With Ebola cases in West Africa again declining sharply, researchers are looking closely at alternatives for getting a vaccine licensed quickly, without traditional efficacy data, and studying how stepped-up strategies for vaccines and other medical tools might be used for future disease epidemics.
Experts at a World Health Organization (WHO) research and development summit discussed both issues today as they wrapped up a 2-day meeting in Geneva, and a US Food and Drug Administration (FDA) advisory group discussed the most advanced vaccine candidates and the available licensing pathways.
WHO group addresses research considerations
At a media briefing today, Marie-Paule Kieny, PhD, the WHO's assistant director-general for health systems and innovation, said it's not clear if phase 3 trials now under way in the main West African outbreak countries will be able to show even a hint of efficacy, with regulators thinking about other pathways, such as the FDA's "animal rule," for registering the experimental vaccines.
In the week from May 4 through May 10, only 9 lab-confirmed cases were reported in Guinea and Sierra Leone, she said. The total reflects another steep decrease compared with the 18 cases reported the week before.
Kieny said that trials on Ebola drugs still might be able to show some efficacy indications and that researchers may be able to gauge the efficacy of convalescent serum treatment, now that more than 100 patients, mainly in Guinea, have received it.
Even if Guinea and Sierra Leone join Liberia in reaching zero cases soon, research will continue, because there is still much to learn from the trials, such as safety and immunogenicity, she said.
The Ebola outbreak and the accelerated development of vaccines, drugs, and diagnostics have produced a research and development model with potential to reach far beyond the current epidemic, Kieny said, adding that the Geneva group is working not on an exact blueprint for responding to future disease threats but a general roadmap based on lessons learned.
Getting two vaccines into advanced trials and delivering commercial diagnostics to the outbreak region took about 10 months with the unprecedented global collaboration, compared with 5 to 10 years with more traditional approaches, she said.
"Even as Ebola wanes and some of the R&D efforts may not reach the goals aspired to, the pioneering work done so far can be leveraged to put in place standards and best practices to improve expedited data and results sharing," said Kieny.
Some examples of fast-track strategies have included having the WHO coordinate phase 1 trials and collaboration links, emergency-use assessment and listing, and joint ethics and regulatory reviews, she said. Another option could be banks of biological samples that could be used to ease and speed future research.
Kieny emphasized that one important lesson experts have learned is the importance of deep involvement of affected countries in the research agenda.
FDA advisors weigh licensing pathways
At today's FDA meeting, the agency's Vaccines and Related Biological Products Advisory Committee (VRBPAC) grappled with the use of immune markers from human and nonhuman primate studies to show the effectiveness of Ebola vaccines as well as whether, if an Ebola vaccine was approved through an alternative pathway, what approaches postmarketing studies would need to show vaccine benefits.
If conditions don't allow phase 3 trials to show the vaccine's efficacy profile, the FDA has two other licensing pathways: accelerated approval, which uses a surrogate endpoint, such as immune response, and the "animal rule," which uses well-controlled animal studies showing a reasonably likely clinical benefit and evidence that the vaccine is safe in humans.
Both pathways would require that postmarketing studies be conducted in a current or future outbreak. With the increasing difficulty of conducting randomized, placebo-controlled clinical trials to show effectiveness at this step, alternative study designs for researchers could include step-wedge randomized trials, which involve sequential roll-out of vaccines to participants, and test-negative case-control studies.
VRBPAC members heard from FDA regulators, scientists from the FDA and Centers for Disease Control and Prevention (CDC), researchers, and vaccine makers. Some of the groundwork for today's discussion was set by participants in a National Institutes of Health Ebola vaccine workshop in December.
The group discussed the complexities of correlates of immune protection against Ebola in humans, which so far haven't been determined. Several members of the group said test-negative studies would be preferable for postmarketing studies and might be more practical to conduct in the outbreak region's urban centers.
- Inovio Pharmaceuticals, based in Plymouth Meeting, Pa., today announced the launch of a phase 1 clinical trial for its DNA-based Ebola monoclonal antibody (dMAB) treatment. In preclinical tests, the drug protected 100% of immunized animals against experimental Ebola infection. The trial is the first step in an Inovio-headed consortium selected by the US Defense Advanced Research Projects Agency (DARPA) to pursue a multifaceted approach to products to prevent and treat Ebola infection, according to a company press release.
- A study of travelers returning from West Africa's outbreak region found that among sick people, malaria was the most common specific diagnosis, present in 40.3%, followed by acute diarrhea, upper respiratory tract infection, urinary tract infection, and flulike illness. An international team of researchers published their findings from 57 travel or tropical medicine clinics in 25 different countries in today's issue of Annals of Internal Medicine.
- In a separate Annals report, clinicians from three US hospitals described the clinical management of the first three patients diagnosed with Ebola on US soil, a man who had recently traveled to Liberia and died from his infection and two Dallas nurses who cared for him. The clinicians noted that the man had high Ebola RNA levels and experienced respiratory and renal failure requiring critical care before he died. The secondary infections in the nurses were moderate, which probably resulted from earlier diagnosis and prompt delivery of supportive care. Patients received several experimental therapies, a factor that limited determination of possible benefits of each, the authors noted.
May 12 WHO media briefing audio file
VRBPAC meeting materials
May 12 Inovio press release
May 12 Ann Intern Med abstract on Ebola differential diagnosis in travelers
May 12 Ann Intern Med abstract on Ebola clinical management