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. 2013 Oct 30;39(ACS-5):1–52. doi: 10.14745/ccdr.v39i00a05
Evidence for Immunogenicity
STUDY DETAILS SUMMARY
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality
Kumar, 2008 (19) Placebo-PNEU-P-23
PNEU-C-7/PNEU-P-23
Route: IM Schedule:
0 weeks,
8 weeks
Dose: 0.5 mL single dose		 Randomizeddouble-blind, Placebo-controlled trial
Length of follow-up: 16 weeks
Power: 80% to detect a 25% difference
Response: ≥ 2-fold increase and level at least 0.35 mg/L		 N= 130
N1= 65
N2 = 65
Baseline
characteristics –patients post-liver transplant ≥ 3 months earlier; PNEU-P-23 ≥ 5 years prior.
Previous PNEU-P-23 (%): 8%, 14% P = 0.17 Prednisone (%): 28, 44 (P = 0.09) Previous anti-thymoglobulin therapy p = 0.064
In multivariate and univariate analysis, corticosteroid use was significantly associated with lower antibody response (OR = 5.0; 95% CI 1.29 – 19.6; p = 0.02)		 Immunogenicity
Response to at least 1 serotype of ≥ 2 fold increase in titer from baseline at 16 weeks:
85.7% vs. 91.2%; p = NS
Mean number of serotypes to respond at week 16:
3.7 ± 2.3 vs., 4.4 ± 2.2 (p= NS)
Response to each serotype at week 16 (%):
48.2-76.8 vs. 36.8 – 64.9 (p = NS)
Serotype-specific GMT at week 16 (μg/mL):
Serotype 4: 0.67 vs. 1.24; p = 0.25
Serotype 6B: 1.8 vs. 2.63; p = 0.56
Serotype 9V: 2.37 vs. 1.96; p = 0.28
Serotype 14: 12.42 vs. 15.49; p = 0.84
Serotype 18C: 4.34 vs. 3.79 p = 0.46
Serotype 19F: 4.95 vs. 5.10; p = 0.78
Serotype 23 F: 1.54 vs. 2.57; p = 0.22
Opsonophagocytic activity ≥ 4 fold from baseline(%): 16.7 – 45.8 vs. 11.5 – 42.3 (p = NS for 6/7 serotypes)		 Level I Good
Kumar, 2003 (20) PNEU-C-7
PNEU-P-23
Dose = 0.5 mL
Route: IM
Study period: Sept–Dec 2001		 Randomized double-blind Controlled trial
Length of follow-up: 8 weeks
Renal transplant: 3 months to 3 years post transplant
Exclusions: splenectomy or PNEU-P-23 in past 5 years		 N = 60 –
Renal transplant
N= 30 (PNEU-P-23)
N= 30 (PNEU-C-7)
Baseline: 2 groups similar in demographic and clinical characteristics including renal function, time since transplantation and immunesuppression.
Response: ELISA: ≥ 2-fold increase with absolute titer of at least 1μg/mL
OPA: ≥4-fold increase with absolute value >1:8		 Immunogenicity (IgG):
Serotype-specific GMT mean fold-increase at 8 weeks compared to baseline (PNEU-C-7 vs. PNEU-P-23):
Serotype 4, 6B, 14, 18C, 19F; p = NS Serotype 23F: 16.8 (range, 0.8 -160) vs. 2.2 (range, 0.4 -23.5); p = 0.046 Serotype 9: 17 vs. 2.6, p = 0.09
Proportion that responded (PNEU-C-7 vs. PNEU-P-23):
Serotypes 4, 9V, 18C, 19F: PNEU-C-7>PNEU-P-23; p = NS
Serotype 23F (%): 40 vs. 16.7; p = 0.046
Serotype 6B: 33.7 vs. 13.3; p = 0.067
≥1 serotype (%): 53.3 vs. 73.3
Median number of serotypes responding: 1.0 vs. 2.5; p= 0.069
Serotype-specific OPA titers –fold increase:
No significant difference between two groups for all 7 serotypes.
