David J. West

Overview of clinical studies with hepatitis B vaccine made by recombinant DNA

The Merck, Sharp and Dohme hepatitis B vaccine formulated from HBsAg produced by a recombinant strain of Saccharomyces cerevisiae has proven to be highly immunogenic and safe. A 10 micrograms dose of the vaccine produced an anti-HBs response of greater than or equal to 10 IU/l in 91% or more of healthy adults who completed the three-dose regimen. Children responded well to all levels of vaccine antigen utilised but developed maximum anti-HBs titres with 5 micrograms doses. The age of the vaccine recipient affected responsiveness. Younger adults (20-29 years) responded more rapidly and with higher anti-HBs titres than did older adults (greater than or equal to 50 years). Children responded faster and with higher anti-HBs levels than younger adults. Clinical reactions reported after vaccination were mild and transient.

Clinical experience with hepatitis B vaccines

The hepatitis B vaccine which is commercially available in the United States consists of noninfectious hepatitis B surface antigen (HBsAg) which is purified from the plasma of asymptomatic chronic carriers of the hepatitis B virus (1,2,3). The excess HBsAg subunit present in large quantities in the plasma of these individuals first is separated from the heavier hepatitis B virus and from extraneous blood proteins by two ultracentrifugation steps. It then is subjected sequentially to three chemical treatments (pepsin at pH 2, 8M urea and formaldehyde) to insure killing of any residual hepatitis B virus as well as any other infectious agent which might be present in human plasma. The vaccine manufacturing facility provides total physical separation of each of the critical inactivation steps and prevents introduction of untreated materials into later process steps. All chemical reagents are assayed for potency before and after use to insure proper inactivation at each of the steps. All lots of vaccine are extensively tested for purity, potency and safety, including a test for safety in susceptible chimpanzees.

The risk of hepatitis B infection among health professionals in the United States: a review

Many physicians, dentists, and allied health personnel sustain occupational exposures to blood and other body fluids that increase their risk of contracting type B viral hepatitis. Overall, the risk of hepatitis B among persons employed in health-related fields is estimated to be approximately four times that in the general adult population. Studies on the incidence of infection and the prevalence of hepatitis B serologic markers have further defined risk in specific occupational categories and work activities. Physicians and dentists are five to ten times more likely than the general adult population to experience hepatitis B infection. Infection rates ten or more times above the average have often been characteristic of surgeons, patient care personnel in dialysis units and institutions for the mentally handicapped, and clinical laboratory workers having frequent contact with blood samples.

Haemophilus influenzae type b conjugate vaccine stability: catalytic depolymerization of PRP in the presence of aluminum hydroxide.

The structural stability of the Haemophilus influenzae type b (Hib) capsular polysaccharide, polyribosylribitolphosphate (PRP) in an aluminum hydroxide adsorbed, polysaccharide-protein conjugate vaccine was monitored using modifications of an HPLC assay developed by Tsai et al. [Tsai C-M, Gu X-X, Byrd RA. Quantification of polysaccharide in Haemophilus influenzae type b conjugate and polysaccharide vaccines by high-performance anion-exchange chromatography with pulsed amperometric detection. Vaccine 1993;12:700-706.]. As applied to products containing PRP conjugated to the outer membrane protein complex (OMPC) from Neisseria meningitidis, this assay allows direct measurement of the total PRP content in very complex samples including commercial vaccine products. In addition, with the use of a high-speed centrifugation step, the assay can be used to directly quantify any PRP that is not conjugated to the OMPC carrier protein. These results provide evidence of what appears to be a catalytic reaction taking place between the phosphodiester bond of PRP and the aluminum hydroxide adjuvant that results in hydrolysis of the PRP polymer into smaller chain lengths and liberation of PRP oligomers from the conjugate particle. The reaction approaches an asymptotic limit after approximately two years at 2-8 degrees C. Clinical studies which span this time period confirm that the modest decrease in conjugated PRP content over time does not impact the overall clinical effectiveness of PRP-OMPC-containing vaccines.

Vaccination of infants and children against hepatitis B.

Hepatitis B infection and its sequelae constitute a significant public health problem in the United States. It is estimated that 300,000 acute hepatitis B infections occur each year, with about 25% accompanied by both clinical illness and jaundice. Some infections become chronic and ultimately may cause development of liver cirrhosis or primary hepatocellular carcinoma. The risk of chronicity is especially great with infections that occur in infancy. Highly effective vaccines comprised of purified hepatitis B surface antigen (HBsAg) particles are now available for the prevention of hepatitis B infection. A first-generation vaccine utilized HBsAg derived from the plasma of infected persons; this has now been replaced by two similar vaccines that incorporate HBsAg produced by genetically engineered strains of the common bakers yeast, Saccharomyces cerevisiae. Improved use of vaccine is needed to reduce and ultimately eliminate hepatitis B infection. Vaccination already is recommended for persons recognized to be at increased risk of exposure to virus-containing blood or other body fluids (e.g., infants born to carrier mothers, household or sexual contacts of carriers); however, mass vaccination of adolescents and infants is needed to interdict effectively a majority of all exposures to the hepatitis B virus.

Comparative safety and immunogenicity of yeast recombinant hepatitis B vaccines containing S and pre-S2+S antigens

One hundred and four healthy, hepatitis B virus (HBV) seronegative males were enrolled in a single blind, randomized pilot study to compare antibody and clinical responses to a yeast recombinant pre-S2 + S vaccine and a yeast recombinant S antigen vaccine (Recombivax HBR). Participants received either a 12, 24 or 48 micrograms dose of pre-S2 + S vaccine (with a 1:5 ratio by weight of pre-S2 and S antigens) or a 10 micrograms dose of Recombivax HBR by intramuscular injection at 0, 1 and 6 months; their serological and biochemical responses were measured at 0, 1, 2, 3, 6 and 7 months, while their clinical responses were monitored for 5 days after each injection. The proportion of vaccines with minor local or systemic complaints (mainly sore arm, malaise, myalgia, fatigue) and the proportion developing antibody to surface antigen (anti-HBs) were similar for all vaccine groups. Transient elevations in alanine aminotransferase occurred infrequently. By 7 months almost all vaccinees developed anti-HBs, but titres were generally higher among recipients of pre-S2 + S vaccine. Antibody to pre-S2 antigen developed in 70-75% by 2 months and in 91-96% by 7 months. These data imply that the recombinant yeast pre-S2 + S vaccine is as well tolerated and as immunogenic as Recombivax HBR. Further studies are being conducted to assess antibody responses in larger numbers of healthy adults as well as in special populations with sub-optimal responses to currently licensed hepatitis B vaccines.

Development and persistence of antibody in a high risk institutionalized population given plasma-derived hepatitis B vaccine

Three hundred and twenty-two (322) persons with severe mental handicaps were given plasma-derived hepatitis B vaccine (20 micrograms dose at 0, 1 and 6 months). Following the third injection, 95% of the vaccinees were positive for anti-HBs, while 92% achieved a protective level of antibody (greater than or equal to 10 mIU ml-1) with a geometric mean titre of 2568 mIU ml-1. Females responded better than males. Antibody responses declined with increasing age in both sexes, but they were not significantly influenced by body weight. Persistence of antibody in responders was followed over 4 years. The proportion of responders maintaining greater than or equal to 10 mIU ml-1 was a function of initial antibody titre but was not significantly affected by sex, age or body weight. Overall, 76% of the responders are estimated to have greater than or equal to 10 mIU ml-1 of anti-HBs 4 years after the first injection of vaccine.