Physicians in the early 1900s recognized that hepatitis A was spread by person-to-person contact 46, food, and possibly water 262. Cockayne extensively reviewed previous literature, generally selecting statements and observations that we now know to be correct. For example, he reports "One man already infected travelled to Flintshire and there passed on the disease to three others." Whereas person-to-person contact was evident, an alimentary mode of spread was not generally accepted. Although most physicians considered that a respiratory-type droplet infection was more likely 33, 54, 81, 84, 92, 154, gastrointestinal transmission was predicted by some authors in Europe 2 and the United States 181.
Experimental transmission of infective hepatitis by feeding duodenal juice was first reported by Voegt 255; cited in reference 82). Of note, although published in Germany (in Muenchener medizinische Wochenschrift [Munich Medical Weekly]) in 1942, the findings were referenced by British investigators in 1943 82 and Americans in 1944 104 despite World War II. An underground network apparently procured scientific publications through neutral countries (H. Mayo, personal communication), permitting efficient dissemination of knowledge.
In the United States, Havens and colleagues successfully transmitted jaundice by feeding either serum or a filtrate of stool extract to 12 conscientious objectors who volunteered for studies at Yale University 104. The incubation period was 20 to 30 days in the four persons who became icteric, consistent with transmission of hepatitis A. Stool samples obtained during convalescence were not infectious, whereas hepatitis was transmitted with stool samples collected 5 days after the onset of symptoms 105. In parallel studies, three of five volunteers became jaundiced after intracutaneous inoculation of serum. The incubation period was longer, suggesting hepatitis B 104. In later publications from this group, a distinction between infectious hepatitis (short incubation) and serum jaundice (long incubation) was made 189, 190. Infectious hepatitis (hepatitis A) was transmitted to four of five volunteers by ingestion of preicteric sera and to two of three volunteers after ingestion of stool 190. Hepatitis was apparent less than 40 days after exposure in all volunteers. In contrast, serum jaundice (hepatitis B) was transmitted to 10 of 23 volunteers inoculated with serum but not to three volunteers ingesting serum 190. All in this group developed hepatitis more than 50 days after exposure.
Voegt injected preicteric serum and produced jaundice in studies performed at the same time as those investigating oral transmission (255; cited in reference 190). Working with British troops in Palestine in 1941 to 1942 and unaware of Voegt's findings (as judged by the references cited and the geographic separation), Cameron injected whole blood or serum from jaundiced patients into seven volunteers 42. One recipient developed jaundice a month after injection, consistent with the incubation period of hepatitis A (10 to 50 days). The serum for this recipient was collected 2 days after the onset of jaundice in the donor. Jaundice eventually developed in five volunteers after various periods of time on active duty. Cameron abandoned further human experiments when he became aware of case fatalities (not from his own series).
Havens and colleagues at Yale also transmitted infectious hepatitis (hepatitis A) by parenteral means to 6 of 11 recipients. Using preicteric serum obtained from volunteers who developed short-incubation hepatitis following ingestion of infected material 190, they observed a short incubation period similar to that noted after ingestion of infected material. Serum obtained 11 days before and 31 days after the onset of symptoms did not transmit hepatitis to any of six volunteers (three in each group), whereas serum collected 4 days after the onset was infectious in three of six recipients 105. Three volunteers were infected sequentially with hepatitis B and then hepatitis A, demonstrating a lack of cross-reactive immunity. The authors interpreted their findings conservatively, as not indicating a fundamental difference between the two diseases, since the clinical features were indistinguishable with the exception of the incubation phase 190.
Infectious Hepatitis versus Serum Jaundice
By the late 1940s, the differentiation between infectious hepatitis and serum jaundice was distinct enough, and the nomenclature was confusing enough, that MacCallum proposed using the terms hepatitis A and hepatitis B in 1947 16. Whether the differences were explained by two distinct viruses or different strains of the same organism remained uncertain. The term catarrhal jaundice was finally abandoned following the general acceptance that a virus(es) was the etiologic agent(s), because the transmission experiments used filtered material 106, 189.
Willowbrook State School MS-1 and MS-2
Definitive evidence of two different types of hepatitis virus was provided by a series of experiments carried out at the Willowbrook State School on Staten Island. The goal of the original studies was to control hepatitis, which was endemic in this residential school for the mentally disabled. The early work demonstrated the period of infectivity of serum and fecal material 139, 140, 257 and also the usefulness of measurements of serum glutamic oxaloacetic transaminase (SGOT) in the diagnosis of anicteric and asymptomatic infections 139.
Second attacks of hepatitis were observed in some residents 138. To investigate this observation more thoroughly, pools of serum obtained during the two separate episodes in one resident (Mir) were inoculated into newly admitted residents kept in isolation. One pool, designated MS-1 (Mir serum-1), caused hepatitis in seven of eight children after a relatively short incubation (hepatitis A), whereas the second pool, MS-2, resulted in long-incubation hepatitis (hepatitis B) in seven of nine children 138. The MS-1 pool was used in the first successful transmission of hepatitis A to animals (marmosets) 116 and to transmit hepatitis to volunteers (in Joliet prison) whose clinical samples were the sources of material for the first detection of virus particles 78. Marmoset livers became the source of infectious material not only for the development of serologic assays but also for cell culture experiments.