Serotype-specific OPA response rate:
83.3 vs. 80; p = NS
Median number of serotype-specific OPA response:
2.0 vs. 3.0; p = NS.		 Level I Good
Kumar, 2007 (21) PNEU-C-7
PNEU-P-23
Original dose: 0.5 mL		 Three-year follow up prospective cohort study of a RCT Renal transplant patients
At 3 years, majority of patients were receiving calcineurininhibitors (95.7%) and MMF (78.7%)		 60 randomized Renal transplant 47 analyzed =
PNEU-C-7 = 23
PNEU-P-23 = 24
14: lost to follow-up due to refusal of consent (7), death (1), unreachable (5)
Baseline characteristics between the two groups were similar with respect to mean age, gender, time from transplant, imunonosuppression, graft loss, serum creatinine, acute rejection during study period.		 Immunogenicity:
Overall (PNEU-P-23 and PNEU-C-7) serotype-specific response rate (≥ 0.35 μg/mL and 2-fold increase from baseline) to each of 7 serotypes at
8 weeks: 12.8% (Serotype 6B)-44.7% (serotype 9V)
At 3 years: 42.1% (serotype 4) -85.0% (serotype 14) of initial responders at 8 weeks. No difference in the percentage of patients maintaining a serotypespecific response at 3 years between PNEU-C-7 and PNEU-P-23 groups for all 7 serotypes. P = NS
Overall GMT at 8 weeks postvaccination was significantly greater for all 7 serotypes compared to baseline; p < 0.001
Overall GMT at 3 years declined significantly for 4, 6B, 9V, 14, 18C, 23F as compared to eight-week titers; p < 0.001 except serotype 19F; p = NS
Significantly greater than prevaccination titers (p < 0.05) for all serotypes except serotype 14
No significant difference in decline of titer between PNEU-C-7 or PNEU-P-23 group at 3 years compared to 8 week titers; p = NS
Single factor predictive of response durability by logistic regression analysis - the number of serotypes patient responded to at 8 weeks (OR 2.63, 95% CI 1.49 -4.76, p = 0.0007)
At 13 months: similar for both groups except serotype 6B - 14.8 μg/mL vs.
4.22 μg/mL p = 0.046		 Level I Good
Tobudic et al. (22) PNEU-C-7
PNEU-P-23		 Single center randomized, single blind, controlled trial N=80 (renal transplant recipients) 9 withdrew 9 lost to follow-up 62 analyzed Immunogenicity
Response Rate (GMT 8 weeks post dose of PNEU-C-7 vs. PNEU-P-23) all had significant rise as compared to baseline except serotypes 6B and 19F in PNEU-P-23.
Response Rate – one year post initial vaccination: (GMT) declined in for all serotypes in both vaccines
Response Rate – 8 weeks post booster with PNEU-P-23 (GMT)
Serotypes (4,6B,14,18C,23F) had better responses than in recipients of one dose PNEU-P-23
Vaccine response ≥ 2-fold rise in antibody concentration and an absolute value of >1ug/mL.
• A response to >1 serotype after one vaccination:
77.1% PNEU-C-7
93.1% PNEU-P-23 (p=0.046)
• A response to >1 serotype after boost with PNEU-P-23:
87.5% PNEU-C-7/PNEU-P-23
87.1% PNEU-P-23/PNEU-P-23 (not significant)
• Median number of serotypes with response:
3.5 in PNEU-C-7/PNEU-P-23
5 in PNEU-P-23		 Level 1 Good
Cordonnier 2009 (23) PNEU-C-7
PNEU-P-23
Schedule: 3 doses of PNEU-C-7 given 1 month apart at:
3 (early) or 9 (late) months post-transplant
PNEU-P-23 at 12 (early) or 18 (late) months post-transplant		 Multicenter, randomized, non-inferiority study.
Non inferiority margin = -20%
Length of follow-up: 24 months
Response = titer at least 0.15 mg/L 1 month after 3rd PNEU-C-7		 N = 158 (Allogeneic HSCT)
Early group = 75
Late group = 83
Analyzed after 3rd dose of PNEU-C-7: 57 (early) 57 (late).
Baseline: Similar
Both groups were balanced with respect to underlying disease, status of HSCT, source of stem cells, Donor age, sex and type, prior vaccination of donor, acute and chronic GVHD, and time from HSCT to first dose of PNEU-C-7.
The 2 groups differed significantly in the % of patients with antibody titer ≥ 0.15 μg/mL prior to PNEU-C-7 vaccination.		 Immunogenicity Early vs. Late
Response rate (antibody titers ≥ 0.15 μg/mL to all 7 PNEU-C-7 serotypes at 1 month after 3rd dose of vaccine): 79% vs. 82%, (90% CI, -15.6 to 8.6)
Response rate (GMT ≥ 0.5 μg/mL to all 7 antibodies at 1 month after 3rd dose): 56% vs. 54% (p = 0.85, 90% CI -13.5 – 17)
Response rate (GMT ≥ 0.15μg/mL to all 7 PNEU-C-7 serotypes at 24 months post-transplantation): 59% vs. 83%; p = 0.013
Response rate (GMT ≥ 0.5 μg/mL to all 7 serotypes at 24 months post-transplantation): 34% vs. 55%; p = 0.054
GMT for all 7 antibodies at 1 month after 3rd dose of PNEU-C-7 were not significantly different between the two groups except for 19F p < 0.001
GMT at 24 months after transplantation following the 3rd dose of PNEU-C-7 and 1 dose of PNEU-P-23 were significantly lower in the early vaccination group than in late vaccination group for 7 serotypes, except 23F p = 0.12		 Level I Good
Molrine, 2003 (24) PNEU-C-7
Single dose IM
Schedule Donors and recipients randomized to PNEU-C-7 vs. nothing 10 days pre-HSCT
All HSCT recipients: PNEU-C-7 at 3, 6, 12 months post-HSCT
Serotypes tested: 4, 6B, 9V, 14, 18C, 19F, 23F
Non T-cell depleted allogeneic HSCT
Donors who had received PNEU-P-23 in past 6 years were excluded		 Randomized-controlled trial
Length of follow up: 13 months *comparison of GMT made with patients in another study with similar baseline clinical characteristics, who received PNEU-P-23 at 12 months
Randomization stratified by age
Subjects ≥ 2 years		 96 pairs randomized – Allo HSCT
Evaluable immunized donors = 30
Evaluable unimmunized donors = 35
Non-evaluable = 31
Baseline: similar in both groups for recipient age, donor age, race, sex, diagnosis, total body irradiation, presence of GVHD, and IVIG after HSCT.
