Vaccine 32 (2014) 2364–2374
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Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age Richard N. Greenberg a,∗ , Alejandra Gurtman b , Robert W. Frenck c , Cynthia Strout d , Kathrin U. Jansen b , James Trammel e , Daniel A. Scott b , Emilio A. Emini b , William C. Gruber b , Beate Schmoele-Thoma f a
University of Kentucky School of Medicine, Department of Medicine, Room MN-663, 800 Rose Street, Lexington, KY 40536-0084, United States Pfizer Vaccines Research, Pfizer Inc., 401 N Middletown Road, Pearl River, NY 10965, United States c Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6014, Cincinnati, OH, United States d Coastal Carolina Research Center, 1156 Bowman Road, Suite 102, Mount Pleasant, SC, United States e inVentiv Health Clinical, LLC, 504 Carnegie Center, Princeton, NJ, United States f Pfizer Vaccines Research, Pfizer Pharma GmbH, Linkstrasse 10, 10785 Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 23 September 2013 Received in revised form 18 December 2013 Accepted 4 February 2014 Available online 5 March 2014 Keywords: Adult Pneumococcal conjugate vaccine Recall responses
a b s t r a c t Background: Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T–cell–dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations. Methods: We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60–64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination. Results: OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose. Conclusion: In pneumococcal vaccine–naïve adults 60–64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations. ClinicalTrials.gov Identifier: NCT00574548. © 2014 Elsevier Ltd. All rights reserved.
Abbreviations: ACIP, Advisory Committee on Immunization Practices; AE, adverse event; CI, confidence interval; CRM197 , cross-reactive material 197; GMR, geometric mean ratio; GMT, geometric mean titer; LLOQ, lower limit of quantitation; LOD, limit of detection; OPA, opsonophagocytic activity; PCV, pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; SAE, serious adverse event. ∗ Corresponding author. Tel.: +1 859 323 6327; fax: +1 859 323 1631. E-mail addresses: [email protected] (R.N. Greenberg), alejandra.gurtman@pfizer.com (A. Gurtman), [email protected] (R.W. Frenck), [email protected] (C. Strout), kathrin.jansen@pfizer.com (K.U. Jansen), [email protected] (J. Trammel), dan.scott@pfizer.com (D.A. Scott), emilio.emini@pfizer.com (E.A. Emini), bill.gruber@pfizer.com (W.C. Gruber), beate.schmoele-thoma@pfizer.com (B. Schmoele-Thoma). http://dx.doi.org/10.1016/j.vaccine.2014.02.002 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
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1. Introduction
2.2. Vaccines and administration
The incidence and mortality of pneumococcal disease in adults increase with advancing age [1,2]. A single dose of 23-valent pneumococcal vaccine containing free (unconjugated) polysaccharides (PPSV23) is currently recommended for adults ≥65 years and for younger adults with certain chronic medical conditions or other indications [2]. The duration of the immune response of PPSV23 is likely limited, indicating a need for periodic revaccination [3]. However, the United States Advisory Committee on Immunization Practices (ACIP) does not recommend routine PPSV23 revaccinations, in part due to the diminished immune responses that have been observed following revaccination [2,4]. In contrast, polysaccharide conjugate vaccines typically elicit T–cell–dependent immunity with an associated ability to induce a recall response upon revaccination with polysaccharide antigen [5]. We conducted a randomized clinical trial in pneumococcalvaccine naïve adults 60–64 years of age to evaluate safety and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) when administered as an initial dose of a 2-dose regimen with either PPSV23 or PCV13 with vaccine administrations given 1 year later. The purpose of the study was to assess the immunological influence of the initially administered vaccine on antipneumococcal responses following the second vaccine administration. This study was part of the adult PCV13 clinical development program.
PCV13 (Prevnar 13/Prevenar 13® ; Wyeth Vaccines; Lot Number 7-5095-005A) contains polysaccharides of pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, and 23F individually conjugated to a nontoxic mutant form of diphtheria toxin cross-reactive material 197 (CRM197 ). Each 0.5-mL dose contains 2.2 g of each serotype, except serotype 6B, which is included at 4.4 g. Each dose is formulated in 5.0 mM succinate and 0.85% sodium chloride at pH 5.8 with 0.125 mg aluminum as aluminum phosphate and 0.02% polysorbate 80. The vaccine is supplied in single-dose syringes without preservatives and stored at 2–8 ◦ C. PPSV23 (Pneumovax 23® ; Merck & Company, Inc.; Lot Number 0486U) consists of a purified capsular polysaccharide from 12 of the serotypes included in PCV13 (all except serotype 6A), as well as 11 additional serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F). The vaccine is formulated to contain 25 g of each of the 23 purified polysaccharide serotypes per 0.5-mL dose of vaccine, contains phenol as a preservative, and stored at 2–8 ◦ C. Vaccines were administered by intramuscular injection in the deltoid using 25G 1-inch needles.
2. Methods 2.1. Study design and populations This was a phase 3, parallel-group, randomized, activecontrolled, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60 through 64 years of age, conducted at 21 medical centers in the United States. The study was undertaken in accordance with the Declaration of Helsinki and Good Clinical Practice [6,7]. After obtaining informed consent, subjects were randomly assigned in a 3:5:4 ratio to receive either PCV13 at year 0 and a subsequent dose of PCV13 at year 1, PCV13 at year 0 and a subsequent dose of PPSV23 at year 1, or PPSV23 at year 0 and a subsequent dose of PCV13 at year 1 (Fig. 1). In this modified double-blind design, PCV13 and PPSV23 were dispensed and administered by unblinded study staff members who were not involved in subsequent subject assessments. All other study staff members, in particular the individuals who evaluated subject safety, were blinded, as were the study subjects. As the study vaccines were different in physical appearance, the study vaccine syringes were labeled in a manner that prevented the study subjects from identifying the vaccine type based on its appearance. The study allowed enrollment of subjects with pre-existing chronic underlying conditions (e.g., cardiovascular, pulmonary, and liver diseases including alcoholic liver disease and alcoholism; renal and urinary disorders; or diabetes mellitus). Disease had to be stable, defined as not requiring significant change in therapy or hospitalization for worsening disease 12 weeks prior to vaccination. To be eligible for enrolment, subjects could not have received a diphtheria toxin–containing vaccine in the previous 6 months or be receiving antibiotics at the time of vaccination. Clinic visits occurred at vaccination and 1 month (29–43 days) after vaccination with a telephone visit for a safety assessment at 6 months after vaccination. Blood samples were obtained before and 1 month after vaccination.
