SPEEDIER - Surveillance integrating Phylogenetics and Epidemiology for Elimination of Disease: Evaluation of Rabies Control in the Philippines

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci

Abstract

Rabies, a horrific but preventable disease, kills over 200 people annually in the Philippines. The National Rabies Prevention and Control Program in the Philippines has catalysed rabies control efforts with some provinces now aiming to declare freedom from disease. However, incursions and outbreaks continue and human deaths still occur. While improved postexposure prophylaxis (PEP) access has reduced mortality, it has proven expensive. Indeed rising PEP use has put a strain on local and national budgets, even as rabies circulation has declined, raising the question of how these efforts can be sustained. Meanwhile, routine rabies surveillance in the Philippines has major shortcomings and is not sufficiently sensitive for international agencies to recognize rabies free areas or to rapidly respond to incursions which remain a risk while rabies circulates in other provinces. As a result, surveillance measures need strengthening and use of PEP needs rationalizing for the Philippines to fully benefit from rabies control measures that are currently underway.

Our overarching aim is to deliver a cost-effective, epidemiologically robust surveillance package that can be rolled out across the Philippines to guide and sustain the elimination of canine rabies. Through implementation research we will develop best practice for an enhanced surveillance approach using Integrated Bite Case Management (IBCM) as a strategy to detect rabid animals, with risk assessment of bite patients triggering epidemiological investigations. IBCM has been identified as a potential strategy that can sufficiently enhance surveillance to enable verification of rabies freedom by international organizations and rapid detection of incursions for effective outbreak responses to maintain rabies freedom. Operationalizing IBCM as a key component of enhanced surveillance will have immediately beneficial applications within the Philippines and is of critical importance for the global campaign to eliminate human rabies deaths by 2030.

IBCM has also been demonstrated as an effective way to improve PEP administration, ensuring at risk persons are treated and unnecessary PEP use is reduced. Within our implementation study, we will conduct a pragmatic stepped-wedge cluster randomized controlled trial to evaluate the potential for cost savings and improved patient care through rationalized PEP. We estimate that if implemented effectively, rationalized PEP could save over $9 million every year in the Philippines.

Focusing on the low socio-economic class provinces of Romblon, Occidental Mindoro, and Oriental Mindoro, that include geographically isolated and disadvantaged communities, SPEEDIER will provide learning opportunities to local health and veterinary professionals and support communities to attain disease freedom, contributing to the Philippines developmental goals (2014 Kalusugang Pangkalahatan ('Universal Health') Road Map). Integrated, intersectoral, surveillance and response systems are advocated by international agencies, but rarely operationalized in resource-poor settings. Using our detailed epidemiological understanding of rabies and experience of deploying new technologies, we will develop an integrated surveillance and response system that enables effective working between sectors at multiple scales of governance. This is important; international agencies like the World Health Organisation and the World Organisation for Animal Health recognize the essential need to develop effective surveillance and sustainable approaches to guide rabies elimination programmes. The tools and best practice produced by SPEEDIER will therefore be invaluable for the global target to achieve zero human rabies deaths by 2030.

Technical Summary

SPEEDIER's aim is to deliver a cost-effective, epidemiologically robust, enhanced surveillance and response package to guide and sustain the elimination of rabies from the Philippines. The package includes integration of surveillance and response activities by the human and animal health sectors ('One Health') through a program of Integrated Bite Case Management to improve patient care and trigger early detection of animal rabies cases. As part of the package we will develop a genomic surveillance platform as a decision support tool to inform control activities and assess incursions risks, and undertake epidemiological modeling to inform contingency planning for managing re-emergence and maintaining disease freedom.

We will specifically develop protocols, integrated training and surveillance tools with comprising: 1) risk assessments of bite victims as part of Integrated Bite Case Management; 2) the latest WHO recommended PEP protocols; 2) Epidemiological investigations including animal observation, sample collection and rapid diagnostic testing and 3) use of a mobile phone application for reporting by human and animal health workers and 4) real-time whole genome sequencing of viruses using a multiplex/MinION approach incorporated into genomic surveillance platform for communicating risks of rabies spread and progress towards elimination. This enhanced surveillance will be implemented over across 3 provinces: Romblon, Mindoro Occidental and Mindoro Oriental to generate comprehensive data on dog bite incidence, associated rabies risk, PEP use and circulating viruses. Within this implementation study, a pragmatic stepped-wedge cluster-randomised trial of rationalized use of PEP will assess potential for cost savings and improved patient care.

