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Infection and Immunity, November 2001, p. 6696-6701, Vol. 69, No. 11
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.11.6696-6701.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Effects of Alum Adjuvant or a Booster Dose on Immunogenicity
during Clinical Trials of Group B Streptococcal Type III
Conjugate Vaccines
L. C.
Paoletti,1,*
M. A.
Rench,2
D. L.
Kasper,1
D.
Molrine,3,
D.
Ambrosino,3, and
C.
J.
Baker2
Channing Laboratory, Brigham and Women's
Hospital,1 and Children's Hospital
Medical Center,3 Harvard Medical School, Boston,
Massachusetts 02115, and Baylor College of Medicine, Houston,
Texas 770302
Received 18 April 2001/Returned for modification 3 July
2001/Accepted 1 August 2001
 |
ABSTRACT |
Phase 1 and 2 clinical trials of group B streptococcal (GBS)
capsular polysaccharide (CPS)-protein conjugate vaccines in healthy adults have demonstrated their safety and improved immunogenicity compared with uncoupled CPSs. Two recent trials sought to determine (i)
whether adsorption of conjugate vaccine to aluminum hydroxide would
improve immunogenicity and (ii) whether the CPS-specific immunoglobulin
G (IgG) response could be boosted by administration of a second dose.
Adsorption of GBS type III CPS-tetanus toxoid (III-TT) conjugate
vaccine to alum did not improve the immune response to a 12.5-µg dose
in healthy adult recipients. Four weeks after vaccination, the
geometric mean antibody concentrations (GMCs) for the 15 recipients of
III-TT with or without alum were 3.3 and 3.6 µg/ml, respectively. In
the second trial, 36 healthy adults vaccinated previously with GBS
III-TT conjugate were given a second 12.5-µg dose 21 months later. At
4 weeks after the second dose, the GMCs of type III CPS-specific IgG
were similar to those measured 4 weeks after the primary vaccination,
suggesting a lack of a booster response. However, 8 (22%) of the 36 participants who had undetectable III CPS-specific IgG (<0.05 µg/ml)
before the first dose of III-TT conjugate exhibited a booster response to the second dose, with a fourfold-greater GMC of type III
CPS-specific IgG than after the initial immunization. These results
suggest that prior natural exposure to type III GBS or a related
antigen may be responsible for the brisk IgG response to CPS noted in most adults after vaccination. However, a second dose of GBS III-TT conjugate vaccine may be required for adults whose initial CPS-specific IgG concentrations are very low and would also restore the initial peak-specific III CPS-IgG in responders to previous vaccination.
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INTRODUCTION |
Improved vaccines against group B
streptococci (GBS) have been developed by covalent coupling of variably
immunogenic capsular polysaccharide (CPS) antigens to immunogenic
protein carriers (13). Phase 1 and 2 clinical trials in
healthy, nonpregnant adults have shown that capsular types Ia, Ib, II,
and III (1, 2, 9) and type V (L. C. Paoletti, C. J. Baker, and D. L. Kasper, Abstr. First Annu. Conf. Vaccine Res.,
abstr. P16, 1998) GBS conjugate vaccines are well tolerated and
have superior immunogenicity to uncoupled, homologous polysaccharides.
Serotype-specific antibodies elicited by these conjugate vaccines are
primarily of the immunoglobulin G (IgG) class, are active in promoting
opsonization for killing of homologous GBS by human peripheral blood
neutrophils in vitro, and prevent lethal GBS infection in newborn mice
treated before challenge (15).
With these principles established, research has focused on ways of
further improving immune responses to GBS conjugate vaccines. Each of
the monovalent conjugate vaccines tested to date elicit a rise in
CPS-specific IgG concentrations 2 weeks after administration of a
single dose without adjuvant; peak concentrations are achieved 4 to 8 weeks postimmunization (1, 2, 9). These results support
the hypothesis that maternal vaccination with GBS conjugates administered early in the third trimester would elicit specific antibodies available for placental transport and at concentrations capable of preventing invasive GBS infection in neonates and young infants (2). Alternatively, vaccination of women of
childbearing age might benefit future offspring if antibody
concentrations remained at protective levels for several years. Both
vaccination scenarios involve placental transfer of GBS-specific IgG to
provide protection to the young infant and require that maternal
GBS-specific IgG concentrations be higher than those potentially
suitable for protection in a single nonpregnant adult. Two doses of
vaccine may therefore be necessary, particularly if nonpregnant women are the chosen target population and there is a long time lapse between
vaccination and pregnancy or if there is a failure or a low response to
primary vaccination.
