Canine rabies control and management in Southeast Asia : from data to models

Canine rabies is a significant public health concern and economic burden in most low- and middle-income countries across Africa and Asia. Global targets for elimination of dog-mediated rabies have been set for 2030. Though fatal once clinical symptoms appear, rabies is preventable through appropriate administration of human and dog vaccines. Postexposure prophylaxis (PEP) is highly effective in averting the onset of rabies if delivered promptly after a person is bitten by a rabid animal. However, its unequal distribution creates disparity between settings. Where access to PEP is limited and the personal costs prohibitive, many people die having been refused appropriate healthcare. On the other hand, indiscriminately administered PEP results in excessive expenditure on non-case patients, subsequent financial strains and vaccine shortages, whilst vulnerable communities remain untreated. The lack of formal surveillance leads to suboptimal detection of the disease, preceding unrestricted transmission and misleading representation of its magnitude, undermining advocacy for funding of control programmes. While mass dog vaccination can eliminate rabies from the source population, it requires extensive resources and is currently not conducted systematically and at scale in most rabies endemic countries. The main objectives of this thesis were first to critically review and evaluate accomplishments and failures of the existing rabies control and management strategies in Southeast Asia (Chapters 1 and 2), and secondly to use these assessments to draw and test potential improvements to accelerate the elimination targets across the region (Chapters 3 and 4). We used a combination of long-term epidemiological datasets, experimental design and theoretical models to examine the theory and implementation of intersectoral, enhanced surveillance and dog quarantine in the context of canine rabies in domestic dogs. Several key themes have emerged from this work. First and foremost, to eliminate rabies will require time, resources and commitment as well as a combination of strategies following the One Health concept. An effective One Health approach entails long-term planning, intersectoral communication and collaboration, and sustained effort using tried and tested methods. Efforts should be directed towards well-coordinated high-coverage annual dog vaccinations using high-quality vaccines and enhanced surveillance targeted through investigations of biting animals. The logistics of vaccinating a very large, free-roaming dog population that is typical of most Southeast Asian countries may be challenging but certainly not impossible. Lessons can be drawn from Bali, Indonesia for other large and dense dog populations, where dog management and rabies control appear difficult. Well-trained teams with nets can rapidly catch and vaccinate large numbers of dogs where central-point vaccinations are insufficient, and post-vaccination surveys of collared dogs can be used to evaluate coverage and target supplementary vaccinations. However, careful planning is required to ensure all communities are reached during campaigns and sufficient vaccine is available over consecutive years. Effective communication strategies are needed to coordinate intersectoral activities, and to keep communities as well as rabies practitioners engaged. Using detailed questionnaires on animal bite histories combined with phone follow-ups and field investigations, we demonstrated the effectiveness of Integrated Bite Case Management (IBCM) in detecting rabies in the dog population, offering a more sensitive alternative to routine surveillance conducted at random. We noted that the reported patient bite incidence reflects the availability of the vaccine and proximity of bite patients to clinics rather than the actual disease incidence in the dog population and should not be taken as an indicator of rabies burden alone without further field investigations. In fact, rabies transmission between dogs appears to take place mostly locally with cases from neighbouring areas, and focal cases from the previous month having been most significantly predictive of future rabies occurrence both in Bali and the Philippines. We advocate that joint investigations such as Integrated Bite Case Management have the potential to foster intersectoral relationships, opening much needed space for collaborative investments between public health and veterinary services. Triage of patients and investigations of suspect dogs offer an effective tool for improved PEP recommendations and reduction of potentially unnecessary expenditures and can provide real-time guidance for tailored quarantine of high-risk contacts. Temporary exclusion of infected dogs appears powerful in curtailing rabies transmission despite the low prevalence of the disease, particularly in settings where optimal vaccination coverage is yet to be achieved, providing a critical stopgap to reduce the number of human deaths due to rabid bites. We conclude that all of the control and prevention activities discussed in this thesis will be necessary for complete interruption of transmission of the virus and sustained elimination of rabies, especially given the enduring risk of re-introductions from neighbouring populations

Competition among native and invasive Phragmites australis populations: An experimental test of the effects of invasion status, genome size, and ploidy level