The tools and best practice produced by SPEEDIER will enable sustainable national roll out and provide a model for the global target to achieve zero human rabies deaths by 2030.

Planned Impact

Rabies causes an estimated 60,000 human deaths every year, with at least 15 million people needing costly life-saving post-exposure prophylaxis (PEP). Rabies disproportionately affects developing countries like the Philippines, an ODA compliant country, where it kills 200-250 people annually, mainly children. While empirical evidence supports the feasibility of rabies elimination, there is little research to underpin the formulation of efficient cost-effective strategies for managing the final stages of elimination programs. This project will build the scientific knowledge to support national, regional and global policy frameworks for the progressive elimination of rabies.

The immediate beneficiary of SPEEDIER is the people in the provinces of Romblon, Occidental Mindoro and Oriental Mindoro, especially children. Successful implementation will result in a) annual cost savings of at least $30,000 per province; b) treatment of rabies exposed bite victims who would otherwise be missed; and c) increased case detection. As a result, after 24 months without detection, these provinces can be internationally recognized as Rabies-free. Tailored guidance will also be developed for how to imminently achieve freedom for provinces encountering challenges. Disease freedom will enhance their economies, including emerging tourism industries. SPEEDIER will enable a cost-effective and epidemiologically robust surveillance package to be rolled out across the Philippines to guide and sustain the elimination of rabies contributing to the Philippines' developmental goals (2014 Kalusugang Pangkalahatan ('Universal Health') Road Map). In the long-term, this approach is expected to save more than $9 million per year in the Philippines.

SPEEDIER will improve inter-sectoral collaboration in the Philippines by building effective working relationships between human and animal health workers at local and national levels, informing and empowering them to act more effectively. SPEEDIER will demonstrate the effectiveness of a One Health approach that explicitly recognises interconnected challenges rooted in socio-cultural, economic, policy and technical areas. We will enhance technical skills, surveillance and analytical methods to evaluate and manage rabies outbreaks and to improve public health policy. As a result, the human and animal health sectors as well as policy makers in the Philippines will benefit from programmatic success towards rabies elimination that will act as a template for successfully addressing other development and health challenges. This will be particularly important for other zoonoses and emerging infections that require a One Health Approach.

Through SPEEDIER, the Philippines will contribute to the WHO Global Business Plan for the elimination of human deaths from dog-mediated rabies by 2030. SPEEDIER will operationalise the latest WHO guidelines for rabies surveillance, prevention and elimination and provide a practical model for implementation in similar settings elsewhere. This will be particularly important for GAVI-eligible countries (low- and lower-middle income countries), in anticipation of the 2018 Vaccine Investment Strategy including human rabies vaccine. Knowledge exchange of the Philippines' experience in operationalising guidelines and their successful implementation of enhanced surveillance to verify freedom from rabies can ultimately inform global health policy and practice, supported by WHO, the World Organisation for Animal Health, the Global Alliance for Rabies Control, GAVI, the Vaccine Alliance, the FAO, and global pharmaceuticals.

Publications

10 25 50
 
Description We have generated considerable data about the incidence of rabies in the province of MIMAROPA in both animals and humans, and the risks of the disease, given access to healthcare. We have also generated considerable learning about the barriers and facilitators to effective surveillance for rabies that we expect to be broadly transferrable across the Philippines and to a large extent to other settings with endemic rabies. With the data we have collected to date we expect to be able to quantify the burden of disease and to be able to interrogate how the process of surveillance leads to underreporting given the intersectoral nature of surveillance for this zoonosis.
We have also generated considerable learning about the application of genomic surveillance which has directly translated into genomic surveillance for SARS-CoV-2.
Exploitation Route We anticipate development of policy briefs and direct dissemination to stakeholders in the Philippines (some of which are already taking place online).
We also expect direct uptake of recommendations into global policy through the United Against Rabies Forum (https://uarforum.org/) driving the global 'Zero by 30' strategy to eliminate human deaths from dog-mediated rabies by 2030, and through regional stakeholder meetings and training programmes led by the tripartite (WHO/OIE/FAO).
Sectors Agriculture, Food and Drink,Communities and Social Services/Policy,Healthcare

