Fondation Mérieux event
12-13 January 2015, Les Pensières, Annecy (France)
Keynote Lectures: Ebola - An overview
David L. Heymann, M.D.
Head and Senior Fellow, Chatham House Centre on Global Health Security and Professor, Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
Through meticulous reconstruction of the events that led to the first outbreak of Ebola in Yambuku, DRC (then Zaire) in 1976; and from continued research during and between successive outbreaks after 1976 until the present outbreaks in West Africa, a clear understanding of the epidemiology of Ebola has been gained. From this understanding, and from successful containment of all pervious outbreaks while they remained in rural areas, three containment strategies have been shown to be effective: rapid diagnosis and isolation of patients where infection control is able to prevent further spread; tracing of contacts of patients with temperature monitoring and rapid diagnosis of those who develop fever; and helping communities understand the means to stop transmission including the provision of safe and respectful means of patient and dead body transport and burial. In some outbreaks attempts were made to treat patients using convalescent bloods from survivors, but there were no active research and development programmes for treatments and vaccines until there was a massive infusion of US funding in the early part of this century related to fears of bioterrorism. There are now candidate vaccines, medicines and other treatments that have been shown to be effective in animal models, and the current sustained outbreak provides a means of testing them for efficacy in humans. Should they prove effective, they would then be of potential use in containing this and future Ebola outbreaks.
Session 1: Ebola vaccine research agenda: A status
Jenner Institute, University of Oxford
A phase I clinical trial of a single dose of a monovalent formulation of a chimpanzee adenovirus 3 (ChAd3) vectored vaccine encoding the surface glycoprotein of the Zaire strain of Ebolavirus, matched to the outbreak strain, is being conducted by the University of Oxford. Following expedited regulatory and ethical approvals, 60 healthy adult volunteers in Oxford, UK were immunised with ChAd3 EBO Z vaccine at three dose levels: 1x1010 viral particles (vp), 2.5x1010 vp and 5x1010 vp (n = 20 per group). Safety was assessed over the next four weeks. Antibodies were measured by ELISA and T cell responses by ELISpot and flow cytometry assays. No safety concerns were identified at any of the dose levels studied. Geometric mean antibody responses by ELISA were highest at four weeks in the highest dose group (90% response rate). In the high dose group there was a 100% response rate for T cells measured by ELISpot, peaking at day 14. Flow cytometry revealed more CD4+ than CD8+ T cell responses. At the vaccine doses tested, both antibody and T cell responses were detected, but at levels lower than those induced in macaques protected by the same vaccine.
Session 2: Challenges in Ebola vaccine research
Today much more data can be generated in early phase I/II vaccine trials, thanks to the availability of new technologies such as microarray (or RNA-seq) for the measurement of gene expression or multiplex platform for cell functionality. Hence, additional questions on the mechanism of the vaccine effect or the prediction of the vaccine response could be explored beyond the assessment of the vaccine immunogenicity. However, the integration of these large datasets generated by multiple platforms on a restricted number of individuals (typically around 20-30) requires specific statistical methods and specific approaches also called “systems biology/vaccinology” approaches. By undertaking a detailed characterization of the innate and adaptive responses to vaccination for yellow fever, seasonal influenza or pneumococcus infection, early signatures that correlated with later immunogenicity have been identified and gave new insight into the mechanisms that underlie immunogenicity. This type of study could also be interesting in the context of vaccine without proven full efficacy such as HIV. A recent example is provided by the DALIA trial where a dendritic-cell based vaccine has been evaluated as a therapeutic vaccine in 19 HIV-infected patients. The integrative analysis of the repeated measures of gene expression as well as the viro-immune response following the vaccination has revealed signatures of the T-cell response, some of them being common with other vaccines. As new vaccines against Ebola virus are under an accelerated development, there are opportunities to design sub-studies aiming at better explored the response to vaccines.
