Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age

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 <1.0.

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For the within-group comparison (i.e., PCV13/PCV13), analyses were performed using data only from those subjects who had received 2 administrations of PCV13 given a year apart and had serotype-specific OPA data after both vaccinations. All analyses were performed using the SAS software package. No imputations were done for missing data. 2.8. Safety analyses Comparisons of the incidence of local reactions and systemic events between vaccine groups were performed with corresponding 95% CIs and p-values based on the Chan and Zhang methodology [10]. AEs were categorized according to the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by vaccine group/sequence.

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6A were significantly lower after receipt of the second vaccination while responses to serotype 3 were statistically significantly greater (Table 3). 3.2.6. PPSV23/PCV13 compared with initial PCV13 OPA GMTs following PCV13 administered 1 year after PPSV23 were statistically significantly lower for all 13 serotypes compared with responses after a single administration of PCV13 (Table 3). 3.2.7. PCV13 compared with PPSV23 OPA GMTs elicited by PCV13 were statistically significantly greater after a single administration of PCV13 than after a single administration of PPSV23 for 10 of 12 common serotypes and for serotype 6A (Table 3). 3.3. Population responses

3. Results 3.1. Baseline characteristics and disposition of subjects A total of 720 subjects were enrolled and randomized with 482 subjects to receive PCV13. Of these, 706 (470 PCV13 recipients) were included in the evaluable immunogenicity population and 715 subjects in the safety population for the first vaccination (Year 0). For Year 1, 569 subjects (133 PCV13/PCV13 recipients, 237 PCV13/PPSV23 recipients, and 199 PPSV23/PCV13 recipients) were included in the evaluable immunogenicity population and 650 subjects in the safety population (Fig. 1). Distribution of age, sex, race, and ethnicity at first vaccination were similar in both groups. At the time of the first vaccination, 26.4% of PCV13 recipients and 23.6% of PPSV23 recipients had ≥1 chronic underlying diseases (Table 1). 3.2. Immune responses 3.2.1. PCV13/PPSV23 compared with initial PPSV23 OPA GMTs following PPSV23 administered 1 year after PCV13 were noninferior for all 12 common serotypes and statistically significantly greater for 6 of 12 common serotypes, and for serotype 6A, compared with responses after a single administration of PPSV23 (Table 2). 3.2.2. PCV13/PPSV23 compared with PPSV23/PCV13 OPA GMTs following administration of PPSV23 administered 1 year after PCV13 were noninferior for all 12 common serotypes, and for serotype 6A, and statistically significantly greater for 11 of the 12 common serotypes (except serotype 14), compared with responses following PCV13 administered 1 year after PPSV23 (Table 2). 3.2.3. PCV13/PCV13 compared with initial PCV13 OPA GMTs following 2 administrations, delivered 1 year apart, of PCV13 met noninferiority criteria for 9 of the 13 serotypes compared with a single administration of PCV13. The responses were statistically significantly lower for 7 of 13 serotypes and statistically significantly greater for serotype 23F (Table 3). 3.2.4. PCV13/PCV13 compared with PPSV23/PCV13 OPA GMTs following a second administration of PCV13 met noninferiority criteria for all serotypes and were statistically significantly greater for 10 of 13 serotypes compared with responses following PCV13 given 1 year after PPSV23 (Table 3). 3.2.5. PCV13/PPSV23 compared with initial PCV13 OPA GMTs following PPSV23 administered 1 year after PCV13 met noninferiority criteria for 8 of the 12 common serotypes when compared with responses following a single administration of PCV13. Responses for 8 of 12 common serotypes and serotype

Reverse cumulative distribution curves of the population antipneumococcal OPA responses for the vaccination sequences PCV13/PCV13, PCV13/PPSV23, and PPSV23/PCV13 were compared (Fig. 2). As seen when comparing OPA GMTs, population responses were generally greater, depending on serotype, following administration of PPSV23 given after PCV13 compared with responses following administration of PCV13 given after PPSV23. Responses following two administrations of PCV13, given 1 year apart, were also generally greater than responses following the sequence of PPSV23/PCV13. However, responses after the PCV13/PCV13 sequence were similar or lower (with the exception of serotypes 6A, 6B, and 23F) than responses following PCV13/PPSV23. 3.4. Safety Local reactions were generally mild across all groups. Injection site pain was the most frequent local reaction and significantly more frequent after PCV13 than PPSV23, although mostly mild. Local reactions were comparable after one or two doses of PCV13. New generalized muscle pain, fatigue, and headache were the most common systemic events after each vaccination. Decreased appetite, aggravated generalized muscle pain, new generalized joint pain, and use of medication to treat fever were significantly more frequent after PPSV23 than PCV13. Fever was rare and no fever >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)

