Superior Immune Response to Protein-Conjugate versus Free Pneumococcal Polysaccharide Vaccine in Chronic Obstructive Pulmonary Disease

Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 07/2009; 180(6):499-505. DOI: 10.1164/rccm.200903-0488OC
Source: PubMed
ABSTRACT
Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults.
We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness.
One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups.
Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses.
PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).

Full-text

Available from: Meilan K Han
Superior Immune Response to Protein-Conjugate versus
Free Pneumococcal Polysaccharide Vaccine in Chronic
Obstructive Pulmonary Disease
Mark T. Dransfield
1
, Moon H. Nahm
2
, MeiLan K. Han
3
, Sarah Harnden
4
, Gerard J. Criner
5
,
Fernando J. Martinez
3
, Paul D. Scanlon
6
, Prescott G. Woodruff
7
, George R. Washko
8
, John E. Connett
4
,
Nicholas R. Anthonisen
8
, and William C. Bailey
1
, for the COPD Clinical Research Network
1
Division of Pulmonary, Allergy and Critical Care Medicine and
2
Departments of Pathology and Microbiology, University of Alabama at Birmingham,
Birmingham, Alabama,
3
Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, Michigan,
4
Division of Biostatistics, School of
Public Health, University of Minnesota, Minneapolis, Minnesota,
5
Pulmonary and Critical Care Medicine and Temple Lung Center, Temple
University, Philadelphia, Pennsylvania,
6
Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota,
7
Division of Pulmonary and
Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California,
8
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, and
9
Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Rationale: Debate exists about the immunogenicity and protective
efficacy of antibodies produced by the 23-valent pneumococcal
polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary
disease (COPD). The 7-valent diphtheria-conjugated pneumococcal
polysaccharide vaccine (PCV7) induces a more robust immune
response than PPSV23 in healthy elderly adults.
Objectives: We hypothesized that serotype-specific IgG antibody
concentration and functional antibody activity would be superior
after PCV7 vaccination compared with PPSV23inmoderatetosevere
COPD. We also posited that older age and prior PPSV23 vaccination
would be associated with reduced vaccine responsiveness.
Methods: One hundred twenty patients with COPD were randomized
to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations
were determined by ELISA; functional antibody activity was assayed
with a standardized opsonophagocytosis assay and reported as an
opsonization killing index (OPK). Increases in serotype-specific IgG
and OPK at 1 month post vaccination were compared within and
between vaccine groups.
Measurements and Main Results: Both vaccines were well tolerated.
Within each study group, postvaccination IgG and OPK were higher
than baseline (P , 0.01) for all serotypes. Adjusted for baseline
levels, postvaccination IgG was higher in the PCV7 group than the
PPSV23 group for all seven serotypes, reaching statistical signifi-
cance for five (P , 0.05). PCV7 resulted in a higher OPK for six of
seven serotypes (statistically greater for four) compared with
PPSV23. In multivariate analyses, younger age, vaccine naivety,
and receipt of PCV7 were associated with increased OPK responses.
Conclusions: PCV7 induces a superior immune response at 1 month
post vaccination compared with PPSV23 in COPD. Older age and
prior PPSV23 reduce vaccine responsiveness.
Clinical trial registered with www.clinicaltrials.gov (NCT00457977).
Keywords: pneumococcal vaccines; vaccination, COPD; immune
responses; immunization
Streptococcus pneumoniae is a major cause of morbidity and
mortality among older adults and disproportionately affects
patients with comorbid illnesses, including chronic obstructive
pulmonary disease (COPD) (1). It is estimated to cause 500,000
cases of pneumonia and 40,000 deaths each year and frequently
causes COPD exacerbations (1, 2). Consequently, the Centers
for Disease Control and Prevention recommend that the 23-
valent pneumococcal polysaccharide vaccine (PPSV23) be ad-
ministered to all patients with COPD (1). The Centers for
Disease Control and Prevention Advisory Committee on Immu-
nization Practices has also recently recommended that PPSV23
vaccination be extended to all adult smokers (3). PPSV23
contains the capsular polysaccharide antigens from the 23 most
pathogenic pneumococcal serotypes that are responsible for 90%
of all invasive infections in adults (4). Reasonable effectiveness
for this vaccine has been demonstrated in cohort studies in adults
with lung disease (5, 6). Despite evidence that antibodies pro-
duced in response to PPSV23 can protect against invasive disease
in healthy adults, debate remains about its immunogenicity and
effectiveness in COPD.
