V(H)3 antibody response to immunization with pneumococcal polysaccharide vaccine in middle-aged and elderly persons.
ABSTRACT Pneumococcal disease continues to cause substantial morbidity and mortality among the elderly. Older adults may have high levels of anticapsular antibody after vaccination, but their antibodies show decreased functional activity. In addition, the protective effect of the pneumococcal polysaccharide vaccine (PPV) seems to cease as early as 3 to 5 years postvaccination. Recently, it was suggested that PPV elicits human antibodies that use predominantly V(H)3 gene segments and induce a repertoire shift with increased V(H)3 expression in peripheral B cells. Here we compared V(H)3-idiotypic antibody responses in middle-aged and elderly subjects receiving PPV as initial immunization or revaccination. We studied pre- and postvaccination sera from 36 (18 vaccine-naïve and 18 previously immunized subjects) middle-aged and 40 (22 vaccine-naïve and 18 previously immunized subjects) elderly adults who received 23-valent PPV. Concentrations of IgGs to four individual serotypes (6B, 14, 19F, and 23F) and of V(H)3-idiotypic antibodies (detected by the monoclonal antibody D12) to the whole pneumococcal vaccine were determined by enzyme-linked immunosorbent assay (ELISA). PPV elicited significant IgG and V(H)3-idiotypic antibody responses in middle-aged and elderly subjects, regardless of whether they were vaccine naïve or undergoing revaccination. Age did not influence the magnitude of the antibody responses, as evidenced by similar postvaccination IgG and V(H)3 antibody levels in both groups, even after stratifying by prior vaccine status. Furthermore, we found similar proportions (around 50%) of elderly and middle-aged subjects experiencing 2-fold increases in V(H)3 antibody titers after vaccination. Age or repeated immunization does not appear to affect the V(H)3-idiotypic immunogenicity of PPV among middle-aged and elderly adults.
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ABSTRACT: Outer membrane protein antigens usually have strong immunogenicities, closely interact with the immune system and play a significant role in the development of new vaccines. The outer membrane proteins of Salmonella paratyphi A (S. paratyphi A) were screened for immunogenicity and immunoprotection for potential vaccine targets. In this study, the bactericidal effect of antiserum against the total outer membrane proteins of S. paratyphi A CMCC 50973 strain was determined, and their immunoprotection was detected with a challenge experiment on vaccinated mice. The immunogenic outer membrane proteins were identified via immunoproteomic technology, and recombinant outer membrane proteins were expressed and purified. The immunoprotection provided by the immunogenic membrane proteins was verified through active and passive immunity challenge experiments. The result revealed a number of S. paratyphi A outer membrane proteins that were proven as strong protective antigens. Twelve immunogenic outer membrane proteins were located and identified. Five recombinant proteins (LamB, pagC, TolC, nmpC and fadL) with strong immunoprotective abilities were found via the active immunity challenge experiment, with protection rates of 95, 95, 85, 80 and 70%, respectively. They were also proven to induce good immunoprotection via the passive immunity challenge experiment, with protection rates of 65, 55, 60, 55 and 50%, respectively. The immunoprotective rate of the five-antiserum combination was 85%. In conclusion, the LamB, pagC, TolC, nmpC and fadL outer membrane proteins, with strong immunogenicities and immunoprotection, are effective protein candidate targets for the development of new vaccines, whereas the recombinant outer membrane proteins are a promising tool for improving immunoprotection.Molecular Medicine Reports 09/2011; 5(1):78-83. · 1.48 Impact Factor
CLINICAL AND VACCINE IMMUNOLOGY, Mar. 2011, p. 362–366
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Vol. 18, No. 3
VH3 Antibody Response to Immunization with Pneumococcal
Polysaccharide Vaccine in Middle-Aged and Elderly Persons?