World Health Organization, Geneva, Switzerland
Strategies to shorten the time between emergence of a vaccine-preventable public health emergency and access to safe and effective human vaccines are of the highest priority. Regulators and ethicists have a critical role. On the one hand they can help accelerate the development of investigational products for the emergency situation and facilitate access to investigational products. At the same time they need to ensure that an appropriate level of regulatory oversight is applied so that any risks associated with use of unproven interventions are reasonable and justified in the context of the public health needs. Some National Regulatory Authorities (NRAs) currently have in place regulatory processes and procedures that permit expedited review, clinical trial approval, and licensure of vaccines (and other medicinal products) to respond to an emergency situation, but many NRAs do not have such procedures and processes in place.
Process and procedural solutions adopted by NRAs for emergency situations are intended to achieve more rapid regulatory decision making on potential vaccines. Strategies that are being used by well-resourced regulators include temporary re-assignment of staff to work on the emergency; provision of rapid pre-submission advice to product developers on development plans; adoption of a flexible approach to the receipt and review of data for review; and agreements to waive certain data requirements, on the basis of a scientific assessment and a risk-based rationale. For less-resourced regulators the strategies are necessarily different and may include reliance, for some parts of a submission, on the regulatory oversight already provided by another NRA; joint reviews with peer regulators; or reliance, in toto, on decisions from another NRA or from the WHO prequalification team. These solutions need to be supported by clearly defined regulatory pathways to allow expedited review of vaccines in emergency situations. Provisions must be in place for either stopping, or putting trials on temporary hold, if safety concerns emerge.
In an emergency situation Ethics Committees have to be flexible and willing to review information as it becomes available rather than waiting for all documentation to be available. As there likely will be telescoping of all phases of the trials, very intense and close collaboration and interaction of all those involved with the trial is necessary – sponsors, Principle Investigators, regulatory bodies, Ethics Committees, Data Safety Monitoring Boards, clinical monitors, and communities. Sharing of information and transparency in all aspects is always important, but is of greater relevance in the context of an emergency. Children and pregnant women are vulnerable and require special protection, but should not be arbitrarily excluded from trials - a risk benefit analysis is necessary. It is ethically advisable to ensure adequate follow up of participants until the study end point, and practicalities to do this must be considered in complex emergency circumstances.
Key common challenges for regulators and ethicists in an epidemic of an emerging disease, and which is well illustrated in the current Ebola virus disease emergency, is that there may be limited scientific understanding of the pathogen, the host response to the pathogen, and the protective mechanisms of candidate vaccines. These challenges may be compounded by the use of novel vaccine technologies for which there is limited prior experience. This means that guidance and specifications from regulators may need to be provided as a work in progress and modified as new data emerge. International cooperation between authorities is a strategy being used extensively in the current Ebola emergency to help develop clear consensus on important criteria to support national regulatory decision making. WHO is facilitate collaborations between regulators and ethicists in countries where products are being developed with countries where the products will be evaluated and, if found safe, used.
Médecins Sans Frontières - Operational Center of Brussels
The most immediate challenge to front line investigators in any vaccine trial will be the handling of the investigational agent in an environment at tropical temperatures with unreliable power supply. However, the current outbreak poses its own challenges. Its spatial extension has left the target population spread throughout West Africa. There will need to be procedures for the handling of people who have a fever shortly after vaccination, as some will have this as a result of vaccination and some may have this as their first manifestation of disease. Each target population brings its own challenges. The project staff providing vaccination will be vulnerable to illness and this must be planned for. Healthcare workers receiving the vaccine may adopt counterproductive behaviors. Finding and vaccinating home care providers in the community presents the same challenges as finding cases along with security concerns. Asking them to come to a vaccination site creates an identification challenge. In either case, doing so in a manner that provides timely protection is a challenge. The communities of West Africa may have varied acceptance of vaccines as well as study designs that involve chance in their receiving the active investigational agent. The study teams being in possession of a material that offers the hope of protection from a disease that has caused so much fear may itself pose a security concern. All these challenges are surmountable, but planning for them will be needed.
