Title: NIHR Global Health Research Group on African Snakebite Research, Liverpool School of Tropical Medicine
Funder: Department of Health and Social Care

Abstract: VISION We seek to significantly & sustainably improve health outcomes after snakebite in sSA. We will conduct multidisciplinary research to significantly improve snakebite management, provide data supporting international advocacy and capacity to improve antivenom efficacy and access. BUILDING ON LSTM’S VISION LSTM’s mission is to save lives in the poorest LMIC communities through translational research, education and capacity strengthening. The ASRG aims and objectives align with, and builds upon LSTM’s vision because we seek to deliver disease burden data, translational research, education, and capacity strengthening outputs to substantially and sustainably benefit African snakebite victims, some of the continent’s most disadvantaged peoples. LSTM IS THE ONLY UK INSTITUTION WITH THE RESOURCES NEEDED FOR THIS APPLICATION LSTM’s snakebite expertise, resources, technical platforms and extensive collaboration network has engendered a reputation for excellence in basic and therapeutic research of snake venoms. The unit has the most comprehensive collection of sSA snake venoms, venom proteomes, transcriptomes, toxinomes and anti-venom antibodies in the world, and houses UK’s only antivenom efficacy testing facility. Adding skills and partners in diagnostics, epidemiology, economics and pharmacology will enable this modest unit (2 staff, 2 postdocs, 1 technician) to expand its translational activity to directly benefit human health in sSA. LINKING WITH LSTM AND EXTERNAL PARTNERSHIPS Within LSTM, this project will capitalise on expertise not previously engaged in snakebite. Dr E Adams in the Research Centre for Drugs and Diagnosis (RCDD) has extensive experience in developing diagnostics for NTDs will help develop near-patient diagnosis of biting species. Prof Niessen and Dr Kahn will apply their extensive experience in health system and economic research to snakebite. We will also work with Professors de Silva (University of Kelaniya, Sri Lanka) and Isbister (University of Newcastle, Australia) to capitalise on their respective epidemiological and pharmacological experience of snakebite in Asia and Australia. This project therefore substantially extends LSTM’s spectrum and contribution to snakebite research in Africa. Institutional and individual capacity in research expertise will be strengthened in Nigeria, Kenya and Cameroon to stimulate new LMIC-driven applied research and attract BioTech-partnerships to sustain the project after NIHR funding. RESEARCH PROGRAMME ASRG VISION ALIGNS WITH THE GLOBAL SNAKEBITE AGENDA Our ambition and strategy aligns with the priority actions recommended for global snakebite management [39] by key international stakeholders (including WHO, MSF, DNDi, Wellcome Trust, Global Health Investment Fund, Global Snakebite Initiative and Mr Kofi Annan) attending recent Wellcome Trust- and Kofi Annan Foundation-convened meetings (both chaired by Harrison). ASRG PARTNERSHIP FRAMEWORK LSTM will collaborate with partners in Nigeria (Prof Habib), Kenya (Dr Omondi) and Cameroon (Prof Awono) to instigate multi-disciplinary pilot projects. We selected these partners based upon (i) the specific expertise/resources each brings to the project and (ii) to ensure our outputs are applicable throughout the diverse medical and cultural landscape of sSA. Adding the epidemiology and pharmacological expertise of Professors de Silva and Isbister to that of the LSTM & LMIC partners gives ASRG a critical mass of snakebite expertise to achieve its many objectives. ASRG enables the Nigeria, Cameroon and Kenya partners to become the regional focal points for implementing effective management systems for this deeply neglected tropical disease. RESEARCH PLAN: 6 MONTH DELIVERABLES: Staff recruited; Ethics approval acquired; Delivery and training in use of: Patient & Survey forms; Equipment; Venom extraction. A. NOVEL CLINICAL TOOLS: SNAKEBITE RAPID DIAGNOSTIC TEST research will be focused in LSTM and the Kenyan lab because it has excellent links with hospitals admitting patients envenomed by a variety of snakes and will create E, C & W African venom standards from snakes housed in its new Herpetarium. YRS 1-2: Using our existing proteome/transcriptome databases [16-18], we will identify circulating venom proteins in victims envenomed by haemorrhagic/coagulopathic vipers, neurotoxic mambas & cobras, and dermonecrotic spitting cobras. An existing series of toxin-specific IgGs will be tested on patient sera/urine to select those that differentiate envenoming by snakes causing haemotoxic & dermonecrotic pathologies from those causing neurotoxicity. Kenyan staff/students will be central to the science and work both in Kenya and UK labs. YRS 2-3: The most specific & sensitive of these two groups of IgGs will be translated into monoclonal antibodies for incorporation into Africa’s first lateral