Biostat researchers discuss roles in ongoing Ebola vaccine trial

Biostat researchers discuss roles in ongoing Ebola vaccine trial

Since August 2014, when the Ebola crisis in West Africa began capturing the world’s attention, UF biostatistics professor Ira Longini has been collaborating with a team of scientists at the World Health Organization (WHO) to develop a vaccine capable of protecting the most at-risk populations from the disease.

Working with unprecedented speed and precision, the research team began a phase 3 vaccine trial last March. The preliminary findings, released in July in the prestigious medical journal The Lancet, captured the world’s attention with their indication that the vaccine is 100 percent effective at protecting at-risk groups of people from Ebola.

“It takes years, normally, or even decades to bring a vaccine to phase 3,” Longini said. Given the scale and impact of the Ebola epidemic, however, an international coalition that included the WHO, Merck, the Norwegian Ministry of Foreign Affairs, and other organizations supported tireless research into methods to stop the spread of the disease.

Longini was integral to the design of the vaccine’s phase 3 trial, which relied on a ring-vaccination strategy of identifying those most at risk of contracting Ebola. The trial took place in Basse-Guinée, a coastal region of the West African nation of Guinea that includes the nation’s capital and largest city, Conakry. Ebola response teams based in the region identified “rings” of people connected to confirmed cases of Ebola. These rings were then randomized into two groups: an “immediate vaccination” group that would receive the vaccine immediately following cluster randomization, and a “delayed vaccination” group that would receive it 21 days post-randomization.

Working with Longini, Natalie Dean, a postdoctoral researcher in the Department of Biostatistics, carried out the data analysis used to report the trial’s findings in The Lancet.

“We faced some challenges in the analysis,” Dean said, “primarily because we didn’t expect to observe no cases in the immediately vaccinated arm.” Considering the unprecedented results of Guinea’s Ebola ça Suffit! trial, Dean and Longini had to adopt alternative approaches for the primary analysis.

The trial was innovative from the beginning. Using ring vaccination to test vaccine efficacy exemplifies the novel approach factored into the trial’s design.

“We’ve done cluster-randomized vaccine trials before but not ring vaccination,” Longini said. The method mirrored that of the ring-vaccination strategy implemented in the 1970s to eradicate smallpox.

By the time the vaccine trial team in Guinea was administering the vaccine to volunteers, previous trials had confirmed its immunogenicity. Additionally, researchers found that non-human primates developed an immune response to Ebola within seven days of taking the rVSV-ZEBOV Ebola vaccine.

Still, the non-human primate response was no guarantee that the vaccine would be just as effective in a human immune system – or just as safe. Researchers had to weigh concerns about the safety of the vaccine against the desire to protect as many people as possible from contracting Ebola.

So far, analysis of the phase 3 trial has been overwhelmingly positive: in both the immediate and the delayed groups, no one given the vaccine began developing Ebola symptoms more than six days after receiving it.

Initially developed in 2011, rVSV-ZEBOV was significantly reengineered prior to phase 1 trials last October. It works by expressing a surface glycoprotein of the Zaire ebolavirus, which, when introduced into the body, elicits an immune response without actually causing the disease.

In the delayed vaccination group, 16 people contracted Ebola 10 or more days following randomization; the fact that no one developed symptoms in the immediate rings ten or more days after randomization established that the vaccine, during the trial in Guinea, was 100 percent effective in preventing Ebola infection.

The ring vaccination methodology, which Longini helped develop, was an important tool in the trial’s efforts to test the efficacy of the vaccine and mitigate the spread of the disease. Following identification of a new Ebola case by Guinea-based Ebola response teams, the trial team would formulate a list of the case’s “contacts” and “contacts of contacts.”

Using this design strategy enabled researchers to target those most at risk of contracting Ebola, blanketing high-risk rings with vaccine as opposed to incorporating randomized clusters of people from the general population, many of whom may not be connected to a live case of the disease.

Additionally, the 21-day period between immediate and delayed vaccination rings serves as a control for the trial, eliminating the need for a placebo. All eligible participants, therefore, receive access to this potentially effective intervention – just not all at the same time.

Although researchers published their findings this past July, the phase 3 trial is ongoing.

“This was just the interim analysis,” Longini said. “We’re kind of at the half-way point, but on the 27th of July we stopped randomizing. From that point on, every ring got vaccinated immediately. Now, we have moved the trial into Sierra Leone where there are currently more cases. But there are no delayed rings anymore.”

The high level of efficacy revealed during the interim analysis, coupled with reduced availability of ring-defining index cases, prompted the data and safety monitoring board (DSMB) overseeing the trial to advise discontinuing the delayed rings, determining that it would be unethical to deny people access to this life-saving intervention when the interim analysis showed evidence that rVSV-ZEBOV is both safe and effective.

In Sierra Leone, which borders Guinea to the south, the trial is called the “STRIVE” study. Merck, an American-based pharmaceutical company, is responsible for producing and distributing the vaccine, and altogether more than 9000 volunteers have received it.

The international response effort to the crisis has not been without criticism, however. The WHO came under scrutiny during the fall of 2014 when reports came out showing that the surveillance and containment methods used to control previous outbreaks of Ebola were ineffective. Going forward, Longini said that it would be important for the WHO and other public health organizations to make interventions simultaneous with their evaluations of disease mitigation strategies. He believes the trial’s ring-vaccination method exemplifies this approach.

“While we were doing the ring vaccination trial,” he said, “we were also controlling Ebola – blanketing areas where transmission was occurring with vaccine. Had we simultaneously intervened and evaluated earlier, we could have possibly figured out why the surveillance and containment method wasn’t working initially in Liberia, Sierra Leone, and Guinea. But we didn’t have good evaluations to determine that.”

Disease outbreak prevention and mitigation is discussed extensively in “Design and Analysis of Vaccine Studies,” which Longini published in 2010 with Elizabeth Halloran and Claudio Struchiner.

New data from the ongoing phase 3 trial will further elucidate the vaccine’s role in the ongoing effort to stop the spread of Ebola in West Africa.

“We are now preparing for the final analyses,” Dean said. “A wealth of data has been and continues to be collected from this trial, including genetic data, epidemiological networks, and spatial coordinates. There are a lot of interesting and important questions that we hope to address.”

Findings from the phase 3 trial’s final analysis will be published in February