2.3. Study objectives The two primary study objectives were focused on the immune responses after the second vaccine administration: (1) demonstration that PPSV23 administered 1 year after an initial dose of PCV13 is noninferior to the initial dose of PPSV23 for the 12 common serotypes, as measured by opsonophagocytic activity (OPA) titers 1 month after vaccination; and (2) demonstration that PPSV23 administered 1 year after an initial dose of PCV13 is noninferior with regard to elicited OPA responses to PCV13 administered 1 year after an initial dose of PPSV23. Two key secondary objectives were linked to the primary objectives to demonstrate that PPSV23 administration after PCV13 (PCV13/PPSV23) elicits statistically significantly higher responses for at least some of the 12 common serotypes compared with an initial dose of PPSV23 or to PCV13 administration after PPSV23 (PPSV23/PCV13). Additional analyses included evaluations (1) to demonstrate that the response following a second dose of PCV13 given 1 year after an initial dose of PCV13 (PCV13/PCV13) is noninferior to the response observed after the initial dose of PCV13; and (2) to demonstrate that the responses following PCV13 administered 1 year after a dose of PPSV23 (PPSV23/PCV13) are inferior compared with responses after a single PCV13 administration, for at least some of the 12 common serotypes. Additional immune response comparisons were also performed as described in Section 3. 2.4. Analysis populations The evaluable immunogenicity population was the primary population for immunogenicity analyses and consisted of eligible subjects who had ≥1 valid and determinate assay result, received both study vaccines as assigned and no prohibited vaccines, and had no other major protocol violation. The safety population included all subjects who received ≥1 dose of study vaccine. 2.5. Immunogenicity assessments Primary endpoints were the functional antibacterial OPA titers for the 13 serotypes in PCV13 measured using serotype-specific validated OPA assays in samples obtained immediately before and approximately 1 month after each vaccination [8]. Titers were defined as the interpolated reciprocal serum dilution that resulted in complement-mediated phagocytic killing of 50% of the assay
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720 subjects randomized
Year 0
482 subjects randomized to receive PCV13
238 subjects randomized to receive PPSV23
12 subjects excluded
a
470 subjects included in the evaluable immunogenicity population 478 subjects included in the safety population
2 subjects excluded
a
236 subjects included in the evaluable immunogenicity population 237 subjects included in the safety population
Year 1
180 subjects as randomized at Y0 to receive PCV13/PCV13
47 subjects excluded
302 subjects as randomized at Y0 to receive PCV13/PPSV23
a
133 subjects included in the evaluable immunogenicity population 160 subjects included in the safety population (PCV13/PCV13)
65 subjects excluded
237 subjects included in the evaluable immunogenicity population 267 subjects included in the safety population (PCV13/PPSV23)
238 subjects as randomized at Y0 to receive PPSV23/PCV13
a
39 subjects excluded
a
199 subjects included in the evaluable immunogenicity population 223 subjects included in the safety population (PPSV23/PCV13)
Fig. 1. Study design and disposition of subjects. a Subjects could be excluded for >1 reason. Reasons for exclusion include: not receiving vaccination, protocol violations, ineligibility for the study, and invalid assay results. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.
bacteria. The lowest titer that can be determined in the assay (limit of detection [LOD]), regardless of serotype, is 1:8. However, to quantify functional antibodies with appropriate precision and accuracy, the lower limit of quantitation (LLOQ) was determined for each serotype-specific OPA assay during assay validation. Titers below the LLOQ were set to a value of 1:4 (i.e., half of the LOD). 2.6. Safety assessments Subjects recorded local reactions, systemic events, and oral temperature in an electronic diary on the evening of vaccination and for the next 13 days. Adverse events (AEs) were recorded from enrollment through the month 1 postvaccination visit, serious AEs (SAEs) from enrollment through the 6-month follow-up telephone contact after each vaccination, and deaths through the end of the study. 2.7. Statistical analysis 2.7.1. Sample size considerations The sample size estimation was based on the 1-year OPA response to 7 of the 13 serotypes in PCV13 that were reported in a previous trial of 7-valent pneumococcal conjugate vaccine (PCV7)
in adults ≥70 years of age naïve to pneumococcal immunization [9]. The sample size of approximately 400 evaluable subjects in the PCV13 group (with 150 and 250 in the subgroups at year 1) and of approximately 200 evaluable subjects in the PPSV23 group was determined to provide ≥90% overall power to declare noninferiority of either PCV13/PPSV23 vs. PPSV23, or PCV13/PPSV23 vs. PPSV23/PCV13, for the 12 pneumococcal antigens common to both vaccines using a 2-fold noninferiority criterion of 0.5, 2-sided type 1 error rate of 0.05, and a dropout rate of not more than 15%.
2.7.2. Immunogenicity analyses For the pairwise comparison of OPA geometric mean titers (GMTs) between vaccine groups or vaccination sequences, the 2-sided 95% confidence intervals (CIs) based on the Student t distribution for the geometric mean ratio (GMR; defined as GMT group 1/GMT group 2) for each of the common serotypes were calculated. Noninferiority of group 1 relative to group 2 was declared if the lower limit of the 2-sided 95% CI for the GMR was >0.5 (2-fold criterion). Statistically significantly higher response was declared if the lower limit of the 95% CI for the GMR was >1.0 (or >2.0 for serotype 6A). Statistically significantly lower responses were declared if the upper limit of the 95% CI for the GMR was 40 ◦ C was reported (Table 4). Incidences of local reactions were highest after PCV13/PPSV23 and lowest after PPSV23/PCV13. Generally similar rates of local reactions were observed when PCV13/PCV13 and PPSV23/PCV13 were compared to a single administration of PCV13. However, rates of all types of local reactions were generally higher when PCV13/PPSV23 was compared to a single administration of PPSV23. Incidences of systemic events after PCV13/PCV13 and PPSV23/PCV13 compared to PCV13, as well as PCV13/PPSV23 compared to PPSV23, were generally similar, with statistically significant differences for only a few systemic events considered not clinically important. The incidences of subjects reporting any unsolicited AEs were low and were similar in the PCV13 group (19.2%) and the PPSV23 group (20.7%). The most frequent category of AEs in each vaccine group was infections and infestations, which occurred in 8.6% and 13.1% of those who received PCV13 and PPSV23, respectively. The most common individual AEs were nasopharyngitis (1.9% for PCV13; 2.5% for PPSV23) and upper respiratory tract infection (1.5% for PCV13; 3.4% for PPSV23). After vaccination 2, the incidences of any AEs were 13.8%, 19.1%, and 14.8% for the PCV13/PCV13, PCV13/PPSV23, and PPSV23/PCV13 groups, respectively. The most frequent category of AEs in each vaccine group was infections and infestations, reported in 7.5% of subjects in the PCV13/PCV13 and PCV13/PPSV23 groups and 4.0% of subjects in the PPSV23/PCV13 group, with the most common
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Table 1 Baseline characteristics. Initial vaccine
Characteristic Female, % Race, % White Black or African American Other American Indian or Alaska Native Asian Native Hawaiian or Other Pacific Islander Mean age at vaccination, years (±SD) Any chronic underlying diseases at study entry, % Cardiovascular diseases Pulmonary diseases Diabetes mellitus Liver diseases Renal and urinary disorders
Vaccine sequences
PCV13
PPSV23
PCV13/PCV13
PCV13/PPSV23
PPSV23/PCV13
n = 478 58.8
n = 237 56.5
n = 160 57.5
n = 267 57.3
n = 223 55.6
94.6 3.6 0.8 0.6 0.2 0.2 61.7 (±1.4) 26.4 5.9 9.4 15.3 0.4 0.2
97.0 3.0 0 0 0 0 61.7 (±1.4) 23.6 6.3 8 13.1 0.8 0.8
93.8 3.8 1.3 0.6 0.6 0 62.6 (±1.4)
96.6 3.0 0 0.4 0 0 62.6 (±1.3)
96.9 3.1 0 0 0 0 62.7 (±1.4)
Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; SD, standard deviation.
