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Safety, Tolerability and Immunogenicity of 15-valent Pneumococcal Conjugate Vaccine in Toddlers Previously Vaccinated With 7-valent Pneumococcal Conjugate Vaccine

Sobanjo-ter Meulen, Ajoke MD, MSc; Vesikari, Timo MD; Malacaman, Edgardo A. MD; Shapiro, Steven A. DO; Dallas, Michael J. PhD; Hoover, Patricia A. BS; McFetridge, Richard BS; Stek, Jon E. MS; Marchese, Rocio D. PhD; Hartzel, Jonathan PhD; Watson, Wendy J. MD; Musey, Luwy K. MD

The Pediatric Infectious Disease Journal: February 2015 - Volume 34 - Issue 2 - p 186–194
doi: 10.1097/INF.0000000000000516
Vaccine Reports
Free
SDC

Background: Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) in children has led to significant reduction in pneumococcal disease in children and adults. However, diseases caused by serotypes not included in PCV7 have increased. A 15-valent pneumococcal conjugate vaccine (PCV15) containing serotypes in PCV7 and 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in toddlers 12 to 15 months of age.

Methods: Ninety toddlers who completed an infant series with PCV7 received a single dose of either aluminum-adjuvanted PCV15, nonadjuvanted PCV15, or PCV7. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination and serious AEs (SAEs) were collected for 30 days postvaccination. Solicited AEs included local (pain/tenderness, swelling, nodule and redness) and systemic (fatigue, arthralgia and myalgia) AEs. Serotype-specific immunoglobulin G (IgG) and opsonophagocytic (OPA) responses were measured immediately prior and 30 days postvaccination.

Results: Incidences of local and systemic AEs were comparable across vaccine groups. The majority of reported events, regardless of vaccine received, were transient and of mild to moderate intensity. No clinically significant differences were observed when comparing duration and severity of AEs. No vaccine-related SAEs or discontinuations from the study due to AEs were reported. Pneumococcal IgG concentrations and OPA titers increased postvaccination, with appreciable fold rises for all serotypes. Antibody levels were comparable between both PCV15 formulations and generally comparable to PCV7 for the shared serotypes.

Conclusion: Both formulations of PCV15 display acceptable safety profiles and induce IgG and OPA responses to all vaccine serotypes.

Supplemental Digital Content is available in the text.

From the *Merck & Co., Inc., Whitehouse Station, NJ; University of Tampere, Tampere, Finland; MD Research, Canton, OH; and §Pediatric Medical Associates, Rydal, PA.

Accepted for publication August 4, 2014.

Study identification: V114-001.

The trial registration number was clinicaltrials.gov identifier: NCT01215175.

Data from this manuscript were presented in poster format (abstract #292) at the 29th Annual Meeting of the European Society for Paediatrics Infectious Diseases, The Hague, 2011.

Funding for this research was provided by Merck & Co., Inc.

A.S.M., M.J.D. and W.J.W. were employed by Merck at the time of this research. Other than employees of Merck & Co., Inc. (as indicated on the title page), all authors have been investigators for the sponsor. Employees may hold stock and/or stock options in the company. The authors have no funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Luwy K Musey, MD, Merck & Co., Inc., P.O. Box 1000, UG3CD-28, Whitehouse Station, NJ 08889. E-mail: luwy_musey@merck.com.

Streptococcus pneumoniae is a leading cause of pneumonia, bacteremia without focus, and meningitis, and is associated with significant morbidity and mortality among children and adults worldwide. Strains of drug-resistant S. pneumoniae have become increasingly common in the United States and in other parts of the world.1,2 The most common pneumococcal disease syndromes are classified as invasive pneumococcal disease (IPD) and non-IPD. IPD consists of bacteremia without focus (approximately 90%) and other diseases such as meningitis (5%–10%) and arthritis (<5%). Non-IPD mainly consists of pneumococcal pneumonia (without bacteremia) and acute otitis media.3–5