Among the traits whose relevance for plant invasions has recently been suggested are genome size (the amount of nuclear DNA) and ploidy level. So far, research on the role of genome size in invasiveness has been mostly based on indirect evidence by comparing species with different genome sizes, but how karyological traits influence competition at the intraspecific level remains unknown. We addressed these questions in a common‐garden experiment evaluating the outcome of direct intraspecific competition among 20 populations of Phragmites australis, represented by clones collected in North America and Europe, and differing in their status (native and invasive), genome size (small and large), and ploidy levels (tetraploid, hexaploid, or octoploid). Each clone was planted in competition with one of the others in all possible combinations with three replicates in 45‐L pots. Upon harvest, the identity of 21 shoots sampled per pot was revealed by flow cytometry and DNA analysis. Differences in performance were examined using relative proportions of shoots of each clone, ratios of their aboveground biomass, and relative yield total (RYT). The performance of the clones in competition primarily depended on the clone status (native vs. invasive). Measured in terms of shoot number or aboveground biomass, the strongest signal observed was that North American native clones always lost in competition to the other two groups. In addition, North American native clones were suppressed by European natives to a similar degree as by North American invasives. North American invasive clones had the largest average shoot biomass, but only by a limited, nonsignificant difference due to genome size. There was no effect of ploidy on competition. Since the North American invaders of European origin are able to outcompete the native North American clones, we suggest that their high competitiveness acts as an important driver in the early stages of their invasion

Towards elimination of dog-mediated human rabies: experiences from implementing a large-scale demonstration project in Southern Tanzania

No abstract available

One health surveillance for rabies : a case study of integrated bite case management in Albay Province, Philippines

Canine rabies is a significant public health concern and economic burden in the Philippines. Animal Bite Treatment Centers (ABTCs) that provide post-exposure prophylaxis (PEP) to bite patients have been established across the country, but the incidence of bite patient presentations has grown unsustainably, whilst rabies transmission in domestic dogs has not been controlled. Moreover, weak surveillance leads to low case detection and late outbreak responses. Here we investigated the potential for Integrated Bite Case Management (IBCM) to improve rabies detection in Albay province. Using information obtained from animal bite histories combined with phone follow-ups and field investigations, we demonstrated that IBCM resulted in a fourfold increase in case detection over 13 months of study compared to the prior period. Bite patient incidence across Albay was very high (>600/100,000 persons/year) with PEP administered mostly indiscriminately. Clinic attendance reflected availability of PEP and proximity to ABTCs rather than rabies incidence (<3% of patient presentations were from “probable” or confirmed rabies exposures) and is therefore not a suitable indicator of rabies burden. Further analysis of the IBCM data suggests that rabies transmission is mostly localized with focal cases from the previous month and current cases in neighbouring villages being most predictive of future rabies occurrence. We conclude that investigations of suspicious biting incidents identified through IBCM have potential to foster intersectoral relationships, and collaborative investments between public health and veterinary services, enabling the One Health ethos to be applied in a more sustainable and equitable way. Triage of patients and investigations of suspect dogs offer an effective tool for improved PEP provisioning and reduction of unnecessary expenditure, whilst targeted field investigations should lead to increased and earlier detection of rabid dogs. Given the enduring risk of re-introductions from neighbouring populations, enhanced surveillance is critical to achieving and maintaining rabies freedom

Towards the elimination of dog-mediated rabies: development and application of an evidence-based management tool

Abstract: Background: International organizations advocate for the elimination of dog-mediated rabies, but there is only limited guidance on interpreting surveillance data for managing elimination programmes. With the regional programme in Latin America approaching elimination of dog-mediated rabies, we aimed to develop a tool to evaluate the programme’s performance and generate locally-tailored rabies control programme management guidance to overcome remaining obstacles. Methods: We developed and validated a robust algorithm to classify progress towards rabies elimination within sub-national administrative units, which we applied to surveillance data from Brazil and Mexico. The method combines criteria that are easy to understand, including logistic regression analysis of case detection time series, assessment of rabies virus variants, and of incursion risk. Subjecting the algorithm to robustness testing, we further employed simulated data sub-sampled at differing levels of case detection to assess the algorithm’s performance and sensitivity to surveillance quality. Results: Our tool demonstrated clear epidemiological transitions in Mexico and Brazil: most states progressed rapidly towards elimination, but a few regressed due to incursions and control lapses. In 2015, dog-mediated rabies continued to circulate in the poorest states, with foci remaining in only 1 of 32 states in Mexico, and 2 of 27 in Brazil, posing incursion risks to the wider region. The classification tool was robust in determining epidemiological status irrespective of most levels of surveillance quality. In endemic settings, surveillance would need to detect less than 2.5% of all circulating cases to result in misclassification, whereas in settings where incursions become the main source of cases the threshold detection level for correct classification should not be less than 5%. Conclusion: Our tool provides guidance on how to progress effectively towards elimination targets and tailor strategies to local epidemiological situations, while revealing insights into rabies dynamics. Post-campaign assessments of dog vaccination coverage in endemic states, and enhanced surveillance to verify and maintain freedom in states threatened by incursions were identified as priorities to catalyze progress towards elimination. Our finding suggests genomic surveillance should become increasingly valuable during the endgame for discriminating circulating variants and pinpointing sources of incursions

Rapid in-country sequencing of whole virus genomes to inform rabies elimination programmes.