individual AEs in the 3 groups combined being nasopharyngitis, sinusitis, upper respiratory tract infection, and bronchitis. The difference in incidence of related AEs after PCV13 (15 subjects, 3.1%) and PPSV23 (3 subjects, 1.3%) was not significant. Most frequently reported were general disorders and administration site conditions, reported by 10 (2.1%) PCV13 recipients and 2 (0.8%) PPSV23 recipients, with the most frequently related individual AEs being injection site erythema (4 subjects, 0.8% for PCV13; 1 subject, 0.4% for PPSV23) and injection site hematoma (3 subjects, 0.6% for PCV13; 1 subject, 0.4% for PPSV23). Overall, 1, 5, and 2 subjects had AEs assessed as related in the PCV13/PCV13, PCV13/PPSV23, and PPSV23/PCV13 groups, respectively. Most frequently observed were general disorders and administration site conditions, including hematoma, pain, erythema, induration, and rash, with no significant differences between groups. After initial vaccination, SAEs were reported in 2 (0.4%) subjects who received PCV13 (breast cancer, squamous cell carcinoma of the skin) and 1 (0.4%) subject who received PPSV23 (3 cardiac events; myocardial infarction, unstable angina, and arrhythmia). The SAEs reported after vaccination 2 included 2 subjects in the PCV13/PPSV23 group (prostate cancer, dyspnea) and 1 subject in the PPSV23/PCV13
group (prostate cancer). At the 6-month follow-up telephone contact after vaccination 2, SAEs were reported for 5 (3.1%) subjects who received PCV13/PCV13, 6 (2.2%) subjects who received PCV13/PPSV23, and 3 (1.3%) subjects who received PPSV23/PCV13. None of the SAEs in the study were vaccine related and no deaths were reported. 4. Discussion The incidence and mortality of pneumococcal disease increase with age among older adults; however, the current recommended use of PPSV23 does not allow for maintenance of the vaccineelicited protective immune response over the period of risk. In the United States, PPSV23 is not generally recommended for adults 50–64 years of age and only a single administration is recommended for adults ≥65 years of age [2,4,11]. Importantly, receipt of a first dose of the free (unconjugated) polysaccharide vaccine has been shown to negatively impact the immune responses to subsequent doses of PPSV23 [12–14]. Similar reductions in immune responses upon re-administration of other free polysaccharide vaccines, such as Neisseria meningitidis vaccines have been reported
Table 2 Primary study objective anti-pneumococcal immune response comparisons. Vaccine groups
Vaccine comparisons PPSV23 na = 214–229 GMTb
PPSV23/PCV13 na = 180–196 GMTb
PCV13/PPSV23 vs. PPSV23
PCV13/PPSV23 vs. PPSV23/PCV13
Serotype
PCV13/PPSV23 na = 216–233 GMTb
GMT ratioc (95% CI)d
GMT ratioc (95% CI)d
1 3 4 5 6Ae 6B 7F 9V 14 18C 19A 19F 23F
148 125 1385 199 1268 1215 537 373 622 1062 467 774 198
148 80 1357 140 275 706 331 288 734 789 376 509 70
77 50 935 85 1133 710 126 114 435 564 289 286 124
1 (0.75, 1.33) 1.6 (1.24, 1.94) 1 (0.74, 1.41) 1.4 (1.01, 2.00) 4.6 (3.05, 6.98) 1.7 (1.18, 2.51) 1.6 (1.07, 2.47) 1.3 (0.79, 2.12) 0.8 (0.58, 1.25) 1.3 (0.94, 1.93) 1.2 (0.96, 1.61) 1.5 (1.09, 2.12) 2.8 (1.86, 4.35)
1.9 (1.43, 2.57) 2.5 (1.95, 3.16) 1.5 (1.12, 1.96) 2.4 (1.67, 3.31) 1.1 (0.80, 1.57) 1.7 (1.19, 2.47) 4.3 (2.76, 6.61) 3.3 (1.97, 5.45) 1.4 (0.98, 2.10) 1.9 (1.32, 2.69) 1.6 (1.27, 2.07) 2.7 (1.96, 3.74) 1.6 (1.05, 2.45)
Abbreviations: CI, confidence interval; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. a n = number of subjects with a determinate OPA antibody titer to the given serotype. b GMTs were calculated using all evaluable subjects with available data for the specified blood draw. c Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale. d 95% CIs for the ratio are back transformations of a CI based on the Student t distribution for the mean difference of the logarithms of the measures. e Serotype 6A is uniquely present in PCV13.