On the basis of the observed improvement in CPS-specific IgG response
in mice (8) and nonhuman primates (12)
vaccinated with GBS conjugate vaccines adsorbed with alum, we
hypothesized a heightened response in healthy adults given a GBS
conjugate vaccine adsorbed to alum. If successful, alum would serve to
reduce the effective dose of both vaccine components, particularly that of the carrier protein, which could be at prohibitively high
concentrations if a multivalent GBS vaccine is formulated based on the
most immunogenic dose (~60 µg) of polysaccharide (1, 2,
9).
Another method of improving immune response could be administration of
a second dose. Support for the hypothesis that a second dose would
provide a booster response was reported for baboons in which a
heightened antibody response was observed after each of three doses of
GBS type III polysaccharide-tetanus toxoid conjugate (III-TT)
administered with alum, suggesting induction of a memory response upon
repeat vaccination (12). However, in a previous study,
healthy nonpregnant women of childbearing age who received a primary
dose of GBS III-TT vaccine without alum and a dose of uncoupled type
III CPS 2 months later failed to show an improved type III CPS-specific
IgG response (C. M. Mink, H.-K. Guttormsen, K. R. Lottenbach,
J. C. Cannon, L. C. Paoletti, P. McInnes, and D. L. Kasper, Abstr. 35th Intersci. Conf. Antimicrob. Agents Chemother., abstr. G6, 1995).
We present the results of two clinical trials with healthy, nonpregnant
adults that sought to address these questions. The first study examined
the effect of alum adjuvant on the immune response to GBS III-TT
conjugate vaccine. The second study determined the effect of two doses
of GBS III-TT conjugate vaccine separated by a nearly 2-year interval,
since we hypothesized that a second dose of GBS III-TT conjugate
vaccine would serve to restore or improve III CPS-specific IgG
concentrations achieved after the primary dose.
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MATERIALS AND METHODS |
Vaccines.
GBS III-TT vaccine lots 1-1-95 and 3-1-96 were
prepared according to good manufacturing practices at The Salk
Institute, Swiftwater, Pa., by using CPS purification, conjugation, and
conjugate vaccine purification methods described in detail elsewhere
(9). The degree of sialic acid oxidation of type III CPS
used to prepare the vaccines was 32 and 30%, respectively. Purified
III-TT vaccines were lyophilized in multidose vials with sucrose
excipient. GBS III-TT lot 1-1-95 was composed of 61% (wt/wt) CPS and
39% protein; therefore, a 50-µg CPS dose contained 32 µg of TT.
Lot 3-1-96 was composed of 44% (wt/wt) CPS and 56% (wt/wt) protein;
therefore, a 12.5-µg CPS dose contained 15.9 µg of TT. Purified TT
used as the carrier protein for both lots of vaccine was purchased from the Massachusetts Public Health Laboratory, Jamaica Plains, Mass. Both
lots of GBS III-TT passed tests for general safety, microbial sterility, and pyrogenicity as required by the Food and Drug
Administration (FDA).
Adsorption studies.
Aluminum hydroxide gel in 0.9% saline
(alum) was prepared for the National Institutes of Health at the
Massachusetts Biologic Laboratories, University of Massachusetts
Medical School, Jamaica Plains, under good manufacturing
practices using Alhydrogel 1.3% (aluminum hydroxide gel
adjuvant manufactured by Superfos Biosector a/s, Vedbæk, Denmark) as
the starting material. The elemental aluminum concentration in the
vialed alum was 500 µg/ml, and vials were maintained at 2 to 8°C.
Alum passed tests for general safety, microbial sterility, and
pyrogenicity as required by the FDA.
Complete adsorption of the III-TT vaccine by the alum preparation was
ensured by mixing a series of five tubes containing 0.6 ml of III-TT
vaccine lot 1-1-95 reconstituted with 0.45% saline plus 0.01%
thimerosal with 0.6 ml of alum to a final CPS concentration of 12.5 µg/0.5 ml. A second set of tubes was prepared to test the adsorption
of alum to III-TT at a final CPS concentration of 3.125 µg/0.5 ml.
Tubes were incubated at room temperature (25°C) for 30 min and then
processed immediately or stored at 2 to 8°C for 1, 2, 4, or 7 days.
