MMWR Morbidity and Mortality Weekly Report, December 14, 1984 / 33(49);685-7
Centers for Disease Control and Prevention

Recent studies have provided important additional assurances concerning the safety of hepatitis B (HB) vaccine. The vaccine currently licensed in the United States is produced from pooled plasma of hepatitis B surface antigen-positive individuals, some of whom are also in high-risk groups for acquired immunodeficiency syndrome (AIDS). Concern has been expressed that the etiologic agent of AIDS might be present in the vaccine and survive the inactivation steps used in the manufacturing procedure. The concerns persisted, despite the fact that these steps were reportedly able to inactivate representative members of all known virus groups. The recent identification of a retrovirus as the etiologic agent of AIDS has allowed workers to (1) directly test the inactivation of the AIDS virus by the inactivation steps used in the vaccine manufacturing procedure; (2) look for the AIDS virus' nucleic acid sequences in the vaccine; and (3) look for serologic markers of infection from the AIDS virus in vaccine recipients. Concurrently, monitoring of AIDS patients and high-risk groups has continued in order to look for any epidemiologic evidence of an association between HB vaccine and AIDS.

The effect of the HB vaccine inactivation process on the AIDS virus and two other human retroviruses (HTLV-I and HTLV-II) was studied. Three separate inactivation steps are used in the manufacture of the U.S.-licensed HB vaccine: (1) 1 ug/ml pepsin, pH 2, 37 C (98.6 F), 18 hours; (2) 8 molar urea, 37 C (98.6 F), 4 hours; and (3) 0.01% formaldehyde, 37 C (98.6 F), 72 hours. In separate studies conducted between CDC and the vaccine manufacturer Merck, Sharp & Dohme (MSD), and between State University of New York (SUNY) Upstate Medical Center and MSD, cell culture supernatant fluid containing the AIDS virus and cultured cells containing HTLV-I, HTLV-II, and the AIDS virus were transported to MSD and individually exposed to the three inactivation steps. The materials were then returned to CDC and SUNY for detection of residual viral infectivity. Virus infectivity was assayed by adding the treated material to cultured lymphocytes and periodically monitoring these for signs of viral replication (reverse transcriptase activity and virus antigen expression) (1) and in the case of HTLV-I and HTLV-II, transformation (2,3). No residual virus was detected in material treated with formalin or urea, while material treated with pepsin at pH 2 did have residual virus present. Heat, an inactivation step used in vaccines manufactured outside the United States, has also been shown to inactivate the AIDS virus (4).

The second approach, which attempted to detect AIDS virus-related nucleic acid sequences using dot blot hybridization analysis of the vaccine with an AIDS virus deoxyribonucleic acid (DNA) probe, was done at MSD using as a positive control infected cellular (ribonucleic acid) RNA preparations provided by CDC. The vaccine contained no detectable AIDS virus-related sequences at a sensitivity of less than one picogram of DNA per 20-ug dose of vaccine.

The third approach attempted to detect seroconversion to AIDS virus antibodies in paired sera of HB vaccine recipients. Paired sera were examined at CDC using a highly sensitive and specific ELISA assay for the AIDS virus. No seroconversions were detected in 19 individuals who had received vaccine manufactured from plasma pools that contained plasma of homosexual men. Previous workers have reported that sera of HB vaccine recipients did not show helper-T/supressor-T ratio inversion, a finding common in AIDS patients (5).

Epidemiologic approaches to detect an association between HB vaccine and AIDS have included analysis of data on AIDS cases reported to CDC concerning their receipt of HB vaccine and monitoring rates of AIDS in groups of homosexually active men who did or did not receive HB vaccine in the vaccine trials conducted by CDC in Denver, Colorado, and San Francisco, California. To date, 68 AIDS cases have been reported among approximately 700,000 U.S. HB vaccine recipients; 65 have occurred among persons with known AIDS risk factors, while risk factors for the remaining three are under investigation. In addition, the rate of AIDS for HB vaccine recipients in CDC vaccine trials among homosexually active men in Denver and San Francisco does not differ from that for men screened for possible participation in the trials but who received no HB vaccine because they were found immune to HB. Reported by B Poiesz, MD, R Tomar, MD, B Lehr, J Moore, PhD, State University of New York Upstate Medical Center, Syracuse Veterans Administration Medical Center, Syracuse, New York; Merck, Sharp & Dohme Research Laboratories, West Point, Pennsylvania; AIDS Br, Hepatitis Br, Div of Viral Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The Immunization Practices Advisory Committee (ACIP) (6) has recommended preexposure HB vaccination for susceptible members of the following groups in the United States: health-care workers (medical, dental, laboratory, and support groups) judged to have significant exposure to blood or blood products; clients and selected staff of institutions for the mentally retarded; hemodialysis patients; homosexually active males; users of illicit, injectable drugs; recipients of certain blood products (patients with clotting factor disorders); and household and sexual contacts of HB virus (HBV) carriers. In addition, vaccine may be warranted for classroom contacts of deinstitutionalized mentally retarded HBV carriers; special high-risk populations (Alaskan Eskimos and immigrants and refugees from areas with highly endemic disease); inmates of long-term correctional facilities; and some U.S. citizens living or traveling abroad (7). The ACIP has also recommended screening all pregnant women belonging to high-risk groups for HB and treating their newborn infants with hepatitis B immune globulin and HB vaccine (8).

HB vaccine acceptance in the United States has been seriously hindered by the fear of possible AIDS transmission from the vaccine. The recent identification of AIDS' etiologic agent has made possible direct laboratory measurement of virus inactivation, nucleic acid presence, and serologic evidence of infection. These studies were unable to detect the AIDS virus' viral protein or nucleic acid in the purified vaccine product and clearly indicate that if virus were present, it would be killed by the manufacturing procedures. In addition, epidemiologic monitoring of AIDS cases and high-risk groups confirms the lack of AIDS transmission by HB vaccine. This information should remove a major impediment to vaccine use.

References

1. Feorino PM, Kalyanaraman VS, Haverkos HW, et al. Lymphadenopathy associated virus infection of a blood donor-recipient pair with acquired immunodeficiency syndrome. Science 1984 Jul 6;225(4657):69-72.

2. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980 Dec;77(12):7415-9.

3. Kalyanaraman VS, Sarngadharan MG, Robert-Guroff RM, et al. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science 1982 Nov 5;218(4572):571-3.

4. CDC. Update: acquired immunodeficiency syndrome (AIDS) in persons with hemophilia. MMWR October 26, 1984 / 33(42);589-91.

5. Jacobson IM, Dienstag JL, Zachoval R, Hanrahan BA, Watkins E, Rubin RH. Lack of effect of hepatitis B vaccine on T-cell phenotypes. N Engl J Med 1984 Oct 18;311(16):1030-2.

6. Recommendation of the Immunization Practices Advisory Committee (ACIP) Inactivated Hepatitis B Virus Vaccine. MMWR June 25, 1982 / 31(24);317-22,327-8.

7. CDC. Adult immunization: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1984;33:1S-68S.

8. Recommendation of the Immunization Practices Advisory Committee (ACIP) Postexposure Prophylaxis of Hepatitis B. MMWR June 01, 1984 / 33(21);285-90.

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