Genomic surveillance is an important aspect of contemporary disease management but has yet to be used routinely to monitor endemic disease transmission and control in low- and middle-income countries. Rabies is an almost invariably fatal viral disease that causes a large public health and economic burden in Asia and Africa, despite being entirely vaccine preventable. With policy efforts now directed towards achieving a global goal of zero dog-mediated human rabies deaths by 2030, establishing effective surveillance tools is critical. Genomic data can provide important and unique insights into rabies spread and persistence that can direct control efforts. However, capacity for genomic research in low- and middle-income countries is held back by limited laboratory infrastructure, cost, supply chains and other logistical challenges. Here we present and validate an end-to-end workflow to facilitate affordable whole genome sequencing for rabies surveillance utilising nanopore technology. We used this workflow in Kenya, Tanzania and the Philippines to generate rabies virus genomes in two to three days, reducing costs to approximately £60 per genome. This is over half the cost of metagenomic sequencing previously conducted for Tanzanian samples, which involved exporting samples to the UK and a three- to six-month lag time. Ongoing optimization of workflows are likely to reduce these costs further. We also present tools to support routine whole genome sequencing and interpretation for genomic surveillance. Moreover, combined with training workshops to empower scientists in-country, we show that local sequencing capacity can be readily established and sustainable, negating the common misperception that cutting-edge genomic research can only be conducted in high resource laboratories. More generally, we argue that the capacity to harness genomic data is a game-changer for endemic disease surveillance and should precipitate a new wave of researchers from low- and middle-income countries

Cost-effectiveness analysis of One Health surveillance strategies for rabies control

ObjectiveTo evaluate public health and economic impact of intersectoral One Health enhanced surveillance strategies of canine rabies in the Philippines to inform vaccine procurement and provision plans.IntroductionRabies control programmes are being implemented across the Philippines, with a number of islands and provinces on track for the elimination of both human and dog rabies [1,2]. In spite of considerable progress in control programmes, costs of post exposure prophylaxis (PEP) remain high with bite incidence rapidly increasing every year. Indiscriminate PEP administration can strain healthcare budgets, and eventually redirect focus from essential mass dog vaccination campaigns. It is an ethical imperative to improve access to PEP for those at risk; however, under the current framework operating in the Philippines, indiscriminate PEP administration results in excessive expenditure on non-case patients and subsequent financial strains and vaccine shortages, whilst vulnerable communities remain undetected. At the same time, incursions represent an obstacle to achieving and maintaining rabies freedom [3,4]and have been shown to pose a threat to elimination goals [5]. The lack of formal surveillance is the primary cause, leading to late detection of disease at which point substantial secondary transmission within the dog population already occurs. There is, therefore, an urgent need to enhance and streamline surveillance to maximize detection potential for rapid outbreak response and to guide policy decisions regarding public health practice. Workable surveillance criteria are needed for more judicious and effectiveuse of PEP to identify high risk exposures and thus prevent unnecessary risk and further transmission when vaccine stocks are limited.MethodsIntegrated models that capture epidemiological and health dynamics are essential to evaluate cost-effectiveness of control strategies and have the potential to directly inform rabies control programmes. Here we sought to develop an epidemiological model for rabies transmission within the dog population and from dogs to humans, incorporating information on health-seeking behaviour collected through a longitudinal enhanced surveillance study of dog bite-injury patientsongoing atanti-rabies clinics in Albay province, Philippines.Through computational simulations, we investigated changes in rabies dynamics and economic benefits of three potential surveillance scenarios: (1) current practice of indiscriminate PEP administration with no investigation of bite-incident histories, (2) quarantine of suspect dogs identified through bite-histories of patients presenting at clinics and (3) quarantine of suspect dogs with detailed triage of patients and follow up outbreak investigations.ResultsUtilizing data collected at anti-rabies clinics, we found that bite incidence in Albay is high (monthly mean=796, sd=337) with PEP administered unsystematically. All patients presented at clinics received at least 1 dose of PEP, 95% of patients received 2 doses and 89% of patients received 3 doses. Only 3% of patients received the fourth dose, likely owing to the cost patients are charged for the last dose (first three doses are provided free of charge). Additionally, 17% received a dose of costly RIG. This is consistent with previous reports of generous use of PEP and RIG in the Philippines [6].We found that in comparison to the current practices (scenario1) the integrated bite-case management strategies – quarantine of suspect dogs (scenario 2) and quarantine of suspect dogs with detailed triage of patients and outbreak investigations (scenario 3) – demonstrated a substantial reduction in costs through savings on expensive PEP and RIG despite additional expenditures on surveillance. The total costs for rabies prevention in humans would be reduced by 47% and 57% deploying scenarios 2 and 3 respectively. However, an ongoing risk of human deaths persists for as long as rabies continues to circulate in domestic dog populations. We have, therefore, investigated the impact of dog quarantine on rabies dynamics in the context of disease elimination and persistence. Scenarios 2 and 3 resulted in a clear decline in incidence of both dog and human cases. Moreover, under increased detection of infected dogs through field investigations (scenario 3) rabies appears to persist solely through repeat exogenous incursions.ConclusionsCoalescing our understanding of health landscapes with that of transmission dynamics enables us to evaluate the demand of PEP provisioning, how this demand will evolve across the elimination timeframe, and the effectiveness of individual intervention strategies in preventing human deaths.Joint investigations foster intersectoral relationships and collaborative investments between public health and veterinary services. Triage of patients and investigations of suspect dogs allows for improved PEP recommendations and reduction of the current unnecessary expenditures whilst active field investigations lead to increased and early detection of rabies in dogs and identification of rabies exposed persons who would otherwise not seek care. Quarantine of rabies suspect dogs appears powerful in curtailing transmission, but large-scale vaccination of dogs is necessary for complete interruption of transmission of the virus and sustained elimination of rabies, given the enduring risk of re-introductions from neighbouring populations [7-9]. However, early detection of incursions is critical and can preclude an undesired outbreak. Integrated One Health approaches of rabies surveillance have the potential to substantially increase case detection [10, 11] and ultimately generate vital evidence for verifying freedom from disease [12].References[1] Miranda LM et al., 2017, Transbound Emerg Dis.; [2] Barroga TRM et al., 2018, Trop Med and Inf Dis.; [3] Zinsstag J et al., 2017, Science Translational Medicine.; [4] Bourhy H et al., 2016, PLOS Pathogens.; [5] Tohma K et al., 2016, Genetics and Evolution.; [6] Hampson Ket al., 2015, PLOSNeg Trop Dis.; [7] Putra AAG et al., 2013, Emerg Inf Dis.; [8] Bamaiyi PH et al., 2015, J Vet Advanc.; [9] Windiyaningsih C et al., 2004, J Med Assoc Thai.; [10] Rajeev M et al., in print, Vaccine.; [11] Rysava K et al., in print, Vaccine.; [12] Hampson K et al., 2016, BioRxiv.