Worldwide, the incidence of IPD has been noted to vary by age, regional and racial differences. In 2000, it was estimated that about 14.5 million episodes of serious pneumococcal disease and 826,000 deaths, largely due to pneumonia, were reported worldwide in children < 5 years of age.6 Prior to licensure of the PCV7 (Prevnar, Pfizer, Philadelphia, PA), crude annual incidence rate of IPD in the United States was highest among children < 5years of age, adults ≥ 65 years of age and adults 50–64 years of age, estimated at 98.7, 60.1 and 24.0 per 100,000 population, respectively. Disease incidence was significantly lower in older children 5–17 years of age (4.2 per 100,000 population) and young adults 18–49 years of age (13.3 per 100,000 population).7 Moreover, death rates due to IPD in 1998 were highest among older adults ≥ 65 years of age (10.03 per 100,000 population), adults 50–64 years of age (3.11 per 100,000 population) and children < 5 years of age (0.7 per 100,000 population) than in older children and young adults (<0.5 per 100,000 population).8 Regardless of age, individuals living in crowded, closed settings (ie, shelters, long-term care facilities) and patients with certain chronic illnesses are at increased risk of developing pneumococcal infection and severe pneumococcal illness. Children ≥ 2 years of age and young adults with sickle-cell anemia, Hodgkin disease, congenital or acquired immunodeficiency (including HIV), diabetes mellitus, nephrotic syndrome and functional or anatomic asplenia are at increased risk of developing IPD in comparison to healthy individuals without these conditions.9 The estimated global case-fatality rates (CFR) among children < 5 years of age are generally higher for IPD (eg, 59% for meningitis cases) than for pneumonia cases (5%).6 In the United States, case-fatality rate for meningitis ranges from 1% to 2.6% among children, and mortality from pneumonia is rare.9

The introduction of pneumococcal conjugate vaccines (PCVs) to the infant immunization programs in the United States and many other developed countries was associated with a significant decrease in the incidence of IPD, and moderate impact on all-cause pneumonia and acute otitis media in the population targeted by the vaccination (children < 5 years of age). PCV infant immunization was also associated with significant reduction in the incidence of IPD in unvaccinated persons from other age groups (herd protection). Among children < 5 years of age in the United States who were targeted by the vaccination, the overall incidence of IPD caused by any serotype decreased from 98.7 per 100,000 population in 1998–1999 to 23.6 per 100,000 per population in 2007 and 9 per 100,000 population in 2012. Incidence of IPD also decreased in other age groups not targeted by the vaccination with PCV as demonstrated by the significant decrease in IPD among adults ≥ 65 years of age, estimated at 60.1, 37.9 and 29.6 per 100,000 population in 1998–1999, 2007 and 2012, respectively). In all age groups, a greater impact of the vaccine was observed when analyzing the decrease in disease caused by the serotypes included in PCV7 than the nonvaccine types.7–11 The estimated rates of deaths due to IPD followed similar patterns, decreasing from 0.7 to 0.09 per 100,000 population among children < 5 years of age and from 10.03 to 4.24 per 100,000 population among adults ≥ 65 years of age between 1998 and 2012.8

Vaccination with pneumococcal vaccine represents a great public health tool that can be used to reduce disease caused by vaccine serotypes in vaccinated individuals. The success of PCV7 highlights the value of PCVs to address an ongoing medical need. However, there are limitations in serotype coverage with PCV7 as evidenced by the emergence of disease caused by the serotypes not included in the vaccine.7,11–13 While the overall rates of IPD have decreased substantially in the younger population and modestly in the older age group, a statistically significant increase in the relative risk of IPD cases due to certain serotypes, including 19A, 22F and 33F, was noted in both populations. Between 1998–1999 and 2007, the proportion of IPD cases caused by these serotypes among children < 5 years of age increased from 2.6% to 47.2% for serotype 19A, from 0.6% to 4.8% for serotype 22F and from 0.7% to 4.8% for serotype 33F. Similar changes in the contributions of these serotypes in IPD cases were observed during the same time period among adults ≥ 65 years of age, with increases from 3.7% to 14.9% for serotype 19A, from 4.5% to 7.1% for serotype 22F and from 0.9% to 2.7% for serotype 33F.7 Since the implementation of PCV13 (which contains serotype 19A but not 22F and 33F) in infant immunization programs in the United States in 2010, the proportion of IPD cases caused by serotype 19A decreased from 47.2% in 2007 to 11.2% in 2012 among children < 5years of age and from 14.9% to 8.0% among adults ≥ 65 years of age during the same time period. By 2012, IPD cases caused by serotypes 22F among children < 5 years of age and adults ≥ 65 years of age were 12.4% and 12.5%, respectively, while serotype 33F contributed for 7.9% and 2.7% of IPD cases in children < 5 years of age and adults ≥ 65 years of age, respectively.7,8