*Donors immunized with a single dose of PNEU-C-7 had a significantly higher GMT to all 7 vaccine serotypes compared to unimmunized donors.		 Immunogenicity
Response rate (%) – immunized vs. unimmunized donors (GMT of ≥0.5 μg/mL to all 7 serotypes) at
3 months: 57 vs. 54%; p=NS
6 months: 67 vs.36%; p=0.05
12 months: 60 vs. 35%; p= NS
13 months: 75 vs.64%; p= NS
Differences in GMT between 2 groups at:
6 months (after 1st dose):
significant for 5 of 7 serotypes
6B (p =0.036)
9V (p = 0.019)
18C (p = 0.039)
19F (p = 0.043)
23F (p = 0.03)
12 months (after 2nd dose): significant for 4 of 7 serotypes
6B (p = 0.013)
14 (p = 0.019)
19F (p = 0.023)
23F (p = 0.0004)
*GMT concentrations in group who received PNEUMO-C-7 at 3, 6, 12 months (n= 45) was significantly higher for all 7 serotypes compared with GMT of PNEU-P-23 group of another study (n= 22) who received initial dose of PNEU-P-23 at 12 months.
Factors independently influencing GMT following HSCT using linear regression analysis:
Donor immunization – higher GMT Administration of IVIG prior to PNEU-C-7 after HSCT – higher GMT at 3 months Level I Fair		 Level I Fair
Kumar, 2007 (25) PNEU-P-23
PNEU-C-7
Dose: 0.5 mL
Donors – recipients pairs
Donors: 1 dose of either vaccine ≥ 2 weeks before harvesting
Recipient: 1 dose of either vaccine 6 months after HSCT.
Route: IM
Serotypes tested: 4, 6B, 14, 18C, 19F, 23F.		 Randomized, double-blind, controlled trial.
Pairs randomized
Length of follow-up: 12 months post HSCT.
Response: 2-fold increase in GMT and absolute titer ≥ 0.35 μ/mL		 N = 64 donorrecipient pairs (Allo HSCT)
PNEU-C-7
pairs = 32
PNEU-P-23
pairs = 32
Baseline: Similar for donors and recipients		 Immunogenicity
GMT in donor: no difference between PNEU-P-23 and PNEU-C-7 GMT at 6 months post-HSCT: No difference for 6 of 7 serotypes, except 6B (p< 0.05) – higher after PNEU-C-7
GMT at 12 months post-HSCT:
No difference for 5 of 7 serotypes, except 14 (p=0.034) and 18C (p=0.013) – higher after PNEU-C-7
Response to at least 1 serotype (≥ 0.35 μg/mL at 6 months post-HSCT):
PNEU-C-7 vs. PNEU-P-23 = 38.1 vs. 0%; p = 0.003
Mean # of serotypes with response at 6 months post HSCT:
PNEU-C-7 vs. PNEU-P-23 = 0.7 vs. 0
Response to at least 1 serotype (≥ 0.35 μg/mL at 12 months) PNEU-C-7 vs. PNEU-P-23 = 90.9 vs. 55.6%; p = 0.02
Response rate was generally poor in both groups.
*Factors shown to impact vaccine response at 12 months by multivariate analysis: vaccine type OR 8.85 (95% CI, 1.62 – 47.6)		 Level I Good
Feikin, 2002 (26) Combination of PNEU-C-7, PNEU-P-23, or placebo
PNEU-C-7/PNEU-C-7
PNEU-C-7/PNEU-P-23
Placebo/PNEU-P-23
Placebo/Placebo
Route:
Intramuscular deltoid injection
Schedule:
0, 8 weeks.		 Randomized controlled trial.