Jose A. Serpa,1Josemon Valayam,1,2Daniel M. Musher,1,2Roger D. Rossen,3
Liise-anne Pirofski,4and Maria C. Rodriguez-Barradas1,2*
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine,1Section of Infectious Diseases,
Veterans Affairs Medical Center,2Department of Pathology and Immunology and Department of Medicine,
Baylor College of Medicine, and Section of Allergy, Immunology, and Rheumatology, Veterans Affairs Medical Center,3
Houston, Texas, and Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine
Montefiore Medical Center, Bronx, New York4
Received 24 September 2010/Returned for modification 8 December 2010/Accepted 30 December 2010
Pneumococcal disease continues to cause substantial morbidity and mortality among the elderly. Older
adults may have high levels of anticapsular antibody after vaccination, but their antibodies show decreased
functional activity. In addition, the protective effect of the pneumococcal polysaccharide vaccine (PPV) seems
to cease as early as 3 to 5 years postvaccination. Recently, it was suggested that PPV elicits human antibodies
that use predominantly VH3 gene segments and induce a repertoire shift with increased VH3 expression in
peripheral B cells. Here we compared VH3-idiotypic antibody responses in middle-aged and elderly subjects
receiving PPV as initial immunization or revaccination. We studied pre- and postvaccination sera from 36 (18
vaccine-naïve and 18 previously immunized subjects) middle-aged and 40 (22 vaccine-naïve and 18 previously
immunized subjects) elderly adults who received 23-valent PPV. Concentrations of IgGs to four individual
serotypes (6B, 14, 19F, and 23F) and of VH3-idiotypic antibodies (detected by the monoclonal antibody D12)
to the whole pneumococcal vaccine were determined by enzyme-linked immunosorbent assay (ELISA). PPV
elicited significant IgG and VH3-idiotypic antibody responses in middle-aged and elderly subjects, regardless
of whether they were vaccine naïve or undergoing revaccination. Age did not influence the magnitude of the
antibody responses, as evidenced by similar postvaccination IgG and VH3 antibody levels in both groups, even
after stratifying by prior vaccine status. Furthermore, we found similar proportions (around 50%) of elderly
and middle-aged subjects experiencing 2-fold increases in VH3 antibody titers after vaccination. Age or
repeated immunization does not appear to affect the VH3-idiotypic immunogenicity of PPV among middle-aged
and elderly adults.
Streptococcus pneumoniae is the leading cause of bacterial
pneumonia and bacterial meningitis in the United States, re-
sulting in 175,000 hospitalizations and 7,000 to 12,000 deaths
annually. Groups with the highest incidences of pneumococcal
infection include the very young, the elderly, persons who are
immunocompromised, smokers, and certain other demo-
graphic groups (2, 8). In persons 65 years or older, the inci-
dence of invasive pneumococcal disease (IPD) is around 50 per
100,000 individuals per year and is associated with a case fa-
tality rate of 20%, whereas among those aged 85 years or older,
the fatality rate increases to 40% (2, 34).
The Advisory Committee on Immunization Practices recom-
mends vaccinating all adults aged 65 years or older with the
23-valent pneumococcal polysaccharide vaccine (PPV). One-
time revaccination for this age group is also recommended if
subjects received their first dose ?5 years previously and be-
fore the age of 65 years (6). A recent meta-analysis provided
evidence supporting the recommendation for PPV to prevent
IPD in adults. However, it did not provide compelling evidence
to support the routine use of PPV to prevent all-cause pneu-
monia or mortality (15). In addition, significant protection
against IPD seems to be lost as early as 3 to 5 years after
vaccination in persons older than 65 years (28, 29).
A common surrogate for antibody-mediated protection is
the measurement of postvaccination IgG antibody to capsular
polysaccharides contained in PPV. Validation of this measure
may be disputed given the fact that even adequate IgG con-
centrations in the elderly may have significant reductions in
antibody functional activity toward pneumococcal polysaccha-
ride antigens (25). Molecular characterization of the immune
response to pneumococcal polysaccharides is seldom per-
formed in clinical vaccine studies (24); however, there is a large
body of literature on this subject (3, 5, 7, 22, 38). Recent
studies have demonstrated that PPV stimulates increased ex-
pression of variable region heavy chain family 3 (VH3) genes in
peripheral B cells from immunocompetent subjects, yielding
serum polysaccharide-specific antibodies and/or B cells that
express VH3 (1, 7, 32, 33). VH3 responses may also correlate
with functional activity of antipneumococcal antibodies (3).