Management tool to guide rabies elimination programmes

ObjectiveTo provide surveillance tools to support policymakers andpractitioners to identify epidemiological situations and inform theprogressive implementation of rabies elimination programmes.IntroductionGlobal targets for elimination of human rabies mediated by dogshave been set for 2030. In the Americas countries are progressingtowards interruption of transmission and declaration of rabiesfreedom1. Guidance for managing elimination programmes toensure continued progress during the endgame is critical, yet oftenlimited and lacking in specific recommendations. Characteristicspatiotemporal incidence patterns are indicative of progress, andthrough their identification, tailored guidance can be provided.MethodsUsing SIRVERA, a surveillance database for rabies in theAmericas2, we developed a classification framework for identificationof epidemiological situations at subnational level. Each situationexhibits a characteristic pattern identified via a set of objective criteriaincluding trends in case detection, assessment of virus variants, caselocations and measures of incursion risk.We refined our framework through application to Mexico inconsultation with stakeholders. To understand factors predictingincursions we analysed state-level data on vaccination campaigns,populations and socioeconomic indicators employing multivariateregression models.ResultsWe were able to classify all states in Mexico and providecorrespondingly tailored guidance. Control efforts have resultedin progress towards elimination; however rabies still circulatesendemically in one state Chiapas, putting its neighbours at risk ofre-emergence.Epidemiological and socioeconomic factors associated withincursions were primarily geographic proximity to endemic and high-prevalence states, and inconsistent vaccination campaigns associatedwith a low human development index.ConclusionsOur management tool can support rabies programme managersat subnational levels to identify their epidemiological situation,develop tailored plans to meet targets, and sustainably maintainrabies freedom, as demonstrated for Mexico. Effective surveillanceis critical for disease elimination. Control options differ dependingon whether disease circulates intermittently through reintroductionsor persists focally, but with poor detection these situations mightbe indistinguishable. Our analysis enables identification of at-riskareas and methods to reduce risk. Investment in remaining endemicareas, through improved implementation and monitoring of mass dogvaccinations, is expected to provide the most cost-effective approachto elimination whilst preventing re-emergence elsewhere.Decision-tree framework.Rabies incursions in Mexico, 2005-2015. Blue circles indicate incursionlocations, and resulting outbreak sizes, with darker shading for more recentincursions. Red shading indicates the duration of endemic circulation over theten-year period