The Story behind Human Experiments with Hepatitis

In Dangerous Medicine: the Story behind Human Experiments with Hepatitis, Sidney A. Halpern tells the story of America’s decades-long investment in hepatitis inoculation experiments, of which the infamous Willowbrook study was only the final and perhaps most egregious example. The experiments began in 1943 in response to an epidemic of “serum” hepatitis among military draftees who had received yellow fever vaccine. The initial idea was to characterize the infectious agent that caused the disease and to examine its clinical features under controlled conditions. In later years, studies involved testing various preventive measures, both for serum (B) and infectious (A) hepatitis.  

During World War II, the Armed Forces Epidemiology Board (AFEB) initiated a series of inoculation studies among conscientious objectors, prisoners, and mental patients. Most of the subjects were conscientious objectors who volunteered, despite having a wide variety of service options. “Virtually all the men serving as hepatitis subjects spoke of a desire to engage in meaningful and consequential humanitarian service.” (p. 63) Investigators told the volunteers, “It is our judgment that the possibility of permanent or even protracted or severe impairment of liver function following participation in the jaundice experiment is very slight.” (p. 48) At that time, of course, long-term consequences of hepatitis B infection—chronic infection, cirrhosis, and hepatocellular carcinoma—were unknown. However, many of the subjects did develop clinical disease and at least one subject developed fulminant liver failure and died.  

After the war, hepatitis researchers relied almost exclusively on institutionalized subjects. For example, Joseph Stokes Jr. of the AFEB “not only drew subjects from a mental hospital and multiple institutions for children, but he also enlisted inmates from five state correctional facilities… in New Jersey.” (p. 101) Stokes claimed the research was “beneficial for both the facility and its residents.” (p. 96) Later, researchers at Johns Hopkins, Yale, and the NIH conducted studies at other institutions. For prisoners, participation offered multiple benefits, including the possibility of early release. Among the objectives of studies during the 1950s were attempts to eradicate the infectious agent by sterilizing the infected serum, which were unsuccessful. During these studies, four subjects died of fulminant hepatitis, two at McNeil Island Penitentiary in Washington and two at Lewisburg Penitentiary in Pennsylvania.  

Willowbrook was one of two long-term hepatitis inoculation programs begun in 1956. At the time, Willowbrook State Hospital on Staten Island had one of the largest populations of the cognitively impaired in the USA. It was the overcrowded home to some of the state’s most disabled patients – 39% were non-ambulatory, and 64% unable to feed themselves. A New York University team, later headed by Saul Krugman, professor of pediatrics, established a hepatitis unit which each year admitted approximately forty-eight children between three and ten years of age. Many of the experiments involved injecting subjects with serum containing live infectious (A) or serum (B) hepatitis virus. Major study findings included clearly distinguishing between the natural history and characteristics of hepatitis A and B, and discovering that gamma globulin was an effective means of preventing clinical illness in hepatitis A. 

This decades-long sequence of inoculation studies occurred despite post-war developments in research ethics. The Nuremberg Code was promulgated in 1947, followed in 1964 by the Helsinki Declaration. These documents established principles designed to protect the rights and welfare of research subjects, including respect for individuals, voluntary participation, informed consent, risk/benefit analysis, confidentiality, and scientific integrity. However, at least in the United States, hepatitis investigators, among others (e.g. Tuskegee syphilis study), ignored or evaded these principles.

Except for wartime experiments on conscientious objectors, hepatitis inoculation studies violated almost every ethical principle set forth in the Nuremberg Code and Helsinki Declaration. The vast majority were conducted in closed institutions among subjects who either lacked the ability to consent, or whose participation was not necessarily voluntary (i.e. prisoners). Where consent was obtained (e.g., from a prisoner or surrogate), the investigators provided incomplete or false information (e.g. stating that risk was minimal), despite several deaths from fulminant liver failure. Yet, Joseph Stokes claimed that virus inoculation could “in our opinion be of benefit to the individual himself.” (p. 98) In addition, coercive tactics were used (e.g., quicker admission to an institution, or earlier release from prison).  

Dangerous Medicine highlights unethical practices in American hepatitis research throughout the mid-20^th century. While contemporary ethical standards had yet to be established, broad ethical principles articulated by the Nuremberg Code and Helsinki Declaration and reiterated (at least, in part) by the American Medical Association, were ignored. Public outcry in 1972 against Willowbrook, Tuskegee and other unethical research led in 1974 to the establishment of the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research and, subsequently, to the Belmont Report, the Common Rule, Institutional Review Boards, and contemporary standards in human subjects research. Interestingly, as far as Dr. Halperin is aware, no follow-up studies have ever been done to ascertain the long-term health consequences of these hepatitis study subjects.  

Dangerous Medicine tells a sobering story, well-worth reading. And, given the prevalence of academic incentives and multiple conflicts of interest, I’m afraid the story of unethical research is far from over 

1. Beecher HK. The Ethics of Clinical Research. New England Journal of Medicine. 1966; 274: 1354-1360. 

Dangerous Medicine: The Story behind Human Experiments with Hepatitis
Sydney A. Halpern
Yale University Press, 2021
304 pages 

Web image of Hepatitis B from Wiki Commons