R.N. Greenberg et al. / Vaccine 32 (2014) 2364–2374

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 <40 ◦ C) Mild (≥38 ◦ C but <38.5 ◦ C) Moderate (≥38.5 ◦ C but <39 ◦ C) Severe (≥39 ◦ C but ≤40 ◦ C) Fever >40 ◦ C Fatigue Headache Chills Rash Vomiting Decreased appetite New generalized muscle pain Aggravated generalized muscle pain New generalized joint pain Aggravated generalized joint pain Use of medication to treat pain Use of medication to treat fever Any systemic eventg

PCV13/PCV13 vs. PCV13/PPSV23 vs. PPSV23/PCV13

PCV13 %

PPSV23 %

N = 258–374

N = 127–180

12.2 8.3 6.4 1.2

11.2 9.7 3.9 0.8

10.0 8.2 3.8 0

p-Valuea

p-Valueb

PCV13/PCV13 %

PCV13/PPSV23 %

PPSV23/PCV13 %

N = 82–130

N = 131–234

N = 115–171

0.808 0.637 0.353 0.892

12.8 7.2 7.2 2.4

27.8 19.4 12.3 6.9

4.3 4.3 0.9 0

<0.001 <0.001 <0.001 0.006

10.4 6.1 7.6 0

0.931 0.495 0.140 >0.99

14.0 10.6 6.1 1.2

25.8 20.1 12.3 6.1

5.0 5.0 0.9 0

<0.001 <0.001 <0.001 0.007

69.2 66.1 20.1 2.3

58.3 52.9 21.7 0.8

0.014 0.004 0.708 0.338

75.2 72.4 24.2 2.4

85.7 78.5 49.4 12.9

69.8 68.1 17.8 0.9

<0.001 0.072 <0.001 <0.001

23.5 22.7 1.2 1.1 71.4 N = 258–383

28.2 26.1 3.1 2.3 62.2 N = 127–202

0.311 0.458 0.297 0.414 0.032

28.0 27.2 3.6 1.2 78.5 N = 81–117

53.4 47.4 10.4 8.1 86.8 N = 127–222

18.5 16.9 0 1.7 71.3 N = 115–169

<0.001 <0.001 <0.001 0.018 <0.001

4.2 3.8 0.8 0.4 0 50.5 49.7 19.9 8.6 3.1 14.7 46.9 22.0 15.5 14.0 31.3 8.6 74.9

1.6 0.8 0 0.8 0 49.1 46.1 26.9 13.4 3.1 23.0 51.5 32.5 23.8 21.1 32.7 17.5 78.2

1.3 0 1.3 0 0 39.0 41.7 18.9 10.5 3.7 18.0 50.0 26.6 14.9 17.6 26.9 13.8 70.9

3.1 3.1 0 0 0 51.9 49.7 29.0 24.0 4.6 17.0 61.2 41.5 25.5 17.5 46.2 17.4 78.8

0.9 0.9 0 0 0 41.1 40.3 19.7 8.3 6.8 13.0 45.0 28.7 19.5 21.4 20.3 19.4 62.7

0.191 0.087 0.455 0.693 >0.99 0.781 0.460 0.108 0.153 >0.99 0.038 0.349 0.020 0.040 0.068 0.779 0.012 0.378

