WHO EBOLA SCIENCE COMMITTEE

Transcription

1 WHO EBOLA SCIENCE COMMITTEE Prioritized Research Agenda World Health Organization 19 October 2015 The epidemic of Ebola Virus Disease (EVD) in West Africa found the world unprepared, lacking critical knowledge and proven disease control interventions. This provided a sharp reminder that investing in research is vital for ensuring effective control and prevention of future outbreaks of filoviruses and other severe emerging infectious diseases. In the spring of 2015, WHO convened the Ebola Science Committee (see Annex 1) to define the necessary research, and the requirements for its successful implementation. This research agenda provides a framework for future research activities on EVD and other filoviruses by identifying broad thematic research priorities and key research foci for the development of specific proposals, and articulating the relationship between them. Sustained delivery of this agenda depends on the necessary infrastructure, funding, and support, and must foster the integration of this research into wider efforts to strengthen public health capacity, including health research capacity, in affected countries and globally. As part of broader WHO efforts to develop a research and development Blueprint for public health emergencies, this will involve providing key knowledge and human capacity to address future EVD outbreaks, as well as to leverage linkages with efforts to address other ebolavirus species, other filoviruses, and other severe emerging diseases from the perspectives of scientific and operational research. I. Objectives This research agenda is intended to facilitate progress towards: A. An effective global emerging disease surveillance and response system B. Vaccine(s) to prevent EVD acquisition and to prevent or reduce virus transmission; 1 C. Therapeutics to treat EVD and reduce or prevent sequelae in EVD survivors; 1 D. Validated EVD treatment algorithms; E. Robust diagnostics, including for use at point of care; 1 F. An ethical framework for research in epidemic situations; G. Effective community engagement and mobilization strategies; H. Response and research capacity building for resilient health systems in currently and potentially-affected countries. 1 Detailed development of vaccines, therapeutics and diagnostics is being addressed through the WHO STAC- EE but has been included in this research agenda as a prioritized objective. 1

2 II. Research priorities Seven areas of research were identified as priorities: 2 1. Genomics and implications of viral genetic diversity The current EVD outbreak has highlighted the importance of genetic diversity. Variations in sequence could impact many different facets of the outbreak, from transmissibility to clinical outcomes. Linkages between sequence differences at different geographic locations may provide critical insights into molecular epidemiology. Genome data can further help shape control measures and therapeutic interventions. It could also offer novel insights into developing drugs and vaccines. 2. Biomarkers - This term has multiple uses, but in this context is considered to encompass immunological, virological, biochemical, and metabolic indices as well as other clinical parameters or host genotypic markers. Identifying and monitoring biomarkers may reveal patterns characteristic of different syndromes and stages of illness, and be of use for improving future responses, by improving diagnosis and enhancing the timing of therapeutic and public health interventions. 3. Public health practice - Further research is needed into the impact and improvement of public health measures and practices in three broad areas: transmission dynamics and ecologic factors, such as the impact of activities and understandings amongst health workers, the impact of different clinical manifestations, how best to break transmission chains, relevant human-animal interactions and predictive tools; surveillance, such as improvements to case definitions, monitoring methods, rapid detection capabilities and contact tracing; as well as prevention strategies, such as determining what interventions led to diminution of cases, how they were perceived, what metrics might be needed to assess efficacy, and how this impacts measures to prevent international spread. In addition, the value of research into the recovery and resilience of public healthcare systems was also emphasised. 4. Data, information and knowledge The outbreak highlighted a number of missed opportunities for collecting data during a public health emergency which could be important for subsequent research, for example, meta-data associated with biological samples. It also highlighted a need to develop systems to better link data being generated by different facets of a response, for example epidemiological, virological, and clinical data. More work is also needed to ensure that information and knowledge generated from data collected during an outbreak can be usefully fed back into those communities which produced the data. 2 The First Meeting of the Ebola Science Committee identified a number of different areas of potential interest, they were further refined into this format at the Second Meeting. For more details of this process, see the relevant meeting reports. 2

