As experimental Ebola vaccines start to head toward large clinical trials in Africa, a report released today by academic experts and a British charitable foundation spelled out the complexity of the challenges involved in providing a vaccine to help stop West Africa's sprawling epidemic.
The interim report, titled "Fast-Track Development of Ebola Vaccines: Principles and Target Product Criteria," lays out a 14-point set of principles to guide the process of providing vaccines, plus optimal and minimal criteria the vaccines should meet. The document points up a host of questions that vaccine developers and health authorities will face.
For example, it notes that clinical trial plans must consider the possibility of a fluctuating or decreasing incidence of Ebola, which could make it difficult to ensure large enough sample sizes to identify statistically significant vaccine benefits. Also, it suggests that an early, strong performance by one vaccine should not lead to a premature halt to work on others.
The report says that an optimal vaccine for use in the current epidemic would have 90% efficacy, induce immunity quickly, not require an adjuvant, and be available on a scale of 5 million doses by the third quarter of this year.
The report was developed by the University of Minnesota's Center for Infectious Disease Research and Policy, which publishes CIDRAP News, in partnership with the Wellcome Trust, a major British foundation. Twenty-six leading global experts in vaccine research, development, manufacturing, distribution, and financial support worked on the report.
The effort is co-chaired by Jeremy Farrar, MD, PhD, director of the Wellcome Trust, and Michael T. Osterholm, PhD, MPH, director of CIDRAP. The team includes experts from several African countries, Doctors without Borders (MSF), other foundations, and several US and Canadian universities.
The authors call themselves "Team B" in recognition of the principal role played by the World Health Organization (WHO) and national governments in leading the international Ebola response, the Wellcome Trust said in a press release.
Vaccine push must continue
In a statement, Farrar said Ebola vaccine efforts must continue even as West Africa makes headway in its battle with the virus.
"As Guinea, Liberia, and Sierra Leone make encouraging progress in containing Ebola, we must not lose sight of the immense contribution that a safe and effective vaccine would make towards controlling both this and future epidemics," he said. "We need urgent global collaboration between governments, industry, and philanthropy to ensure candidate vaccines progress through trials to manufacture and delivery as swiftly as possible.
"The draft road map we publish today, agreed by a global group of experts, offers solutions to the great scientific, social, logistical, and financial challenges of delivering an Ebola vaccine on this urgent timescale. It is a living document that will evolve as we learn more about Ebola and the candidate vaccines that are available. As well as being of great value in the present crisis, it will enable vaccine strategies to begin without delay in future outbreaks, and provide a model for vaccine development in response to other emerging infectious diseases."
Osterholm praised the Ebola vaccine development efforts to date and said the Team B report, far from being critical of anything being done, is meant to be supportive.
"The important thing is we really compliment the WHO and the many other organizations that are working on this issue. It has been nothing short of a remarkable response," he said in an interview. "Our effort is meant to be complementary to that. There's a benefit to being able to take a step back and look at all the same information that those on the front lines are looking at.
"While many experts are involved in one way or another with this issue, we've been able to build upon what WHO and other governments and private-sector companies are dong. We're trying to take a big-picture view in a way that we intend to be helpful."
He said the current report is an interim version and that a much more comprehensive report will be released in a few weeks.
Osterholm said it's "great news" that Ebola case numbers in West Africa are dropping, but it does complicate the testing of vaccines. "We'll constantly be in a reevaluation mode in study design and approach, because we're making assumptions today about numbers of cases, but if they don't occur, that creates challenges in studying how vaccines work," he commented.
Vaccine trial plans
The report's release comes just as global health officials are digesting the results of small phase 1 safety trials of the two leading vaccines and making plans for large efficacy trials.
Following a Jan 8 meeting, the WHO said Jan 9 that the two vaccines' safety profiles look acceptable, but it would be 2 to 4 more weeks before they have an idea of what dose is required to generate an ideal immune response.
One of the two leading vaccines, called ChAd3, is a US-GSK product based on a chimpanzee adenovirus engineered to carry a Zaire Ebola virus gene. The other one, VSV-EBOV, licensed to NewLink Genetics and Merck, uses a vesicular stomatitis virus to present an Ebola gene.
WHO officials said the next step will involve vaccine efficacy trials starting within a few weeks in the outbreak nations of Liberia, Sierra Leone, and Guinea.
The largest test will be a randomized controlled trial in Liberia, which could start by the end of this month, the WHO said. The idea is to have 9,000 volunteers in each of three arms: the ChAd3 vaccine, VSV-EBOV, and placebo. In Sierra Leone and Guinea, officials envision somewhat smaller trials using different designs.