Length of follow up: 24 weeks
Serotypes tested:
4, 6B, 9V, 14, 23F
GMC (IgG)
GMT (OPA)		 N = 90
N = 67
(completed study)
HIV-infected adults with ≥ 200 CD4 cells/μl received 2-dose combinations of vaccines		 Immunogenicity
Serotype specific IgG (ELISA)
Serotype 23F:
PNEU-C-7/PNEU-C-7>Placebo/PNEU-P-23; p=0.024
Serotype 4:
PNEU-C-7/ PNEU-P-23> Placebo/PNEU-P-23; p=0.011
Serotype 6B:
PNEU-C-7/ PNEU-P-23> Placebo/PNEU-P-23; p=0.01
Serotype 9V:
PNEU-C-7/ PNEU-P-23> Placebo/PNEU-P-23; p=0.024
*2nd dose not adding any additional benefit
After 2nd dose: GMC equivalent for PNEU-C-7/PNEU-C-7 and PNEU-C-7/PNEU-P-23
OPA titers
Serotype 9V:
PNEU-C-7/ PNEU-P-23> Placebo/PNEU-P-23; p= 0.034
Serotype 23F:
PNEU-C-7/ PNEU-P-23> Placebo/PNEU-P-23; p=0.028
Serotype 4:
PNEU-C-7/PNEU-C-7> Placebo/PNEU-P-23; p <0.005
Serotype 6B:
PNEU-C-7/PNEU-C-7> Placebo/PNEU-P-23; p=0.012
Serotype 9V:
PNEU-C-7/PNEU-C-7> Placebo/PNEU-P-23; p=0.038
Proportion of subjects with 4-fold rises in titers after 2nd dose higher in groups who received PNEU-C-7 compared to group who received placebo/PNEU-P-23
*2nd dose not adding any increase in OPA titers		 Level I Good
Penaranda 2010 (27) PNEU-C-7
PNEU-P-23
Schedule Group 1:
Single dose PNEU-C-7 at 0 weeks followed by single dose PNEU-P-23 at 4 weeks.
Group 2:PNEU-P-23 at 0 week.		 Randomized, open-label multicenter study
Previously unimmunized adults with HIV and CD4 count between 200–500 cells/μl and HIV viral load <5 log copies/mL
Length of follow-up: 8 weeks.		 N= 220 (110 each group)
Randomized to: PNEU-C-7/PNEU-P-23 4 weeks later
OR
PNEU-P-23 alone Patient characteristics:
Similar at baseline except for proportion of patients taking
HAART:
98% in group 1 vs. 91% in group 2		 Primary end points
1) Specific IgG ≥ 2 fold
2) Specific IgG increase 2-fold AND reaching 1μg/mL
Percentage of responders at 8 weeks using criteria 1 and 2:
No difference between 2 groups except for serotype 23F:
26% (combined) vs. 14% responders (alone)
OR = 2.2; 95% CI 1.07-4.56
No difference in avidity		 Level I Good
Crum-Cianflone, 2010 (28) Revaccination using
PNEU-C-7 or PNEU-P-23
Single 3 to 8 years after previous PNEU-P-23		 Randomized controlled trial.
HIV infected randomized 2:1 (PNEU-C-7: PNEU-P-23)
HIV uninfected: 1 dose PNEU-C-7
Patients:
18–60 years
Length of follow-up: 180 days.
Duration of study: Feb 2006–September 2008		 N = 131
(PNEU-C-7)
N = 73
(PNEU-P-23)
HIV-infected adults vaccinated with PNEU-P-23 3–8 years earlier
N= 25 in HIV-uninfected arm not vaccinated a priori
Baseline: similar (median CD4 count > 500 cells/mm3) except for HAART (%)		 Primary end point:
Proportion of subjects with positive antibody response to at least 2 of 4 (4, 9V, 14, 19F) serotypes at day 60. Positive response: ≥ 2 fold response in IgG level
Proportion with response to 2 of 4 serotypes at 60 days:
PNEU-C-7 = 57% vs. PNEU-P-23 = 36%; p=0.004 (HIV uninfected = 88%)
Mean changes in IgG concentration from baseline to
Day 60: PNEU-C-7 > PNEU-P-23 for serotypes 4, 9V, 19F (p < 0.05), not for serotype 14.
Day 180: PNEU-C-7 = PNEU-P-23 HIV-uninfected group: greater response in frequency and magnitude compared to HIV-infected group.