To address the potential risk associated with the emerging serotypes, 2 additional PCVs were developed. A 10-valent PCV (Synflorix, GlaxoSmithKline, Rixensart, Belgium) containing the 7 serotypes in PCV7 plus 3 additional serotypes (1, 5 and 7F) was licensed in Europe and other countries in 2009 based on the demonstration of noninferiority of antibody response to PCV7 for the shared serotypes and efficacy against acute otitis media. Additionally, a 13-valent PCV (Prevnar 13, Pfizer, Philadelphia, PA) containing the 7 serotypes in PCV7 plus 6 additional serotypes (1, 3, 5, 6A, 7F and 19A) was approved in Europe in 2009, the United States in 2010 and subsequently in other countries worldwide.

Merck & Co., Inc. has developed a candidate PCV that contains pneumococcal polysaccharides from 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F) conjugated with CRM197 protein carrier. The PCV15 has the potential to address important medical and public health needs by providing broader coverage for the leading serotypes associated with pneumococcal disease worldwide. This study evaluated the safety and immunogenicity of a single dose of PCV15 in healthy toddlers who have completed a 3-dose infant series with PCV7.

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METHODS

Study Design

This randomized, double-blind, multicenter clinical trial was conducted in the United States and Finland from September 2009 to March 2010. The protocol (see Supplemental Digital Content 1, http://links.lww.com/INF/B999) was approved by the ethical review committee of each country or site and conducted in conformance with applicable country or local requirements.

This study evaluated the safety, tolerability and immunogenicity of PCV15 versus the currently marketed (at the time of the study) PCV7 in toddlers who had previously completed a 3-dose infant series of PCV7. The study was designed to have approximately 90 subjects randomized 1:1:1 to receive a single booster dose of (1) aluminum-adjuvanted PCV15, (2) nonadjuvanted PCV15 or (3) PCV7 (control). This was an estimation study with no formal statistical hypotheses.

Study vaccine was allowed to be administered concomitantly with other licensed pediatric vaccines normally administered at 12 to 15 months of age. Subjects were allocated to treatment assignment using a randomized schedule. All study personnel, including investigators, study site personnel, subjects, monitors and central laboratory personnel, remained blinded to treatment allocation throughout the study. The sample size (30 subjects/arm) was chosen to allow for clinically sufficient determination of the vaccine’s safety and tolerability with respect to the assessment of AEs of high frequency and whether further clinical evaluation of PCV15 should be pursued in infants.

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Study Subjects

Healthy, afebrile toddlers (12–15 months of age) who previously completed a documented 3-dose infant series of PCV7 at 2, 4 and 6 months of age were eligible for the study. Once parental informed consent was obtained, the subject’s medical history (including age, gender, weight, race, medication use and health status) was recorded. Exclusionary criteria included documented hepatitis B surface antigen positive, history of IPD, known hypersensitivity to any vaccine components, documented maternal HIV infection, receipt of corticosteroids within 2 weeks prior to study entry, receipt of investigational drugs or vaccines within 42 days prior to study entry or if scheduled to be given during the study, receipt of any licensed live virus vaccine within 14 days prior to study entry or receipt of a blood transfusion or other blood-derived product within 2 months prior to study entry.

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Vaccine Descriptions

Randomized subjects received a single 0.5 mL dose of adjuvanted PCV15, nonadjuvanted PCV15 or PCV7 administered intramuscularly on day 1. PCV15 contained 2 μg of pneumococcal capsular polysaccharide of serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F and 4 μg of serotype 6B conjugated with approximately 32 μg of CRM197 per 0.5 mL dose. Adjuvanted PCV15 additionally contained 125 μg of elemental aluminum as Merck aluminum phosphate adjuvant per 0.5 mL dose. The commercially available PCV7 contained 2 μg of serotypes 4, 9V, 14, 18C, 19F and 23F and 4μg of serotype 6B conjugated to approximately 20 μg of CRM197 and formulated with 125 μg of aluminum per 0.5 mL dose. To maintain study blinding, unblinded study personnel not otherwise associated with the study administered vaccine and maintained study vaccine supplies.

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Safety

All subjects were followed for safety during days 1 to 14 after receipt of study vaccine (date of vaccination considered day 1), with subjects’ parents/guardians recording any AEs using a vaccination report card. Solicited injection-site AEs included redness, swelling, nodules and pain/tenderness, and solicited systemic AEs included muscle pain (myalgia), joint pain (arthralgia), and tiredness (fatigue). SAEs were collected from day 1 through day 30 (study completion). Subjects’ parents/guardians were also instructed to record rectal/axillary temperatures for the first 7 days following vaccination. Body temperature was also measured if fever was suspected during day 8 through day 14.

