Current Trends Hepatitis B Vaccine: Evidence Confirming Lack of
AIDS Transmission
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
Feorino PM, Kalyanaraman VS, Haverkos HW, et al.
Lymphadenopathy
associated virus infection of a blood donor-recipient pair with
acquired immunodeficiency syndrome. Science 1984;225:69-72.
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. Medical Sci 1980;77:7415-9.
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;218:571-3.
CDC. Update: acquired immunodeficiency syndrome (AIDS) in
persons with hemophilia. MMWR 1984;33:589-91.
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;311:1030-2.
ACIP. Inactivated hepatitis B virus vaccine. MMWR
1982;31:317-22, 327-8.
CDC. Adult immunization: recommendations of the Immunization
Practices Advisory Committee (ACIP). MMWR 1984;33:1S-68S.
ACIP. Post-exposure prophylaxis of hepatitis B. MMWR
1984;33:285-90.
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