Control tubes that contained 0.9% saline instead of alum were treated
similarly. The solutions were clarified by centrifugation (13,600 × g) for 4 min at room temperature, and supernatant fluids
were collected and further clarified by a second centrifugation. The
amount of type III CPS and TT remaining in solution (i.e., not
absorbed) was measured by inhibition enzyme-linked immunosorbent assays
(ELISAs) specific for each component. The type III CPS inhibition ELISA
was performed as follows. Supernatant fluids from the adsorbed and
nonadsorbed vaccines were serially diluted threefold on a microtiter
plate. A standard curve was prepared with GBS type III CPS serially
diluted twofold starting at 625 ng/ml. Standard rabbit reference serum
raised to III-TT vaccine was diluted 1:100,000, and 60 µl was added
to all wells except blank control wells. Supernatant-antibody mixture
(100 µl) was transferred to microtiter plates coated with 0.1 µg of GBS type III CPS-poly-L-lysine per well and
allowed to react for 1 h at 37°C. The plates were washed three
times, and 100 µl of goat anti-rabbit IgG (gamma and light
chains)-alkaline phosphatase conjugate, diluted 1:3,000, was added to
each well for 1 h at 37°C; the plates were then washed again
three times before the addition of 200 µl of substrate solution
(Sigma 104 substrate tablets; 1 mg/ml). The plates were incubated at
37°C for 75 min in the dark, and the absorbance values at 405 nm were
measured. The concentration of type III CPS that resulted in the
inhibition of 50% (IC50) of antibody binding was
determined from the linear portion of the standard curve. The dilution
of the adsorbed and nonadsorbed samples that resulted in an
IC50 was determined. The amount of type III CPS
in the supernatant fluid was calculated by multiplying the type III CPS
IC50 by the reciprocal of the dilution of test
sample that resulted in the IC50. The percent adsorption was calculated as follows: [1 
(amount of adsorbed type III CPS divided by the amount of nonadsorbed type III CPS)] × 100. The same methods were used to measure the amount of TT in solution
except that the standard curve was prepared with TT serially diluted
twofold starting at a concentration of 25 µg/ml, and TT-specific
rabbit serum was used at a 1:10,000 dilution.
Study designs.
Data from two separate phase 1 clinical
trials are presented. These studies were approved by the Institutional
Review Board for Human Subject Research at Baylor College of Medicine,
Houston, Tex., and at Children's Hospital, Boston, Mass. The first
trial, performed in Boston and Houston, was designed to determine the safety and effect of alum adsorption on the immunogenicity of III-TT
lot 1-1-95. For this trial, 60 healthy nonpregnant adults, ages 18 to
50 years, were randomized into four groups (n = 15 per
group) to receive 0.5 ml of GBS III CPS intramuscularly at one of the
following CPS doses: 50 µg without alum, 12.5 µg with alum, 12.5 µg without alum, or 3.125 µg with alum. Blood was obtained before
and 4 weeks after vaccination. These 60 volunteers included 33 women
and 27 men; 39 were white, 9 were Hispanic, 8 were black, 3 were Asian,
and 1 was other or unknown.
The second trial performed in Houston was designed to assess the safety
of and immune response to a second dose of GBS III-TT
vaccine.
Thirty-six healthy adults (24 to 49 years of age), vaccinated
21 months
previously with 12.5 µg of III-TT lot 3-1-96 either
alone or in
combination with a GBS type II CPS-TT conjugate vaccine,
received a
second dose of 12.5 µg of III-TT lot 3-1-96. Adjuvant
was not used in
this trial. There were 21 women and 15 men; 21
were white, 8 were
Asian, 4 were black, and 3 were Hispanic. Blood
was obtained before and
at 4, 8, and 26 weeks after subjects received
the primary dose of GBS
III-TT and before (21 months after the
first dose) and at 4, 8, and 20 weeks after they received the
second
dose.
For assessment of reactogenicity and safety in the alum trial, subjects
and study personnel, except for the nurse administering
the vaccine
injections, were blinded to vaccine group assignment.
The second dose
study of GBS III-TT conjugate vaccine was of open-label
design. Study
personnel in the clinic observed volunteers for
15 to 30 min after
vaccination. Subjects in the first trial were
instructed regarding the
completion a vaccine diary form, how
to record oral temperature, and
regarding the occurrence of systemic
symptoms or injection site
symptoms or signs daily for 8 days.
For the second trial, the vaccine
diary was completed for 3 days
unless symptoms existed, which were
monitored until resolution.
Any volunteer with a temperature of
>100.0°F or with grade 3 symptoms
within 48 h of vaccination
came to the clinic for examination
by a study
physician.