Table 3 Antipneumococcal immune response comparisons following vaccination with PCV13 and/or PPSV23. Serotype 1
3
4
5
6Aa
6B
PCV13/PCV13 (nb = 102–127) PCV13 (nb =102–127) PCV13/PCV13 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
142 215 0.7 (0.54, 0.82)
89 73 1.2 (0.99, 1.49)
1214 2255 0.5 (0.43, 0.68)
98 170 0.6 (0.43, 0.77)
2281 2682 0.9 (0.67, 1.08)
1882 2112 0.9 (0.71, 1.12)
PCV13/PCV13 (nb = 121–131) PPSV23/PCV13 (nb = 216–233 PCV13/PCV13 vs. PPSV23/PCV13
GMTc GMTc GMT ratiod (95% CI)f
139 77 1.8 (1.27, 2.56)
89 50 1.8 (1.33, 2.36)
1212 935 1.3 (0.91, 1.85)
96 85 1.1 (0.73, 1.76)
2354 1133 2.1 (1.43, 3.03)
1879 710 2.6 (1.74, 4.03)
PCV13/PPSV23 (nb = 189–221) PCV13 (nb = 189–221) PCV13/PPSV23 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
140 220 0.6 (0.55, 0.75)
129 74 1.7 (1.52, 2.01)
1430 2517 0.6 (0.49, 0.66)
188 227 0.8 (0.67, 1.03)
1302 3068 0.4 (0.37, 0.49)
1351 2012 0.7 (0.57, 0.79)
PPSV23/PCV13 (nb = 180–196) PCV13 (nb = 410–455) PPSV23/PCV13 vs. PCV13
GMTc GMTc GMT ratiod (95% CI)f
77 207 0.4 (0.28, 0.49)
50 75 0.7 (0.53, 0.85)
935 2536 0.4 (0.28, 0.48)
85 215 0.4 (0.28, 0.56)
1133 2766 0.4 (0.30, 0.56)
710 1948 0.4 (0.26, 0.52)
PCV13 (nb =410–457) PPSV23 (nb = 214–229) PCV13 vs. PPSV23
GMTc GMTc GMT ratiod (95% CI)f
207 148 1.4 (1.07, 1.83)
75 80 0.9 (0.75, 1.16)
2536 1357 1.9 (1.40, 2.49)
215 140 1.5 (1.09, 2.14)
2766 275 10.1 (7.15, 14.18)
1948 706 2.8 (1.96, 3.88)
Serotype Measure
7F
9V
14
18C
19A
19F
23F
PCV13/PCV13 (nb = 102–127) PCV13 (nb =102–127) PCV13/PCV13 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
323 930 0.3 (0.24, 0.49)
335 919 0.4 (0.26, 0.51)
384 492 0.8 (0.60, 1.02)
986 1440 0.7 (0.54, 0.87)
385 583 0.7 (0.53, 0.82)
502 566 0.9 (0.69, 1.15)
456 291 1.6 (1.15, 2.13)
PCV13/PCV13 (nb = 121–131) PPSV23/PCV13 (nb = 216–233 PCV13/PCV13 vs. PPSV23/PCV13
GMTc GMTc GMT ratiod (95% CI)f
335 126 2.7 (1.51, 4.70)
356 114 3.1 (1.72, 5.69)
389 435 0.9 (0.56, 1.43)
1015 564 1.8 (1.16, 2.78)
410 289 1.4 (1.05, 1.91)
501 286 1.8 (1.18, 2.61)
472 124 3.8 (2.33, 6.25)
PCV13/PPSV23 (nb = 189–221) PCV13 (nb = 189–221) PCV13/PPSV23 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
533 1252 0.4 (0.35, 0.52)
406 758 0.5 (0.41, 0.69)
616 664 0.9 (0.75, 1.15)
1074 1532 0.7 (0.58, 0.85)
457 696 0.7 (0.58, 0.74)
773 696 1.1 (0.89, 1.39)
216 358 0.6 (0.50, 0.73)
PPSV23/PCV13 (nb = 180–196) PCV13 (nb = 410–455) PPSV23/PCV13 vs. PCV13
GMTc GMTc GMT ratiod (95% CI)f
126 1063 0.1 (0.08, 0.18)
114 767 0.1 (0.10, 0.22)
435 650 0.7 (0.46, 0.98)
564 1576 0.4 (0.26, 0.50)
289 709 0.4 (0.32, 0.52)
286 711 0.4 (0.29, 0.56)
124 354 0.3 (0.23, 0.52)
PCV13 (nb =410–457) PPSV23 (nb = 214–229) PCV13 vs. PPSV23
GMTc GMTc GMT ratiod (95% CI)f
1063 331 3.2 (2.20, 4.69)
767 288 2.7 (1.78, 3.98)
650 734 0.9 (0.61, 1.28)
1576 789 2.0 (1.44, 2.77)
709 376 1.9 (1.48, 2.40)
711 509 1.4 (1.02, 1.92)
354 70 5.1 (3.43, 7.52)
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Measure
Abbreviations: CI, confidence interval; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. a Serotype 6A is uniquely present in PCV13. b n = number of subjects with a determinate OPA antibody titer vs. the given serotype. c GMTs calculated using all evaluable subjects with data for a given blood draw. d Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale. e For within group comparisons the GMT ratio (95% CI) accounts for each subject as their own control across time and GMTs are derived for subjects with data at both time points. f CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures.
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[15,16]. The underlying mechanism for the blunting of the immune response with revaccination is not fully understood, but may be due to the loss of memory B cells upon initial or follow-on administration of free polysaccharides [17–20]. In contrast, conjugated vaccines, like PCV13, in which the polysaccharide is covalently attached to an immunological “carrier” protein, elicit a T-cell–dependent anti-polysaccharide response.
In contrast to free polysaccharide vaccines, an efficient recall response is typically observed with conjugated polysaccharide vaccines [9,18–21]. Therefore, PCV13 may induce a qualitatively different immune response than that elicited by PPSV23, resulting in immunological memory and an improved immune response upon subsequent vaccine administration of PCV13 or PPSV23 with the potential for re-immunization. In the United States, the ACIP
Fig. 2. Reverse cumulative distribution curves for OPA titers measured 1 month after sequential vaccination with PCV13/PPSV23, PCV13/PCV13, and PPSV23/PCV13 administered using a 1-year interval between doses in adults 60–64 years of age. Antipneumococcal OPA titers are depicted on the x-axis using a log scale. The cumulative percentage ) PCV13/PPSV23; ( ) PCV13/PCV13; and ( ) PPSV23/PCV13. Abbreviations: OPA, opsonophagocytic activity; of subjects with given OPA titers is on the y-axis. ( PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.