University of Siena and Sclavo Vaccines Association
University of Geneva
Ebola outbreak urgently calls for the development of an effective vaccine. Candidate Ebola vaccines, that have already shown 100% protection in non-human primates, have entered or are ready to enter clinical testing. To optimize the knowledge yield of the clinical trials of VSV-ZEBOV organized under the auspices of WHO with funding from the Wellcome Trust, we have organized a research network including representatives from vaccine manufacturers, scientists of clinical sites in EU and Africa, world-leaders in immunology and partners of ADITEC (a large FP7- supported collaborative research programme aiming to accelerate the development of novel, powerful immunisation technologies for next-generation vaccines). Our ambitious programme aims to acquire new and critical knowledge of the innate and adaptive immune responses elicited in humans by VSV-ZEBOV vaccination, with specific emphasis on trancriptomics and metabolomics signatures. Cutting-edge technologies will be used to perform an in depth characterization of immune responses of vaccination to ensure that all the information which may be "extracted" from the ongoing first-in-humans clinical studies are fully exploited and shared, to characterize vaccine safety and immunogenicity and thus fill a critical knowledge gap in Ebola vaccine development.
IMMI & Aviesan
The Heads of International (biomedical) Research Funding Organisations (HIRO) agreed in 2013 to create an initiative which would facilitate international collaboration between funders in the field of new and remerging epidemics. On this basis the European Commission, together with funders from Australia, Brazil, Canada, France, Korea, South Africa, Spain, Thailand and the U.S. founded the ’Global Research Collaboration for Infectious Disease Preparedness’ (GloPID-R). The objective of this network of funders is to ensure that there is a coordinated research response within 48 hours of a significant new/re-emerging epidemic outbreak.
The current Ebola crisis has demonstrated that collaboration between global funders is essential to fight epidemics. Severe epidemics threaten the population of the entire planet and it is important to invest in research before a health crisis occurs. Unlike the public health response coordinated by the WHO, there is no forum for the coordination of an international research response. However, the development of diagnostics, epidemiological studies and clinical trials require a rapid international response. GloPID-R ensures that joint work during ’peacetime’ on regulatory, financial and administrative bottlenecks will prepare the ground for constructive collaboration when an outbreak occurs. GloPID-R will not coordinate a public health response and it is not a new funding organisation. It aims to make the work of its members more effective through collaboration.
Specific objectives are:
to address scientific, legal, ethical and financial challenges;
to implement a ’One Health’ approach with close cooperation between human and animal health researchers;
to establish a Strategic Agenda for research responses;
to connect infectious disease research networks;
to actively involve developing countries.
Since the initiative was launched in February 2013 it has progressed to a point where it will engage its full potential from January 2015 onward. At this time the secretariat of the group, selected from an open call for proposals under H2020, will be in place. An agreement on governance was reached at the last meeting in September 2014 in Montreal and membership requires neither a legal nor a financial commitment. GloPID-R welcomes new funding organisations to join.
Currently the members are engaged in close collaboration on Ebola research with regular updates on activities as well as coordination meetings.
Session 3: Cultural and programmatic challenges in the implementation of Ebola vaccine programs
Robert Newman, MD, MPH
Gavi - The Vaccine Alliance, Geneva
Gavi, The Vaccine Alliance, enables a multilateral approach for increasing access to new vaccines, assuring fairness and transparency of funding. Innovative finance is core to Gavi: increasing predictability and flexibility of funds, impact per dollar spent and the diversification of Gavi’s funding sources. Innovative funding mechanisms include: International Finance Facility for Immunisation (IFFIm), Advance Market Commitment (AMC) and Gavi Matching Fund.