Quantification of antibody in serum.
GBS type III
CPS-specific IgG in sera from all subjects was measured by an ELISA as
described previously (7). TT-specific IgG was quantified
by ELISA. Microtiter plates were coated with 2 µg of TT (lot
M1A-A305; Massachusetts Biologic Laboratories, Jamaica Plains,
Mass.)/ml. The ELISA was standardized by using a reference plasma pool
with an assigned TT-specific IgG concentration of 31.2 µg/ml.
Fourfold serial dilutions were performed on each serum sample. After
overnight incubation at 4°C, plates were washed with
phosphate-buffered saline (PBS)-0.05% Tween 20, and mouse anti-human
IgG-alkaline phosphatase conjugate (Southern Biotechnology Associates,
Birmingham, Ala.) was added followed by p-nitrophenyl phosphate substrate (Sigma Diagnostics, St. Louis, Mo.) to detect TT-specific antibody. The reaction was stopped with 1 M NaOH, and
optical densities were measured at 405 nm on a Vmax Microplate Reader
(Molecular Devices, Sunnyville, Calif.).
Statistical methods.
Comparison of antibody data was
performed using two-tailed paired and unpaired t tests on
log-transformed data and Mann-Whitney U tests by using Statview,
version 5.0.1 (SAS Institute, Inc., Cary, N.C.).
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RESULTS |
Adsorption of alum to GBS III-TT vaccine.
Alum preparation at
a concentration of 500 µg of completely (100%) adsorbed III-TT
vaccine lot 1-1-95/ml (Fig. 1) at CPS
concentrations of 25 and 6.25 µg/ml. Both vaccine components were
adsorbed by the alum preparation within 30 min and remained completely
adsorbed over 7 days at 2 to 8°C.
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FIG. 1.
Adsorption of alum to GBS III-TT vaccine. Inhibition of
GBS type III-specific antibody binding to type III CPS-coated
microtiter plates by 12.5 µg of III-TT lot 1-1-95 incubated with
( ) or without ( ) alum. These data were obtained after 1 day of
adsorption and are representative of adsorption measured at each
time point tested.
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Safety and immunogenicity of GBS III-TT adsorbed to alum.
The
GBS III-TT conjugate vaccine was well tolerated by healthy adults
(Table 1). There were no
vaccine-associated systemic symptoms. Most (>86%) recipients,
regardless of the dose received or the presence of alum, experienced
mild or no pain at the injection site and no redness or swelling at the
injection site.
The immune responses of volunteers to GBS III-TT conjugate vaccine in
the presence or absence of alum are summarized in Table
2. The geometric mean concentration (GMC)
of GBS type III CPS-specific
IgG in preimmunization sera from each of
the four groups of volunteers
was similarly low and rose significantly
4 weeks following a single
dose of GBS III-TT conjugate vaccine
(
P < 0.001). The GMCs in
sera from the 15 recipients
of a 12.5-µg dose of III-TT with alum
did not differ
(
P = 0.95) from the GMCs in the sera from recipients
of
the same vaccine dose without adjuvant. A dose response to
the vaccine
was noted, with recipients of the 50-µg dose administered
without
alum achieving the highest postimmunization GBS III CPS-specific
IgG
concentrations in serum and recipients of the 3.12-µg dose
with alum
having the lowest.
The immune responses of subjects to the tetanus carrier protein in the
GBS III-TT conjugate vaccine are shown in Table
3.
The TT-specific IgG in sera from each
of the 60 III-TT conjugate
vaccine recipients increased substantially 4 weeks after vaccination.
Alum did not augment the immune response to
this carrier protein;
the GMCs of TT-specific IgG were similar in the
sera of recipients
of the 12.5-µg dose with or without alum
(
P = 0.089). The highest
TT-specific IgG GMCs were
elicited in recipients of the highest
TT dose and, conversely, the
lowest GMCs were found in sera from
recipients of the lowest TT dose.
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TABLE 3.
Immune response of healthy adults to the protein carrier
in GBS III-TT conjugate vaccine in the absence or presence of aluminum
hydroxide
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Safety and immunogenicity of two doses of GBS III-TT vaccine.