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Fig. 2. (Continued)
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Table 4 Local reactions and systemic events reported up to day 14 after PCV13 vs. PPSV23, and after PCV13/PCV13 vs. PCV13/PPSV23 vs. PPSV23/PCV13. PCV13 vs. PPSV23
Local reactions Rednessc Any Mild Moderate Severe Swellingc Any Mild Moderate Severe Paind Any Mild Moderate Severe Limitation of arm movemente Any Mild Moderate Severe Any local reactionf Systemic events Fever Any (≥38 ◦ C and
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Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age Richard N. Greenberg a,∗ , Alejandra Gurtman b , Robert W. Frenck c , Cynthia Strout d , Kathrin U. Jansen b , James Trammel e , Daniel A. Scott b , Emilio A. Emini b , William C. Gruber b , Beate Schmoele-Thoma f a
University of Kentucky School of Medicine, Department of Medicine, Room MN-663, 800 Rose Street, Lexington, KY 40536-0084, United States Pfizer Vaccines Research, Pfizer Inc., 401 N Middletown Road, Pearl River, NY 10965, United States c Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 6014, Cincinnati, OH, United States d Coastal Carolina Research Center, 1156 Bowman Road, Suite 102, Mount Pleasant, SC, United States e inVentiv Health Clinical, LLC, 504 Carnegie Center, Princeton, NJ, United States f Pfizer Vaccines Research, Pfizer Pharma GmbH, Linkstrasse 10, 10785 Berlin, Germany b
a r t i c l e
i n f o
Article history: Received 23 September 2013 Received in revised form 18 December 2013 Accepted 4 February 2014 Available online 5 March 2014 Keywords: Adult Pneumococcal conjugate vaccine Recall responses
a b s t r a c t Background: Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T–cell–dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations. Methods: We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60–64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination. Results: OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose. Conclusion: In pneumococcal vaccine–naïve adults 60–64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations. ClinicalTrials.gov Identifier: NCT00574548. © 2014 Elsevier Ltd. All rights reserved.
Abbreviations: ACIP, Advisory Committee on Immunization Practices; AE, adverse event; CI, confidence interval; CRM197 , cross-reactive material 197; GMR, geometric mean ratio; GMT, geometric mean titer; LLOQ, lower limit of quantitation; LOD, limit of detection; OPA, opsonophagocytic activity; PCV, pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; SAE, serious adverse event. ∗ Corresponding author. Tel.: +1 859 323 6327; fax: +1 859 323 1631. E-mail addresses: [email protected] (R.N. Greenberg), alejandra.gurtman@pfizer.com (A. Gurtman), [email protected] (R.W. Frenck), [email protected] (C. Strout), kathrin.jansen@pfizer.com (K.U. Jansen), [email protected] (J. Trammel), dan.scott@pfizer.com (D.A. Scott), emilio.emini@pfizer.com (E.A. Emini), bill.gruber@pfizer.com (W.C. Gruber), beate.schmoele-thoma@pfizer.com (B. Schmoele-Thoma). http://dx.doi.org/10.1016/j.vaccine.2014.02.002 0264-410X/© 2014 Elsevier Ltd. All rights reserved.
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1. Introduction
2.2. Vaccines and administration
The incidence and mortality of pneumococcal disease in adults increase with advancing age [1,2]. A single dose of 23-valent pneumococcal vaccine containing free (unconjugated) polysaccharides (PPSV23) is currently recommended for adults ≥65 years and for younger adults with certain chronic medical conditions or other indications [2]. The duration of the immune response of PPSV23 is likely limited, indicating a need for periodic revaccination [3]. However, the United States Advisory Committee on Immunization Practices (ACIP) does not recommend routine PPSV23 revaccinations, in part due to the diminished immune responses that have been observed following revaccination [2,4]. In contrast, polysaccharide conjugate vaccines typically elicit T–cell–dependent immunity with an associated ability to induce a recall response upon revaccination with polysaccharide antigen [5]. We conducted a randomized clinical trial in pneumococcalvaccine naïve adults 60–64 years of age to evaluate safety and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) when administered as an initial dose of a 2-dose regimen with either PPSV23 or PCV13 with vaccine administrations given 1 year later. The purpose of the study was to assess the immunological influence of the initially administered vaccine on antipneumococcal responses following the second vaccine administration. This study was part of the adult PCV13 clinical development program.
PCV13 (Prevnar 13/Prevenar 13® ; Wyeth Vaccines; Lot Number 7-5095-005A) contains polysaccharides of pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, and 23F individually conjugated to a nontoxic mutant form of diphtheria toxin cross-reactive material 197 (CRM197 ). Each 0.5-mL dose contains 2.2 g of each serotype, except serotype 6B, which is included at 4.4 g. Each dose is formulated in 5.0 mM succinate and 0.85% sodium chloride at pH 5.8 with 0.125 mg aluminum as aluminum phosphate and 0.02% polysorbate 80. The vaccine is supplied in single-dose syringes without preservatives and stored at 2–8 ◦ C. PPSV23 (Pneumovax 23® ; Merck & Company, Inc.; Lot Number 0486U) consists of a purified capsular polysaccharide from 12 of the serotypes included in PCV13 (all except serotype 6A), as well as 11 additional serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F). The vaccine is formulated to contain 25 g of each of the 23 purified polysaccharide serotypes per 0.5-mL dose of vaccine, contains phenol as a preservative, and stored at 2–8 ◦ C. Vaccines were administered by intramuscular injection in the deltoid using 25G 1-inch needles.
2. Methods 2.1. Study design and populations This was a phase 3, parallel-group, randomized, activecontrolled, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60 through 64 years of age, conducted at 21 medical centers in the United States. The study was undertaken in accordance with the Declaration of Helsinki and Good Clinical Practice [6,7]. After obtaining informed consent, subjects were randomly assigned in a 3:5:4 ratio to receive either PCV13 at year 0 and a subsequent dose of PCV13 at year 1, PCV13 at year 0 and a subsequent dose of PPSV23 at year 1, or PPSV23 at year 0 and a subsequent dose of PCV13 at year 1 (Fig. 1). In this modified double-blind design, PCV13 and PPSV23 were dispensed and administered by unblinded study staff members who were not involved in subsequent subject assessments. All other study staff members, in particular the individuals who evaluated subject safety, were blinded, as were the study subjects. As the study vaccines were different in physical appearance, the study vaccine syringes were labeled in a manner that prevented the study subjects from identifying the vaccine type based on its appearance. The study allowed enrollment of subjects with pre-existing chronic underlying conditions (e.g., cardiovascular, pulmonary, and liver diseases including alcoholic liver disease and alcoholism; renal and urinary disorders; or diabetes mellitus). Disease had to be stable, defined as not requiring significant change in therapy or hospitalization for worsening disease 12 weeks prior to vaccination. To be eligible for enrolment, subjects could not have received a diphtheria toxin–containing vaccine in the previous 6 months or be receiving antibiotics at the time of vaccination. Clinic visits occurred at vaccination and 1 month (29–43 days) after vaccination with a telephone visit for a safety assessment at 6 months after vaccination. Blood samples were obtained before and 1 month after vaccination.
