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Emerging Infections: Microbial Threats to Health in the United States
another study, the precore variant was found in sera from eight of nine patients who were negative for HBeAg and had fulminant hepatitis B infection, but not in sera from six other patients who had fulminant hepatitis B but were positive for HBeAg. Finally, a nosocomial outbreak of fulminant hepatitis B with five fatalities occurred in Haifa, Israel, in 1989. The outbreak was traced to an intravenous heparin flush bottle that had been contaminated after use in a patient who was a chronic hepatitis B carrier. The same hepatitis B precore variant was detected in each of the patients (Liang et al., 1991). In addition to the single nonsense mutation at nucleotide 1896 (seen in all the precore isolates that have been identified to date), there was an additional mutation at nucleotide 1901, which the authors speculated might be related to the especially high mortality caused by this variant.
A vaccine escape mutant, by contrast, generally does not cause altered pathogenesis but lacks a particular antigenic site, allowing it to infect hosts protected by immunization or passively acquired antibody in much the same way that antigenic drift occurs in influenza A. Hepatitis B vaccine has been used in Italy since 1982 to protect infants born to mothers who are chronic carriers of hepatitis B. The hepatitis B vaccine escape mutant was found during follow-up studies of this population (Carman et al., 1990). Of 1,590 vaccinees (infants and family contacts), 44 became positive for hepatitis B surface antigen, indicating that they had become infected with hepatitis B despite immunization and prophylactic hepatitis B hyperimmune globulin. Another 7 patients were identified later. Viral DNA from a patient (in the original group) chosen for detailed study demonstrated a variant that lacked a major antigenic determinant and was therefore no longer neutralized by hyperimmune globulin or (presumably) by vaccine-induced antibodies. The loss of the antigenic site was due to a point mutation that altered a single amino acid. The other apparent vaccine failures were not as thoroughly investigated. Although it is not known conclusively whether this mechanism accounted for the other cases, there were indications that at least some of the other vaccine failures were due to an escape mutant. The localization of these mutants to a particular geographic region (the Mediterranean) was puzzling. This may have been due to host immunogenetic factors or suboptimal immunization schedules, or to the use of both vaccine and immunoglobulin, which increases selective pressure favoring an escape mutant.
Bacteria cause disease because they produce so-called virulence factors. Virulence factors have several roles in bacterial pathogenesis: they allow the bacteria to resist nonspecific host clearance mechanisms; they help the bacteria acquire nutrients necessary for growth and survival; they assist the