Adjusted OR for response to 2 of 4 serotypes
HIV infected: PNEU-C-7 vs. PNEU-P-23:
OR = 2.6 (1.4-5.0)
PNEU-C-7: HIV infected vs. uninfected:
OR = 0.2 (0.1-0.7)		 Level I Good
Lesprit, 2007 (29) PNEU-C-7/PNEU-P-23 at 4 weeks later
OR
PNEU-P-23 at 4 weeks
Dose – n/a
Route – n/a		 Randomized controlled trial – stratified on CD4 at baseline and prior ARV
Length of follow-up:
24 weeks
Inclusion:
HIV1 with CD4: 200-500
VL: <50,000 copies/mL; ARV naive or stable regimen x at least 3 months; no pneumococcal infection in previous 5 years
Patients screened between December 2002 and December 2003		 N = 212 (HIV-infected patients)
Randomized to:
PNEU-C-7/PNEU-P-23 (106)
PNEU-P-23 alone (106)
Baseline:
No difference in baseline characteristics between 2 groups		 Immunogenicity Outcomes
a) 2-fold increase in serotype-specific IgG levels
b) 2-fold increase AND level of at least 1 mg/L
Baseline: IgG titers not different in both groups
At week 8 (4 weeks after PNEU-P-23 in both groups): IgG titers same for both groups except for 18C and 23F (higher with combined schedule)
At week 24: IgG titers same for both groups except for 18C, 23F, 14, and 19F.
Proportion of subjects who met criteria b above:
No difference between groups at 8 weeks, except for response to 5 of 7 serotypes (59% of combined vs. 40% of PNEU-P-23, p= 0.005) and same for levels at week 24, except for response to 5 of 7 serotypes (30% of combined vs. 10% of PNEU-P-23, p=0.003).		 Level I Good
Frenck, 2012 (30) PNEU-C-13/TIV – placebo (1 month later)
vs. Placebo/TIV – PNEUC-13 1 month later 0.5 mL IM		 Randomized controlled trial
Population: Healthy 50–59 years of age. No previous pneumococcal vaccination		 Multicentric – U.S.
N = 1158
enrolled
N = 1116
randomized
N1 = 554
(PNEU-C-13/TIV)
N2 = 562 (TIV then PNEU-C-13)		 PNEU-C-13 IgG serotype specific response (ELISA) 1 month after pneumococcal vaccination
OPA: serotype specific response
1. GMCs between 1.15 (serotype 3) and 16.80 (19A) μg/mL in concomitant group and between 1.46 (3) and 18.84 (19A) μg/mL in PNEU-C-13 group
2. OPA GMTs between 61 (serotype 3) and 2421 (6B) in concomitant group and between 78 (3) and 3215 (6B) in PNEU-C-13 group
3. Response to TIV: similar in both groups
4. Response to PNEU-C-13:
a) GMCs tended to be lower in the concomitant administration group with ratios from 0.69 to 0.89 – none reached the inferiority criterion;
b) OPA GMTs also tended to be lower in the concomitant group with ratios ranging from 0.5 to 0.8 – serotypes 1, 5, 7F, 9V, and 19F met the inferiority criterion (lower bound of 95% CI <0.5)		 Level I Good
Schwarz, 2011 (31) PNEU-C-13/TIV – placebo (1 month later) vs. Placebo/ TIV – PNEU-C-13 1 month later 0.5 mL IM Randomized controlled trial
All PNEU-C-13 serotypes tested
Healthy 65 years and over. No previous pneumococcal vaccination
Follow-up until 1 month after last vaccine administered		 Multicentric – Europe
N = 1190
participants enrolled; 1160 randomized – 580 in each group
1096 evaluable		 IgG specific GMCs in each arm – ratio of GMCs
1. GMCs between 1.08 (serotype 3) and 11.98 (19A) μg/mL in concomitant group and between 1.15 (3) and 17.10 (19A) μg/mL in PNEU-C-13 group
2. Response to TIV: similar in both groups
3. Response to PNEU-C-13: GMCs tended to be lower in the concomitant administration group with ratios from 0.65 to 0.97 – only serotype 19F was below the non-inferiority value (lower bound CI <0.5).		 Level I Good
Jackson, 2007 (32) PNEU-C-7
PNEU-P-23
Dose (PNEU-C-7):
0.1 mL or 0.5 mL or
1 mL or
2 mL or
*PNEU-C-7 licensed at 0.5 mL in children
Dose (PNEU-P-23): 0.5 mL IM
0.1 Ml challenge with PNEU-P-23 dose at 1 year		 Randomized controlled trial.
Length of follow-up: 1 year and 4 weeks.
Serotypes tested: 4, 6B, 9V, 14, 18C, 19F, 23F.
Population:
Aged 70–79 years who had received PNEU-P-23 on or after 65th birthday, at least 5 years prior		 N = 220
Randomized 4:1 by group of 55 to PNEU-C-7 at 0.1, 0.5, 1, and 2 mL vs. PNEU-P-23
N = 219
(analyzed after 1st vaccination)
N = 208 (before challenge PNEU-P-23 vaccine)
N = 203 (analyzed post-challenge vaccination)		 Immunogenicity
Serotype-specific GMC post enrolment vaccination (0.5 mL vs. 1 mL and 2 mL; 95% CI)
Post-vaccination titers were greater with 1- and 2-mL doses for all serotypes except serotype 14:
0.5 mL-8.8 (5.8-13.2) vs.