Four randomized, placebo-controlled trials of pneumococcal
polysaccharide vaccination (PPSV) in COPD have failed to show
a significant reduction in mortality, hospitalization, or pneumo-
nia in the intention-to-treat population, although these trials
were likely underpowered to detect a vaccine effect (7–10).
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Debate remains about the protective efficacy of antibodies
produced in response to the 23-valent free pneumococcal
polysaccharide vaccine (PPSV23) in chronic obstructive
pulmonary disease (COPD) and no study has accurately
examined its immunogenicity in this population. Prelimi-
nary data suggest that a protein-conjugate pneumococcal
vaccine (PCV7) may elicit superior immune responses to
PPSV23 in healthy elderly patients.
What This Study Adds to the Field
PCV7 induces a superior immune response to PPSV23 in
COPD at 1 month post vaccination. Both vaccines elicit
responses comparable to those previously observed in
healthy elderly patients.
(Received in original form March 31, 2009; accepted in final form June 24, 2009 )
Supported by the National Heart, Lung and Blood Institute of the National
Institutes of Health (U10 HL074441, U10 HL074418, U10 HL074428, U10
HL074409, U10 HL074407, U10 HL074422, U10 HL074416, U10 HL074408,
U10 HL074439, U10 HL074431, U10 HL074424).
Correspondence and requests for reprints should be addressed to Mark
Dransfield, M.D., 422 THT, 1900 University Boulevard, Birmingham, AL 3594.
E-mail: mdransfield99@msn.com
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 180. pp 499–505, 2009
Originally Published in Press as DOI: 10.1164/rccm.200903-0488OC on June 25, 2009
Internet address: www.atsjournals.org
Page 1
Although prior studies have suggested that patients with COPD
can mount an immune response when challenged with PPSV,
interpretation of these results is limited as antibody levels were
measured with a nonspecific ELISA (11). These early-generation
ELISAs routinely measured nonspecific, nonfunctional anti-
bodies to the pneumococcal capsule and cell wall polysaccha-
ride, which overestimated both baseline and postvaccination
levels. The assay has since been modified and standardized but
requires that the samples be preabsorbed with both cell wall
polysaccharide and a pneumococcal capsule other than the
one being tested to remove these nonspecific antibodies. Prior
studies were also limited by the failure to determine functional
antibody activity. Although antibody levels are believed to
correlate reasonably well with protective efficacy, data from both
animal and human studies suggest that measures of antibody
function are better surrogate markers of immunity (11). The
primary method by which S. pneumoniae is killed in vivo is
by antibody coating, activation of complement, phagocytosis, and
cell lysis. This opsonophagocytosis activity can now be assayed
and is the method of choice for measuring vaccine immunoge-
nicity.
There has been increasing interest in the use of protein-
conjugate vaccines to augment the immunogenicity of poly-
saccharide antigens (12). Conjugated vaccines were originally
intended for young children who respond poorly to polysaccha-
ride antigens. The 7-valent diphtheria-conjugated pneumococcal
polysaccharide vaccine (PCV7) (Prevnar; Wyeth, Pearl River,
NY) induces a potent immune response in children and reduces
the nasopharyngeal carriage of vaccine serotypes, episodes of
otitis, and the frequency of invasive disease (13). Although this
vaccine is not currently licensed for use in adults, preliminary
studies in healthy patients older than age 70 years have shown
that PCV7 induces greater functional antibody activity at 1
month post vaccination than does PPSV23, although this re-
sponse is reduced in those who have been previously vaccinated
(14, 15). Jackson and colleagues demonstrated that in these
healthy patients the 1.0-ml dose of PCV7 induced a greater
immune response than the pediatric 0.5-ml dose. No additional
benefit was observed with a 2.0-ml dose (15).
This study was conducted with two hypotheses: (1) the
immunogenicity of PCV7 (1.0 ml) vaccination would be supe-
rior to that of PPSV23 in patients with moderate to severe
COPD, and (2) prior PPSV23 vaccination and older age would
reduce vaccine responsiveness.
METHODS
Study Design
This study was a randomized, open-label trial that compared the safety
and immunogenicity of PCV7 (1.0 ml) to PPSV23 vaccination in 120
subjects with moderate to severe COPD. The study was conducted by
the 10 centers participating in the National Heart, Lung and Blood
Institute’s COPD Clinical Research Network (CCRN). Randomization
was performed after linking to the CCRN coordinating center website
and stratified by study center. The study was approved by the CCRN
Protocol Review Committee, each of the participating center’s In-
stitutional Review Boards, and by the Food and Drug Administration
under an Investigational New Drug approval. The study was registered
on line as a clinical trial. For full methods, including expanded ex-
clusion criteria, vaccine administration, and safety monitoring, please
see the online supplement.
