Granulocyte Macrophage Colony–Stimulating Factor as an Adjuvant
for Hepatitis B Vaccination of Healthy Adults
Muhammad S. Hasan,1Jan M. Agosti,2
Kara K. Reynolds,1Esther Tanzman,1John J. Treanor,1
and Thomas G. Evans1
1Infectious Diseases Unit and Department of Medicine, University
of Rochester School of Medicine and Dentistry, Rochester, New York;
2Immunex Corp., Seattle, Washington
Granulocyte macrophage colony–stimulating factor (GM-CSF) has shown promise as an
adjuvant to improve the kinetics and magnitude of the immune response after vaccination.
It was hypothesized that GM-CSF given intramuscularly (IM) with hepatitis B vaccine would
result in increased seroconversion rates and antibody titers. In total, 108 healthy volunteers
(18–45 years old) received recombinant hepatitis B vaccine IM at 0, 1, and 6 months and were
randomized to receive either concurrent GM-CSF (80 or 250 mg) or placebo IM with the first
two vaccinations. The percentages of subjects achieving a protective level of antibody at day
56 were 58.3%, 58.8%, and 58.3% in the placebo and 80- and 250-mg GM-CSF arms, respec-
tively. The geometric mean titers of antibody measured on days 28, 56, and 189 were not
statistically different between arms. GM-CSF given immediately before recombinanthepatitis
B vaccination was safe and well tolerated but did not appear to provide significant adjuvant
activity at this dose.
Hepatitis B is a serious worldwide infection that is mostly
preventable by vaccination. Hepatitis B vaccine given as three
intramuscular (IM) injections at 0, 1, and 6 months results in
∼90% of healthy adults achieving a protective antibody level
of ?10 mIU/mL. The long-term risk of hepatitis B infection is
inversely related to the maximal antibody titer achieved by
vaccination . However, because of many factors, ∼40%–50%
of vaccinees fail to receive the third 6-month injection [2, 3].
The resultant 2-dose regimen induces insufficient antibody to
provide immediate seroprotection (110 mIU/mL) in many
healthy adults and does not result in the high-titer antibody
associated with long-term protection (11000 mIU/mL). Strat-
egies to produce an earlier seroconversion/seroprotection rate
to hepatitis B vaccine would be highly desirable, especially in
those at immediate risk, such as health care workers or sero-
negative sex partners ofseropositivepersons.Studiesperformed
to improve the kinetics of response have included the use of
higher vaccine dose, intradermal administration, anaccelerated
dosing schedule, and a modification of the adjuvant used with
vaccination (currently alum) . Although dozens of new com-
pounds have been investigated for adjuvant activity in animal
Received 19 March 1999; revised 16 June 1999; electronically published
12 November 1999.
All subjects signed a consent form approved by the institutional review
Financial support: Immunex; NIH (RR-00044).
Reprints or correspondence: Dr. Thomas G. Evans, Box 689, 601 Elm-
wood Ave., Rochester, NY 14642 (email@example.com).
The Journal of Infectious Diseases
? 1999 by the Infectious Diseases Society of America. All rights reserved.
and human vaccine trials in the past decade, an increasing
emphasis has been given to the possibility of using specific
cytokines to elicit vaccine responses, rather than using non-
specific formulations that induce these cytokines .
Granulocyte macrophage colony–stimulating factor (GM-
CSF) is a potent vaccine adjuvant for improving both humoral
and cellular immune responses [6, 7]. The potentialmechanisms
of its adjuvant effects are likely on the antigen-presenting cells
(APCs) and include up-regulation of major histocompatibility
class II  and costimulatory molecules, such as B7, and en-
hanced differentiation of precursors into mature dendritic cells
. This last effect is of special interest, since dendritic cells are
critical for responses to neoantigens.
We hypothesized that GM-CSF given in a paracrine fashion
with hepatitis B IM immunization on days 0 and 28 would
achieve a higher rate of seroconversion/seroprotectionaftertwo
immunizations. Long-term immunity secondary to increased
titers of antibody to surface antigen might therefore also be
improved. Thus, a placebo-controlled, double-blinded, ran-
domized trial of the safety and reactogenicity of IM GM-CSF
given locally as an adjuvant for hepatitis B vaccination was
Study drug and dose.
CSF (sargramostim; leukine) or identical placebo diluent was sup-
plied by Immunex. Recombinant hepatitis B vaccine (Recombivax
HB; Merck,West Point, PA) was used at a dose of 10 mg of hepatitis
B surface antigen (HBsAg)/1.0 mL.
Yeast-derived recombinant human GM-
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