In December 2014, following three months of intensive collaboration between the Gavi Secretariat and a range of Alliance partners including the World Health Organization (WHO), other multilateral development partners, vaccine manufacturers, affected countries, civil society organisations and donors, the Gavi Board endorsed plans for up to US$ 300 million for procurement of WHO recommended Ebola vaccines including production costs and potential scale-up and capacity building costs, under a funding structure potentially including Advance Purchase Commitments (APC). Up to an additional US$ 90 million may be used to support countries to fund vaccine implementation and to assist with the recovery of health and immunisation systems in the countries affected. In addition to supporting control of the current epidemic, Gavi funding could also be used to create stockpiles of first- and second-generation Ebola vaccines. To meet the funding requirements of the approved Ebola initiative, Gavi will use a combination of existing and new sources of funds and will join forces with initiatives that have already pledged funding to address the Ebola crisis. The IFFIm could be used directly or indirectly to support existing vaccine programmes by enabling timely replenishment of temporarily diverted funds, in order to ensure no disruption to liquidities required for existing Gavi programmes. For the majority of the envelope, funding structures will need to be approved by the Gavi Executive Committee in the coming months.
London School of Hygiene & Tropical Medicine
We used a mathematical model, fitted to the latest available data at the country and county level, to forecast the Ebola epidemic over the next few months and simulate the introduction of vaccination under different strategies. I will discuss the potential impact of these different vaccination strategies for the control of Ebola in Guinea, Liberia and Sierra Leone. I will also discuss the value of real time modelling in tracking the epidemic at a finer spatial resolution and informing the implementation of vaccine trials.
Dr Manica Balasegaram
MSF Access Campaign
A strategic approach is required to accelerate access to Ebola vaccines and support the ongoing efforts to tackle the current outbreak in West Africa. MSF has identified a number of tangible policies and approaches that may be adopted to ensure timely and appropriate distribution of vaccines. These can be grouped into four main categories: funding and procurement mechanisms; stronger health systems to address public health needs; ensuring needs based access; preparedness and future outbreaks. Firstly, transparent funding and pull incentives are required for vaccine development, with clear mapping, auditing and publishing of financing and production costs. Secondly, existing weak health systems should be prioritised for strengthening to meet concurrent public health issues. This includes ensuring delayed or interrupted vaccination is carried out for all standard EPI vaccines, according to WHO guidelines. Thirdly, the needs of countries most at risk should be addressed through availability of priority stockpiles and setting of vaccine prices (rather than for biodefense or economic purposes). Finally, to prepare for future outbreaks a number of activities are required: developing second generation vaccines that are more effective, produce longer-lasting immunity or are better adapted to the constraints of the affected countries; ensuring accessible and rapidly deployable vaccine stockpiles; and encouraging additional vaccine manufacturers to invest in technology and production capacities.
Janice E. Graham
"Today we know the best way to prevent the spread of Ebola infection is through public health measures, including good infection control practices, isolation, contact tracing, quarantine, and provision of personal protective equipment. However, a vaccine will ultimately be an important tool in the prevention effort.” NIAID Director Anthony S. Fauci
Slow to be recognized, the West African Ebola Outbreak is first and foremost a humanitarian crisis. The three countries that have experienced the most intense transmission were particularly vulnerable in being already devastated by poverty, limited public health infrastructure, and the understandably endemic distrust that results from past and recent histories of structural violence. It is no small task to parse the cultural and programmatic challenges to implementing an Ebola vaccine program in countries that lack basic health care services and public health systems. This presentation will identify some key issues that address communication, care of the sick and dead, food security, marginalized groups and surveillance. It is valuable too to posit the opportunities to sidestep the fault lines that so many vaccine projects with good intentions have fallen prey. Building real capacity and capabilities for sustainable health systems that offer long-term rewards for a healthier future is integral to any vaccine program. Such a health care system would subsume a comprehensive routine immunization programme and additionally structure in resources for necessary supplies and medicines, training, knowledge and skills development, and secured salaries that incentivise and sustain high quality health care workers in community clinics. Incorporating constructive community engagement strategies that work with the spectrum of traditional and allopathic health care providers to educate and incorporate them in early surveillance, detection and reporting, and leveraging two existing platforms — the EPI and the Global Vaccine Safety Initiative (GSVI) — real and viable capacity within a neglected health system would be built capable of detecting, reporting and rapid response to any disease outbreaks as well as adverse events following immunization.