Study Population
Subjects were men and women older than 40 years of age with a 10 or
more pack-year cigarette smoking history with a clinical diagnosis of
moderate to very severe COPD (as defined by postbronchodilator
FEV
1
/FVC ,70% and FEV
1
,70% predicted). Subjects were eligible
if they had never received PPSV23 or if it was administered more than
5 years before randomization. Exclusion criteria included a diagnosis of
asthma, sensitivity to pneumococcal vaccination, bleeding disorder,
chronic anticoagulation, or the presence of conditions known to impair
pneumococcal vaccine response. Subjects taking oral corticosteroids
were not excluded from the trial. Those suffering an acute illness
requiring antibiotics or steroids within the past month or not expected
to survive 12 months were also excluded.
Serologic Testing
Blood specimens were obtained immediately before and 1 month after
vaccination. The capacity of each serum to opsonize S. pneumoniae for
ingestion and killing by phagocytes was determined by incubating
bacteria in serum and then exposing them in vitro to HL-60 cells (16).
Results are reported as an opsonophagocytosis killing index (OPK),
which represents the reciprocal of the serum dilution that led to 50%
uptake and killing of pneumococci during incubation at 378C for
1 hour. Total IgG antibody concentrations to the seven PCV7 sero-
types were also measured using a WHO-recommended ELISA pro-
tocol (www.vaccine.uab.edu).
Statistics
Antibody levels (IgG) and OPK were transformed using natural
logarithms for statistical analysis to account for their strongly skewed
distributions and are reported as geometric means. A paired t test was
used to assess the increase in serotype-specific IgG and OPK from pre- to
postvaccination within study groups. An unpaired t test was used for
between-group comparisons of postvaccination IgG and OPK. To
correct for differences in prevaccination IgG and OPK, we also
compared the ratios of 1 month to baseline IgG and OPK between
vaccine groups. We performed univariate and multivariate linear re-
gression to determine the relationship between age, sex, vaccine
assignment, lung function impairment (FEV
1
% predicted), and prior
vaccination status with vaccine responsiveness as measured by the
number of serotypes to which a subject exhibited a 10-fold increase in
OPK or a twofold increase in IgG (17). The proportion of subjects
reporting systemic or local adverse reactions during the 7-day diary were
compared using Fisher exact test. P values less than 0.05 were considered
significant. No adjustments were made for multiple comparisons.
RESULTS
Table 1 shows the demographic characteristics, comorbid ill-
nesses, and lung function of the 120 subjects randomized
between April 9, 2007 and May 5, 2008. Forty-four additional
subjects signed informed consent and were screened for the
study but were excluded primarily because they did not meet
spirometric inclusion criteria. Subjects had significant airflow
obstruction and were predominantly male and white, although
a significant proportion of women and minorities were enrolled
compared with prior COPD vaccination studies (7–9). Almost
half the subjects had prior episodes of pneumonia and a similar
proportion had never received the pneumococcal vaccine.
Approximately one-quarter of the subjects had coronary artery
disease, but the burden of other comorbid illness was relatively
low in both groups. Subjects who had not been previously
vaccinated with PPSV23 were younger than those who had
received the vaccine (60 vs. 67 yr, P , 0.001).
Both vaccines were well tolerated with only three episodes of
grade III toxicity (Table 2). Local and systemic side effects were
more common in the PPSV23 group. There was no increased rate
of adverse events in subjects who had been previously vaccinated
with PPSV23 compared with those who were vaccine naive (data
not shown). No subjects required unscheduled visits within the
first 7 days after vaccination and only one patient had a persistent
complaint at 1 month (muscle soreness). One patient died within
30 days of vaccination due to cardiovascular disease but had not
reported any adverse events in their diary or during the Day 7
phone call.