GBS III-TT conjugate vaccine was well tolerated by the 36 adults given
two doses separated by an interval of 21 months (Table 1). One subject
developed an oral temperature of 100.4°F associated with chills,
malaise, and headache 18 h after receiving the first dose of GBS
III-TT conjugate combined with GBS II-TT. These symptoms completely
resolved within 10 h of onset. This patient reported no systemic
symptoms upon receiving a second dose of vaccine. None of the other 35 volunteers reported vaccine-associated systemic symptoms with the first
or second doses. The majority (58.3%) of recipients of the first dose
of GBS III-TT conjugate vaccine experienced no or mild pain, and 94.4%
had no redness or swelling at the injection site (Table 1). After the
second dose, 80.6% had no or mild pain, and 91.7% had no redness or
swelling at the injection site.
Table
4 summarizes the immune response
after the first and second doses of GBS III-TT conjugate vaccine in the
36 adult volunteers.
The GMC of type III CPS-specific IgG increased
significantly from
0.21 µg/ml before vaccination to a peak of 9.3 µg/ml 2 months
after the first dose. Twenty-one months later and
before subjects
had received the second dose of vaccine, the GMC fell
to 2.8 µg/ml.
One month after the second dose of III-TT, the type III
CPS-specific
IgG GMC increased threefold, from 2.8 to 8.4 µg/ml
(
P < 0.0001).
The GMCs of 9.3 µg/ml achieved 2 months after the first vaccine
dose and of 7.8 µg/ml achieved after
the second vaccine dose,
respectively, were similar (
P = 0.32). However, an improved immune
response after a second dose of
vaccine was observed in eight
(22%) of the 36 recipients of III-TT
conjugate vaccine. For these
eight individuals, the type III
CPS-specific IgG in their preimmunization
sera was below the lower
limit of detection (<0.05 µg/ml) (Table
5). In these individuals, the
preimmunization GMC rose from below
the level of detection (i.e., 0.05 µg/ml) to 1.4 µg/ml 2 months
after the first vaccine dose.
Twenty-one months later, the GMC
was 0.5 µg/ml, and the GMC increased
to 4.2 µg/ml 1 month after
a second dose of III-TT conjugate vaccine
(Table
5). This latter
value was 300% higher than the peak GMC
achieved after the primary
vaccine dose (
P = 0.008)
(Fig.
2). In contrast, sera from the
remaining 28 subjects whose sera had >0.05 µg/ml of type III
CPS-specific
IgG before the subjects had received an initial vaccine
dose had
a GMC of 0.37 µg/ml before and 16 µg/ml after their first
vaccine
dose (Table
5). One month after their second dose of III-TT
vaccine,
the GMC for this group was 10.3 µg/ml, a concentration lower
(
P = 0.05) than the GMC at 1 month after administration
of the primary
vaccine dose (Table
5 and Fig.
2).
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TABLE 5.
Immune response of healthy adults to two doses of GBS
III-TT conjugate vaccine by preimmunization status
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FIG. 2.
Immune response in healthy adults to two doses of GBS
III-TT conjugate vaccine. The data presented are the percentages of
peak type III CPS-specific GMCs elicited after the first dose in 28 of
36 subjects with prevaccination concentrations of type III CPS-specific
IgG of >0.05 µg/ml ( ) and in 8 subjects with prevaccination
concentrations of <0.05 µg/ml ().
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| |
DISCUSSION |
The most cost-effective and potentially lasting method of
preventing invasive group B streptococcal infections in all age groups
is active immunization (11). The decline in the incidence of early-onset GBS disease in neonates that has been associated with
the widespread use of maternal intrapartum antibiotic prophylaxis could
also be associated with the emergence of antibiotic-resistant organisms
(4, 16, 18). Phase 1 and phase 2 trials in healthy adults
have tested conjugate vaccines for the five serotypes of GBS that
account for an estimated 98% of invasive disease cases in the United
States. Further, successful preclinical studies of GBS types VI and
VIII conjugate vaccines (serotypes prevalent thus far only in Japan
[10]) suggest the ability, if necessary, to extend
vaccine coverage (14).
Vaccines against invasive GBS disease must be safe and sufficiently
immunogenic to evoke protective, and durable, concentrations of
GBS-specific antibodies. As a prelude to examining potential target
populations for these vaccines, we examined the effect of alum adjuvant
or a second dose of GBS III conjugate vaccine in healthy adults.
Whether GBS conjugate vaccines are administered to women before or late
in pregnancy to prevent maternal and infant infections, to healthy
adults older than 65 years of age, or to those with defined underlying
medical conditions (18), information regarding conditions
that would optimize immune response to vaccination is needed.
