Vaccine Trial

U.S. Military Sponsored Vaccine Trials and Resistance in Nepal
In the fall of 1995, the U.S. Armed Forces Research Institute of Medical Sciences (AFRIMS), the Thai-based branch of Walter Reed Army Institute of Research, established a field unit in Kathmandu, Nepal. Founded primarily for the study of Hepatitis E, a waterborne virus, the unit was cleverly named Walter Reed/AFRIMS Research Unit-Nepal, or, by acronym, WARUN, the name of an important Hindu water god. During the controversy that would ensue, some pointed to this name as a way in which the researchers were attempting to take advantage of the strong religious beliefs of the people. But by then, that was the lesser of their concerns.
AFRIMS researchers had been studying Hepatitis E in Nepal for the previous eight years, and the establishment of WARUN coincided with the successful immunization of cynomolgus monkeys against Hepatitis E by researchers at the NIH in 1994. The vaccine was patented by Genelabs, a California based biotech company, and licensed by SmithKline Beecham Biologicals (now GlaxoSmithKline). In 1998, WARUN researchers, in collaboration with SmithKline Beecham, carried out successful Phase I trials of the vaccine, demonstrating its safety and immunogenicity in healthy Nepalese and American volunteers (Shrestha et al., 1999).
In late 1999, plans for a Phase II/III clinical trial of the vaccine were approved by the Nepal Health Research Council and the U.S. Army’s Human Subjects Research Review Board. Then, on February 2, 2000, WARUN held a press conference announcing that the trial was to begin in two weeks, with the screening of 8,000 volunteers (3,000 of whom would receive the vaccine or placebo) from Lalitpur, also known as Patan, one of the three cities in the Kathmandu valley. In the week following the announcement, Genelabs’ stocks nearly doubled, reaching their highest level in the nine year history of the company, and things appeared to be steaming along.
By mid February, however, articles criticizing the trial began to appear almost daily in local newspapers. Headlines read, “Belgium Drugs to be Tested on Nepalese Bodies,” “Nepal Being Made a Laboratory for Medicines,” “For American Selfishness, Patan Residents are Being Made Victims,” and “Patanites: Beware Beware!” (translations from Newari and Nepali). Concerned about the emerging controversy, Lalitpur’s local governing body met to discuss the trial, with the deputy mayor and twenty-two Ward representatives upset to find that the mayor had approved the city as a trial site without consulting them (though, notably, he did express the concern to the research director that the underlying problem of a lack of clean drinking water was not being addressed). The conclusion of the meeting was the issuance of a temporary prohibition against the trial, until WARUN satisfied the governing committee that “it had followed all the rules and regulation [sic] for performance of such a clinical trial.”
The controversy continued to intensify over the following month. Concerns were raised about the risks, benefits (individual and community), whether participants and community were adequately informed, selection of subjects (the recruiting organization was one that targets the urban poor), and why researchers wouldn’t clean up the water supply in lieu of the trial. One question, simple but frequently on the tongues of local leaders, was: “why is the American military interested in making a vaccine for a disease found in Nepal?”
Local non-governmental organizations (NGOs) took up the issue; some went door-to-door handing out fliers warning people against participation in the trial, others pursued self-directed crash courses on international research ethics. Opposition strengthened as Dr. Mathura Prasad Shrestha, a former Minister of Health, took a stance against the trial and began to work with the NGOs in their protest against the trial.
A public meeting of the researchers, government regulators, politicians, and interested NGOs was held in attempt to resolve the questions and debate concerning the trial. Ramesh Chitrakar, the deputy mayor, put forth a series of questions, echoing many of the concerns mentioned above. First among these was how Lalitpur would benefit from the research. He inquired about profit-sharing after completion of the trial, to which the Nepal Health Research Council secretary responded, “the profit margin for a drug company may be quite minimal considering their own research expenses. The movement is to make drugs affordable and available to all” (Giyawali 2000), a statement that appeared to contradict WARUN’s explanations: “the U.S. army is interested in this vaccine because it has military implications for American soldiers. SmithKline Beecham has the rather different motivation of wanting to come up with a profitable traveller’s vaccine” (Stevenson 2000). He asked the researchers to build a hospital; instead, according to him, they offered wrist watches to him and the Ward representatives. Chitrikar asked the question of why WARUN wouldn’t simply improve the water supply, eliminating not only Hepatitis E but a number of other endemic waterborne diseases. After all, Thailand had been considered as a site for the trial, but the disease was largely eradicated due to sanitation improvements in the late ‘80s and early ‘90s. WARUN produced a written response to Chitrikar’s questions, but this final concern was not mentioned or addressed.