3 5. Social and community interactions - Whilst noting that they are distinct concepts, there are important roles for research both in social science and community engagement. Connecting these, community-engaged research, following a participatory paradigm, is important to ensure that the views and knowledge of those affected are heard, and can influence the response and future research. Whenever possible, research encompassing these topics should be community-led. To this end, there is particular value in using exploratory and participatory methods and tools within communities (for example, rapid ethnography, participatory appraisal methods and mixed-group dialogues), as well as systematic, representative and quantitative research approaches. 6. Safeguarding future research - There is a need to ensure that studies in pursuit of the priorities identified in this agenda are undertaken in such a way to promote robust, scalable, excellence in research practice whilst minimizing accidental or deliberate risks to those undertaking the research, in the facilities in which they are working, in the communities in which those facilities are situated, and society more broadly, as well as the environment. 7. Implementation science - To facilitate future response readiness and ensure that opportunities to learn from the current outbreak are not missed, the efficacy of, and impact of interactions between, key interventions should be researched. For these research activities to contribute to achieving the objectives listed above, they will have to be coordinated with each other around matters of common concern. The implication is that there will be important cross-disciplinary elements which must be facilitated so that the value chain connecting original research to practical outcomes is optimised. A number of specific research questions in each of these areas were also identified, and have been included in Annex 2. III. Implementation of the research agenda The research agenda is intended to be a living document, evolving to meet changing needs over time. It will require revisiting and revision on a regular basis. A number of specific actions to facilitate the implementation of this research agenda have been included in Annex 3. A number of key factors were identified for translating this agenda into effective action. The need for ongoing work in this space will necessitate the development of a dedicated infrastructure. Implementation of this agenda will also need to be integrated into broader efforts to strengthen public health capacity. Wherever possible, efforts should increase preparedness and response planning for future events. Fostering and leveraging relevant research capacity in affected countries is an overarching principal for ensuring that this research agenda contributes to efforts to ensure the world is better prepared for the next EVD outbreak. Research under this agenda will require rigorous ethical oversight, and support to enhance relevant ethics review capacity may be needed. Data and knowledge management capacities will also require augmentation. 3

4 If this research agenda is to encourage the best use of available resources, prevent unnecessary duplication of effort and unethical exposure of subjects to avoidable harm, it will be necessary to improve information flow. Appropriate relationships will play a key role in identifying research underway and being planned. Appropriate relationships can also help in accessing data both for research purposes, and to help shape responses. Strengthening relevant relationships and timely data-sharing practices would help ensure access to necessary data in a timeframe which can positively inform practice and the design of further necessary research. Practices, systems and relationships can also be formed around access to resources critical for future research. In particular, many of those involved in research in pursuit of this agenda will likely need access to the same resources, including sequence data, non-infectious cloned material, inactivated virus samples, virus isolates, and, sometimes, original clinical samples. Whilst informal relationships will evolve naturally, a more structured approach would help maintain the focus on urgent research for the benefit of the affected countries, so that limited resources are not wasted, and promote longer-term sustainability. Research proposals developed in pursuit of this agenda are expected to follow best practice in research conduct and ethics. When developing specific research projects in pursuit of elements in this agenda, researchers are expected to have considered how the planned research links to objectives and priorities of this agenda, explored appropriate partnerships and collaborations, reviewed existing capabilities and identified opportunities for capacity building. It is essential that both forethought and postresearch reflection be given to how, and to whom, the results will be communicated, and how they might influence future work and identified public health considerations. A more detailed exploration of the specific actions, necessary partnerships, and responsibilities of researchers, to facilitate the implementation of this research agenda can be found in Annex 3. IV. Elements for future action Through its work on a research and development Blueprint for public health emergencies, WHO should develop an action plan to ensure that this research agenda results in effective outcomes, including by considering that: (i) (ii) (iii) management of a research agenda requires active review of both research in progress and research completed. Basic, applied, and implementation research must all be addressed. at regular intervals, the research findings and achievements should be reviewed, and a new gap analysis performed. mechanisms are needed to enable relevant stakeholders to review and reassess the priorities in the light of these analyses, and in the contemporaneous context of global readiness, surveillance and response capacity. This will entail representation from intensely affected and other involved countries, the R&D community, other relevant agencies, institutions and NGOs, and science foundations and funders. 4