0.514 0.303 0.248 N/A N/A 0.054 0.203 0.098 <0.001 0.662 0.516 0.008 0.019 0.143 0.666 <0.001 0.595 0.002

Abbreviations: N/A, not applicable; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine. a p-Value (based on Chan and Zhang) for the difference in proportions, PCV13/PPSV23 (local reactions and systemic events reported within 14 days after vaccination 1). b Omnibus p-values; Fisher exact test, 2-sided, for comparison of all 3 vaccine groups (local reactions and systemic events reported within 14 days after vaccination 2). c Redness and swelling were categorized as: absent, if <2.5 cm; mild, if ≥2.5 cm and ≤5.0 cm; moderate, if >5.0 cm and ≤10.0 cm; and severe, if >10.0 cm. d If pain at the injection site was present, subjects were asked to enter the severity as mild if the symptom was easily tolerated, moderate if there was discomfort sufficient to interfere with usual activity, and severe if the pain was incapacitating. e If limitation of arm movement was present, subjects were asked to enter the severity as: mild, if there was some limitation of arm movement; moderate, if the subject was unable to move his or her arm above the head, but able to move it above the shoulder; and severe, if the subject was unable to move the arm above the shoulder. f Any local reaction = any pain, swelling, redness, or any limitation of arm movement. g Any systemic event = any fever ≥38 ◦ C, any fatigue, headache, chills, rash, vomiting, decreased appetite, new or aggravated generalized muscle pain, and any new or aggravated joint pain.

recently recommended that certain immunocompromised populations be vaccinated initially with PCV13 followed by vaccination with PPSV23 [22]. The present study evaluated PCV13 and PPSV23 administered in 60- to 64-year-old pneumococcal vaccine–naïve subjects using a two-dose regimen. The study evaluated the antipneumococcal immune responses to different vaccine sequences with a 1-year interval between vaccine administrations with the objective of assessing the potential influence of the initial vaccine on subsequent responses. An OPA titer that correlates with protection has not been defined; however, although not an objective in this study, PCV13 responses were statistically significantly greater for 10 of 12 common serotypes and for serotype 6A compared with PPSV23, supporting the results obtained in two separate studies comparing

PCV13 to PPSV23 responses in pneumococcal vaccine–naïve adults in the same age group and in PPSV23 pre-immunized elderly adults [23,24]. Titers were generally higher throughout the full range of OPA responses as shown by reverse cumulative distribution curves suggesting that in PPSV23-naïve and PPSV23 pre-immunized adults, PCV13 will afford the same, and potentially better, protection than PPSV23 against the PCV13-associated serotypes. The study results after sequential vaccine administration showed that subjects who received an initial dose of PCV13 followed 1 year later with PPSV23 exhibited functional antipneumococcal responses after PPSV23 that were at least comparable to responses seen after a single administration of PPSV23, and which were significantly greater for many of the serotypes (Table 2). This response pattern suggests that PCV13 establishes an immunological state that permits a recall response, as well as an augmented

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response, upon follow-on administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, PPSV23 administered before PCV13 established an immunological state that resulted in a diminished response to subsequent administration of PCV13 for all serotypes when compared with the responses after a single PCV13 administration (Table 3), which is consistent with findings of previous studies with conjugate vaccines [25,26]. Importantly, administration of PCV13 prior to PPSV23 induced statistically significantly higher antipneumococcal responses than administration of PPSV23 prior to PCV13 for almost all serotypes, suggesting that PCV13 should be given first when the use of both vaccines is considered (Table 2 and Fig. 2). A limitation of the study was the short interval of 1 year between vaccine administrations. This interval was chosen to provide an assessment of the potential impact of the initial vaccine on subsequent vaccine response using a stringent interval and is not a recommended interval for clinical practice. When compared with the responses seen after a single administration of PCV13, the responses following the vaccine sequences of PCV13/PPSV23 or PCV13/PCV13 using a 1-year interval between vaccinations were found to be either statistically noninferior or significantly lower depending on the serotype (Table 3). A lack of a consistent booster response when using intervals of 3 months to 1 year between pneumococcal conjugate vaccine and PPSV23 vaccine doses has been described earlier [27–29]. Given these observations, a separate study in the PCV13 development program was extended to evaluate whether a longer interval of 3.5–4.0 years between the administrations of the two vaccines could lead to noninferior or improved responses [14]. In this latter study, the responses after PCV13/PPSV23 were significantly greater for most of the common serotypes than those observed after an initial dose of PPSV23 or PCV13. In addition, responses to a second dose of PCV13 were generally at least comparable to initial PCV13 responses and statistically significantly greater for many of the serotypes. The difference in the observed responses between this latter study and the study reported here suggests that the interval between pneumococcal vaccine administrations may be critical to obtaining an optimal immunological effect of the conjugated vaccine. Irrespective of the antipneumococcal responses seen after the 1-year interval PCV13/PCV13 vaccination sequence, the responses were still statistically significantly greater for the majority of serotypes when compared with the responses following the PPSV23/PCV13 sequence, supporting the positive immunological effect of initial conjugated vaccine use (Table 3). Similar observations were seen in a study of elderly adults previously vaccinated with PPSV23 [24]. An acceptable safety profile was seen for all 3 vaccine sequences. Subsequent vaccination with PPSV23 gave rise to more local reactions in those previously administered PCV13 or PPSV23 than did revaccination with PCV13 (Table 4). 5. Conclusion The results reported here document the potential advantage of initial PCV13 administration and support the concept that the protein conjugate vaccine establishes an immune state that results in appropriate recall responses for serotypes in common upon subsequent immunization with either PCV13 or PPSV23. Such a recall response is consistently absent when PPSV23 is administered before PCV13. Funding This study was funded by Wyeth Vaccines Research, which was acquired by Pfizer Inc. in October 2009. The sponsor and all authors