500 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 180 2009
Page 2
Table 3 shows baseline and 1 month postvaccination IgG
antibody levels. Five samples could not be analyzed due to the
following: patient death (1), loss to follow-up (1), inability to
draw blood (2), and quality control issues for one of the two
blood samples (1). Within each study group, postvaccination
IgG levels were higher than baseline (P , 0.01) for all
serotypes. Absolute IgG levels were higher for those receiving
PCV7 compared with PPSV23 for all seven serotypes, reaching
statistical significance for four (P , 0.05, shown in bold in Table
3). One month to baseline antibody concentration ratios were
also higher in the PCV7 treatment arm for all seven serotypes
tested and statistically significant for all serotypes except 14 and
19F (P , 0.05, shown underlined in Table 3). The fraction of
subjects exhibiting a twofold increase in serotype-specific IgG
antibody was also higher in the PCV7 group for five of the seven
serotypes tested: 4 (85 vs. 39%, P , 0.001), 6B (57 vs. 36%, P 5
0.03), 9V (74 vs. 55%, P 5 0.05), 18C (72 vs. 55%, P 5 0.08),
23F (81 vs. 52%, P 5 0.001). There was no difference in the
fraction of subjects achieving this twofold increase for serotypes
14 (59 vs. 65%, P 5 0.57) and 19F (38 vs. 39%, P 5 1.0).
Figure 1 shows the baseline and 1 month post vaccination
OPK. Similar to the ELISA results, within both study groups
postvaccination OPKs were higher than baseline for all serotypes
(P , 0.001). Absolute OPKs were higher in the PCV7 group for
six of seven serotypes, reaching statistical significance in five.
OPK ratios from 1 month to baseline were also greater in the
PCV7 group than in the PPSV23 group for six of the seven
serotypes tested, reaching statistical significance for serotypes
4, 9V, 18C, and 23F.
We also separately compared vaccine responses in subjects
who were vaccine naive and in those who had been previously
vaccinated. Among vaccine-naive subjects, PCV7 elicited
a greater 1 month to baseline OPK ratio than PPSV23 for all
serotypes (reaching significance in five) except for serotype 19F,
for which PPSV23 generated a statistically superior response.
Among those previously vaccinated, PCV7 again elicited a supe-
rior OPK ratio for all serotypes (reaching significance in four)
except for serotype 14, for which PPSV23 elicited a nonsignifi-
cantly higher response. Figure 2 highlights the immune responses
based on prior vaccination status and vaccine assignment for the
four most frequently isolated pneumococcal serotypes in COPD
that are also components of PCV7.
The associations between age, sex, FEV
1
% predicted, prior
vaccination status, vaccine assignment, and OPK response are
shown in Table 4. In total, 42% of subjects exhibited a 10-fold
increase in OPK to five or more serotypes. In both univariate
and multivariate models younger age, vaccine naivety, and
receipt of PCV7 were associated with more frequent 10-fold
increases in serotype-specific OPK. There was no significant
interaction between age and vaccine assignment (P 5 0.64) or
between age and prior vaccination status (P 5 0.36). In a similar
analysis of IgG response, younger age and PCV7 vaccination
were associated with twofold increases in antibody levels
(model not shown). In univariate analyses, we found no
association between OPK responses and patient-reported prior
pneumonia (lifetime) (P 5 0.77), hospitalization or emergency
visit for COPD (P 5 0.37), or courses of antibiotics or steroids
for COPD exacerbations in the prior 12 months (P 5 0.20).
DISCUSSION
This article is the first to report pneumococcal vaccine responses
in people with COPD using measures of functional antibody
activity and the latest generation ELISA. We have demon-
strated that patients with COPD are able to mount immune
responses comparable to those previously reported in healthy
elderly patients (14, 15). We showed that PCV7, when given at
TABLE 1. PATIENT CHARACTERISTICS
PCV7
(n 5 57)
PPSV23
(n 5 63) P Value
Age, years 63 6 10 63 6 10 0.95
Male, % 38 (67) 37 (59) 0.45
White, % 43 (75) 48 (76) 1.0
FEV
1
, L 1.40 6 0.58 1.23 6 0.54 0.12
FEV
1
, % predicted 45 6 16 43 6 15 0.56
FEV
1
/FVC 0.476 0.13 0.44 6 0.13 0.16
Oxygen use, % 12 (21) 21 (33) 0.15
Inhaled corticosteroid use, % 36 (63) 43 (68) 0.57
Pack-years smoking 54 6 32 55 6 34 0.82
Comorbid illness, %
Coronary artery disease 16 (28) 15 (24) 0.68
Congestive heart failure 3 (5) 2 (3) 0.67
Stroke 2 (4) 6 (9) 0.28
Diabetes mellitus 5 (9) 3 (5) 0.48
Prior malignancy 7 (12) 8 (13) 1.00
Anemia 7 (12) 4 (6) 0.35
Previous pneumonia, % 26 (46) 30 (48) 0.86
Exacerbation history
(yr before enrollment)
Hospitalized or unscheduled
emergency visit, %
10 (18) 9 (14) 0.80
Received systemic steroids
and/or antibiotics, %
26 (46) 26 (41) 0.71
Vaccine naive, % 30 (53) 33 (52) 1.00
Years since last vaccination 7.9 8.4 0.56
Definition of abbreviations: PCV7 5 7-valent diphtheria-conjugated pneumo-
coccal polysaccharide vaccine; PPSV23 5 23-valent pneumococcal polysaccha-
ride vaccine.
