Ebola vaccines: keep the clinical trial protocols on the shelf and ready to roll out

Safe and eff ective vaccines to prevent Ebola infection would be useful in the fi ght against this devastating disease. Depending on their effi cacy, onset of immunity, length of protection, and cost and ease of administration, these vaccines could contain or even prevent an outbreak. During an outbreak, a vaccine could prevent infection of front-line health workers and staff who are engaged in patient transport and burial. In terms of containment action, vaccination of whole households of patients could prevent any tertiary cases that might occur from persons infected secondarily by caring for the initial household case. Populations at high risk, eg, villages or urban wards where multiple transmission chains have been identifi ed, could also be targeted in a vaccination programme. Because exposure risk is time-limited in most outbreaks, these vaccination strategies might not need a vaccine that triggers long-lasting immunity. An Ebola vaccine that induces long-lasting immunity could, however, fi nd a place in outbreak prevention. Routine vaccination of health workers in areas where Ebola infection is known to be a risk within west and central Africa, could be a major intervention to prevent Ebola outbreaks. The majority of outbreaks, including the most recent outbreak in DR Congo in 2014, occurred after health workers became infected. Infected heath workers inadvertently serve as a conduit of infection to their own family members or caretakers, and from these initial infections, transmission is sustained in the community by direct contact with patients or dead bodies. Some evidence indicates that if Ebola emerges and its transmission is not amplifi ed by infection of health workers, outbreaks do not occur. More widespread preventive vaccination in general populations living in high-risk areas would depend on cost-benefi t analysis, operational feasibility, and acceptance. Previous Ebola vaccines have been developed with fi nancial aid of grants provided by various US defence and health agencies because of concern that the Ebola virus could be used deliberately for bioterrorism, but no public health call for such vaccines from WHO or other international organisations, African countries, or civil society was ever made prior to the current outbreaks. Although the Board of GAVI, the vaccine alliance, has approved plans of up to US$300 million for vaccine procurement and up to $90 million for the strengthening of infra structure to provide vaccines, a long-term market will depend on the WHO recommendations for vaccine use, once the vaccines have been shown to be safe and eff ective, and the ability of countries and the donor community to provide funding for procurement. Phase 1 clinical trials have been completed for three candidate vaccines, and these vaccines are entering or are about to enter phase 2 and 3 clinical trials in countries where Ebola outbreaks are occurring. Time is of the essence because effi cacy trials can only be completed while the Ebola virus continues to circulate. WHO is facilitating a process to devise an emergency regulatory pathway in these countries such that rapid introduction of vaccines for clinical trials and general distribution is feasible without compromising scientifi c standards and rigour. With the support of UNICEF, WHO, and the clinical trial consortia, eff orts to raise large-scale community engagement are underway in these countries to build trust and allay concerns about clinical trials. Ethical and human participant review processes in the countries where trials will be done are also underway, and fi nal clearance is being sought from heads of state. Logistically, clinical trials will not be easy. Vaccine formulations have yet to be optimised, and some vaccine preparations must be stored well below –20°C until use. Without an understanding of the serological correlates of protection in humans, clinical trials to assess vaccine effi cacy can only be done while the Ebola virus is circulating in human populations. Research consortia are now setting up logistical support platforms, training research assistants for clinical trial conduct, ensuring community engagement, and obtaining national ethical and regulatory clearance and other permissions required so that trials can begin. There is urgency to complete these eff orts because Ebola incidence is decreasing as countries place more emphasis on surveillance and contact tracing and as communities build a better understanding of how to prevent transmission and spread. What will happen if phase 3 trials have insuffi cient power to determine effi cacy as or if incidence continues to wane as hoped? A logical conclusion would be that trials would need to rapidly reassume when and where the next Ebola outbreak occurs. Because emergence that leads to an outbreak is a random and unpredictable event, this emergence might not occur in the countries that are working to prepare for the trials at present. Lessons from the multicentre Mechanisms of Severe Acute Infl uenza Consortium (MOSAIC) project in the UK might be of use. Designed and funded to improve the understanding of clinical and immunological progression of H1N1 virus while it was circulating among UK populations, the MOSAIC project faced many delays in start-up. The conclusions were that expedited ethical approval, a single pre-existing template for any material transfer agreements, and research and Lancet 2015; 385: 1913–15