There were no safety hypotheses for this study. The postvaccination AE profiles for each group were assessed by comparing the percentages of subjects who experienced clinical AEs between treatment groups via point estimates with 95% confidence intervals (CIs).14

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Immunogenicity

A 3- to 5-mL blood sample was collected at day 1 prevaccination and at day 30 (−1day/+5 days) postvaccination to assess antibody responses to the 15 serotypes of S. pneumoniae included in the study vaccine. Sera were separated and stored frozen until shipped to PPD Vaccines and Biologics (Wayne, PA). Sera were tested for (1) IgG serotype-specific antipneumococcal antibodies using an electrochemiluminescence (ECL)-based detection assay15 and (2) OPA killing activity using a multiplex OPA (MOPA-4) assay16 against pneumococcal serotypes included in PCV15. In addition, sera were also tested against serotype 6C by MOPA-4. The pneumococcal ECL and MOPA-4 assays were performed by PPD Vaccines and Biologics and by the University of Alabama at Birmingham, respectively.

There were no immunogenicity hypotheses for this study. The endpoints of interest were (1) serotype-specific IgG geometric mean concentrations (GMCs); and (2) serotype-specific OPA geometric mean titers (GMTs). The GMCs and GMTs were calculated along with 95% CIs. Point estimates of GMCs and GMTs are the exponentiated estimates of the mean log concentrations. The CIs for GMCs and GMTs are the exponentiated CIs for the mean log concentrations based on t-distributions. Although a reference antibody concentration of 0.35 µg/mL has been accepted by the World Health Organization for assessment of vaccine efficacy against IPD,17 it is mostly used for immune responses following the infant series. Since serotype-specific IgG GMCs following vaccination with PCVs are higher following the toddler dose than following the infant series,18 Pn ECL results were also evaluated for each serotype as percent responders at a higher threshold value of 1.0 µg/mL instead of the World Health Organization accepted threshold value of 0.35 µg/mL.

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RESULTS

Study Subjects

Overall, 100% (90/90) of randomized subjects were vaccinated, with 98.9% of subjects completing the study (Fig. 1). A single subject in the nonadjuvanted PCV15 group was lost to follow-up; this subject did not provide any safety follow-up information and is not included in the safety analyses. There were 3 subjects (3.3%) in the adjuvanted PCV15 group, 5 subjects (5.6%) in the non-adjuvanted PCV15 group and 4 subjects (4.4%) in the PCV7 control group that were excluded from the immunogenicity analyses due to protocol violations. Most of these protocol violations (9/12; 75%) were the result of postvaccination blood sample collection occurring outside the protocol-specified visit window.

FIGURE 1

FIGURE 1

Subjects across all vaccination groups were similar with respect to age and race (Table 1). A higher percentage of females (58.9%) were enrolled across all vaccination groups. Approximately 90% of the study population reported a medical condition prestudy that were equally distributed across the three vaccination groups. The most common medical conditions were otitis media (51.1%) and upper respiratory tract infection (35.6%). Only 23.3% of subjects received any prior medications, and these were similar across vaccination groups. The most common prior therapies were amoxicillin (7.8%) and acetaminophen (7.8%). Concomitant medications increased to 66.7% across vaccination groups, compared with the use of therapies prior to study start. This was largely due to the increase in use of ibuprofen (22.2%) and acetaminophen (48.9%). The percentage of subjects with any concomitant medication was comparable across vaccination groups.

Table 1

Table 1

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Safety

Clinical AEs were reported by 89.9% of randomized subjects (Table 2). Although numerically higher proportions of injection-site and systemic AEs were reported among recipients of adjuvanted PCV15 (72.7% and 93.9%, respectively) and nonadjuvanted PCV15 (64.3% and 85.7%, respectively) than PCV7 (57.1% and 82.1%, respectively), these differences were not statistically significant. In the study, 65.2% of subjects reported a vaccine-related injection-site AE, whereas 68.5% reported a vaccine-related systemic AE. The majority of the reported AEs were transient and of mild to moderate intensity. A total of 3 subjects reported severe injection pain and were equally distributed across the 3 vaccination groups. No vaccine-related SAEs or discontinuations from the study due to AEs were reported.