5 (iv) (v) dedicated support and knowledge management infrastructure are needed for effective implementation. leveraging linkages with efforts to address other severe emerging diseases is essential to obtain the greatest benefits for future disease control strategies. 5

6 ANNEX 1 Members of the WHO EBOLA Science Committee Professor Peter Piot, London School of Hygiene and Tropical Medicine, UK (Chair) Dr Sylvain Baize, Institut Pasteur, France Dr Daniel Bausch, Tulane University, USA Dr Philippe Calaine, MSF, Suisse Professor Jean-Francois Delfraissy, INSERM Dr Scott Dowell, Bill and Melinda Gates Foundation, USA Dr John Edmunds, London School of Hygiene and Tropical Medicine, UK Dr Robert Fowler, Sunnybrook Medical Centre, USA Professor Stephan Günther, BNI, University of Hamburg, Germany Dr Lisa Hensley, National Institutes of Health, USA Dr Peter Jahrling, National Institutes of Health, USA Dr Gary Kobinger, Public Health Agency of Canada, Canada Dr Mandy Kader Konde, Chair of Ebola Research Committee, Guinea Professor Jean-Jacques Muyembe, INRB Kinshasa, DRC Dr Abdulsalami Nasidi, Center for Disease Control, Nigeria Dr Stuart Nichol, Centers for Disease Control and Prevention, USA 6

7 ANNEX 2 Specific research questions associated with identified research priorities The Ebola Science Committee concluded that urgent research was indicated in the areas of (1) genomics and the implications of viral diversity, and (2) biomarkers, as these would have an immediate impact on many aspects of outbreak control and in patient care. They also identified a range of key research questions relating to public health practice; data, information and knowledge; social and community interactions; safeguarding future research; and implementation science. The principal questions in each of these categories are listed in this annex. Genomics and implications of viral genetic divergence Five research questions were identified: 1. How much viral genetic diversity has arisen throughout the course of this epidemic across the affected countries? Are different viral genotypes or viral clades associated with different mortality rates, the epidemiology of the outbreak or other variations in the clinical course of infection? 2. How are variations in disease transmissibility, immunopathology, clinical features and outcomes, or intra-host pathogen dynamics linked to particular changes in specific viral genes? 3. Can the patterns of genetic diversification be used to infer the geographic patterns of virus spread, identify missed opportunities for control, and estimate the number of unreported infections? 4. How do mutations in key viral genes affect the accuracy of diagnostic assays in current use? Or the expected utility of vaccine candidates? Or the utility of therapeutic strategies, including antibody-based therapeutics, and immune modulators? 5. How does attenuation affect evaluation of Ebola interventions in animal and in vitro models? What, if any, are the implications for humans of the observed 7U/8U switch? 6. What other non-gp conserved viral targets are there for vaccine design, therapeutics, or diagnostics? How can we identify the most suitable targets? Biomarkers Nine research questions identified were: 1. What biomarkers are associated with (or predict) effective control, or outcome (or lack thereof), of an infection or viral replication at early, middle or late stages in the course of illness? 2. What biomarkers are associated with (or predict) different viral loads? 3. What biomarkers are associated with immunity to re-infection? 4. What biomarkers are associated with (or predict) subclinical or mild infections? 7

