The discovery of the hepatitis viruses

Abstract

Viral hepatitis had a devastating effect on U.S. and foreign troops during World War II. Particularly troublesome were epidemics of hepatitis occurring among recipients of vaccines, especially yellow fever virus vaccine, which had been stabilized with pooled human serum. In addition, hepatitis following therapy with fresh frozen human plasma and following transfusion of whole blood was a serious emerging problem. This, coupled with the recognition of the existence of community-acquired hepatitis unrelated to exposure to blood, provided the stimulus for a series of controlled studies in volunteers on the nature and transmissibility of presumed viral hepatitis. A major contribution of the volunteer studies, as well as epidemiological studies of the time, was the recognition of two types of viral hepatitis differing in primary route of infection and period of incubation. These volunteer studies, principally among prisoners, yielded important information on some of the characteristics of the two putative viruses, and methods for their inactivation and/or removal from blood products are still in use today. Before that time, what we now know as viral hepatitis was known as “catarrhal jaundice.” In 1937, Findlay and MacCallum, in their first report from England on acute hepatitis among recipients of yellow fever vaccine, used the term “common infective hepatic jaundice” as synonymous with catarrhal jaundice and in 1939 suggested the term “infective hepatitis,” first suggested in 19 12 by Cockayne. In 1943, the term “infectious hepatitis” was intraduced in the United States as synonymous with infective hepatitis. “Homologous serum jaundice” was introduced in a memorandum from the Ministry of Health in Great Britain in 1943 to describe cases of hepatitis associated with injection of whole blood, plasma, or serum. At about the same time in the United States and Great Britain, “serum hepatitis” was used synonymously with homologous serum jaundice. The terms “hepatitis A” for infectious hepatitis and “hepatitis B” for serum hepatitis were introduced by MacCallum in 1947. These earlier volunteer studies in adults were confirmed and extended in volunteer studies in mentally retarded children at the Willowbrook State School in New York during the latter half of the 1950s and the first half of the 1960s by Saul Krugman of New York University and his colleagues. Both hepatitis viruses were highly endemic in the school, and most children became infected naturally shortly after admission if not entered into the studies. The studies at Willowbrook confirmed the existence of two distinct hepatitis viruses, distinguishable on epidemiological, clinical, and immunological grounds. They also showed an apparent lack of heterologous immunity between the two agents, and these data provided an explanation for second cases of naturally occurring jaundice among residents of the Willowbrook State School (third cases were never observed). Second cases of jaundice could be duplicated in volunteers under experimental conditions following inoculation with virus-containing serum. The two strains of hepatitis virus, obtained from the serum of patient M.S. during his first and second bouts of hepatitis, were designated “MS-l” and “MS-2.” They were subsequently shown to be hepatitis A virus (HAV) and hepatitis B virus (HBV), respec-