Table 2

Table 2

The most common systemic AEs were fatigue, myalgia, pyrexia and irritability. These AEs were solicited during the study and recipients of either formulation of PCV15 tended to have higher frequencies of these AEs than recipients of PCV7. A higher observed percentage of recipients of adjuvanted PCV15 reported myalgia, irritability or pyrexia versus those who received either nonadjuvanted PCV15 or PCV7. In addition, 1 recipient of adjuvanted PCV15 reported an AE of febrile convulsion (day 10 postvaccination, lasting 2 minutes) that was deemed not related to the study vaccine by the investigator. Previous studies have indicated that the risk windows for febrile seizure following administration of PCV in infants and measles-containing vaccine in toddlers were 0–7 days and 5–12 days postvaccination, respectively. The indicated periods are consistent with the timing during which elevated body temperature is more frequently reported.18–21 On the basis of the timing of the febrile seizure, it was determined by the investigator that the event was likely related to the measles–mumps–rubella vaccine administered concomitantly with the study vaccine on day 1.

During the 7-day postvaccination safety follow-up period, body temperature of ≥38°C was reported by 40.6% (13/32) of PCV15 adjuvanted recipients, 46.4% (13/28) of PCV15 nonadjuvanted recipients and 39.3% (11/28) of PCV7 recipients. Five (15.6%) recipients of aluminum-adjuvanted PCV15 and 2 (7.2%) recipients of PCV7 reported elevated body temperature ≥39.0°C to <40.0°C, with all 7 subjects reporting either a concurrent infection or administration of other pediatric vaccines concomitantly with the study vaccine. All cases of elevated body temperature returned to normal level within 3 days.

From day 8 to day 14 postvaccination, body temperature was measured only if fever was suspected. A total of 4 (40%) recipients of aluminum-adjuvanted PCV15, 1 (25%) recipient of nonadjuvanted PCV15 and 2 (28.6%) recipients of PCV7 reported elevated body temperature ≥39.0°C to <40.0°C. For 6 of these 7 subjects, either a concurrent infection or administration of another pediatric vaccine concomitantly was reported. Five of the 7 subjects (follow-up was not obtained for 2 of them) returned to normal temperature level within 4 days.

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Immunogenicity

Serotypes in Common Between PCV15 and PCV7 (4, 6B, 9V, 14, 18C, 19F and 23F)

Baseline IgG GMCs were generally comparable across the 3 vaccination groups (Table 3). Following vaccination, the IgG GMCs were generally comparable between recipients of PCV15 and PCV7 for the serotypes in common (Table 3), as the analysis demonstrated overlapping 95% CIs for all comparisons except for serotype 19F. GMCs were numerically lower for recipients of adjuvanted PCV15 versus PCV7 for all serotypes except 6B. Additionally, GMCs were numerically lower for recipients of nonadjuvanted PCV15 versus PCV7 for all serotypes except 6B. The proportion of responders that met the IgG cutoff value of ≥1.0 μg/mL by Pn ECL assay varied by serotype and vaccine group at both baseline and postvaccination. With the exception of serotypes 4, 18C and 19F, the proportion of responders was comparable across the 3 vaccination groups at both time points. The observed differences were likely due to the small sample size in our study. In comparison to recipients of PCV7, the differences in the proportion of responders above the specified threshold value for these 3 serotypes were only seen for recipients of aluminum-adjuvanted PCV15 but not for recipients of nonadjuvanted PCV15 (Table 4).

Table 3

Table 3

Table 4

Table 4

The serotype-specific OPA GMTs were generally comparable among subjects who received adjuvanted PCV15, nonadjuvanted PCV15 and PCV7 although OPA GMT to serotype 23F was higher among recipients of PCV7 than recipients of either formulation of PCV15 (Table 5). Postvaccination GMTs were numerically lowest for serotype 19F in all groups (1136.4 adjuvanted PCV15, 1117.8 nonadjuvanted PCV15 and 2493.4 PCV7). The serotype with the highest postvaccination GMT was 23F for adjuvanted PCV15 (7058.5) and 6B for nonadjuvanted PCV15 (6673.5), while the serotype with the highest postvaccination GMT in the recipients of PCV7 was 23F (18352.1).

