sufficiently large population among whom to conduct natural history studies.

An opportunity to undertake just such a study, however, seemed provided by the knowlege of an extensive outbreak of hepatitis that had affected United States Army servicemen during World War II (7-9). This outbreak was first noted in March 1942, prompting an intensive investigation soon after its recognition of the surrounding circumstances. A careful questionnaire survey led to the conclusion that the epidemic appeared attributable to the receipt of presumed hepatitis-contaminated yellow fever vaccine. Accordingly, the Surgeon General ordered on April 14 that the implicated vaccine lots be withdrawn and replaced with vaccine that was serum free. The epidemic reached a peak in June 1942, after which the number of reported cases of “jaundice” slowly returned to the baseline level. It was estimated that there were approximately 50,000 cases of hepatitis involved in this outbreak. Thus, if this epidemic could be shown to be of HBV origin, and if the infected patients could be traced now more than 40 years later, it was believed that the link known to exist in the Far East between chronic HBV infection and HCC might be demonstrable in the United States also.

An essential requirement for such a study would be to have access not only to those who had been overtly infected and developed jaundice in 1942, but also to those who had received the vaccine at that time and had developed inapparent disease, since chronic hepatitis has been believed to evolve more frequently following anicteric than icteric hepatitis (10). Moreover, it would be necessary to evaluate individuals who, during that time, had received non-contaminated vaccine, in order to determine the background prevalence of cirrhosis and HCC in this “control” group. Because it indeed appeared possible to assemble the necessary groups, the present investigation was undertaken with two goals in mind: first, to determine whether HBV was responsible for the epidemic and, second, to establish whether the epidemic, assuming it to be of HBV origin, had increased the rate of development of cirrhosis and/or HCC.

METHODS

A three-pronged approach was planned (11). The first consideration was to define the responsible virus by serologic means; the second was to establish a link between receipt of the contaminated vaccine and the occurrence of cirrhosis and HCC by means of a cohort mortality study, comparing the rates of these endpoints among the selected cohorts; and the third was to conduct a case-control study, comparing the frequency of receipt of the implicated vaccines among World War II veterans who had died from HCC with the frequency of their receipt among those who had



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