Hepatitis B immune globulin (HBIG) has been used in certain defined circumstances. These include: needle-stick or mucous membrane exposures in susceptible individuals with blood from an HBsAg positive individual, and in conjunction with hepatitis B vaccine for a newborn whose mother either has contracted active hepatitis B during pregnancy or is a chronic HBV carrier. HBIG is prepared from the plasma of individuals known to have circulating anti-HBsAg. This commercial product contains approximately 1 to 2x104 times more of this specific antibody than ISG, and therefore is preferred in the immunoprophylaxis of hepatitis B.
The search for a successful vaccine against hepatitis B began in the late 1960s. Krugman and co-workers demonstrated that infective serum (strain MS-2), containing HBV diluted 1:10 in distilled water and heated to 98°C for one minute, prevented or modified the disease in approximately 70 percent of susceptible individuals. The MS-2 serum contained large quantities of hepatitis B surface antigen (HBsAg). Much of the subsequent work focused on the extraction and purification of this non-infectious, viral coat protein for use as the vaccine preparation. This effort was fostered by the observation that replication of hepatitis B virus in infected individuals was not nearly as efficient as the large amounts of excess coat proteins synthesized and passed into the circulation. As patients recovered from viral infection, antibodies to this antigen (anti-HBs) appeared and were protective against recurrent viral attack.
Accumulated evidence also indicated that these HBsAg forms are present in high concentration in carriers of hepatitis B. Thus, carriers with high serum HBsAg titers were originally shown to provide a supply of viral antigen for the production of the first commercially available form of the vaccine. This achievement was crucial to the overall effort, because hepatitis B virus has not yet been routinely cultured in vitro.
Ultracentrifugation was found to be a very effective means for large-scale isolation of HBsAg from asymptomatic hepatitis B carriers. Additional chemical treatment of the isolated surface proteins with the enzyme pepsin, concentrated urea, and formalin was designed to inactivate any residual HBV particles or particles of any other possible virus, and to remove any residual traces of plasma protein as well. These measures produced a vaccine suitable for administration to human beings.
With refinement of the original vaccine (addition of alum as an adjuvant to increase vaccine immunogenicity), it became apparent that an effective prophylactic weapon had been developed. One of the clinical trials with this vaccine assessed its efficacy in a placebo-controlled, randomized, double blind study in 1983 with homosexual men known to be at high-risk for hepatitis B. The vaccine was found to induce high titers of anti-HBs in injected persons (77 percent after primary dose, 96 percent after booster). Of prime importance was the observation that during an 18-month follow-up interval, 18 to 27 percent of the placebo recipients developed clinical or subclinical hepatitis B while only 1.4 to 3.4 percent of the HBsAg-vaccinated subjects did so.
Heptavax-B, the vaccine (Merck and Company), was released for commercial use in 1982. This preparation is a sterile suspension for intramuscular injection. Each 1.0 ml dose of vaccine contains 20 µg of hepatitis B surface antigen formulated in an alum adjuvant, and thimerosal (a mercury derivative) 1:20,000 as a preservative. It was used for immunization against all known subtypes of hepatitis B virus, but did not prevent infection caused by hepatitis A, hepatitis C, or hepatitis E viruses. Subsequent infection with HDV was prevented, however, as hepatitis D cannot develop in individuals who are protected from hepatitis B infection.
The preparation is given in a regimen of three 1.0 ml intramuscular doses. The second and third doses followed one and six months, respectively, after the first. No serious side effects have been attributed directly to parenteral injection of the vaccine. Mild, short-term effects include soreness at the injection site, fever, flu-like symptoms and general malaise. With the development, approval, and marketing of second generation hepatitis B vaccines which do not use plasma from HBV carriers, the original Heptavax-B is currently available only in limited amounts and is reserved for patients with specific medical conditions.
Recombinant (Single-Antigen) DNA Vaccines
The first clinical vaccine prepared using recombinant (produced from a cloned gene) DNA technology was licensed in 1986, and made available for general use in 1987. Recombivax HB (Merck and Company) was developed initially as a newer vaccine to provide an alternative to the plasma-derived vaccine.
This preparation is produced in cultures of Saccharomyces cerevisiae (common baker's yeast), into which a plasmid containing the gene for HBsAg has been inserted. HBsAg is subsequently harvested after lysis of cultured yeast cells. Administered vaccine is designed to contain 10 micrograms (µg) of HBsAg protein per milliliter, absorbed with 0.5 milligrams per ml of aluminum hydroxide (alum), with thimerosal as a preservative.
The immunogenicity of Recombivax HB is comparable to that observed for the plasma-derived preparation. In 1989 Smith, Kline, Beecham received a license in the U.S. for their Engerix-B vaccine. The major difference between the products is the number of steps used in recovery and purification of the antigen from the yeast cultures, which results in different dosage amounts. Both vaccine preparations provide adequate immunity. Table 1includes a chart of the recommended dosage and timeline for receiving the Hepatitis B vaccines.
Combination vaccines have been developed that combine an HBV vaccine with other vaccines. The Comvax, Pediarix, and Twinrix combination vaccines have been combined with other vaccines to reduce the number of injections for infants and children. See Table 1 for recommended dosages and timelines.