Previous studies on gene expression of the total circulating
B-cell population demonstrated a shift toward VH4 and VH1
expression in aging humans, compared with predominant VH3
expression in young subjects (35). This repertoire shift has
been postulated as a possible mechanism of decreased pneu-
* Corresponding author. Mailing address: Infectious Diseases Sec-
tion, Michael E. DeBakey VAMC, Department of Medicine, Baylor
College of Medicine, 2002 Holcombe Blvd., Houston, TX 77030.
Phone: (713) 794-8856. Fax: (713) 794-7045. E-mail: maria.rodriguez
?Published ahead of print on 12 January 2011.
mococcal anticapsular antibody function in older populations.
In this regard, a preliminary report (30) found lower levels of
VH3-idiotypic antibody responses to capsular polysaccharides
from serotype 4, but not serotype 14, in the elderly than in
young individuals. A subsequent study (11) of the VHgene
repertoire of human peripheral B cells specific for these two
capsular polysaccharides (4 and 14) revealed that the re-
sponses in both age groups were dominated by the VH3 gene
family (?90%). The VH1, VH4, and VH5 gene families were
also isolated from both groups, but they constituted ?10% of
the total heavy chain repertoire. Given the attractiveness of the
study of VH3-idiotypic antibody responses to assess the immu-
nogenicity of pneumococcal polysaccharide antigens and the
need for further studies on its role in aging, we evaluated IgG
and VH3-idiotypic antibody responses after administration of
PPV in sera from a subset of vaccine-naïve and revaccinated
middle-aged and elderly subjects enrolled in a pneumococcal
vaccine clinical trial (19).
MATERIALS AND METHODS
Studies were done with pre- and postvaccination sera from 36 (18 vaccine-
naïve and 18 previously immunized subjects) middle-aged (50 to 64 years) and 40
(22 vaccine-naïve and 18 previously immunized subjects) elderly (?65 years)
adults who received one intramuscular dose of the 23-valent pneumococcal
polysaccharide vaccine (Pneumovax 23; Merck, West Point, PA). This vaccine
contains 25 ?g of each of the following polysaccharide types per 0.5 ml: 1, 2, 3,
4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F,
Study subjects were participants in a multisite study evaluating the safety and
immunogenicity of primary vaccination and revaccination with PPV and were
recruited and vaccinated at the Houston Veterans Affairs Medical Center under
a protocol that was approved by the Institutional Review Board, Baylor College
of Medicine, as previously described (19). Subjects were included based on the
availability of sera. Reimmunized subjects had received the initial vaccine 3 to 5
years previously as part of their routine medical care. Blood samples were
obtained before and 4 weeks after initial vaccination or revaccination. Sera were
separated from whole-blood samples by centrifugation and were stored at ?70°C
until analysis. For the current study, all samples were reassayed as described
Isotype expression of antibodies. The pre- and postvaccination concentrations
of IgGs to pneumococcal capsular polysaccharides of types 6B, 14, 19F, and 23F
were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) as
described elsewhere (36). We decided to study four representative serotypes that
are reported to cause a significant number of cases of IPD among middle-aged
and elderly persons in the United States (37).
Serum samples were preabsorbed with 5 ?g/ml pneumococcal cell wall poly-
saccharide (CWPS; Statens Serum Institut) and 5 ?g/ml type 22F CPS (ATCC)
for 30 min at room temperature, following the World Health Organization
guidance protocol for pneumococcal antibody ELISA (36) (this methodology
differs from the one described for the main study, which used serotypes 25 and
72 for adsorption ). Dilutions of a laboratory reference serum (pool 89-SF;
Food and Drug Administration) were included in every ELISA plate. All serum
samples from each individual were studied concurrently.
