of mosquito or land use data was associated with lower skill. We also identified population size, extreme minimum winter temperature, and interannual variation in WNND cases as county-level characteristics associated with variation in forecast skill. CONCLUSIONS: Historical WNND cases were strong predictors of future cases with minimal increase in skill achieved by models that included other factors. Although opportunities might exist to specifically improve predictions for areas with large populations and low or high winter temperatures, areas with high case-count variability are intrinsically more difficult to predict. Also, the prediction of outbreaks, which are outliers relative to typical case numbers, remains difficult. Further improvements to prediction could be obtained with improved calibration of forecast uncertainty and access to real-time data streams (e.g. current weather and preliminary human cases).

Prevalence of Knock-Down Resistance F1534S Mutations in Aedes albopictus (Skuse) (Diptera: Culicidae) in North Carolina.

Knock-down resistance (kdr) mutations in the voltage-gated sodium channel gene of Aedes species mosquitoes are biomarkers for resistance to pyrethroid insecticides. In the United States, few studies have reported kdr mutations among Aedes albopictus (Skuse) (Diptera: Culicidae) populations. In this study, we sought to compare the presence of kdr alleles among Ae. albopictus mosquitoes collected from Fort Bragg and Wake County, North Carolina. We collected 538 Ae. albopictus mosquitoes, including 156 from 4 sites at Fort Bragg, North Carolina and 382 from 15 sites in Wake County, North Carolina to compare the prevalence of kdr mutations. Of those successfully sequenced, we identified 12 (3.0%) mosquitoes with kdr mutations, all of which were attributed to variants at position 1534 within domain 3. All mutations were found in mosquitoes collected at Wake County sites; no mutations were identified in collections from Fort Bragg. There was a focus of mutations observed at the Wake County sites with approximately 92% (11 of 12) of the mosquitoes with the mutation coming from one site, where kdr mutations represented 24.4% (11 of 45) of all mosquitoes collected. We observed highly focal resistance in a suburban area of Raleigh, which may be attributable to peri-domestic mosquito control activities that involve area dispersal of pyrethroid insecticides. More robust surveillance is needed to monitor the emergence and spread of resistance.

Patterns Testing for Tick-Borne Diseases and Implications for Surveillance in the Southeastern US.

Importance: Tick-borne diseases (TBD), including spotted fever group rickettsiosis (SFGR), ehrlichiosis, and, increasingly, Lyme disease, represent a substantial public health concern throughout much of the southeastern United States. Yet, there is uncertainty about the epidemiology of these diseases because of pitfalls in existing diagnostic test methods. Objective: To examine patterns of diagnostic testing and incidence of TBD in a large, academic health care system. Design, Setting, and Participants: This cross-sectional study included diagnostic test results for TBD at UNC Health, a large academic health care system with inpatient and outpatient facilities, from January 1, 2017, to November 30, 2020. Participants included all individuals seeking routine care at UNC Health facilities who had testing for SFGR, ehrlichiosis, or Lyme disease performed during the study period. Main Outcomes and Measures: Rates of test positivity, testing completeness, and incidence of TBD. Results: During the 4-year study period, 11 367 individuals (6633 [58.4%] female; 10 793 [95%] non-Hispanic individuals and 8850 [77.9%] White individuals; median [IQR] age, 53 [37-66] years) were tested for TBD. Among the 20 528 diagnostic tests performed, 47 laboratory-confirmed, incident cases of SFGR, 27 cases of ehrlichiosis, and 76 cases of Lyme were confirmed, representing incidence rates of 4.7%, 7.1%, and 0.7%, respectively. However, 3984 of SFGR tests (79.3%) and 3606 of Ehrlichia tests (74.3%) lacked a paired convalescent sample. Of 20 528 tests, there were 11 977 tests (58.3%) for Lyme disease from 10 208 individuals, 5448 tests (26.5%) for SFGR from 4520 individuals, and 3103 tests (15.1%) for ehrlichiosis from 2507 individuals. Most striking, testing for ehrlichiosis was performed in only 55% of patients in whom SFGR was ordered, suggesting that ehrlichiosis remains underrecognized. An estimated 187 incident cases of SFGR and 309 of ehrlichiosis were potentially unidentified because of incomplete testing. Conclusions and Relevance: In this cross-sectional study, most of the patients suspected of having TBD did not have testing performed in accordance with established guidelines, which substantially limits understanding of TBD epidemiology. Furthermore, the data revealed a large discrepancy between the local burden of disease and the testing performed. These findings underscore the need to pursue more robust, active surveillance strategies to estimate the burden of TBD and distribution of causative pathogens.

Effectiveness of autocidal gravid trapping and chemical control in altering abundance and age structure of Aedes albopictus.