 
Description Our research has generated data that is being used locally within the MIMAROPA region of the Philippines specifically on vaccine provisioning. The skills and infrastructure that have been developed through this project and ongoing knowledge exchange and capacity building have directly contributed to the covid-19 response. Specifically this project contributed to the genomes of SARS-CoV-2 being generated in the Philippines (at RITM, sequenced on the platform procured for SPEEDIER, and undertaken by staff trained by SPEEDIER) and the ongoing generation and interpretation of genomic data.
First Year Of Impact 2020
Sector Healthcare
Impact Types Societal,Policy & public services

 
Description East African Policy Group meeting to inform rabies elimination
Geographic Reach Africa 
Policy Influence Type Participation in a guidance/advisory committee
Impact Informed policy development. Impacts ongoing and dependent on COVID-19 recovery
 
Description Participated in United Against Rabies meeting & development of call to action
Geographic Reach Multiple continents/international 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Awaiting on Gavi decisions due Jun 2023
URL https://www.unitedagainstrabies.org/news/rabies-experts-urge-gavi-to-implement-pep-investment/
 
Description Series of briefings to government of Bangladesh and International Donors
Geographic Reach Asia 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Informed policies and practices throughout the pandemic, especially large-scale interventions across Dhaka - mask wearing, community support teams, lockdown and quarantining, testing and vaccination.
URL http://boydorr.gla.ac.uk/BGD_Covid-19/CEEDS
 
Description Training programmes of provincial health workers and municipal agricultural officers
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
Impact Training 100+ practitioners in improved practices to increase detection of rabies and provide access to life saving emergency medicines.
 
Description WHO rabies expert consultation - December 2022
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a guidance/advisory committee
Impact Guidance being developed for circulation by International organizations
 
Description COVID 19: Epidemiological TA for COVID-19 CST Model in Bangladesh
Amount $400,000 (USD)
Funding ID INV-022851 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 12/2020 
End 08/2021
 
Description Data-driven approaches for rabies elimination
Amount £2,978,215 (GBP)
Funding ID 224520/Z/21/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2022 
End 12/2027
 
Description Implementing genomic surveillance to support SARS-CoV-2 control and mitigation strategies in the Philippines
Amount £607,635 (GBP)
Funding ID MR/V035444/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2020 
End 05/2022
 
Description Newton Studentship
Amount £117,720 (GBP)
Funding ID NA 
Organisation British Council 
Department British Council - Newton Fund
Sector Public
Country United Kingdom
Start 08/2020 
End 08/2023
 
Description One Health Studentship (University of Glasgow & University of Edinburgh)
Amount £70,000 (GBP)
Funding ID NA 
Organisation University of Glasgow 
Sector Academic/University
Country United Kingdom
Start 09/2019 
End 09/2023
 
Title R package for RABV lineage designation 
Description The availability of pathogen sequence data and use of genomic surveillance is rapidly increasing. Genomic tools and classification systems need updating to reflect this. Here, rabies virus is used as an example to showcase the potential value of updated genomic tools to enhance surveillance to better understand epidemiological dynamics and improve disease control. Previous studies have described the evolutionary history of rabies virus; however, the resulting taxonomy lacks the definition necessary to identify incursions, lineage turnover and transmission routes at high resolution. Here we propose a lineage classification system based on the dynamic nomenclature used for SARS-CoV-2, defining a lineage by phylogenetic methods, for tracking virus spread and comparing sequences across geographic areas. We demonstrate this system through application to the globally distributed Cosmopolitan clade of rabies virus, defining 73 total lineages within the clade, beyond the 22 previously reported. We further show how integration of this tool with a new rabies virus sequence data resource (RABV-GLUE) enables rapid application, for example, highlighting lineage dynamics relevant to control and elimination programmes, such as identifying importations and their sources, and areas of persistence and transmission, including transboundary incursions. This system and the tools developed should be useful for coordinating and targeting control programmes and monitoring progress as we work towards eliminating dog-mediated rabies, as well as having potential for broad application to the surveillance of other viruses. 
Type Of Material Technology assay or reagent 
Year Produced 2022 
Provided To Others? Yes  
Impact Just released, but R package is being used by a number of rabies researchers The doi for the tool is: 10.5281/zenodo.5503917 The R package is: devtools::install_github("kathryncampbell/MADDOG", build_vignettes = TRUE, force = TRUE) 
URL https://github.com/KathrynCampbell/MADDOG/tree/v1.0
 