TABLE 2. SOLICITED ADVERSE EVENTS FROM 7-DAY DIARY
PCV7
(n 5 57)(%)
PPSV23
(n 5 63)(%) P Value
Fatigue 0.18
Grade I 22 (39) 33 (52)
Grade II 1 (2) 6 (10)
Muscle aches 0.74
Grade I 29 (51) 37 (59)
Grade II 4 (7) 5 (8)
Headache 0.53
Grade I 8 (14) 12 (19)
Grade II 0 (0) 1 (2)
Itching of vaccinated arm 0.09
Grade I 5 (9) 13 (21)
Grade II 0 (0) 0 (0)
Pain of vaccinated arm 0.74
Grade I 29 (51) 35 (56)
Grade II 2 (4) 4 (6)
Fever 0.54
Grade I 3 (5) 3 (5)
Grade II 1 (2) 0 (0)
Limitation of arm movement 0.35
Grade I 16 (28) 23 (36)
Grade II 2 (4) 6 (10)
Redness or discoloration 0.06
Grade I (<8 cm) 9 (16) 19 (30)
Grade II (.8cmand<15 cm) 1 (2) 8 (13)
Grade III (.15 cm) 0 (0) 2 (3)
Localized swelling 0.59
Grade I (<8 cm) 15 (26) 18 (29)
Grade II (.8cmand<5 cm) 0 (0) 5 (8)
Increase in arm circumference
from baseline
0.74
Grade I (,2 cm) 11 (19) 14 (22)
Grade II (>2cmand,3 cm) 3 (5) 3 (5)
Grade III (>3 cm) 1 (2) 0 (0)
Dransfield, Nahm, Han, et al.: Pneumococcal Vaccines in COPD 501
Page 3
twice the dose recommended for children, induces a superior
immune response to PPSV23 in COPD. We also showed that
both older age and prior PPSV23 vaccination impair PCV7
responsiveness.
Our ELISA results demonstrate that PCV7 (1.0 ml) induces
a superior response to PPSV23 in patients with COPD. Al-
though both the PCV7 and PPSV23 groups showed statistically
significant increases in postimmunization antibody concentra-
tions, PCV7 vaccination resulted in superior responses for all
seven of the tested serotypes (statistically superior for all but
serotype 14 and 19F) and more frequently resulted in a twofold
increase in antibody titer, a traditional marker of adequate
vaccine response (17). Similar results were reported by Jackson
and colleagues who found higher postvaccination antibody
TABLE 3. BASELINE AND 1-MONTH SEROTYPE-SPECIFIC GEOMETRIC MEAN IgG ANTIBODY LEVELS
Baseline IgG mg/ml (95% CI) 1-Month IgG mg/ml (95% CI)
Serotype PCV7 PPSV23 PCV7 PPSV23
4 0.26 (0.17–0.38) 0.32 (0.23–0.44)
2.03 (1.24–3.32) 0.70 (0.47–1.03)
6B 0.90 (0.65–1.25) 0.85 (0.67–1.08)
2.96 (1.96–4.48) 1.76 (1.23–2.52)
9V 0.86 (0.61–1.20) 0.76 (0.55–1.06)
4.69 (3.27–6.74) 2.09 (1.47–2.97)
14 2.88 (1.86–4.46) 2.90 (1.96–4.27) 17.2 (11.7–25.3) 11.22 (7.42–16.96)
18C 1.26 (0.84–1.89) 1.17 (0.83–1.64)
9.26 (6.29–13.6) 3.70 (2.58–5.29)
19F 3.20 (2.43–4.21) 3.16 (2.55–3.93) 7.33 (5.16–10.4) 6.20 (4.75–8.09)
23F 0.75 (0.52–1.07) 0.55 (0.40– 0.76)
7.31 (4.56–11.7) 1.52 (0.99–2.32)
Definition of abbreviations: OPK 5 opsonophagocytosis killing index; PCV7 5 7-valent diphtheria-conjugated pneumococcal
polysaccharide vaccine; PPSV23 5 23-valent pneumococcal polysaccharide vaccine.