1 mL - 7.3(4.7-11.3) vs.
2 mL - 8.9(5.5-14.8)
Post vaccination titers were significantly higher at 2-mL dose than at 0.5-mL dose for:
Serotype 6B; p < 0.05
At 0.5 mL - 2.6 (1.6-4.2)
2 mL - 4.7 (2.9-7.6)
Serotype 9V; p< 0.05
0.5 mL- 3.2 (2.0- 4.9)
2 mL - 6.4 (4.2-9.2)
Serotype 23F: p < 0.05
0.5 mL - 3.4 (1.9-5.9)
2 mL - 7.2 (4.3-12.1)
Post vaccination titers were significantly higher at 1 mL and 2 mL than 0.5 mL for:
Serotype 18C; p < 0.05
0.5 mL - 5.0 (3.3-7.7)
1 mL - 8.8 (6.5-12.0)
2 mL - 8.7 (5.8-13.1)
Serotype 19F; p < 0.05
0.5 mL - 3.4 (2.4-4.9
1 mL - 6.0 (4.0-8.9)
2 mL - 5.6 (4.1-7.8)
After 1 year (pre-challenge): GMC by ELISA were similar to pre-vaccine, regardless of vaccine given and dose
Adjusted for baseline GMC post-PCV7 vs. PPV23
No significant difference between 0.5 mL PNEU-C-7 group and PNEU-P-23 group for all serotypes but when adjusted for baseline GMC: 2 serotypes met criteria for superior immunogenicity for PNEU-C-7 vs. PNEU-P-23
GMC for 1 mL & 2 mL:
PNEU-C-7 > PNEU-P-23 for all
serotypes with significant difference in GMC titers for: (Data shown for PNEU-C-7 1 mL, 2 mL and PNEU-P-23):
Serotype 4:
2.8 (1.6-4.9) vs. 2.8(1.8-4.3) vs. 1.1 (0.7-1.8)
Serotype 9V:
5.3 (3.4-8.0) vs. 6.2 (4.1-9.2) vs. 2.7 (1.8-3.9)
Serotype 18C:
8.8 (6.5- 12.0) vs. 8.7 (5.8-13.1) vs. 4.5 (3.0- 6.5)
Serotype 23F:
5.9 (3.3-10.8) vs. 7.2(4.3-12.1) vs. 2.3 (1.5- 3.5)
When adjusted for baseline GMC: 1 and 2 mL of PNEU-C-7 = 6 serotypes met superiority criteria compared with PNEU-P-23
PNEU-C-7 vs. PNEU-P-23 OPA GMC titers; (95% CI)
Significantly higher at 0.5 mL for 2 of 7 serotypes:
Serotype 9V:
332 (147- 752) vs. 59 (24-146)
Serotype 23F:
4572 (2674- 7818) vs. 502 (207 -1217)
Significantly higher at 1 mL and 2 mL for serotypes 4, 6B, 9V, 18C & 23F There was no significant difference in pre and post-challenge vaccination titers for all serotypes for all four groups		 Level I Good
De Roux, 2008 (33) PNEU-C-7 followed by either PNEU-C-7 or PNEU-P-23 one year later
OR
PNEU-P-23 followed by PNEU-C-7 one year later		 Randomized open-labeled phase 2 study
Length of follow-up: 13 months
Population: 70 years and older with NO previous pneumococcal vaccination		 N= 219
ambulatory elderly adults ≥ 70 years
PNEU-C-7
1st dose = 110
PNEU-P-23
1st dose = 109
PNEU-C-7/
PNEU-C-7 = 43
PNEU-C-7/
PNEU-P-23 = 38
PNEU-P-23/
PNEU-C-7 = 78
Baseline:
pre-immunization antibody levels were similar between initial groups. Mean age at entry was 75 years.		 Immunogenicity
Serotype specific IgG antibody level (μg/mL) (measured 1 month after last dose):
Single dose PNEU-C-7 vs. single dose PNEU-P-23: Significantly higher (p < 0.01) for serotype 4, 6B, 9V, 14, 18C & 23 F.
Difference not significant for serotype 19F
PNEU-P-23/ PNEU-C-7 vs. single dose PNEU-C-7: Significantly lower for all serotypes; p ≤ 0.05
PNEU-C-7/ PNEU-C-7 vs. single dose PCV7: Significantly lower for serotype 9V; p = 0.02
Difference not significant for serotypes 4, 6B, 9V, 14, 18C & 23F.
PNEU-C-7/PNEU-P-23 vs. single dose PNEU-C-7: Significantly higher for serotypes 19F and 23 F.
No significant difference for serotypes 4, 6B, 9V, 14, 18C.