Title RABV-GLUE 
Description RABV-GLUE is a data-centric bioinformatics resource which organises RABV genome sequence data along evolutionary lines. RABV-GLUE aims to leverage new and existing RABV sequences in order to improve our understanding of the epidemiology and pathology of RABV. The web version of RABV-GLUE can be used for basic analysis. An offline version of the resource can be used for more advanced work. The platform provides an analysis tool providing genotyping, analysis and visualisation of submitted FASTA sequences. A database of RABV sequences and metadata from NCBI, updated daily and arranged into major and minor clades. Pre-built multiple-sequence alignments of NCBI sequences, which may be downloaded in user-defined sections. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact The platform is being widely used in the rabies research community, particularly those involved in RABV genomic surveillance and research 
URL http://rabv-glue.cvr.gla.ac.uk/
 
Title Rabies virus MinION sequencing protocol 
Description Protocol for sequencing rabies viruses using the MinION portable sequencer 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact Training provided to researchers and laboratory scientists in several countries, and further training underway, including application of the protocol for sequencing the new coronovirus SARS-CoV-2 
URL https://www.protocols.io/view/rabies-virus-minion-sequencing-protocol-ba4figtn
 
Title MAD DOG lineage assignment and designation tool 
Description The availability of pathogen sequence data and use of genomic surveillance is rapidly increasing. Genomic tools and classification systems need updating to reflect this. Here, rabies virus is used as an example to showcase the potential value of updated genomic tools to enhance surveillance to better understand epidemiological dynamics and improve disease control. Previous studies have described the evolutionary history of rabies virus; however, the resulting taxonomy lacks the definition necessary to identify incursions, lineage turnover and transmission routes at high resolution. Here we propose a lineage classification system based on the dynamic nomenclature used for SARS-CoV-2, defining a lineage by phylogenetic methods, for tracking virus spread and comparing sequences across geographic areas. We demonstrate this system through application to the globally distributed Cosmopolitan clade of rabies virus, defining 73 total lineages within the clade, beyond the 22 previously reported. We further show how integration of this tool with a new rabies virus sequence data resource (RABV-GLUE) enables rapid application, for example, highlighting lineage dynamics relevant to control and elimination programmes, such as identifying importations and their sources, and areas of persistence and transmission, including transboundary incursions. This system and the tools developed should be useful for coordinating and targeting control programmes and monitoring progress as we work towards eliminating dog-mediated rabies, as well as having potential for broad application to the surveillance of other viruses. 
Type Of Technology Webtool/Application 
Year Produced 2022 
Open Source License? Yes  
Impact Being used by research community 
URL https://zenodo.org/record/5503917#.YjPEdBDP1Oc
 
Title RABV-GLUE 
Description RABV-GLUE is a data-centric bioinformatics resource which organises RABV genome sequence data along evolutionary lines. RABV-GLUE aims to leverage new and existing RABV sequences in order to improve our understanding of the epidemiology and pathology of RABV. The web version of RABV-GLUE can be used for basic analysis. An offline version of the resource can be used for more advanced work. An analysis tool providing genotyping, analysis and visualisation of submitted FASTA sequences. A database of RABV sequences and metadata from NCBI, updated daily and arranged into major and minor clades. Pre-built multiple-sequence alignments of NCBI sequences, which may be downloaded in user-defined sections. Use the clade tree to select a clade such as Africa-2. Then under the Download button select "Alignment". 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact The tool is being widely used within the rabies community by genomics researchers and those involved in genomic surveillance. 
URL http://rabv-glue.cvr.gla.ac.uk
 
