Experimental Ebola vaccines
Discussions focused on the main questions that studies should help address, which part of the research should be conducted in non-affected areas and which part in affected areas, and how such decisions could either help expedite or delay the availability of robust evidence.
One overarching conclusion was that the international community, joining the affected countries as a whole, has a responsibility and a role to play in accelerating the evaluation, licensing, and availability of the candidate vaccines – if proven safe and effective.
For all these reasons, the actions emerging from the consultation clearly identify a role for each of the main stakeholders.
Randomized controlled trials
Regarding the issue of how to accelerate the assessment and licensure of the vaccines, experts reiterated that, if feasible, randomized controlled trials are the design of choice because they provide the most robust data, in the shortest amount of time, to judge whether a vaccine is safe and induces protection.
Trials must be expedited, while preserving ethical and safety standards. Efficacy data of high quality must be gathered. Trials need to be carefully designed so that they concomitantly address the most important questions regarding safety, immunogenicity, and efficacy.
While individually randomized controlled trials provide the most robust data, alternative designs should be considered when these trials are not judged feasible. These include cluster-randomized and stepped-wedge designs. As long as the amount of vaccine remains limited, units – such as health or treatment facilities – can be randomized. Regardless of the design chosen, trials should move forward as quickly as possible.
Alternative study designs
Alternative study designs will not delay deployment of vaccine to those who need it. Instead, they will influence the choice of people who receive the vaccine. For some months to come, the critical limiting factor is extremely restricted vaccine supply, and not the need to conduct studies using alternative designs.
Descriptions of the so-called “randomized stepped wedge” design attracted lively interest and much discussion. In this design, a “wedge” (like a slice of a pie or a cake) of the study population is selected for step-wise inclusion in the trials.
As each “wedge” receives the vaccine, all lessons learned or needed to adjust the study design are then applied to the next group to be included in the study. The selection of study populations can be randomized by units, as described above; the entire study population eventually receives the vaccine if trials demonstrate sufficient efficacy.
Such a design makes it possible to roll out vaccinations and evaluate efficacy at the same time. It further has features that meet the explicit objective of fairness.
Other designs will be more relevant when large numbers of vaccine doses are available.
Decisions on study designs and target populations must be made with the active participation of experts from the three hardest-hit countries. Consultations with frontline health workers should be undertaken as a matter of urgency to identify the most feasible approaches to evaluate vaccine efficacy and identify factors influencing acceptability of randomized trials.
The experts discussed the importance of making sure that the trials are appropriately designed to inform the use of these vaccines in all populations, including children, pregnant women, and immunocompromised populations, including people who are HIV positive.
The group also discussed how best to use the doses of experimental vaccine donated by Canada and additional doses that may be available later this year and in 2015.
If vaccine doses are used in the short term, vaccines should be deployed to consenting frontline health workers.
The decision to initiate such deployment should be informed by data emerging from the phase 1 studies, and will occur with data collection on the deployment itself.
Equity is important and therefore vaccine should be made available in an equitable and consensual manner to the affected countries. Maximizing the information gained from the use of these vaccines during this phase is critical.
A cross-cutting issue is the need for data sharing – in real time – among the research, medical, and public health communities, coordinated by WHO. This was considered of paramount importance to inform decisions on future studies and scaling up the production of those experimental vaccines that look most promising.
Vaccine development normally takes a long time and is notoriously costly. Even under the best conditions and with the massive efforts of many partners, a significant number of doses will not be available until late in the first quarter of 2015.
One important factor for the completion of all the above steps is to secure the funding to ensure the production of the vaccine and to support priority studies. Major international funding partners should promptly pledge or commit the necessary funding so that this critical research is completed without further delay.