2.3. Study objectives The two primary study objectives were focused on the immune responses after the second vaccine administration: (1) demonstration that PPSV23 administered 1 year after an initial dose of PCV13 is noninferior to the initial dose of PPSV23 for the 12 common serotypes, as measured by opsonophagocytic activity (OPA) titers 1 month after vaccination; and (2) demonstration that PPSV23 administered 1 year after an initial dose of PCV13 is noninferior with regard to elicited OPA responses to PCV13 administered 1 year after an initial dose of PPSV23. Two key secondary objectives were linked to the primary objectives to demonstrate that PPSV23 administration after PCV13 (PCV13/PPSV23) elicits statistically significantly higher responses for at least some of the 12 common serotypes compared with an initial dose of PPSV23 or to PCV13 administration after PPSV23 (PPSV23/PCV13). Additional analyses included evaluations (1) to demonstrate that the response following a second dose of PCV13 given 1 year after an initial dose of PCV13 (PCV13/PCV13) is noninferior to the response observed after the initial dose of PCV13; and (2) to demonstrate that the responses following PCV13 administered 1 year after a dose of PPSV23 (PPSV23/PCV13) are inferior compared with responses after a single PCV13 administration, for at least some of the 12 common serotypes. Additional immune response comparisons were also performed as described in Section 3. 2.4. Analysis populations The evaluable immunogenicity population was the primary population for immunogenicity analyses and consisted of eligible subjects who had ≥1 valid and determinate assay result, received both study vaccines as assigned and no prohibited vaccines, and had no other major protocol violation. The safety population included all subjects who received ≥1 dose of study vaccine. 2.5. Immunogenicity assessments Primary endpoints were the functional antibacterial OPA titers for the 13 serotypes in PCV13 measured using serotype-specific validated OPA assays in samples obtained immediately before and approximately 1 month after each vaccination [8]. Titers were defined as the interpolated reciprocal serum dilution that resulted in complement-mediated phagocytic killing of 50% of the assay
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720 subjects randomized
Year 0
482 subjects randomized to receive PCV13
238 subjects randomized to receive PPSV23
12 subjects excluded
a
470 subjects included in the evaluable immunogenicity population 478 subjects included in the safety population
2 subjects excluded
a
236 subjects included in the evaluable immunogenicity population 237 subjects included in the safety population
Year 1
180 subjects as randomized at Y0 to receive PCV13/PCV13
47 subjects excluded
302 subjects as randomized at Y0 to receive PCV13/PPSV23
a
133 subjects included in the evaluable immunogenicity population 160 subjects included in the safety population (PCV13/PCV13)
65 subjects excluded
237 subjects included in the evaluable immunogenicity population 267 subjects included in the safety population (PCV13/PPSV23)
238 subjects as randomized at Y0 to receive PPSV23/PCV13
a
39 subjects excluded
a
199 subjects included in the evaluable immunogenicity population 223 subjects included in the safety population (PPSV23/PCV13)
Fig. 1. Study design and disposition of subjects. a Subjects could be excluded for >1 reason. Reasons for exclusion include: not receiving vaccination, protocol violations, ineligibility for the study, and invalid assay results. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.
bacteria. The lowest titer that can be determined in the assay (limit of detection [LOD]), regardless of serotype, is 1:8. However, to quantify functional antibodies with appropriate precision and accuracy, the lower limit of quantitation (LLOQ) was determined for each serotype-specific OPA assay during assay validation. Titers below the LLOQ were set to a value of 1:4 (i.e., half of the LOD). 2.6. Safety assessments Subjects recorded local reactions, systemic events, and oral temperature in an electronic diary on the evening of vaccination and for the next 13 days. Adverse events (AEs) were recorded from enrollment through the month 1 postvaccination visit, serious AEs (SAEs) from enrollment through the 6-month follow-up telephone contact after each vaccination, and deaths through the end of the study. 2.7. Statistical analysis 2.7.1. Sample size considerations The sample size estimation was based on the 1-year OPA response to 7 of the 13 serotypes in PCV13 that were reported in a previous trial of 7-valent pneumococcal conjugate vaccine (PCV7)
in adults ≥70 years of age naïve to pneumococcal immunization [9]. The sample size of approximately 400 evaluable subjects in the PCV13 group (with 150 and 250 in the subgroups at year 1) and of approximately 200 evaluable subjects in the PPSV23 group was determined to provide ≥90% overall power to declare noninferiority of either PCV13/PPSV23 vs. PPSV23, or PCV13/PPSV23 vs. PPSV23/PCV13, for the 12 pneumococcal antigens common to both vaccines using a 2-fold noninferiority criterion of 0.5, 2-sided type 1 error rate of 0.05, and a dropout rate of not more than 15%.
2.7.2. Immunogenicity analyses For the pairwise comparison of OPA geometric mean titers (GMTs) between vaccine groups or vaccination sequences, the 2-sided 95% confidence intervals (CIs) based on the Student t distribution for the geometric mean ratio (GMR; defined as GMT group 1/GMT group 2) for each of the common serotypes were calculated. Noninferiority of group 1 relative to group 2 was declared if the lower limit of the 2-sided 95% CI for the GMR was >0.5 (2-fold criterion). Statistically significantly higher response was declared if the lower limit of the 95% CI for the GMR was >1.0 (or >2.0 for serotype 6A). Statistically significantly lower responses were declared if the upper limit of the 95% CI for the GMR was 40 ◦ C was reported (Table 4). Incidences of local reactions were highest after PCV13/PPSV23 and lowest after PPSV23/PCV13. Generally similar rates of local reactions were observed when PCV13/PCV13 and PPSV23/PCV13 were compared to a single administration of PCV13. However, rates of all types of local reactions were generally higher when PCV13/PPSV23 was compared to a single administration of PPSV23. Incidences of systemic events after PCV13/PCV13 and PPSV23/PCV13 compared to PCV13, as well as PCV13/PPSV23 compared to PPSV23, were generally similar, with statistically significant differences for only a few systemic events considered not clinically important. The incidences of subjects reporting any unsolicited AEs were low and were similar in the PCV13 group (19.2%) and the PPSV23 group (20.7%). The most frequent category of AEs in each vaccine group was infections and infestations, which occurred in 8.6% and 13.1% of those who received PCV13 and PPSV23, respectively. The most common individual AEs were nasopharyngitis (1.9% for PCV13; 2.5% for PPSV23) and upper respiratory tract infection (1.5% for PCV13; 3.4% for PPSV23). After vaccination 2, the incidences of any AEs were 13.8%, 19.1%, and 14.8% for the PCV13/PCV13, PCV13/PPSV23, and PPSV23/PCV13 groups, respectively. The most frequent category of AEs in each vaccine group was infections and infestations, reported in 7.5% of subjects in the PCV13/PCV13 and PCV13/PPSV23 groups and 4.0% of subjects in the PPSV23/PCV13 group, with the most common
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Table 1 Baseline characteristics. Initial vaccine
Characteristic Female, % Race, % White Black or African American Other American Indian or Alaska Native Asian Native Hawaiian or Other Pacific Islander Mean age at vaccination, years (±SD) Any chronic underlying diseases at study entry, % Cardiovascular diseases Pulmonary diseases Diabetes mellitus Liver diseases Renal and urinary disorders
Vaccine sequences
PCV13
PPSV23
PCV13/PCV13
PCV13/PPSV23
PPSV23/PCV13
n = 478 58.8
n = 237 56.5
n = 160 57.5
n = 267 57.3
n = 223 55.6
94.6 3.6 0.8 0.6 0.2 0.2 61.7 (±1.4) 26.4 5.9 9.4 15.3 0.4 0.2
97.0 3.0 0 0 0 0 61.7 (±1.4) 23.6 6.3 8 13.1 0.8 0.8
93.8 3.8 1.3 0.6 0.6 0 62.6 (±1.4)
96.6 3.0 0 0.4 0 0 62.6 (±1.3)
96.9 3.1 0 0 0 0 62.7 (±1.4)
Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; SD, standard deviation.