Idiotype expression of antibodies. The expression of VH3 antibodies to the
pneumococcal vaccine in pre- and postvaccination sera was determined by
ELISA as described elsewhere (1). In brief, 96-well polystyrene plates (Costar;
Corning Glass Works) were coated with 10 ?g/ml of whole PPV in phosphate-
buffered saline (PBS) for 5 h at 37°C and then kept overnight at 4°C. Before use,
plates were blocked with PBS containing 1% bovine serum albumin (Fisher
Scientific) for 1 h and then washed with PBS containing 0.05% Tween 20 (Fisher
Scientific). ELISA plates were incubated for 2 h at 37°C with CWPS-absorbed
pre- and postvaccination serum samples diluted 1:3, beginning with an initial
dilution of 1:10 in PBS. After incubation, the plates were washed and incubated
for 1 h at 37°C with the murine monoclonal antibody D12, which binds to a
variable region determinant expressed by certain antibodies encoded by VH3
genes, at a concentration of 5 ?g/ml. The binding of the D12-bound serum
antibodies was detected with alkaline phosphatase-labeled goat anti-mouse IgG1
(Southern Biotech). The plates were then washed and developed with p-nitro-
phenyl phosphate, and absorbances and titers were calculated.
Statistics. Geometric mean concentrations (GMCs) of IgGs to individual
capsular polysaccharides, geometric mean VH3 titers to the whole vaccine, and
corresponding 95% confidence intervals (95% CI) were calculated. All antibody
concentrations and titers were log10converted before any statistical comparisons
were made. The pre- and postvaccination levels were compared between groups
(middle-aged and elderly) by unpaired Student’s t test. The pre- and postvacci-
nation levels within each group were compared by paired Student’s t test. Strat-
ification by vaccination status was also studied, and comparison of multiple
subgroups was done with analysis of variance. Pearson’s correlation coefficient
was calculated to measure the level of association between IgG and VH3-idio-
typic antibody responses (defined as postvaccination log-converted antibody lev-
els ? prevaccination log-converted antibody levels). Multiple comparisons were
accounted for by using Bonferroni correction. Statistical analyses were imple-
mented using STATA 9.2 (StataCorp., College Station, TX), and P values of
?0.05 were considered significant.
IgG antibody response. GMCs of IgGs to individual pneu-
mococcal capsular polysaccharides (serotypes) are shown in
Table 1 according to age group and vaccination status. Pre-
and postvaccination IgG levels were similar between the mid-
dle-aged and elderly groups. When stratified by vaccine status,
prevaccination IgG levels were higher in previously immunized
subjects than in vaccine-naïve subjects in both groups and for
all serotypes; however, this difference was statistically signifi-
cant only for serotype 14 for both the middle-aged and elderly
groups (P ? 0.03 for both comparisons). Despite these differ-
ences in prevaccination levels, postvaccination IgG levels were
similar in all subgroups. The middle-aged and elderly groups
showed significant increases (within-group comparisons) in
IgG levels for all four serotypes (P ? 0.01 for all comparisons).
Stratified analysis also showed significant IgG increases in all
subgroups for all serotypes (P ? 0.05 for all comparisons).
VH3-idiotypic antibody response. Pre- and postvaccination
VH3 levels were similar between the middle-aged and elderly
groups, even after stratification by vaccine status. Both groups
showed significant increases (within-group comparisons) in
VH3 antibody titers after vaccination with PPV (P ? 0.01 for
both comparisons) (Table 2). Stratified analysis also showed
significant increases in VH3 levels in all subgroups (P ? 0.03
TABLE 2. Geometric mean VH3 antibody titers to pneumococcal
polysaccharide vaccine in pre- and postvaccination sera from
middle-aged and elderly subjects according to vaccine statusa
Geometric mean VH3 antibody
titer (95% CI)
Middle-aged subjects (31)
Vaccine-naı ¨ve subjects (16) 5. 65 (4.73–6.74)
6.48 (5.10–8.24)16.12 (10.92–23.78)
7.51 (4.66–12.13) 11.80 (6.18–22.49)
Elderly subjects (35)
Vaccine-naı ¨ve subjects (20) 6.06 (4.81–7.63)
7.38 (5.87–9.27)20.86 (13.27–32.78)
9.59 (6.19–14.84) 20.60 (9.84–43.16)
aNo significant differences in log-converted pre- or postvaccination titers were
seen between middle-aged and elderly subjects.
bSignificant increases (P ? 0.03) in log-converted VH3 antibody titers (within-
group comparisons) were seen for all groups.