Unsatisfied by WARUN’s plans and explanations, Chitrikar and the Lalitpur Sub-Metropolitan City committee upheld their prohibition against the trial, and the trial was relocated to a population that unsurprisingly did not raise any opposition: the Royal Nepalese Army (RNA). The Phase II/III trials of the vaccine, with RNA soldiers as subjects, were completed in late 2003, but the results have yet to be made public.
The use of Nepalese soldiers for a vaccine trial is concerning in several regards. I have elsewhere described the ways in which this population is vulnerable—including their membership in the armed forces, citizenship in a least developed country, and involvement in an active conflict—as well as the researchers’ failure to satisfy the “special requirements” put forth by CIOMS for the use of a vulnerable population in a clinical trial (Andrews in press). Furthermore, the ongoing, prolific human rights abuses by the RNA, well documented by the State Department, domestic commissions, and international non-governmental organizations, should give research regulators pause when such an institution is being proposed as both a site and partner for research—particularly that carried out with U.S. government funds. Finally, noting the millions of dollars, military training, and arms that the State Department and Military have been giving to the RNA to help them put down the Maoist rebellion, it seems plausible that the resultant military and economic dependence of the host institution/population (RNA) upon the research sponsor (the U.S. Military) threatened the voluntary nature of the institutional and individual participation in the trial. That is, the RNA probably was not in a good position to say ‘no’ to the small request by their generous benefactor. At present, however, there are no policies or mechanisms in place for reviewing and regulating institutional vulnerability in research, and the ethics literature has yet to give serious consideration to the impact and relevance of underlying politico-economic relationships between collaborators and stakeholders in transnational research.
The problems that derailed this trial and resulted in this relocation are ones that we are likely to see again as transnational research continues to expand; in the case of this study, the underlying concerns of the Patanites, or at least their community and political leaders, were two-fold. The first was a feeling of resentment or skepticism towards the researchers that was a result of a perceived lack of transparency and adequate community involvement prior to the commencement of research. Many of the concerns expressed about the trial were the result of misinformation or were ones that likely could have been resolved through early dialogue; however, by failing to sufficiently engage the community in the planning of the trial and announcing the commencement publicly so soon before the anticipated date, the researchers garnered tremendous resentment and a mistrust that could not be unsown. While the appropriate manner in which to approach a community for research is not so much an ethical issue as it is a sociological one, it nevertheless must fall under the purview of the research review bodies. The best practices and conduct for community involvement is very context-dependent; accordingly, the development of country-specific guidelines for incorporation into domestic research practice guidelines would be of great utility.
The second—and related—concern was that of community benefits. The concern of the community about benefits was a particularly legitimate one, in light of similar vaccine trials (for Hepatitis A, Japanese Encephalitis, and Typhoid) carried out by AFRIMS, which resulted in profitable traveler’s vaccines that have proven too expensive for public distribution in the country in which they were tested (Participants 2004; Strickman et al. 2000). The latter of these vaccines—the Typhoid Vi polysaccharide vaccine—was developed in Nepal in the 1980s with the sponsorship of Walter Reed Army Institute of Research but is not widely used in Nepal (aside from the ubiquitous tourists) and typhoid remains endemic in the country (Acharya et al. 1987). The National Ethics Guidelines for Health Research in Nepal stipulate that in order to obtain approval for a trial, researchers should address the issue of the “[p]ossibility of intervention (Vaccine, drug or supplementation) being available to the participant population if found effective” (Nepal Health Research Council 2001, 31). In practice, according to Nepalese researchers, policy-makers, Ministry of Health officials, and the Chairperson of the Nepal Health Research Council, this requirement “requires” little more than that the researchers think about the issue. It is not necessary to actually meet with any relevant government agencies or institutions involved in implementing health programs, much less to make any commitments. Again, part of the problem appears to be the lack of guidelines or precedent to inform the researchers and regulators as to what constitutes an appropriate engagement on the question of post-trial benefits. While the debate about “reasonable availability,” “fair benefits,” and prior agreements will—and should—continue in ethics scholarship, it is important to remain cognizant of the gulf between policy and practice on the ground, where the “how” questions have yet to be adequately addressed.
Jason Andrews
2005. The American Journal of Bioethics 5(3):W1

Discovery of H pylori

Nobel Prize for Medicine recipients, Australians Warren and Marshall toast their success with a champagne at Swan Berry Cafe in Perth] Nobel Prize for Medicine recipients, Australians Robin Warren, left, and Barry Marshall, toast their success. The team discovered the bacterium behind stomach inflammation and ulcers, diseases that affect millions of people.