individual AEs in the 3 groups combined being nasopharyngitis, sinusitis, upper respiratory tract infection, and bronchitis. The difference in incidence of related AEs after PCV13 (15 subjects, 3.1%) and PPSV23 (3 subjects, 1.3%) was not significant. Most frequently reported were general disorders and administration site conditions, reported by 10 (2.1%) PCV13 recipients and 2 (0.8%) PPSV23 recipients, with the most frequently related individual AEs being injection site erythema (4 subjects, 0.8% for PCV13; 1 subject, 0.4% for PPSV23) and injection site hematoma (3 subjects, 0.6% for PCV13; 1 subject, 0.4% for PPSV23). Overall, 1, 5, and 2 subjects had AEs assessed as related in the PCV13/PCV13, PCV13/PPSV23, and PPSV23/PCV13 groups, respectively. Most frequently observed were general disorders and administration site conditions, including hematoma, pain, erythema, induration, and rash, with no significant differences between groups. After initial vaccination, SAEs were reported in 2 (0.4%) subjects who received PCV13 (breast cancer, squamous cell carcinoma of the skin) and 1 (0.4%) subject who received PPSV23 (3 cardiac events; myocardial infarction, unstable angina, and arrhythmia). The SAEs reported after vaccination 2 included 2 subjects in the PCV13/PPSV23 group (prostate cancer, dyspnea) and 1 subject in the PPSV23/PCV13
group (prostate cancer). At the 6-month follow-up telephone contact after vaccination 2, SAEs were reported for 5 (3.1%) subjects who received PCV13/PCV13, 6 (2.2%) subjects who received PCV13/PPSV23, and 3 (1.3%) subjects who received PPSV23/PCV13. None of the SAEs in the study were vaccine related and no deaths were reported. 4. Discussion The incidence and mortality of pneumococcal disease increase with age among older adults; however, the current recommended use of PPSV23 does not allow for maintenance of the vaccineelicited protective immune response over the period of risk. In the United States, PPSV23 is not generally recommended for adults 50–64 years of age and only a single administration is recommended for adults ≥65 years of age [2,4,11]. Importantly, receipt of a first dose of the free (unconjugated) polysaccharide vaccine has been shown to negatively impact the immune responses to subsequent doses of PPSV23 [12–14]. Similar reductions in immune responses upon re-administration of other free polysaccharide vaccines, such as Neisseria meningitidis vaccines have been reported
Table 2 Primary study objective anti-pneumococcal immune response comparisons. Vaccine groups
Vaccine comparisons PPSV23 na = 214–229 GMTb
PPSV23/PCV13 na = 180–196 GMTb
PCV13/PPSV23 vs. PPSV23
PCV13/PPSV23 vs. PPSV23/PCV13
Serotype
PCV13/PPSV23 na = 216–233 GMTb
GMT ratioc (95% CI)d
GMT ratioc (95% CI)d
1 3 4 5 6Ae 6B 7F 9V 14 18C 19A 19F 23F
148 125 1385 199 1268 1215 537 373 622 1062 467 774 198
148 80 1357 140 275 706 331 288 734 789 376 509 70
77 50 935 85 1133 710 126 114 435 564 289 286 124
1 (0.75, 1.33) 1.6 (1.24, 1.94) 1 (0.74, 1.41) 1.4 (1.01, 2.00) 4.6 (3.05, 6.98) 1.7 (1.18, 2.51) 1.6 (1.07, 2.47) 1.3 (0.79, 2.12) 0.8 (0.58, 1.25) 1.3 (0.94, 1.93) 1.2 (0.96, 1.61) 1.5 (1.09, 2.12) 2.8 (1.86, 4.35)
1.9 (1.43, 2.57) 2.5 (1.95, 3.16) 1.5 (1.12, 1.96) 2.4 (1.67, 3.31) 1.1 (0.80, 1.57) 1.7 (1.19, 2.47) 4.3 (2.76, 6.61) 3.3 (1.97, 5.45) 1.4 (0.98, 2.10) 1.9 (1.32, 2.69) 1.6 (1.27, 2.07) 2.7 (1.96, 3.74) 1.6 (1.05, 2.45)
Abbreviations: CI, confidence interval; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. a n = number of subjects with a determinate OPA antibody titer to the given serotype. b GMTs were calculated using all evaluable subjects with available data for the specified blood draw. c Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale. d 95% CIs for the ratio are back transformations of a CI based on the Student t distribution for the mean difference of the logarithms of the measures. e Serotype 6A is uniquely present in PCV13.
