Current Trends Hepatitis B Virus Vaccine Safety: Report of an Inter-Agency Group

On June 25, 1982, the Immunization Practices Advisory Committee (ACIP) recommended using inactivated hepatitis B virus (HBV) vaccine for individuals who are at high risk for HBV infection because of their geographic origins, life styles, or exposures to HBV at home or work (1). The recommendations included statements on vaccine efficacy and safety. However, requests for additional information on safety continue to be received, primarily because of the plasma origins of the antigen used to prepare the vaccine. In response to these requests, the Inter-Agency Group to Monitor Vaccine Development, Production, and Usage, with representatives from the Centers for Disease Control (CDC), Food and Drug Administration (FDA), and National Institutes of Health (NIH), has further reviewed the available data. Its conclusions on vaccine production and safety evaluation follow.

HBV vaccine licensed in the United States is prepared from human plasma containing hepatitis surface antigen (HBsAg) (2). Hypothetical side effects from the vaccine include reactions to blood substances or to infectious agents present in donor plasma. In trials involving approximately 1,900 persons, reactions among vaccine recipients were compared with reactions among placebo recipients, and only minor immediate complaints, primarily of soreness at the injection site, were observed (3,4). Infectious agents that might be present in donor plasma are most likely to be viruses. Virus transmission by blood or blood products requires the virus to circulate in plasma or in cellular elements such as leukocytes. The chance of virus transmission increases with the duration of the viremic state. HBV is the only well-characterized extra-cellular human virus with a prolonged carrier state. Other agents, presumably viruses, which remain unidentified despite their common association with post-transfusion hepatitis, are responsible for non-A/non-B hepatitis.

Beginning in 1978, a disease or group of diseases was recognized, manifested by Kaposi's sarcoma and opportunistic infections, associated with a specific defect in cell-mediated immunity. This group of clinical entities, along with its specific immune deficiency, is now called acquired immune deficiency syndrome (AIDS). The epidemiology of AIDS suggests an unidentified and uncharacterized blood-borne agent as a possible cause of the underlying immunologic defect (5-7). Because AIDS occurs among populations that are sources of HBV-positive plasma, this syndrome should be considered in regard to the inherent safety of HBV vaccine.

Vaccine plasma donors are screened, and only healthy individuals (HBsAg positive) are selected. The plasmapheresis centers are licensed and inspected by the FDA. A physician gives each donor a complete physical examination, which includes a history and suitable laboratory tests. At the time of each donation, the donor's hemoglobin, hematocrit, and serum protein levels must be within normal limits. HBsAg-positive donors' levels of serum aminotransferase activity are permitted to exceed those limits set for otherwise healthy donors, but they must be stable.

The process for producing each lot of licensed HBV vaccine is designed to remove or inactivate infectious HBV and other viruses from the desired immunogen, the 22 nm HBsAg particle. The process relies on both biophysical elimination of infectious particles and treatments which inactivate viruses (pepsin at pH 2, 8M urea, and formalin). The elimination of infectious virus by biophysical purification depends on the density and flotational property of HBsAg in contrast with those of infectious virus particles. The double ultracentrifugation process (isopyknic and rate zonal) has been proven effective in removing 10((4)) infectious doses of HBV/ml, as measured by chimpanzee inoculation (8). Pepsin treatment alone (1 ug/ml, pH 2.0, 37 C for 18 hours) inactivates 10((5)) or more infectious doses of HBV/ml, as measured by chimpanzee inoculation, and has been shown to inactivate viruses in the rhabdovirus, poxvirus, togavirus, reovirus, herpesvirus and coronavirus groups (9,10). Urea treatment alone (8M, 37 C for four hours) inactivates 10((5)) or more infectious doses of HBV/ml and has been shown to inactivate viruses in the rhabdovirus, myxovirus, poxvirus, togavirus, reovirus, picornavirus, herpesvirus, and coronavirus groups (9). Slow viruses, characterized by the viruses of kuru and Creutzfeld-Jakob disease, are inactivated by 6M urea, a lesser concentration than that routinely applied to the HBV vaccine (11). Formalin alone inactivates HBV (9), as well as many other virus groups, including parvoviruses (12), retroviruses (13,14) and the delta agent (15).

Each lot of HBV vaccine is tested for sterility, innocuousness in animals, and pyrogenicity and is free of detectable viruses, as shown by inoculation into both human and monkey cell-culture systems. Additionally, 22 doses of each vaccine lot are inoculated intravenously into four chimpanzees.

