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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality
The public health importance of hepatitis B infection in susceptible populations spurred the search for a vaccine against this virus. While studying serologic polymorphisms, Blumberg discovered an antibody that reacted with the blood from an Australian aborigine (Blumberg et al., 1969). The reactant became known as the Australia antigen (Au) and was the basis of the test used to screen blood for the presence of hepatitis B virus. This work earned B. S. Blumberg the Nobel Prize in 1976. This basic research also led to the development of a vaccine. Krugman and colleagues, in a classic series of studies in the early 1970s, further laid the groundwork for development of the vaccine. They worked with two strains of hepatitis B virus in human volunteer studies. One was labeled MS-1 and was later identified as hepatitis A virus. The other was labeled MS-2 and was later confirmed to be hepatitis B virus. Those investigators found that a 1:10 dilution of serum infected with hepatitis B virus boiled for 1 minute lost its infectivity but retained its antigenicity and prevented or modified hepatitis B virus infection in approximately 70 percent of vaccinated subjects later challenged with infective MS-2 serum (Krugman and Giles, 1973; Krugman et al., 1970, 1971).
Krugman's principle was developed into a more sophisticated vaccine by several groups (Coutinho et al., 1983; Crosnier et al., 1981; McLean et al., 1983; Purcell and Gerin, 1975). The vaccines consisted of inactivated, alum-adsorbed, 22-nm hepatitis B virus surface antigen (HBsAg) particles that had been purified from the plasma of human chronic hepatitis B virus carriers. The method of purification was by a combination of biophysical (ultracentrifugation) and biochemical procedures. Inactivation was a threefold process with 8 M urea, pepsin at pH 2, and formalin at a 1:4,000 dilution. The plasma-derived hepatitis B vaccine was licensed by the U.S. Food and Drug Administration in late 1981. A belief among some prospective vaccinees that the plasma-derived vaccine might be contaminated with human blood pathogens (particularly human immunodeficiency virus [HIV]) was an important deterrent to the optimal utilization of the hepatitis B vaccine in high-risk individuals. The treatment steps described above were shown to inactivate representatives of various viruses found in human blood, including HIV (Francis et al., 1986).
Hepatitis B vaccines derived from human plasma were subsequently developed in countries other than the United States, including countries in Europe and Asia. All of the plasma-derived vaccines were given safety tests in tissue culture systems, in animals, and then in humans. Trials of efficacy were done among infants born to carrier mothers, children, and various groups of adults, including homosexual men. Those trials demonstrated adequate antibody production after a three-dose schedule and a high rate of protection following immunization in populations with higher levels of exposure to the antigen than those populations currently receiving the