Table 3 Antipneumococcal immune response comparisons following vaccination with PCV13 and/or PPSV23. Serotype 1
3
4
5
6Aa
6B
PCV13/PCV13 (nb = 102–127) PCV13 (nb =102–127) PCV13/PCV13 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
142 215 0.7 (0.54, 0.82)
89 73 1.2 (0.99, 1.49)
1214 2255 0.5 (0.43, 0.68)
98 170 0.6 (0.43, 0.77)
2281 2682 0.9 (0.67, 1.08)
1882 2112 0.9 (0.71, 1.12)
PCV13/PCV13 (nb = 121–131) PPSV23/PCV13 (nb = 216–233 PCV13/PCV13 vs. PPSV23/PCV13
GMTc GMTc GMT ratiod (95% CI)f
139 77 1.8 (1.27, 2.56)
89 50 1.8 (1.33, 2.36)
1212 935 1.3 (0.91, 1.85)
96 85 1.1 (0.73, 1.76)
2354 1133 2.1 (1.43, 3.03)
1879 710 2.6 (1.74, 4.03)
PCV13/PPSV23 (nb = 189–221) PCV13 (nb = 189–221) PCV13/PPSV23 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
140 220 0.6 (0.55, 0.75)
129 74 1.7 (1.52, 2.01)
1430 2517 0.6 (0.49, 0.66)
188 227 0.8 (0.67, 1.03)
1302 3068 0.4 (0.37, 0.49)
1351 2012 0.7 (0.57, 0.79)
PPSV23/PCV13 (nb = 180–196) PCV13 (nb = 410–455) PPSV23/PCV13 vs. PCV13
GMTc GMTc GMT ratiod (95% CI)f
77 207 0.4 (0.28, 0.49)
50 75 0.7 (0.53, 0.85)
935 2536 0.4 (0.28, 0.48)
85 215 0.4 (0.28, 0.56)
1133 2766 0.4 (0.30, 0.56)
710 1948 0.4 (0.26, 0.52)
PCV13 (nb =410–457) PPSV23 (nb = 214–229) PCV13 vs. PPSV23
GMTc GMTc GMT ratiod (95% CI)f
207 148 1.4 (1.07, 1.83)
75 80 0.9 (0.75, 1.16)
2536 1357 1.9 (1.40, 2.49)
215 140 1.5 (1.09, 2.14)
2766 275 10.1 (7.15, 14.18)
1948 706 2.8 (1.96, 3.88)
Serotype Measure
7F
9V
14
18C
19A
19F
23F
PCV13/PCV13 (nb = 102–127) PCV13 (nb =102–127) PCV13/PCV13 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
323 930 0.3 (0.24, 0.49)
335 919 0.4 (0.26, 0.51)
384 492 0.8 (0.60, 1.02)
986 1440 0.7 (0.54, 0.87)
385 583 0.7 (0.53, 0.82)
502 566 0.9 (0.69, 1.15)
456 291 1.6 (1.15, 2.13)
PCV13/PCV13 (nb = 121–131) PPSV23/PCV13 (nb = 216–233 PCV13/PCV13 vs. PPSV23/PCV13
GMTc GMTc GMT ratiod (95% CI)f
335 126 2.7 (1.51, 4.70)
356 114 3.1 (1.72, 5.69)
389 435 0.9 (0.56, 1.43)
1015 564 1.8 (1.16, 2.78)
410 289 1.4 (1.05, 1.91)
501 286 1.8 (1.18, 2.61)
472 124 3.8 (2.33, 6.25)
PCV13/PPSV23 (nb = 189–221) PCV13 (nb = 189–221) PCV13/PPSV23 vs. PCV13
GMTc GMTc GMT ratiod , e (95% CI)f
533 1252 0.4 (0.35, 0.52)
406 758 0.5 (0.41, 0.69)
616 664 0.9 (0.75, 1.15)
1074 1532 0.7 (0.58, 0.85)
457 696 0.7 (0.58, 0.74)
773 696 1.1 (0.89, 1.39)
216 358 0.6 (0.50, 0.73)
PPSV23/PCV13 (nb = 180–196) PCV13 (nb = 410–455) PPSV23/PCV13 vs. PCV13
GMTc GMTc GMT ratiod (95% CI)f
126 1063 0.1 (0.08, 0.18)
114 767 0.1 (0.10, 0.22)
435 650 0.7 (0.46, 0.98)
564 1576 0.4 (0.26, 0.50)
289 709 0.4 (0.32, 0.52)
286 711 0.4 (0.29, 0.56)
124 354 0.3 (0.23, 0.52)
PCV13 (nb =410–457) PPSV23 (nb = 214–229) PCV13 vs. PPSV23
GMTc GMTc GMT ratiod (95% CI)f
1063 331 3.2 (2.20, 4.69)
767 288 2.7 (1.78, 3.98)
650 734 0.9 (0.61, 1.28)
1576 789 2.0 (1.44, 2.77)
709 376 1.9 (1.48, 2.40)
711 509 1.4 (1.02, 1.92)
354 70 5.1 (3.43, 7.52)
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Measure
Abbreviations: CI, confidence interval; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. a Serotype 6A is uniquely present in PCV13. b n = number of subjects with a determinate OPA antibody titer vs. the given serotype. c GMTs calculated using all evaluable subjects with data for a given blood draw. d Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale. e For within group comparisons the GMT ratio (95% CI) accounts for each subject as their own control across time and GMTs are derived for subjects with data at both time points. f CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures.
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[15,16]. The underlying mechanism for the blunting of the immune response with revaccination is not fully understood, but may be due to the loss of memory B cells upon initial or follow-on administration of free polysaccharides [17–20]. In contrast, conjugated vaccines, like PCV13, in which the polysaccharide is covalently attached to an immunological “carrier” protein, elicit a T-cell–dependent anti-polysaccharide response.
In contrast to free polysaccharide vaccines, an efficient recall response is typically observed with conjugated polysaccharide vaccines [9,18–21]. Therefore, PCV13 may induce a qualitatively different immune response than that elicited by PPSV23, resulting in immunological memory and an improved immune response upon subsequent vaccine administration of PCV13 or PPSV23 with the potential for re-immunization. In the United States, the ACIP
Fig. 2. Reverse cumulative distribution curves for OPA titers measured 1 month after sequential vaccination with PCV13/PPSV23, PCV13/PCV13, and PPSV23/PCV13 administered using a 1-year interval between doses in adults 60–64 years of age. Antipneumococcal OPA titers are depicted on the x-axis using a log scale. The cumulative percentage ) PCV13/PPSV23; ( ) PCV13/PCV13; and ( ) PPSV23/PCV13. Abbreviations: OPA, opsonophagocytic activity; of subjects with given OPA titers is on the y-axis. ( PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.
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Fig. 2. (Continued)
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Table 4 Local reactions and systemic events reported up to day 14 after PCV13 vs. PPSV23, and after PCV13/PCV13 vs. PCV13/PPSV23 vs. PPSV23/PCV13. PCV13 vs. PPSV23
Local reactions Rednessc Any Mild Moderate Severe Swellingc Any Mild Moderate Severe Paind Any Mild Moderate Severe Limitation of arm movemente Any Mild Moderate Severe Any local reactionf Systemic events Fever Any (≥38 ◦ C and