Description 4th Conference of Continuing Education for the Veterinarians and Animal Husbandry graduates of Bangladesh, December 2020 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The need for mass dog vaccination - Seminar and teaching session for One health practitioners
Year(s) Of Engagement Activity 2021
 
Description Dissecting the transmission dynamics of rabies: From endemic persistence to elimination. Epidemics8 (virtual), November 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited Plenary Presentation to Epidemics8 international conference
Participation on careers panel for early career researchers
Year(s) Of Engagement Activity 2021
 
Description Dissecting the transmission dynamics of rabies: From endemic persistence to elimination. Epidemics8 (virtual), November 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Plenary at the Eighth International Conference on Infectious Disease Dynamics to share three days of intense dialogue on our ideas, data, insight, models and methods.
This conference regularly attracts over 500 scientists, with representatives from many of the major research groups in this area worldwide.
Research on SARS-CoV-2 played a major role at the Epidemics meeting, which also covered many other relevant sessions.
Year(s) Of Engagement Activity 2021
URL https://www.elsevier.com/events/conferences/international-conference-on-infectious-disease-dynamics/...
 
Description Guest on Lancet Voice podcast on rabies elimination (for biennial of Louis Pasteur's birth): https://thelancetvoice.buzzsprout.com/861868/11877507-louis-pasteur-special-edition-rabies 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Guest on Lancet Voice podcast discussing rabies.
Year(s) Of Engagement Activity 2022
URL https://thelancetvoice.buzzsprout.com/861868/11877507-louis-pasteur-special-edition-rabies
 
Description ODA funding: multi media case study 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Multi-media case study for the Glasgow Centre for International Development to contribute to a Universities UK newsletter that will be widely circulated to policy makers and officials. Highlighting how ODA funding has benefited our partner countries, but also highlights how it has been useful here in the UK.
Year(s) Of Engagement Activity 2021
URL https://www.gla.ac.uk/research/az/gcid/research/global_health/headline_824882_en.html
 
Description OIE Webinar on Mass Dog Vaccination Methods and Tools for Rabies Elimination in the SAARC Region, March 2021 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Rabies transmission in domestic dog populations: implications for control measures.
Talk for professionals in One Health
Year(s) Of Engagement Activity 2021
 
Description Plenary Talk - Ecology and Evolution of Infectious Disease Conference (EEID), Atlanta, USA. May 2022. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Plenary talk at the Ecology and Evolution of Infectious Diseases (EEID) which is an international meeting that has led the way in establishing the fields of disease ecology and infectious disease across scales since its inception in 2003. EEID 2022 brought together scientists from around the world to discuss the latest research on pressing issues, including the role of climate change in driving infectious disease, and the importance of racial and other social disparities in causing inequity and preventing effective control of disease. The explicit focus on social justice and infectious disease showcased the crucial integration of biomedical science, social science, public health and ecology. More than 300 participants attended.
Year(s) Of Engagement Activity 2022
URL https://www.eeid-2022-emory.org/
 
Description Plenary Talk - GEOMED, University of California, Irvine, USA. August 2022. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was a plenary talk at GEOMED, an interdisciplinary conference on spatial statistics, spatial epidemiology, and geographical aspects of public health. The conference aims to bring together epidemiologists, geographers, statisticians, computer scientists and public health researchers and professionals to discuss methods of spatial analysis and results and applications of those methods to public health data. More than 400 participants attended.
Year(s) Of Engagement Activity 2022
URL https://sites.uci.edu/geomed2022/
 
Description Tripartite World Rabies Day webinar for FAO in Asia: Scaling up Dog Vaccination to Eliminate Rabies, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Public engagement and training for veterinarians, animal health practitioners and public health workers, September 2021
Year(s) Of Engagement Activity 2021
 
Description United Against Rabies working group on rapid diagnostic testing 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Ongoing working group aiming to inform policy and practice
Year(s) Of Engagement Activity 2022
 
Description Writeshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Objective: To develop a full working draft of a manuscript ready for sharing and final revision for submission to an international peer-reviewed journal.
The writeshop comprised of a series of short-lectures, exercises both individually, in pairs and small groups, and structured intensive periods of writing so as to achieve the writeshop objective.
Year(s) Of Engagement Activity 2023