GMTs of OPA after 1st and 2nd doses:
PNEU-C-7 vs. PNEU-P-23:
Significantly higher for all serotypes tested; p < 0.01 - except 6B and 19F
PNEU-P-23/ PNEU-C-7 vs. single dose PNEU-C-7:
Significantly lower for all serotypes tested (p < 0.01) except serotype 19F
PNEU-C-7/ PNEU-C-7 vs. single dose PNEU-C-7:
No difference for all serotype except 23 F; p < 0.01.
PNEU-C-7/PNEU-P-23 vs. Single dose PNEU-P-23:
Significantly higher for serotypes 4, 9V, 14, 18C, 19F, 23 F; p < 0.01
Difference not significant for serotype 6B.		 Level I Good
Miernyk, 2009 (34) PNEU-P-23
PNEU-C-7
Dose: 0.5 mL IM
Group 1:
PNEU-P-23
Group 2:
PNEU-C-7/PNEU-P-23 2 months later
Group 3:
PNEU-C-7/PNEU-P-23 6 months later
Serotypes tested: 1, 4, 6B, 14, 19F.		 Randomized controlled trial
Population: Alaskan Natives aged 55–70 years Not previously vaccinated against pneumo		 PNEU-P-23 = 28
PNEU-C-7/PNEU-P-23 2 months later = 29
PNEU-C-7/PNEU-P-23 6 months later =29
Baseline: study groups did not differ significantly in age or gender.		 Immunogenicity
Serotype-specific IgG (GMC μg/mL) (95% CI)
No difference in baseline IgG GMCs for serotypes 1, 4, 6B, 14 & 19F between groups 1,2 &3; p > 0.3
*2 months after 1st dose (group 1 = PNEU-P-23 vs. group 2&3 = PNEU-C-7)
All study groups showed significant increases in GMCs to all vaccine specific serotypes compared to baseline and were similar in all groups except for:
Serotype 1: 1.95 (1.21-3.15) after PNEU-P-23 vs. 0.43 (0.31-0.59) after PNEU-C-7; p < 0.001
No significant difference between groups 1,2 & 3 for Serotypes 4, 6b, 14, 19F; p> 0.2
*2 months after final dose:
No difference between groups 1, 2&3 for all serotypes tested; p> 0.3
Median OPA (Range)
Baseline OPA s against all serotypes tested were similar among all 3 study groups; p > 0.05
*2 months after 1st dose
(group 1 vs. groups 2&3)
All study groups showed significant increase in GMCs against vaccine specific serotypes except
Serotype 1 which showed no increase in all 3 groups
Serotype 4 which showed nonsignificant increase in group 3; p = 0.122
No difference between groups 1, 2, &3 for all serotypes tested; p > 0.15
*2 months after final dose:
No difference between groups 1, 2, &3 for all serotypes tested; p > 0.2		 Level I Good
Goldblatt, 2009 (35) PNEU-C-7
PNEU-P-23
Group 1:
PNEU-C-7/
PNEU-C-7 6 months later
Group 2:
PNEU-C-7/
PNEU-P-23 6 months later
Group 3:
PNEU-P-23
Group 4:
PNEU-C-7		 Randomized open-labeled controlled trial
Length of follow-up:
12 months
IgG titers cut-off:
0.35ug/mL		 Group 1=133
Group 2=171
Group 3=159
Group 4=136
Study patients were 50–80 yrs, did not receive either pneumo vaccine in 3 ≤ 5 yrs before recruitment. There were similar numbers of individuals in the 50–59, 60–69, 70–79 age in each group.
No baseline characteristics provided		 Immunogenicity
GMC (serotype-specific IgG) at 4–6 weeks after vaccination (PNEU-C-7 vs PNEU-P-23):
Serotypes 4,9, 23F: PNEU-C-7 > PNEU-P-23
Serotype 19F: PNEU-P-23 > PNEU-C-7
GMC at 1 year (PNEU-C-7 vs. PNEU-P-23)
No significant difference for serotypes 4, 6B, 9V, 14, 18C, 19F.
Serotype 23F: 4.11 (PNEU-C-7; 95%CI, 3.19-5.29) vs. 2.3 (PNEU-P-23; 95% CI1.81-2.92)
GMC 4–6 weeks after 2nd dose:
Serotype 19 F: 9.9 (PNEU-C-7/PNEU-P-23; 95% CI 8.27 -11.85) > 6.74 (PNEU-C-7/PNEU-C-7; 95% CI 5.76 -7.19)
No difference between PNEU-C-7/PNEU-P-23 and PNEU-C-/PNEU-C-7 for remaining 6 serotypes.