Within each study group, postvaccination antibody levels and OPK were higher than baseline (P , 0.01) for all serotypes.
Bolded items represent a significant difference in absolute postvaccination IgG levels between vaccine groups and underlined
items represent a significant difference in 1 month to baseline IgG ratio.
Figure 1. The serotype-specific baseline and 1-month opsonophagocytosis killing index (OPK) are shown for each patient. The 7-valent diphtheria-
conjugated pneumococcal polysaccharide vaccine (PCV7) resulted in statistically significantly higher 1 month to baseline OPK ratios for serotypes 4
(75.5 [95% confidence interval, 43.9–130] vs. 10.3 [6.1–17.6]; P , 0.001), 9V (18.7 [10.3–34.0] vs. 5.7 [3.6–9.2]; P 5 0.003), 18C (31.3 [16.2–
60.4] vs. 9.5 [5.7–16.1]; P 5 0.006), 23F (52.4 [26.2–104] vs. 7.2 [4.1–12.7]; P , 0.001). PCV7 vaccination elicited a nonstatistically significant but
superior response for serotypes 6B (20.8 [11.3–38.1] vs. 11.2 [6.3–19.88]; P 5 0.09) and 14 (22.8 [9.9–52.2] vs. 10.7 [5.8–19.8]; P 5 0.24),
whereas 23-valent pneumococcal polysaccharide vaccine (PPSV23) elicited a similar improved response for serotype 19F (20.65 [11.05–38.61] vs.
10.6 [5.5–20.4]; P 5 0.20). Horizontal bars indicate geometric mean OPK.
502 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 180 2009
Page 4
levels in previously vaccinated healthy patients older than 70
years of age using the 1.0-ml PCV7 dose and by de Roux and
coworkers who demonstrated the same results using the tradi-
tional pediatric dose (0.5 ml) in a vaccine-naive elderly pop-
ulation (14, 15). Taken together, these studies suggest that
although protein-conjugate vaccines may induce superior im-
mune responses to the free polysaccharide vaccine, the optimal
dose is uncertain and higher doses may be needed in those
previously vaccinated with PPSV23.
In our study, both PPSV23 and PCV7 elicited increases in
OPK, although this was superior after PCV7 for all serotypes
except 19F and reached statistical significance for serotype 4,
9V, 18C, and 23F. These results are comparable to those
observed by Jackson and colleagues in healthy elderly patients
(15). Only one prior study has examined OPK in people with
COPD after PPSV23 with only a single serotype tested and
demonstrating a nonsignificant increase from baseline (18). Our
OPK results suggest that patients with COPD can mount
TABLE 4. UNIVARIATE AND MULTIVARIATE ASSOCIATIONS BETWEEN AGE, SEX, FEV
1
% PREDICTED,
PRIOR VACCINATION STATUS, AND VACCINE ASSIGNMENT AND IMMUNE RESPONSE
Univariate Multivariate
Estimate (95% CI) P Value Estimate (95% CI) P Value
PCV7 1.25 (0.44, 2.06) 0.003 1.31 (0.58, 2.05) 0.001
Age (per 10 yr) 20.84 (21.23, 20.44) ,0.001 20.66 (21.06, 20.27) 0.001
Previously vaccinated 21.37 (22.17, 20.57) 0.001 21.07 (21.87, 20.28) 0.009
FEV
1
, % predicted 20.01 (20.04, 0.01) 0.36 20.02 (20.04, 0.01) 0.13
Female sex 20.38 (21.24, 0.48) 0.38 20.04 (20.80, 0.72) 0.91
Definition of abbreviations:CI5 confidence interval; OPK 5 opsonophagocytosis killing index; PCV7 5 7-valent diphtheria-
conjugated pneumococcal polysaccharide vaccine.
Immune response was assessed as the number of serotypes to which each subject exhibited a 10-fold increase in OPK.
Figure 2. Shown are the serotype-specific baseline and 1-month opsonophagocytosis killing index (OPK) for the four most frequently recovered
pneumococcal serotypes in patients with chronic obstructive pulmonary disease (27) divided by prior vaccination status and vaccine assignment.