8 5. What biomarkers could be used for diagnosis prior to onset of clinical manifestations in exposed persons, or those with early, non-specific symptoms? 6. What biomarkers are associated with (or which could predict) infectivity, transmissibility or virulence? 7. What early biomarkers are associated with (or which could differentiate between) different presentations and syndromes? 8. Which biomarkers, including reductions in viral loads, differ in human recipients of different vaccines and therapies compared to those observed in infections without previous immunization or treatment? 9. What are the functional correlates of immunity following natural infection and post-vaccination? What biomarkers are associated with (or predict) effective post-immunization protection? Public health practice Specific research questions identified included: Transmission dynamics and ecologic factors 1. With regards to healthcare workers in an affected community (including alternative medicine practitioners): What role do they play in amplifying an epidemic? How effective are current infection prevention and control (IPC) practices, including personal protective equipment (PPE) selection, use, and training? 2. How did health workers and other potentially exposed professionals (especially from affected communities) understand the duty, or freedom, to provide care? 3. What is the potential infectivity of people with subclinical, mild or more severe infections, and the potential impact of different syndromes on transmission risk? 4. What are the viral, host, behavioural, and social factors explaining the heterogeneity in transmission and susceptibility including super-spreading events? 5. What are the effective and ethically acceptable approaches for follow up of contacts in order to prevent further transmission (e.g. temperature, or symptom monitoring, quarantine in households or villages, quarantine in healthcare or hotel setting, self-imposed verses system imposed measures)? 6. How do we integrate genomic sequencing into new case investigation and contact tracing to differentiate chains of transmission (e.g. late transmission from recovered patients) and distinguish new zoonotic transmission events? 7. What therapeutic options may be indicated to prevent or interrupt infection of contacts (e.g. vaccine, drugs for post-exposure prophylaxis)? 8. How can efforts to predict future outbreaks be improved? What outbreak characteristics might be employed in forecasting and modelling future outbreaks? 9. What are the relevant human-animal interactions in their ecological and social contexts? What are the animal reservoirs and how can they be monitored 8

9 Surveillance efficiently for risk of zoonotic transmission events? What can the urban nature of this epidemic tell us about potential animal reservoirs relevant to such settings? 10. How do we use the clinical and outbreak data to revise and risk-stratify the case definition, as might be indicated over the course of an outbreak? 11. What are feasible methods to monitor and detect EVD in a low frequency transmission state during outbreaks (e.g. event-based surveillance, targeted post-mortem swabs, skin biopsy, verbal autopsy)? 12. How can we develop and employ rapid detection assays for screening in primary care facilities, within communities, and at mass gatherings that balance needs to maximize case detection while allowing the progress of common life-saving care (e.g., motor vehicle accident trauma response, management of maternal haemorrhage)? 13. How important is contact tracing, how could relevant methodologies be improved, and what procedures and practices should be used during future epidemics? Prevention strategies 14. What factors and sequences had the strongest associations with decreases in cases in each of the countries with sustained transmission of Ebola (e.g. prevention and mitigation strategies, policy decisions, community learning, resources)? How can procedures and practices to identify such factors, and integrate them to prevention, mitigation, response and post-response efforts be improved in advance of the next outbreak? 15. How did survivors and patient s relatives understand isolation and quarantine orders (in terms of rationale, choices, coercion, etc.), and what was the impact and roles of case finders? 16. What metrics, such as those linked to patient and community outcomes, can be reproducibly assessed for community engagement and risk communications? How did these vary by community according to cultural, ethnic and political context, and what lessons emerge from using those metrics regarding the best approaches? 17. Which strategies are most practical and effective to prevent international spread during an outbreak, including quarantine measures and temperature monitoring? Data, information and knowledge Four research questions were identified: 1. How best to develop a system to link or integrate laboratory, epidemiological, and clinical data? 2. How best to develop a strategy to collect meta-data connected to individual physical samples, and design the databases connected to them? 9