VOL. 18, 2011VH3 ANTIBODY RESPONSE TO PNEUMOCOCCAL VACCINE 363
for all comparisons) (Fig. 1). Comparable proportions of mid-
dle-aged and elderly patients experienced 2-fold increases in
VH3 antibody titers (54.8% and 45.7%, respectively; P ? 0.46).
Although the differences were not statistically significant,
larger proportions of vaccine-naïve subjects than revaccinated
subjects had 2-fold increases in VH3 antibody titers (75% and
55% versus 33.3% and 33.3% for middle-aged and elderly
patients, respectively) (P ? 0.06).
Correlations. VH3-idiotypic antibody responses were corre-
lated with IgG responses to serotypes 14 (r ? 0.36; P ? 0.03)
and 23F (r ? 0.45; P ? 0.01). No significant correlations were
observed for the other two serotypes.
In our study, age did not influence the magnitude or quality
of the antibody responses elicited by the pneumococcal poly-
saccharide vaccine among either vaccine-naïve or previously
immunized subjects. This was evidenced by similar postvacci-
nation IgG and VH3 antibody levels in middle-aged and elderly
groups even after stratifying by prior vaccine status. Further-
more, our study showed similar proportions of healthy elderly
and middle-aged subjects experiencing 2-fold increases in VH3
antibody titers after receiving pneumococcal polysaccharide
Several previous studies have shown IgG antibody responses
to pneumococcal polysaccharides in elderly individuals similar
to those of their younger counterparts (4, 17, 26, 27); however,
these levels do not always accurately correlate with functional
antibody activity (25) or with protection against pneumococcal
disease (20). In addition, other studies have suggested that
humoral responses among elderly subjects correlate better
with their functional status than with their chronological age
(4, 23). Our patients were all ambulatory subjects, without
concomitant debilitating acute or chronic illness, who were
expected to survive for 5 years after study enrollment (19).
Therefore, our results on VH3 antibody responses among am-
bulatory elderly subjects may not be extrapolated to frail el-
As a vaccine composed of polysaccharide antigens, PPV
induces a T-cell-independent response, and thus an anamnes-
tic response (i.e., booster) is unlikely (31). Immunologic toler-
ance or hyporesponsiveness induced by prior polysaccharide
antigen exposure constitutes a potential concern in considering
revaccination with PPV (9, 21). Although prevaccination IgG
levels in response to some serotypes were higher in previously
immunized subjects, postvaccination levels actually reached
similar levels in all subgroups. However, as a result of higher
prevaccination titers, a smaller proportion of revaccinated sub-
jects achieved a 2-fold-increased response. Our results are
concurrent with those of the main study (19). In addition, in a
different substudy, Manoff and collaborators showed that re-
vaccination of adults aged ?65 years was comparable to pri-
mary vaccination for inducing elevated and persistent func-
anticapsular antibodies; in this study, the results of the func-
tional assays correlated with the IgG antibody responses (14).
These results agree with those of earlier studies showing that
revaccination elicits a significant response, but not one of
greater intensity than that to the initial vaccination (10, 14, 16,
TABLE 1. GMCs of IgG antibodies to individual pneumococcal capsular polysaccharides in pre- and postvaccination sera from middle-aged and elderly subjects
according to vaccine status
IgG GMC (95% CI)
Middle-aged subjects (36)
Vaccine-naı ¨ve subjects (18)
Elderly subjects (40)
Vaccine-naı ¨ve subjects (22)
aSignificant difference (P ? 0.03) in log-converted prevaccination concentrations (?g/ml) between previously vaccinated and vaccine-naı ¨ve subjects.
bSignificant increases (P ? 0.05) in IgG concentrations (within-group comparisons) were seen for all groups.