United States licensed vaccine (produced by Merck, Sharp, and Dohme) has been given to over 19,000 persons, 6,000 of whom received vaccine between October 1975 and December 1981 and 13,000 of whom received it in 1982. The vaccine has been demonstrated to protect recipients from HBV infection (3,4), and no evidence of hepatitis has been observed as a result of HBV vaccination. Also, studies by CDC, FDA, and others of aminotransferase levels in chimpanzees and humans confirm that HBV vaccine does not transmit the non-A/non-B agent(s).

In three vaccine-placebo trials (two among homosexual men between 1978 and 1980 (3,4) and one among hospital employees in 1981), 549, 714, and 664 persons, respectively, received vaccine, and equal numbers received placebo. Follow-up surveillance of participants in these studies was 24, 15, and 18 months, respectively, after the first dose of vaccine with no cases of AIDS being reported. In addition to the vaccine/placebo trials, 17,602 persons (including 8,94l health-care workers and 5,985 healthy adults, children, and infants from non-high-risk group settings) have received Merck HBV vaccine in various study settings. Periods of follow-up of these vaccine recipients have ranged from a few months to over 7 years. However, lots used in early studies may have been produced before the occurrence of AIDS. Some of the groups from which HBV vaccine is prepared or for which it is recommended are also at high risk for AIDS; therefore reports of AIDS among donors and vaccinees at some future time may be expected on the basis of chance alone.

To summarize, these findings support the ACIP statement on hepatitis vaccine: 1) immediate side effects are minimal after receipt of HBV vaccine; 2) no long-term reactions have been reported; 3) the purification and inactivation process is known to inactivate representatives of all known groups of animal viruses; 4) each lot is safety tested in primates; 5) no known cases of hepatitis B or non-A/non-B hepatitis have been transmitted by the vaccine and no known occurrence of AIDS has been associated with the vaccine. Reported by the Inter-Agency Group to Monitor Vaccine Development, Production, and Usage, represented by the Centers for Disease Control, Food and Drug Administration, and National Institutes of Health.

References

1. ACIP. Inactivated hepatitis B virus vaccine. MMWR 1982;31:317-22, 327-8.

2. Hilleman MR, Buynak EB, McAleer WJ, McLean AA, Provost PJ, Tytell

1. Hepatitis A and hepatitis B vaccines. In: Szmuness W, Alter HJ, Maynard JE, eds. Viral hepatitis, 1981 International Symposium. Philadelphia: Franklin Institute Press, 1982:385-97.

3. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980;303:833-41.

4. Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine: report of the CDC multi-center efficacy trial among homosexual men. Ann Intern Med (In press).

5. CDC Task Force on Kaposi's Sarcoma and Opportunistic Infections. Epidemiologic aspects of the current outbreak of Kaposi's sarcoma and opportunistic infections. N Engl J Med 1982;306:248-52.

6. CDC. Pneumocystis carinii pneumonia among persons with hemophilia

1. MMWR 1982;31:365-7.

7. Fauci AS. The syndrome of Kaposi's sarcoma and opportunistic infections: an epidemiologically restricted disorder of immunoregulation. Ann Intern Med 1982;96:777-9.

8. Gerety RJ, Tabor E, Purcell RH, Tyeryar FJ. Summary of an international workshop on hepatitis B vaccines. J Infect Dis 1979;140:642-8.

9. Tabor E, Buynak E, Smallwood LA, Suoy P, Hilleman M, Gerety RJ. Inactivation of hepatitis B virus by three methods: treatment with pepsin, urea, or formalin. J Med Virol (In press).

10. Buynak EB, Roehm RR, Tytell AA, Bertland AU, Lampson GP, Hilleman MR. Development and chimpanzee testing of a vaccine against human hepatitis B. Proc Soc Exp Biol Med 1976;151:694-700.

11. Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977;197:943-60.

12. Eugster AK. Studies on canine parvovirus infections: development of an inactivated vaccine. Am J Vet Res 1980;41:2020-4.

13. Gross L. Oncogenic viruses. New York: Pergamon Press, 1961

14. Walker JF. Formaldehyde, 3rd ed. Huntington, NY: Krieger, 1975:395-404, 601-3.

15. Purcell, R. Unpublished data.

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