Proportion of subjects with serotype-specific IgG concentration > 1.0 μg/mL at 12 months after PNEU-C-7/PNEU-C-7 vs. PNEU-P-23 alone for serotypes:
4B: 0.74 (0.65-0.81) vs. 0.67 (0.59-0.75) 6B: 0.86 (0.79-0.92) vs. 0.80 (0.73-0.86) 9V: 0.94 (0.89-0.98) vs. 0.84 (0.77-0.89) 14: 0.98 (0.94-1.0) vs. 0.95 (0.91-0.98) 18C: 0.95 (0.9-0.98) vs. 0.91 (0.86-0.95) 19F: 0.97 (0.92-0.99) vs. 0.96 (0.91-0.99) 23F: 0.86 (0.79-0.92) s. 0.74 (0.66-0.81)
Overall PNEU-C-7/PNEU-C-7 = PNEU-P-23 (p = NS)		 Level I Good
Schenkein, 2008 (36) PNEU-P-23
0.5 mL x1 IM
Serotypes tested: 4, 6B, 9V, 14, 18C, 19F, 23F tested 28 days post vaccine		 Randomized controlled trial
Comparative study of immune response in those aged 65 years and above vs. aged 45 years and less		 <45 years =45
≥ 65 years =58
Older adults were community dwelling individuals taken from control group subset of a previously reported randomized, double-blind, placebo controlled trial.
Younger adults were healthy volunteers recruited from lab research personnel from large university medical center.		 Immunogenicity
Serotype-specific IgG GMC:
No difference in GMC between younger and older age group for serotypes 4, 6B, 9V, 14, 18C & 23F. Serotype 19F: 9.14 vs. 5.24; p = 0.001
Serotype specific OPA titers (95% CI)
Serotype 4: 1735 (1074-2804) vs. 453 (250-821); p < 0.01
Serotype 6B: 1707(1046-2787) vs. 377 (188-756); p < 0.01
Serotype 9V: 3957(1921-8151) vs. 411(203-832); p < 0.001
Serotype 14: 3715 (1888-7309) vs. 1250 (717-2179); p <0.01
Serotype 18C: 1344 (721-2505) vs. 933 (500-1740); p =0.09
Serotype 19F: 1254 (707-2223) vs. 266 (133-532) p< 0.01
Serotype 23F: 766 (377-1554) vs. 147 (76-285); p < 0.001
Antibody potency (OT/IgG):
Significantly higher for all serotypes in the younger age group than in the older age group; p<0.05 for all serotypes.		 Level I Good
Musher, 2010 (37) PNEU-P-23
Placebo
Followed 30 days later by other product in alternate arm
Route: IM
Follow-up:
5 years – yearly blood samples thereafter		 Randomized controlled trial
Exclusion: prior IPD, splenectomy, immune suppression
Stratified by age group and prior history of pneumococcal vaccination (at least 3 years before for those aged 50–64 and 3 to 5 years before for those aged 65 years and older)		 50–65 yrs, primary vaccination = 222
50–65 yrs, revaccination= 157
≥ 65, primary vaccination = 222
≥65 revaccination = 407
Total n = 1008;
721 participated in persistence up to 5 years (average 3.9 years)
Baseline characteristics similar between four groups except revaccination subjects within each age group were more likely to report risk factors IPD.
Baseline IgG levels similar between younger and older adults who had not previously received PNEU-P=23 and between younger and older adults who had been previously vaccinated.
Baseline IgG levels were 2–3 fold higher in those previously vaccinated and not vaccinated.		 Immunogenicity
Serotype-specific IgG at Day 30:
Level significantly higher compared to baseline for all 4 groups
Primary vs. revaccination IgG levels at Day 30
≥65 years: Same in 2 groups for all
serotypes except
Serotype 8: 8.5 vs. 6.6 (p< 0.5)
Serotype 14: 28.7 vs. 20.8 (p< 0.5)
50–65 years: Same in 2 groups for all serotypes except
Serotype 14: 36.1 vs. 24.6 (p<0.5)
For all other serotypes, no significant difference between primary and revaccination groups in both age groups, although marginally higher in the primary vaccination group.
Serotype specific IgG at day 60:
Higher compared to day 30 in older revaccination and older primary vaccination and younger revaccination group for all serotypes; p = NS
Higher in younger revaccination group for serotypes 4, 6B, 14, 23F; p = NS
Serotype-specific IgG at 5 years:
Serotype 3 IgG levels returned to baseline in all 4 study groups by year 2.
Re-vaccinated patients:
For remaining 7 serotypes (except 3), IgG levels were similar compared to baseline (p = NS) and at least 2-fold higher than vaccine naive recipients (baseline of primary vaccines)
Primary vaccinees:
In 50–65 group, levels were greater than baseline for serotypes 4,6B, 8, 9V, 12 F, 14 and 23 F; p =N
In ≥ 65 years serotypes 4, 6B, 9V, 12F, 14 and 23F; p = NS		 Level I Good