BACKGROUND: Aedes albopictus is a nuisance pest mosquito of public health importance commonly managed with adulticides and larvicides. We investigated whether adding Gravid Aedes Traps (GATs), Autocidal Gravid Ovitraps (AGOs) or In2Care traps would extend the effectiveness of chemical control methods in Wake County, North Carolina, USA, by combining barrier sprays and larval habitat management (LHM) with each trap type at suburban households. We compared these three treatment groups to untreated controls and to backyards treated only with barrier sprays and LHM. Once a week, for ten weeks, we collected adult mosquitoes at each house using lure-baited surveillance traps and dissected a portion of Ae. albopictus females to determine parity. RESULTS: Barrier sprays and LHM alone or combined with any supplemental autocidal ovitrap significantly reduced female Ae. albopictus through Week 3 post-treatment. GATs significantly extended chemical control effectiveness for the duration of the study. Compared to the untreated control, the AGO and GAT treatment groups had significant overall female Ae. albopictus reductions of 74% and 80.4%, respectively, with populations aging significantly slower at houses treated with AGOs. CONCLUSION: This household-level study, though limited in size, observed significant reductions in nuisance Ae. albopictus when combining AGOs and GATs with chemical controls for an eight-week period. Delayed population aging in AGO-treated yards suggests that traps also could mitigate disease transmission risk. Future studies should test these control methods at the neighborhood level to evaluate large-scale effectiveness as well as assess the effect of autocidal ovitraps without chemical intervention. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Dihydroartemisinin-Piperaquine Chemoprevention and Malaria Incidence After Severe Flooding: Evaluation of a Pragmatic Intervention in Rural Uganda.

BACKGROUND: Malaria epidemics are a well-described phenomenon after extreme precipitation and flooding. Yet, few studies have examined mitigation measures to prevent post-flood malaria epidemics. METHODS: We evaluated a malaria chemoprevention program implemented in response to severe flooding in western Uganda. Children aged ≤12 years from 1 village were eligible to receive 3 monthly rounds of dihydroartemisinin-piperaquine (DP). Two neighboring villages served as controls. Malaria cases were defined as individuals with a positive rapid diagnostic test result as recorded in health center registers. We performed a difference-in-differences analysis to estimate changes in the incidence and test positivity of malaria between intervention and control villages. RESULTS: A total of 554 children received at least 1 round of chemoprevention, with 75% participating in at least 2 rounds. Compared with control villages, we estimated a 53.4% reduction (adjusted rate ratio [aRR], 0.47; 95% confidence interval [CI]: .34-.62; P < .01) in malaria incidence and a 30% decrease in the test positivity rate (aRR, 0.70; 95% CI: .50-.97; P = .03) in the intervention village in the 6 months post-intervention. The impact was greatest among children who received the intervention, but decreased incidence was also observed in older children and adults (aRR, 0.57; 95% CI: .38-.84; P < .01). CONCLUSIONS: Three rounds of chemoprevention with DP delivered under pragmatic conditions reduced the incidence of malaria after severe flooding in western Uganda. These findings provide a proof-of-concept for the use of malaria chemoprevention to reduce excess disease burden associated with severe flooding.

Short-Term, Large-Area Survey of Container Aedes spp. (Diptera: Culicidae): Presence and Abundance is Associated with Fine-scale Landscape Factors in North Carolina, USA.

Container Aedes mosquitoes are responsible for the transmission of anthroponotic and zoonotic viruses to people. The surveillance and control of these mosquitoes is an important part of public health protection and prevention of mosquito-borne disease. In this study, we surveyed 327 sites over 2 weeks in late June and early July in 2017 in North Carolina, USA for the presence and abundance of Aedes spp. eggs in an effort to better target potential Ae. aegypti collections. We examined the ability of 2 types of landscape data, Light Detection And Ranging (LIDAR) and National Land Cover Database (NLCD) to explain the presence and abundance of eggs using principal component analysis to deal with collinearity, followed by generalized linear regression. We explained variation of both egg presence and abundance for Aedes albopictus (Skuse) and Aedes triseriatus (Say) using both NLCD and LIDAR data. However, the ability to make robust predictions was limited by variation in the data. Increased sampling time and better landscape data would likely improve the predictive ability of our models, as would a better understanding of oviposition behavior.

After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections.

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

Efficacy and Spatial Extent of Yard-Scale Control of Aedes (Stegomyia) albopictus (Diptera: Culicidae) Using Barrier Sprays and Larval Habitat Management.

The Asian tiger mosquito, Aedes (Stegomyia) albopictus (Skuse), is a peridomestic, container-ovipositing mosquito commonly found throughout the southeastern United States. In the United States, Ae. albopictus is typically considered a nuisance pest; however, it is capable of transmitting multiple pathogens. Ae. albopictus is an important pest species and the target of numerous mosquito control efforts in the United States. Here, we evaluate the effectiveness and spatial extent of Ae. albopictus population reduction using a bifenthrin (AI Bifen IT, 7.9%) barrier spray and larval habitat management (LHM) in a temperate, suburban setting. Sixteen pairs of adjoining neighbors were randomly assigned to treatment groups with one neighbor receiving a treatment and the other monitored for evidence of a spillover effect of the treatments. Ae. albopictus populations in both yards were monitored for 33 d, with treatments occurring on the eighth day. Barrier sprays, both alone and combined with LHM, resulted in a significant reduction in Ae. albopictus abundance posttreatment. While LHM alone did not result in a significant reduction over the entire posttreatment period, Ae. albopictus populations were observed to be in decline during this period. No treatments were observed to have any reduction in efficacy 25 d posttreatment, with treatments involving LHM having a significantly increased efficacy. Yards neighboring treated yards were also observed to have reduced population sizes posttreatment, but these differences were rarely significant. These results provide insights into the population dynamics of Ae. albopictus following two common treatments and will be useful for integrated pest management plans.

Locally Fixed Alleles: A method to localize gene drive to island populations.

Invasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the "Locally Fixed Alleles" approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to alleles at multiple genomic loci becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.