Dr. Barry Marshall was so determined to convince the world that bacteria —not stress — caused ulcers that he drank a batch of it.
Five days later he was throwing up, and he had severe stomach inflammation for about two weeks.

It was just the result he was hoping for. His bold action over 20 years ago symbolized the perseverance Marshall brought to proving a controversial idea — one that gained the ultimate validation Monday as he and Dr. Robin Warren won the Nobel Prize in medicine.
The discovery by the two Australians that ulcers weren't caused by stress, but rather by the bacterium Helicobacter pylori, turned medical dogma on its head. As a result, peptic ulcer disease has been transformed from a chronic, frequently disabling condition to one that can be cured by a short regimen of antibiotics and other medicines, said the Nobel Assembly of the Karolinska Institute in Stockholm.
'No one believed it'

Warren, a retired pathologist, said it took a decade for others to accept their findings.
The long-standard teaching in medicine was that "the stomach was sterile and nothing grew there because of corrosive gastric juices," he said. "So everybody believed there were no bacteria in the stomach."
"When I said they were there, no one believed it," he added.

The two researchers began working together in 1981. "After about three years we were pretty convinced that these bacteria were important in ulcers and it was a frustrating time for the next 10 years though because nobody believed us," said Marshall, a researcher at the University of Western Australia.

"The idea of stress and things like that was just so entrenched nobody could really believe that it was bacteria. It had to come from some weird place like Perth, Western Australia, because I think nobody else would have even considered it."

Marshall later wrote that he consumed the germ-laden drink himself in July 1984 because it was impossible to infect rats, mice and pigs with the bug. He was fine for about five days, then he began to get early-morning nausea and vomiting.

The stomach inflammation he was hoping for lasted about two weeks, he told The Associated Press on Monday.

"I didn't actually develop an ulcer, but I did prove that a healthy person could be infected by these bacteria, and that was an advance because the skeptics were saying that people with ulcers somehow had a weakened immune system and that the bacteria were infecting them after the event."


Curing ulcers with antibiotics

He and Warren believed the bacteria came first, causing inflammation, then ulcers. The experiment helped establish that.
Dr. David A. Peura, president of the American Gastroenterological Association, said the prize-winning work "revolutionized our understanding of ulcer disease" and "gave millions of people hope."
He read about the H pylori theory in 1983 while serving as a gastroenterologist in the Army, and "I thought it was crazy," he recalled Monday.

But he and a colleague were intrigued, and soon they discovered they could cure ulcers in their own patients with antibiotics targeted at H pylori.

"It was such an intriguing theory that everybody tried to disprove it and couldn't, so we all became believers," said Peura, now a professor of medicine at the University of Virginia at Charlottesville.

Peura, who met Marshall when both worked at the university and considers him a friend, said Marshall's perseverance was responsible for the eventual acceptance of the theory. "Any lesser of a person probably would not have been able to withstand some of the ridicule and scorn that was thrown at him initially," Peura said.

Marshall and Warren celebrated their new honor with champagne and beer.
"Obviously, it's the best thing that can ever happen to somebody in medical research. It's just incredible," Marshall said by telephone from Perth, the Western Australia state capital, where the pair were celebrating with family members.
Warren said he was "very excited also a little overcome."

Their work has stimulated research into microbes as possible reasons for other chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis and atherosclerosis, the Nobel assembly said in its citation.

The discovery came about after Warren had observed bacteria colonizing the lower part of the stomach of patients and noted that signs of inflammation were always present close to the bacteria. Marshall became interested in Warren's findings and together they launched a study of more patients.

Marshall also succeeded in cultivating the previously unknown bacterium from patient biopsies, in part because he accidentally left a sample in his lab over the Easter holiday in 1982 — unwittingly giving his cultures time enough for success.
Together, the two men found H pylori present in almost all patients with stomach inflammation or ulcers in the stomach or the part of the small intestine called the duodenum.

2005 The Associated Press.