flow Snakebite Rapid Diagnostic Test kit (LSTM’s RCDD has contacts appropriate to commercialising this research output). The Snakebite RDT will be an affordable tool enabling physicians in rural hospitals to (i) confirm envenoming (most snakebites are not venomous) (ii) anticipate clinical pathologies and (iii) select which antivenom to administer. This simple, inexpensive hospital tool will significantly improve the accuracy of tropical snakebite treatment and remove current dependency upon poorly discriminating symptoms and the dangerous practice of victims bringing the dead snake to hospital. B. NEW SNAKEBITE RESEARCH DATA (YRS1-3) ON: 1. VENOM-INDUCED PATHOLOGIES AND ANTIVENOM EFFICACY. Kaltungo and Zamko hospitals in NE Nigeria each admit 30+ snakebite patients/day in the rain season – providing sufficient power for robust statistical analysis. We will investigate associations between circulating venom proteins, acute-phase and coagulation factors and the onset/duration/clinical description of venom-induced (i) consumption coagulopathy, (ii) systemic haemorrhage and (iii) neurotoxicity. We will assess the pharmacodynamics of venom protein and antivenom IgG interactions to inform treatment time frames. Measuring serum markers of pro-inflammatory responses will identify/assess the potential therapeutic role of chemical inhibitors. 2. DISEASE BURDEN. Based on published protocols used in Sri Lanka and Australia, prospective hospital and community surveys will be done in each country. With MoH collaboration, national data will be collected from (i) 25-30 rural hospitals in each country and (ii) 4 community locations (80-100 randomly-selected households/location). This data will provide MoHs with regional evidence of snakebite disease-burden, therapeutic gaps – enabling design of effective intervention and advocacy strategies. 3. HEALTH ECONOMICS. Health economic evaluations will be performed throughout the project. A cost-of-illness analysis will capture the snakebite economic burden and DALYs used to calculate health burden. Cost-benefit and cost-effectiveness analyses will be conducted taking household and health system perspectives into consideration. Data from study areas will be extrapolated to estimate the costs and benefits/effectiveness of national interventions in each country. The benefits of motorcycle ambulance (and other) interventions will be estimated and compared with cost of illness and DALYs averted. We will conclude with a value-for-money estimation to provide information on maximizing the impact of each pound spent on reducing the effects of snakebites. 4. PRECLINICAL ANTIVENOM EFFICACY. Inappropriate and dangerously ineffective antivenoms are widely used in sSA [29-32] because of inadequate QC testing. We will establish expertise for providing MoHs with independent antivenom QC data and the evidence needed to reject ineffective antivenoms. YRS 1-2: We will collect the requisite venom standards from snakes housed in the new Kenyan herpetarium. LSTM and Kenyan scientists will modify existing protocols to develop rapid and cost-effective protocols for assessing antivenom efficacy. YRS 2-3: The knowledge gained from Kenya will be used to install preclinical testing expertise in Nigeria and Cameroon. C. ASRG CAPACITY-STRENGTHENING BENEFITS 1. REGIONAL SNAKEBITE CLINICAL GUIDELINES YRS 1-2: We will develop region-specific first aid, hospital and rehabilitation guidelines using systematic reviews of relevant literature, our clinical and community/hospital survey data from Kenya, Nigeria and Cameroon. YR 3: ASRG units and collaborating MoHs will organise clinical training seminars and publish the guidelines in regional clinical journals, ASRG websites and hospital posters. Pilot before and after studies will assess impact of training. 2. SNAKEBITE EMERGENCY RESPONSE SYSTEM (SERS). Rapid access to hospital treatment improves outcome but snakebite primarily occurs in remote locations with poor infrastructures. Most sSA victims take at least 6-12 hours to reach hospital. YRS 1-2: Based upon the model of motorcycle ambulances improving outcomes in obstetric emergencies in sSA, we will pilot a smartphone App-activation of motorcycle ambulances equipped with a paramedic and snakebite first aid kit in Baringo, Kenya (2 ambulances serving different rural hospitals). The ambulances will be integrated into local health services and respond to all emergencies. The SERS-App will collect response data and transmit it to a central database in Nairobi. We will assess impact by comparing hospital and community data pre/post SERS intervention. YRS 2-3: Once proven, SERS will be extended to Cameroon and Nigeria. D. SUSTAINABILITY PLANS Each ASRG objective is structured to impart research skills, resources and capacity benefits to each LMIC partner. Together we will extend the ASRG with new research grant income and encourage LMIC units to attract independent income streams and partnerships, particularly with MoHs and WHO regional offices.