The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) elicited statistically superior 1 month to baseline OPK ratios
compared with PPSV23 in vaccine-naive subjects for serotypes 9V (P 5 0.04), 14 (P 5 0.006), and 23F (P , 0.001). The 23-valent pneumococcal
polysaccharide vaccine (PPSV23) elicited a superior response for serotype 19F (P 5 0.05). Among previously vaccinated subjects, PCV7 elicited
superior OPK ratios for serotypes 9V (P 5 0.01) and 23F (P 5 0.05). There was no statistical difference in OPK responses for serotype 14 (P 5 0.22)
and 19F (P 5 0.94). Horizontal bars indicate geometric mean OPK.
Dransfield, Nahm, Han, et al.: Pneumococcal Vaccines in COPD 503
Page 5
functional antibody responses to both PPSV23 and PCV7,
although the conjugate vaccine is likely to offer greater pro-
tection against pneumococcal disease.
We also examined the impact of older age and prior vac-
cination with PPSV23 on the response to vaccination and found
that both were associated with reduced OPK responses in mul-
tivariate modeling. It has been repeatedly shown that elderly
adults develop antibodies with reduced function and our data
suggest that this is not eliminated by the administration of
a protein-conjugate vaccine (11, 19). Immune hyporesponsive-
ness after polysaccharide vaccination has been observed with
various vaccines, including meningococcal serogroup C vaccine
(20) and in recent comparative trials of sequential vaccination
with PPSV23 and PCV7 (14, 21). In one of these studies,
subjects who received PPSV23 followed by PCV7 1 year later
had threefold lower ELISA and OPK than those who received
PCV7/PCV7 or PCV7/PPSV23 vaccination regimens (14). In
our study, although all subjects who had been previously
vaccinated had received PPSV more than 5 years before
enrollment, immunologic hyporesponsiveness was still appar-
ent. Taken together these data suggest that PPSV23 vaccination
is associated with a reduction in the availability of memory B
cells to respond to subsequent vaccinations, whereas PCV7 may
prime the immune system for such reimmunization. Results of
the multivariate analysis for IgG response were similar to that
for OPK in that PCV7 and younger age were also associated
with an increased frequency of twofold increases in serotype-
specific IgG. Vaccine naivety was not a significant predictor of
response in this model suggesting that prior PPSV23 may re-
duce postvaccination antibody activity to a greater extent than
antibody concentration. Importantly, we also demonstrated that
PCV7 was comparably or more immunogenic than PPSV23
regardless of prior vaccination status.
Both PCV7 and PPSV23 were well tolerated and associated
with few local or systemic side effects. Although increased
reactogenicity has been associated with repeated dosing of
polysaccharide vaccines (22), we observed no increase in
adverse events in those who had been previously vaccinated
compared with those who had not. This may be due to the
requirement that prior vaccinations were received more than
5 years before enrollment.
We believe there are several strengths to this study. Prior
studies have examined the immunogenicity of PPSV23 in
patients with COPD by ELISA, but older methodology did
not detect specific immunological responses and measured non-
specific, nonfunctional antibodies to the pneumococcal capsule
and cell wall polysaccharide, which overestimated antibody
levels (11). Prior studies of PPSV immunogenicity in COPD
are also limited by the use of ELISA antibody levels as the only
surrogate for immunity. The standard ELISA cannot differen-
tiate between functional and nonfunctional antibodies, and
measures of antibody-mediated killing, such as opsonophago-
cytosis, are superior surrogates of protection against pneumonia
and bacteremia (19, 23, 24).
It should be noted that there are limitations to the PCV7
vaccine. First, although the greater immunogenicity of PCV7
may provide improved protection against invasive pneumococ-
cal disease and pneumonia, it is not clear that the vaccine will
prevent acute exacerbations of COPD. Prior studies have
shown that patients with COPD are frequently colonized with
S pneumoniae and that this colonization is a predictor of sub-
sequent exacerbation, but higher levels of anti-pneumococcal
IgG and OPK have not been associated with bacterial clearance
(25). It is possible that protein-conjugate vaccines may elicit
greater IgA antibody responses as compared with polysaccharide
vaccines and this may augment the mucosal immune response
and better protect against both colonization and exacerbation
(26). Second, the serotypes contained within PCV7 account for
only about one-third of pneumococcal isolates recovered from
patients with COPD suffering an acute exacerbation (27). If the
vaccine were to offer protection against cross-reactive serotypes
(such as 23A/B and 9L/N) then this could be extended to about
two-thirds of exacerbation-associated isolates but this would
still be inferior to PPSV23, which theoretically protects against
90% of serotypes. In addition, we did not demonstrate a clearly
superior immune response after PCV7 vaccination for serotype
14 and in fact, as in most studies, we demonstrated an inferior
response to serotype 19F after PCV7 vaccination as compared
with PPSV23 (14, 15). This is of particular concern as these
antibodies do not appear to cross-protect against serotype 19A,
which is frequently antibiotic resistant and has become a more
common cause of invasive disease since the introduction of
routine PCV7 vaccination among children (28). A 13-valent
pneumococcal conjugate vaccine (PCV13) is in development
that will extend the coverage against COPD-associated pneu-
mococcal serotypes to more than 80% and also contains
serotype 19A but the phenomenon of replacement disease
may ultimately limit the protection offered by any serotype-
specific vaccine (29).
