The hurdles faced in developing any new drug or vaccine are numerous and daunting. Still, rarely if ever do clinical trials face the sort of difficulties as those encountered in Nepal, where a research team drawn from the Walter Reed Army Institute of Research (WRAIR) and its field research unit in Kathmandu; GlaxoSmithKline Biologicals; and the Nepalese Army Medical Department tested the efficacy of the hepatitis E vaccine.
Outbreaks of hepatitis E. (Credit: CDC)
The vaccine could not be tested for its protective efficacy in the United States because hepatitis E disease is exceedingly rare here. On the other hand, in Nepal, the virus causes annual outbreaks during the flooding season and is a leading cause of hospitalization, striking all age groups and socioeconomic classes. Nepal seemed an ideal site for the trial.
Plus, much of the groundwork in Nepal was already done. Bruce Innis, M.D., one of the leaders of the team formed to conduct clinical trials, had been based in Thailand for much of the previous decade with the U.S. Armed Forces Research Institute for Medical Sciences. Since 1987, he and his colleagues had been working with Mrigendra P. Shrestha, F.R.C.P., of Kathmandu, to investigate the causes of viral hepatitis in Nepal and to characterize the epidemiology of hepatitis E there.
In 1993, after completing a huge field efficacy trial of hepatitis A vaccine in Thailand, Dr. Innis returned to the WRAIR in Washington, DC, and began planning clinical trials for testing a hepatitis E vaccine. This was a commitment he pledged to pursue when he first met Dr. Shrestha. Dr. Innis was aware of the work being done by Robert Purcell, M.D., and colleagues with GlaxoSmithKline Biologicals; and his institution embraced a goal shared by NIAID to develop a vaccine against hepatitis E.
Over the next two years, Dr. Innis obtained support to establish a field research station in Kathmandu, and he recruited his colleague, Robert McNair Scott, M.D., to join the nascent U.S. Army hepatitis E effort. Dr. Scott relocated to Kathmandu in 1995, where for the next 10 years, he and Dr. Shrestha, also recruited by WRAIR to the research unit, led the vaccine development effort in Kathmandu.
There was much to be done. The Nepal field unit was supported by a sister unit of WRAIR, located in Bangkok, the Armed Forces Research Institute of Medical Sciences. A team drawn from these two institutes established a reliable procedure to confirm a diagnosis of hepatitis E, a necessity for vaccine efficacy trials.
They carefully evaluated the incidence of hepatitis E in several populations, another necessity for an efficacy trial. By 1998, it was time to start clinical evaluation of the vaccine in Nepal with a pilot clinical trial. In this, the vaccine appeared safe and induced promising immune responses in volunteers. By 2000, the team was ready to conduct a large trial of the vaccine’s protective efficacy.
In retrospect, says Dr. Innis, if they knew how difficult the trial would be, they may never have conducted it.
Nepal is a land of extremes. A country about the size of Tennessee nestled in between China and India, its terrain varies from subtropical river plains in the south to the rugged and cold Himalaya Mountains in the north. The country has about 29 million people and 8 of the 10 highest mountains in the world, including the tallest, Mt. Everest.
According to the research team, completing the trial seemed an even steeper ascent at times. The trial, which almost collapsed in the planning stage, had to be redesigned. And when it was just under way in 2001, the King of Nepal and other members of the Royal Family were assassinated, throwing the country into turmoil. In the political uncertainty that followed, a Maoist insurgency that had begun a few years earlier in the western part of the country intensified.
The Nepalese Army became involved in the fighting, which had unexpected and strange consequences. Clinical trial monitors from the U.S. Army and GlaxoSmithKline Biologicals, who had responsibility to assure quality during the trial’s conduct, found it difficult to move in and out of the country. Soldiers who had volunteered for the trial were suddenly deployed to the fighting areas. The Nepalese Army wound up having to ferry trial volunteers back and forth between the conflict and the clinic, and the study team became airborne, collecting follow-up samples from soldiers in the field.
In this clinical trial, “battle injury” was one of the more commonly reported serious adverse events, since during clinical trials, all medically significant untoward events must be recorded, whether overtly linked to the treatment under study or not, as part of a full safety assessment.
“It was a time of testing,” says Dr. Innis. “It was testimony to the tenacity and commitment of the Walter Reed investigators, who really held this together.”
In the end, the WRAIR, Nepalese Army, and GlaxoSmithKline teams did finish the trial, and the vaccine proved highly effective. After three doses, only 3 of 898 soldiers who received the vaccine compared with 66 of 896 soldiers who received the placebo developed clinical hepatitis E. This meant that the vaccine was 96 percent effective at preventing the disease. The trial also showed two doses of vaccine to be 87 percent efficacious. They also found the vaccine to be safe: There were no serious adverse side effects attributed to the vaccine.
“It was a great result,” says Dr. Innis, who is now with GlaxoSmithKline. “It’s what everyone hopes to see with every new vaccine.”
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Last Updated August 30, 2007