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were involved in the study design and the data collection, analysis, and interpretation of data, writing of the manuscript and in the decision to submit the manuscript for publication. Disclosure statement AG, KUJ, DAS, EAE, WCG, and BS-T are current employees of Pfizer and may hold stock options. RNG, RWF, and CS received funding from Pfizer to conduct this study. RNG received support from Pfizer for attendance at a scientific meeting. The University of Kentucky was supported in part by a National Institutes for Health research grant to their Aging Center (P30AG028383) and has received research grants from Viropharma, T2, PaxVax, and Bavarian-Nordic. CS receives funding from Pfizer for the conduct of several vaccine clinical trials as well as funding for studies in other Pfizer clinical trial programs. JT is an employee of inVentiv Health Clinical, a contract research organization providing services to Pfizer and other pharmaceutical companies. Acknowledgments The investigators of the 6115A1-3010 study group: Dr Donna M. DeSantis, Dr Robert Wilson Frenck Jr, Dr Larry I. Gilderman, Dr John E. Ervin, Dr Judith Lee Kirstein, Dr Randle Thomas Middleton, Dr Terry L. Poling, Dr Ernie Riffer, Dr John Rubino, Dr Mark Alan Turner, Dr Martin van Cleeff, Dr David J. Morin, Dr Richard Glover, Dr Dirk M. Smith, Dr Richard N. Greenberg, Dr David L. Fried, Dr Mira Baron, Dr Cynthia B. Strout, and Dr Cynthia Brinson. The authors wish to thank programming staff at inVentiv Health Clinical for support with data analysis; at Pfizer Inc, Carmel Devlin for regulatory support. Editorial support was provided by Vicki Schwartz, PhD, at Excerpta Medica and was funded by Pfizer Inc. References [1] Lynch 3rd JP, Zhanel GG. Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention. Semin Respir Crit Care Med 2009;30:189–209. [2] Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46:1–24. [3] Jackson LA. Pneumococcal polysaccharide vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 6th ed. China: Saunders, Elsevier; 2013. p. 542–72. [4] Centers for Disease Control Prevention (CDC); Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep 2010;59:102–106. [5] Granoff DM, Gupta RK, Belshe RB, Anderson EL. Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination. J Infect Dis 1998;178:870–4. [6] World Medical Association (WMA). WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. [accessed 2.08.13]. [7] International Conference on Harmonisation of Technical for Registration of Pharmaceuticals for Human Requirements (ICH). Efficacy Guidelines. Good Clinical Practice E6. Use [accessed 2.08.13]. [8] Cooper D, Yu X, Sidhu M, Nahm MH, Fernsten P, Jansen KU. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A. Vaccine 2011;29:7207–11. [9] de Roux A, Schmöle-Thoma B, Siber GR, Hackell JG, Kuhnke A, Ahlers N, et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis 2008;46:1015–23. [10] Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial proportions. Biometrics 1999;55:1202–9. [11] Centers for Disease Control and Prevention (CDC). Licensure of 13-valent pneumococcal conjugate vaccine for adults aged 50 years and older. MMWR Morb Mortal Wkly Rep 2012;61:394–5.

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