364SERPA ET AL.CLIN. VACCINE IMMUNOL.
34) and, most importantly, indicate that any possible differ-
ences initially observed in the antibody responses of revacci-
nated and vaccine-naïve subjects do not persist over time.
Among HIV-infected patients on highly active antiretroviral
therapy (HAART), the VH3 antibody responses to polysaccha-
ride antigens after revaccination were similar to those after
initial vaccination (32). Similarly, our data indicate that adults
aged 50 to 65 years or ?65 years do mount significant serotype-
and VH3-specific antibody responses after revaccination with
PPV. However, we have not evaluated the functional activity of
the VH3-specific antibodies, and correlation of VH3-specific
antibodies with function, although supported by one small
study (3), continues to be speculative.
We found a linear correlation between VH3 antibodies to
the whole vaccine and IgG responses to two serotypes (14 and
23F). In a previous study (1) utilizing the same assay, antibod-
ies to capsular polysaccharides of serotypes 3, 6B, and 14 did
not yield VH3 determinants recognized by the D12 monoclonal
antibody. The prior study evaluated antibody responses among
a younger group of subjects. It is possible that there is a
differential expression of VH3 epitopes among different sero-
types that is influenced by age (11, 29).
We measured VH3 antibody responses with the use of the
D12 monoclonal antibody and a whole-vaccine ELISA because
we had previously demonstrated that the determination of
whole-vaccine D12-positive antibodies is a reliable method of
demonstrating pre-to-postvaccine increases in D12-positive
antibodies (32). With this assay, 23 (35%) of 66 patients had no
detectable VH3 antibody response. The D12 monoclonal anti-
body does not appear to recognize all VH3 family antibodies,
and it is possible that by the use of a panel consisting of several
monoclonal antibodies that recognize different VH3 epitopes,
we would have been able to detect greater VH3 responses (1).
Hence, we are limited in our ability to detect additional dif-
ferences in age-related responses, responses based on prior
immunization status, or correlation with IgG responses. In
addition, we did not study any other VHgene families, which
limits our ability to detect any subtle shifts in VHfamily use. A
more complex PCR-based methodology would have increased
our ability to better characterize the entire VHantibody rep-
ertoire (12, 39).
A decreased production of VH3 antibodies and a shift to the
VH5 gene family after receiving PPV have been postulated as
contributing factors to the increased susceptibility to S. pneu-
moniae infections among HIV-infected patients (1, 7, 32).
Thus, it appears reasonable to hypothesize that the study of
VH3 antibody responses may offer an additional approach to
test the antibody response after administration of the pneu-
mococcal polysaccharide vaccine. We demonstrated that vac-
cination with pneumococcal polysaccharide vaccine elicits
significant IgG and VH3-idiotypic antibody responses in mid-
dle-aged and elderly subjects, whether they are vaccine naïve
or undergoing revaccination 3 to 5 years after primary immu-
nization. The VH3 antibody response was not impaired among
FIG. 1. Log10-converted VH3-idiotypic antibody titers to pneumococcal polysaccharide vaccine in pre- and postvaccination sera from middle-
aged and elderly subjects, stratified according to vaccination status.*, P ? 0.05.
VOL. 18, 2011VH3 ANTIBODY RESPONSE TO PNEUMOCOCCAL VACCINE365
elderly adults. Vaccination and revaccination with pneumococ-
cal polysaccharide vaccine after 3 to 5 years appear to be
effective strategies to elicit isotypic and VH3-idiotypic immu-
nogenicity in middle-aged and elderly adults (10, 13, 16, 18, 27,
This work was supported by the Department of Veterans Affairs
through Merit Review Funding (to D.M.M. and M.C.R.-B.).
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