Adsorption of aluminum hydroxide gel to GBS III-TT conjugate vaccine at
levels exceeding 80% as recommended by the World Health Organization
(6) did not enhance the immune response of healthy adults
to either the CPS or the tetanus component of the vaccine. This result
was unexpected based on previous experiments demonstrating anamnestic
responses in mice and baboons given GBS III-TT conjugate with alum
(8, 12). With baboons, the presence of alum was required
for immunogenicity, with the III CPS-specific IgG response after each
of three doses exceeding that after the previous dose (12). Unlike mice and baboons, adults vaccinated with GBS
III-TT conjugate were not immunologically naive to tetanus. Each had received a primary series of TT during infancy, with periodic booster
doses, but none in the 12 months prior to study enrollment. The
concentrations of TT-specific IgG in serum before vaccination with GBS
III-TT conjugate ranged from 5 to 310 µg/ml, confirming immune
priming to the carrier protein. Priming mice with carrier protein
before administration of a conjugate vaccine can either augment or
suppress immune response (17); perhaps the latter effect
explains the lack of adjuvant effect of alum in our study population. A
recent study with children of an 11-valence pneumococcal conjugate
vaccine with both diphtheria and TT as carrier proteins also found that
alum had no significant effect on immunogenicity (21).
Despite the effectiveness of aluminum-based adjuvants in improving
immune response to toxoids (6) and the mechanism described
to explain its potent effect in vivo (20), little information exists regarding the effect of alum adjuvant on the immunogenicity of conjugate vaccines.
Although multiple doses of conjugate vaccines have been administered to
children, there are few studies of this design have been conducted with
adults. In one study of healthy adults who received multiple doses of
Pseudomonas aeruginosa type 5 O-polysaccharide-toxin A
conjugate vaccine, responses to O-polysaccharide antibody were not
boosted, although improved responses to toxin A were stimulated (3). In contrast, significantly higher geometric mean
Haemophilus influenzae type b CPS-specific IgG
concentrations were noted after a second dose of H. influenzae type b conjugate vaccine in a study with adult patients
undergoing bone marrow transplantation (5). These
differences in response may be related to the immunocompromised state
of the host.
In our study, a second dose of GBS III-TT vaccine restored specific
antibody levels to those obtained after the primary vaccination. The
ability of a second dose to augment the immune response was apparent
only in the minority of healthy adults who had very low concentrations
(<0.05 µg/ml) of CPS-specific IgG. In this group, the second dose
resulted in specific IgG GMC that was threefold higher than that
obtained after a single dose. Therefore, for adults with very low
levels of type III CPS-specific IgG, two doses of III-TT vaccine may be
required to achieve high levels of specific antibody. We speculate that
prior exposure to GBS type III CPS or an immunochemically similar
antigen may account for the brisk response after the first dose in the
majority of volunteers with >0.05 µg of type III CPS-specific IgG/ml
before immunization. For this population, a single dose of III-TT
vaccine may be sufficient to induce high levels of type III
CPS-specific IgG.
The amount of type III CPS-specific IgG elicited by 15 adults before
and 4 weeks after receiving GBS III-TT lot 1-1-95 (12.5-µg CPS dose,
no adjuvant) or lot 91-1 (14.5-µg CPS dose, no alum) (9)
vaccines were similar (P > 0.6). This indicates the
reproducibility in the manufacture of these GBS conjugate vaccines that
were prepared 4 years apart in two different laboratories.
Of the 26 candidate vaccines analyzed recently by the Committee to
Study Priorities for Vaccine Development for the Institute of Medicine,
GBS conjugate vaccines were listed as one of seven in the most
favorable (level I) rating or those likely to save money and
quality-adjusted life years (19). Of course, successful implementation of a vaccination program relies on proper vaccine formulation and administration. Results from the studies presented here
may assist in determining the optimal formulation of a multivalent GBS
vaccine and in establishing a vaccination schedule that would ensure a
high degree of protective immunity.
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ACKNOWLEDGMENTS |
Kenneth Johnson, Melissa Hickman, and Claire Skeeter provided
invaluable technical assistance on many aspects of this study.
This work was supported by NIH-NIAID contracts AI-25152 and AI-75326.
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FOOTNOTES |
*
Corresponding author. Mailing address: Channing
Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-2678. Fax: (617) 525-2682. E-mail:
lpaoletti{at}channing.harvard.edu.
Present address: Massachusetts Biologic Laboratories, University of
Massachusetts Medical School, Jamaica Plains, MA 02130.
Editor:
E. I. Tuomanen
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Infection and Immunity, November 2001, p. 6696-6701, Vol. 69, No. 11
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.11.6696-6701.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
