One year into the Ebola epidemic. January 2015

Accelerated work on new medical products for preventing, diagnosing, and treating Ebola virus disease shows how scientists and the pharmaceutical industry are compressing into a matter of months work that normally takes 2 to 4 years.

CHAPTER 9 - In mid-August 2014, the WHO response moved into a new phase aimed at quickly taking the steps needed to safely add experimental vaccines and therapies to the meagre arsenal of response tools. New tools were urgently needed to reduce the risk of infection, especially among health care workers, and get the high fatality rate, at 71% across all three countries, down. In stepping up these efforts, WHO drew on decades of collaboration with the pharmaceutical industry to make good quality medical products available, at affordable prices, in the developing world.

The first step occurred on 11 August, when a group of experts convened by WHO reached consensus that the use of experimental vaccines and therapies under the exceptional circumstances of the Ebola epidemic was ethically acceptable.

That consensus opened the way for a large international consultation, convened by WHO from 4 to 5 September, to assess potential Ebola vaccines and therapies and prioritize the most promising products for further investigation. The experts also assessed the likely role of these experimental medical products in containing the outbreak and mapped out the most urgent next steps to take.

Two candidate Ebola vaccines move ahead

The next consultation, held from 29 to 30 September, brought together more than 70 experts from all regions of the world, including Africa, to assess the state-of-the-art of work to test and eventually license two candidate Ebola vaccines. The expertise among participants ranged from the virology of emerging infections, to regulatory requirements that must be met, to medical ethics and the clinical management of Ebola patients. Corporate executive officers and other officials from the pharmaceutical industry also presented their views.

The objective was to take stock of the many efforts currently under way to rapidly evaluate Ebola vaccines for safety and efficacy. The next step, if the vaccines are proven safe, is to make them available as soon as possible – and in sufficient quantities – to protect critical frontline workers and also, if possible, to make a difference in the epidemic’s future evolution.

The consultation reached 11 conclusions that will shape how WHO, industry, and the scientific, medical, and public health communities take this work forward with the fastest possible speed. The ambition was clear: to give the African people and their health authorities the best product that the world’s scientists, working collectively, can offer.

The timeframe was equally ambitious: to accomplish, within a matter of months, work that normally takes from two to four years, without compromising international standards for safety and efficacy. As was later recognized, the speed of work to develop, test, and license Ebola vaccines was historically unprecedented.

Ebola vaccines: a significant impact on all scenarios

As the next step, a high-level emergency meeting was convened on 23 October at the request of several governments and representatives of the pharmaceutical industry to explore the many complex policy issues that surround eventual access to Ebola vaccines. More than 90 participants came on short notice to discuss ways to ensure the fair distribution and financing of these vaccines.

Again, a high sense of urgency was readily apparent as participants discussed plans for the different phases of clinical trials to be performed concurrently rather than consecutively, the formation of innovative partnerships to expedite clinical trials, and proposals for getting all partners moving in tandem at the same accelerated pace.

The meeting concluded that vaccines will have a significant impact on the further evolution of the epidemic in any scenario, from best-case to worst-case. All efforts to develop, test, and approve Ebola vaccines must be followed through to completion at the current accelerated pace, even if dramatic changes in the epidemic’s transmission dynamics reduce the perceived need for vaccines.

Clinical trials have moved forward quickly to test for safety and immunogenicity. If all goes as planned, phase 2 efficacy trials of GlaxoSmithKline’s vaccine could start during the second half of January 2015 in affected and neighbouring countries. While early results are encouraging, public expectations need to be carefully managed. Even if proven safe and effective, vaccines may confer only partial or short-term protection. A second booster dose, possibly with a different vaccine, may be needed to improve efficacy or prolong the duration of protection.

Depending on the results of efficacy trials, millions of doses at the Merck vaccine could be available in early 2015. As long as supplies are limited, experts agree that first priority should go to frontline health care workers, who have placed their lives at risk. The logistical demands are formidable. For example, both vaccines need to be stored at minus 80o C. The severe deterioration of health services and interruption of routine immunization programmes present further challenges. Finally, populations who have been suspicious of foreign medical teams and medicines may likewise be reluctant to accept new vaccines.

Ebola convalescent blood therapies

Experimental therapies were also assessed by WHO. On 26 September, WHO issued a state-of-the-art report on experimental therapies, including convalescent blood therapies involving the transfusion of whole blood or plasma from recovered patients.

The first clinical trials of convalescent therapies began in in Guinea and Liberia in December. WHO and its country offices have supported these trials, which required sophisticated blood machines that were rapidly moved through customs. Convalescent blood therapies were undertaken in Sierra Leone, but not in the context of clinical trials.

WHO has provided a system for blood typing of Ebola positive patient blood and coordinated the training of staff in safety procedures and personal protection. The training, equipment, and facilities needed to conduct these trials will upgrade country capacities to provide a safe and good-quality blood service to manage multiple diseases and emergencies, including blood transfusions needed during complications of childbirth and following accidents.

Drug therapies

On 11 November, WHO convened a meeting of its newly created Scientific and Technical Advisory Group on Ebola Experimental Interventions. The group reviewed clinical trial protocols and data for blood products and medicines. Based on test-tube evidence of activity against the virus, a number of pre-existing medicines were evaluated for their possible use as drug therapies for Ebola.

In the view of the experts, only two of these – favipiravir and brincidofovir – demonstrated sufficient activity in non-human primates infected with the Ebola virus to warrant further investigation. Favipiravir entered clinical trials in early December in Guinea. Clinical evaluation of brincidofovir is planned to start in early 2015 in Liberia.

A new generation of diagnostic tests for Ebola

As the goal of interrupting chains of Ebola virus transmission depends heavily on laboratory support, WHO has stimulated the development of rapid, safe, and reliable point-of-care diagnostic tests. Containment efforts have been slowed by cumbersome, time-consuming, and complex diagnostic tests that, while highly accurate, impose a number of additional logistical challenges, including transportation needs and requirements for a high level of laboratory biosafety and staff expertise in using sophisticated machines.

Delays in receiving test results are especially detrimental to outbreak control. Apart from posing a severe risk to families and communities, undiagnosed and unmanaged patients contribute to the cyclical transmission pattern currently being seen, whereby cases begin to fall as control measures take effect, only to spike again as new chains of transmission are ignited. The inability to get rapid diagnostic results can mean that uninfected people are placed together with confirmed cases in transit centres, where the risk of infection is high. Better diagnostic tests would make patient triage quicker, safer, and most efficient.

Equally important, a recent study of more than 700 Ebola patients treated in Monrovia strongly suggests that clinical decisions guided by results from rapid point-of-care diagnostic tests could significantly improve patient outcomes.

On 12 December, WHO, MSF, and the Foundation for Innovative New Diagnostics, or FIND, held a consultation to evaluate the status of new point-of-care diagnostic tests that can deliver results within 15 minutes to one hour. Manufacturers have submitted 19 diagnostics which are undergoing laboratory evaluations, coordinated by WHO, to validate claims about test performance and suitability for use in resource-constrained settings. No technical obstacles stand in the way of making these tests rapidly available. WHO has made arrangements to make patient samples available for use during performance evaluation.

Field trials of one of the most promising tests are expected to begin in February 2015 in either Sierra Leone or Guinea. Trials, which should take only two to four weeks, will look at ease of use, training requirements, and feasibility of implementation outside the environment of a high biosafety-level laboratory.

Rapid point-of-care-diagnostic tests will boost the Ebola response considerably, both now and later as the number of cases declines and the strategy shifts to detecting and breaking the last chains of transmission.