There are also limitations to our study. Although the use of
a twofold increase in IgG antibody titer has been used pre-
viously as a measure of vaccine response (17), it is not clear how
this threshold or the 10-fold increase in OPK, which was
selected on the basis of the distribution of the data, correlate
with clinically relevant outcomes. It should also be noted that in
many cases PPSV23 does elicit immune responses that meet
these thresholds and yet appears to have limited efficacy against
pneumococcal pneumonia and acute exacerbations in patients
with COPD. As a result, it cannot be inferred that the more
frequent achievement of serologic responses after PCV7 would
definitively translate into improved clinical outcomes. In addi-
tion, we excluded subjects with comorbid illnesses known to
impair vaccine responses, such as diabetes and alcoholic cirrho-
sis. As these conditions are very common, it is likely that the
immune responses we observed would not be replicated fully in
clinical practice. Our study was designed to examine the
independent effect of the presence of COPD on pneumococcal
vaccine responses as this has not been adequately examined
previously.
In conclusion, we show that PCV7 induces a superior im-
mune response to PPSV23 in COPD at 1 month post vaccina-
tion, and that both vaccines elicit responses comparable to those
previously observed in healthy elderly patients. Despite con-
troversy about the clinical efficacy of PPSV23 in preventing
pneumonia (11), these findings suggest that patients with COPD
respond adequately to the vaccine and support its use to prevent
episodes of invasive disease in this population. We have also
confirmed that prior PPSV23 vaccination and older age are
associated with relative immune hyporesponsiveness. Addi-
tional studies are needed to confirm the superior immunoge-
nicity of PCV13 in COPD, to determine the relative duration of
the immune response after PPSV23 and conjugate vaccination,
and to identify the immunologic correlates of protection against
both invasive and noninvasive pneumococcal disease. In addi-
tion, we believe our data provide the rationale for further study
of the clinical efficacy of protein-conjugate pneumococcal
vaccines in the high-risk COPD population.
Conflict of Interest Statement: M.T.D. served on the Advisory Board for
GlaxoSmithKline ($1,001–$5,000) and AstraZeneca ($1,001–$5,000). He also
received Industry-Sponsored Grants for Contracted COPD Research from Aeris
Therapeutics ($10,001–$50,000), Boehringer Ingelheim ($100,000 or more),
Novartis ($50,001–$100,000), and GlaxoSmithKline for Contracted Asthma
504 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 180 2009
Page 6
Research ($100,001 or more). M.H.N. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. M.K.H.
has received a consultancy with Novartis (,$1,000) and served on an advisory
board for CSL Behring ($1,001–$5,000). S.H. does not have a financial relation-
ship with a commercial entity that has an interest in the subject of this
manuscript. G.J.C. has served on an advisory board for Study Design at Philips-
respironics ($1,001–$5,000) and for Dey ($1,001–$5,000). F.J.M. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. P.D.S. has been an investigator for Phase II, III, and IV clinical
trials sponsored by Boehringer Ingelheim, Dey LP Pharmaceutical, GlaxoSmith-
kline, Novartis AG, and Pfizer Inc. He has served as an ad hoc consultant for
Inflazyne Pharmaceuticals. P.G.W. has received a research grant from Genentech
($100,001 or more) and Boehringer ($100,001 or more). G.R.W. does not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript. J.E.C. has served as an expert witness for Carlson, Caspers,
Vandenbergh & Lindquist, receiving $1,001–5,000; he has received a grant from
Covidien Surgical Staples worth over $100,000. N.R.A. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript. W.C.B. does not have a financial relationship with a commercial
entity that has an interest in the subject of this manuscript.
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