Lay abstract: The African Snakebite Research Group (ASRG) is a 3.5 year project hosted by LSTM working in partnership with Bayero University Kano, Nigeria and the Institute of Primate Research, Kenya to address the diverse causes of the continuing high mortality (32,000 deaths pa) and morbidity (100,000 disabilities pa) of snakebite victims in sub-Saharan Africa. We are conducting multidisciplinary research activities to devise systems, protocols and recommend policies to significantly improve snakebite management across Africa. THE 6 OBJECTIVES: 1: ESTABLISH INDEPENDENT PRECLINICAL ANTIVENOM-EFFICACY TESTING FACILITIES IN AFRICA. The outputs will provide Government Regulatory Agencies with critical data to better regulate antivenom brand approval/importation systems. It will also inform national/regional physicians and health agencies as to the likely clinical efficacy of locally available antivenoms. This activity is designed to prevent the use and distribution of several dangerously ineffective antivenoms that are very successfully marketed throughout Africa. 2: GENERATE REAGENTS APPROPRIATE FOR DEVELOPING A POINT-OF-CARE SNAKEBITE RAPID DIAGNOSTIC TEST. This objective aims to gather clinical information (identification of venom proteins in blood circulation of victims) to guide the future development of Africa’s first snakebite Rapid Diagnostic Test. 3: DEFINE PATHOPHYSIOLOGY OF ENVENOMING TO GUIDE THERAPY AND DIAGNOSIS. This clinical research activity will significantly improve our understanding of venom-induced coagulopathy, neurotoxicity and local necrosis. The new data on the time course of these pathologies will provide clinical evidence to inform improved treatment guidelines, therapies and diagnostics. 4: DETERMINE THE MEDICAL AND SOCIOECONOMIC BURDEN OF SNAKEBITE. Our epidemiology and health economic community and hospital surveys will accurately determine the incidence, mortality and morbidity of snakebite and the cost of illness to victims and health infrastructures. The data will be extrapolated to provide Governments, donors and health agencies with accurate estimates of the socioeconomic burden of snakebite in Nigeria and Kenya. 5: ESTABLISH REGION-SPECIFIC FIRST AID, HOSPITAL AND REHABILITATION GUIDELINES AND CLINICAL TRAINING. The evidence/lessons learned from our research will be collated into new in-country guidelines; published as hospital booklets, posters and detailed documents for dissemination and training to MoHs, hospitals, medical charities and the public. 6: DETERMINE THE COST EFFECTIVENESS OF THE SNAKEBITE EMERGENCY RESPONSE SYSTEM (SERS). We will determine the cost effectiveness, in Kenya and Nigeria, of this novel motorcycle ambulance delivery of victims to hospital. CAPACITY STRENGTHENING: The project’s strategy includes a strong focus on capacity building to sustain these impacts. Thus, units in each partnering institute have been established as national Snakebite Research & Intervention Centres (SRIC) serving as national & regional centres of expertise providing guidance, information and advocacy on all aspects of snakebite. We seek WHO Collaborative Centre status for each SRIC. The unique biological, clinical and laboratory resources, expertise, policy reach of these SRICs will translate into acquisition of new research partners, income to expand and extend their stature and influence – thereby sustaining these benefits to African victims of snakebite.

Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INJURIES AND ACCIDENTS