10 3. How best to develop a strategy to transition knowledge and technological capacity to affected countries and countries which might potentially be affected in future outbreaks? 4. How best to develop strategies to further the harmonization, accessibility, and interpretation of data and dissemination of findings in a timely fashion? Social and community interactions Nine research questions were identified: 1. How have social, cultural and epidemiological dynamics interacted over the course of the epidemic, how has this varied from place to place, and what have been the consequences? 2. What have communities learned during the outbreak so far about managing EVD risk, and what do they see as the key priorities for knowledge or intervention? 3. How have social and behavioural norms (for example around visits, care and funerals) changed in the short- and longer-term during the course of the outbreak, and what have been the respective roles of community learning, externally-led social mobilization, and interactions between these? 4. How do people perceive and judge the effectiveness of interventions whether around outbreak control, treatment trials, vaccination studies, laboratories, and social mobilization efforts - in the context of local social understandings and dynamics around disease and social life? 5. How did patients who participated in interventional research (such as treatment trials or vaccination studies) understand consent, risks, benefits and choices? How were such concepts communicated to them? 6. What perceptions and experiences underlie community anxieties, resistances and rumours, and what political and economic factors shape these? What broader lessons are suggested for future governance, trust-building and development policy in the affected countries? 7. How do these perceptions and experiences differ between communities (for example, by region, rural-urban areas, and ethnic group), and within them (for example, by gender, age, ethnicity/religion, wealth)? 8. Which local actors and institutions are best positioned to convey and build trust and community ownership in messages and interventions around epidemic control? What are the roles of, for example, local societies, youth groups, local health workers, or survivors? 9. How can community engagement and trust be built and reinforced during the re-building of health systems following the epidemic? Safeguarding future research Research is needed into: 1. How to develop capacity to rapidly scale up research in response to epidemics and to integrate the results of such efforts into preparedness, mitigation, response and post-response efforts in as close to real time as possible? 10

11 2. In varied resource settings and in partnership with relevant practitioners, how best to develop a comprehensive strategy to implement and expand practices for safe handling, methods for inactivation, and disposal of samples and waste in both outbreak settings and containment facility settings? 3. What strategies ensure that necessary safety and security practices are in place and implemented in all relevant facilities, including those used in emergency response operations which may be widely distributed and mobile? 4. What strategies should be used to engage with other communities (such as biosafety, biosecurity professionals, law enforcement, transportation official or customs officers) to work together to ensure that the needs of all stakeholders are met, for example when moving material and personnel into and out of affected areas? Implementation Science Further research is needed into the efficacy of, and impact of interactions between, key interventions, including: 1. Quarantine; 2. Isolation at home; 3. Isolation at health facilities; 4. Infection prevention and control in health facilities; 5. Infection prevention and control at home; 6. Prevention of mass gatherings; 7. Local or national travel restrictions; 8. International travel restrictions; 9. Temperature monitoring; 10. Safe burials; 11. Entry into the Healthcare System, including effective triaging; 12. Use of near-patient or point-of-care tests; 13. Real-time quality assurance and quality control of field use of near patient and point of care tests; 14. Data, information and knowledge gathering, curation, integrations and dissemination; 15. Ethics and regulatory systems during a crisis; 16. Epidemic intelligence; 17. Projection and modelling; 18. Optimal IPC practice. 11