Lofty vaccine criteria
As noted above, the authors of the new report set a high bar for an optimal Ebola vaccine for use in the current epidemic for future ones—what they call "reactive use." They say it should require just one dose, have 90% efficacy, elicit rapid onset of immunity and 2 years of protection, and not require an adjuvant. It should be suitable for everyone, including special populations such as pregnant women and those with chronic disease.
The optimal vaccine should be a monovalent product for the Zaire strain of Ebola and show evidence of postexposure efficacy in nonhuman primates, the report says. The authors would like to see 5 million doses available by the third quarter of this year.
In recognition that the optimal vaccine may not be quickly achievable, the report also lays out "minimal" criteria for a vaccine to be used in the current epidemic. It would provide 50% protection lasting 1 year and could involve a prime-boost regimen, with an adjuvant if necessary, rather than a single dose. The target population would be healthy older adolescents and nonpregnant adults, and the supply goal would be to have 5 million doses by the first quarter of 2016.
For both optimal and minimal criteria, the report says the safety profile should be consistent with that of a licensed vaccine, with only mild or transient side effects.
Looking beyond the present epidemic, the report also suggests standards for a vaccine for prophylactic use, such as in areas where Ebola may be endemic. The optimal product would provide 10 years of protection against not only Zaire Ebola but also Sudan Ebola and Marburg virus (a close relative of Ebola). The dose of antigen should be small enough to permit a high production yield, and ideally the vaccine should be produced as a single product, not requiring a booster or diluent.
The "minimal" standards for a prophylactic vaccine call for a monovalent product yielding 3 years of protection and the ability to be produced in large enough quantities for use in all regions. Most of the other optimal and minimal criteria for a prophylactic vaccine are similar to those for a reactive-use product.
The set of guiding principles in the report begins with the need to recognize that the epidemiology of Ebola may be changing and that the world must therefore prepare for a range of different outbreak scenarios, ranging from small, infrequent eruptions to large epidemics.
It says that vaccination will probably play a key role, with other public health measures, in responding to future outbreaks. One vaccine may not fit all scenarios, "so ongoing research and development will be critical to overall long-term success in combatting this serious disease."
The report calls for "sustained, integrated global funding" of Ebola vaccines and stresses that community engagement will be essential in deploying any vaccine, which should be part of a multi-pronged Ebola response tailored for each affected country. Community engagement should be supported by ethics and regulatory oversight, with the participation of local experts, if possible.
As for clinical trial design, the report calls for devising innovative approaches to address the challenges of testing vaccines during the current epidemic, particularly if case numbers drop, making it difficult to achieve adequate sample sizes. It also notes that early success for one vaccine may create special challenges.
"While it is highly desirable to have more than one efficacious vaccine developed, the wisdom of continuing other trials may be challenged if sufficient doses of a vaccine with demonstrated efficacy are available for widespread use," the report says. "Planning for such a scenario is an urgent priority because if a premature down-selection to a single vaccine candidate occurs, this could create a significant point of vulnerability if that vaccine eventually encounters obstacles (eg, manufacturing, changed tolerability, early waning immunity) or fails."
The authors also recommend efforts to determine "correlates of protection"—immunity markers that predict vaccine effectiveness. "Identifying correlates of protection may have an immediate benefit of providing an alternative path to licensure if sufficient efficacy data cannot be obtained because of declining disease incidence or other challenges in the field," they wrote.
In the same vein, tests for evaluating the antibody response to vaccines should be standardized to allow for meaningful comparisons of different products and to establish correlates of protection, the report says.
As for regulation and licensing of vaccines, the report says "transnational public-private partnerships should continue efforts to streamline and harmonize approval requirements." It also notes that regulatory mechanisms to authorize the use of unapproved vaccines under certain conditions may be an option, after the fashion of the US Food and Drug Administration's emergency use authorizations.
The authors list several different vaccination strategies that might be appropriate in the current epidemic. Among them are ring vaccination (targeting contacts of cases); vaccination of high-risk groups such as healthcare and funeral workers, which may be helpful if vaccine is in short supply; targeting of people who maintain critical infrastructure; or a regional, population-based approach, like that used to fight yellow fever.
Other principles address such topics as manufacturing capacity and ease of use, vaccine access and pricing, strategies for controlling future epidemics and endemic disease, and developing post-marketing surveillance.
The authors stress that the report is intended to be "a dynamic document that will be revised and refined as more information becomes available and additional input is sought and obtained."
Jan 12 Wellcome Trust press release
Jan 9 CIDRAP News story on Ebola vaccine development