12 ANNEX 3 Specific actions to aid in the implementation of the research agenda The Ebola Science Committee described a set of factors to be addressed to ensure that implementation of the research agenda would yield progress toward the desired outcomes of better prevention and control of EVD, and eventually for other severe emerging infectious diseases. The Committee also discussed how partnerships and stakeholder engagement could support and sustain the necessary work. Finally, they reviewed the role of researchers, and the matters researchers should consider when developing research proposals Key factors to facilitate implementation Nine factors will assist in transitioning from talk to action: 1. Ensuring dedicated infrastructure to provide key support and engender sustainability, including development of sample biobanks and data repositories; 2. Including research considerations in mainstream public health sector development throughout future work in affected countries in order to effectively prepare and respond to EVD and other severe disease outbreaks which may occur; 3. Addressing longer-term sustainability of human resources and key resources, such as reagents and relevant supplies and equipment for research activities; 4. Approved and funded protocols for key activities and needs, on the shelf and ready to use ; 5. Leveraging research and researchers to strengthen response planning, including participation of senior biomedical investigators, anthropologists and social scientists in such responses; 6. Fostering strong and full involvement of national and local researchers in contributing their expertise, and ensuring appropriate ownership of research questions, processes, findings and translation into policy and practice; 7. Ensuring the presence of robust ethical and regulatory capacity in countries, including mechanisms to provide, upon request, advice on research, as well as model material transfer agreements to be used for exporting samples; 8. Enabling ethical reviews at all stages of international studies, including exploring, where feasible, joint reviews at the regional or sub-regional level; 9. Strengthening knowledge and data management, to provide a clearer picture of what research has been conducted (including the reporting of negative results) as well as what is planned Building partnerships Stronger relationships are necessary between stakeholders, including the scientific research community, government health agencies from affected and responding countries, NGOs and other operational partners, scientific foundations, funding agencies as well as recovered patients and their communities. The unique convening power of the WHO to bring together such diverse constituencies will be of particular importance. 12

13 Some models for innovative partnerships already exist, such as the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), which brings together 11 major preparedness research funders 3. The goal of is to facilitate collaboration and coordination among funders during the inter-epidemic period, so that a rapid and effective research response is ready to be deployed in the case of a significant outbreak. There may be other models for the alignment of diverse stakeholder groups to be found in different spheres. During a crisis, it is difficult to form new operational networks to link researchers to country surveillance, for example. There is value in developing pre-existing frameworks for forming such connections and networks, so that there will be no interference with field operations in emergency conditions, and at the same time avoid hindering access to data and samples for essential research. In some cases, existing networks, such as the Emerging and Dangerous Pathogens Laboratory Network(EDPLN), The Emerging Disease Clinical and Research Network(EDCARN), ISARIC, and others, could be leveraged to improve systematic data collection, integration and information flow. In other areas, such as for clinical data or biobanking of samples, new networks with dedicated infrastructure and governance may be necessary. It is desirable that geographical participation be as wide as possible in such networks. Given the importance of data and resources, there is an urgent need to identify and promote the added value for partners and global public health in the early sharing of data, and for open access to data and results. In particular, cooperative resource collection and management confers an increased responsibility to ensure that affected and at risk communities realize benefit from such arrangements. Considerations when developing research proposals When developing projects to address the priorities in this research agenda, researchers should attempt to address: How the research being planned connects to the research agenda, or how the proposal would enable progress towards addressing the priorities; Which national and international partners will be involved; What capacities need to be in place with which partners, and who is intended to provide such capacities; How the research will help to build relevant capacity in countries and among partners, including helping set priorities for patients and sites for research, and the use of limited funds. Who needs the results of the research and why it represents a priority. How the outcomes of the research will be shared and communicated. 3 European Commission, CIHR, Canada, U.S. Office of the Assistant Secretary for Preparedness and Response, INSERM/IMMI/AVIESAN France, FIOCRUZ and BUTANTAN Institutes Brazil, Instituto de Salud Carlos III Spain, NRF Korea, South African Medical Research Council and Department of Science and Technology South Africa, Institut Pasteur Korea, Thai National Institute of Health, Department of Medical Sciences (Thai NIH, DMSc. MoPH) Thailand, National Health and Medical Research Council Australia. Mexico is currently in the process of joining the initiative. 13

14 How the research will impact future work (including any new avenues of research it may open). How the research will be fed back into preparedness, response, recovery planning and activities, or future system-building. How the research results will be fed back into refining the research agenda. 14