Table 5

Table 5

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Additional Serotypes Only in PCV15 (1, 3, 5, 6A, 7F, 19A, 22F and 33F)

Serotype-specific IgG GMCs measured at 1 month postvaccination were expectedly higher among recipients of either formulation of PCV15 than recipients of PCV7 for the serotypes unique to PCV15, except for serotypes 6A and 19A; the lack of difference in GMCs for these serotypes is likely due to cross-reactivity to serotypes 6B and 19F that are contained in PCV7. The postvaccination IgG GMCs for all of the serotypes contained in PCV15 that are not included in PCV7 were comparable among recipients of either PCV15 formulation (Table 3). The lowest postvaccination GMCs in both PCV15 groups were observed for serotype 33F (0.9 and 1.1 μg/mL, respectively), and the highest GMCs were observed for serotype 22F (12.5 and 8.8 μg/mL, respectively). The proportion of responders that met the Pn ECL IgG cutoff value of ≥1.0 μg/mL by Pn ECL assay for the serotypes unique to PCV15 was generally comparable between recipients of the 2 formulations of PCV15 (Table 4).

The OPA GMT responses demonstrate that both PCV15 formulations were immunogenic following vaccination for all additional serotypes (Table 5). In the group that received PCV7, a high GMT relative to the PCV15 formulations was observed for the cross-reacting serotype 6A (2435.8), even though this serotype is not contained in PCV7.

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DISCUSSION

Previous studies of PCVs have demonstrated that a booster dose is required following primary infant immunization to provide long-term protection against bacterial disease due to the waning of functional antibodies.22 Studies evaluating the kinetics of antibody responses following vaccination with PCV7, PCV10 or PCV13 have documented a rapid decline in serotype-specific antibody levels following the administration of a 2-dose or 3-dose PCV regimens during the first 6 months of life; a booster dose administered at ≥12 months of age was generally associated with a significant increase in anticapsular pneumococcal antibodies.18,23–28 Despite the paucity of clinical studies evaluating the significance of the increased antibody levels in toddlers, it is believed that the association of high antibody titers and the establishment of a large pool of memory T and B cells greatly contribute to the long-term protection against pneumococcal disease.22,29 This study suggests that either formulation of PCV15 has comparable safety and immunogenicity profiles versus PCV7; these results are consistent with recent studies evaluating the safety and immunogenicity of PCV10 or PCV13 administered as a toddler dose to children previously vaccinated with PCV7 as infants.26,30,31 In these studies, the safety profiles of PCV10 or PCV13 were comparable to that previously observed in toddlers who received PCV7. Moreover, toddlers given either PCV10 or PCV13 achieved comparable serotype-specific IgG and OPA responses to recipients of PCV7 for the 7 serotypes in common between the tested vaccines and had high levels of antibodies to the additional serotypes that are not included in PCV7.

In this study, the safety profiles of the adjuvanted and nonadjuvanted formulations of PCV15 were generally comparable to that of PCV7. The 2 formulations of PCV15 displayed an acceptable safety profile with no SAEs reported during the follow-up period. While a numerically higher proportion of recipients of adjuvanted PCV15 reported solicited injection-site reactions (ie, erythema, swelling) and systemic AEs (ie, pyrexia, irritability) compared with recipients of nonadjuvanted PCV15 or PCV7, toddlers vaccinated with nonadjuvanted PCV15 also reported higher incidence of injection-site reactions (mostly pain) and systemic AEs (mostly myalgia) than those vaccinated with PCV7. These findings are consistent with previous studies demonstrating a slightly higher incidence of injection-site reactions and some systemic AEs for adjuvanted than nonadjuvanted vaccine formulations and for higher-valency than lower-valency PCVs.18,32

Overall, the immune responses generated by both the adjuvanted and nonadjuvanted PCV15 formulations were generally comparable to those elicited by PCV7 with the exception of the significantly higher OPA GMTs to serotype 23F that was observed in recipients of PCV7 than recipients of either formulation of PCV15. For the 7 serotypes in common between PCV7 and PCV15, recipients of PCV7 had numerically higher GMCs than recipients of either formulation of PCV15 for 6 shared serotypes, but these differences were not statistically significant. Further analysis showed that these responses were affected by 2 to 3 outliers in the group with higher GMC (data not shown, Merck & Co., Inc.). These results are supported by the OPA GMTs, which were comparable among the 3 vaccination groups indicating an adequate functional immune response following a single dose of PCV15.

Both formulations of PCV15 were immunogenic for the additional 8 serotypes not in common with PCV7 (6 of which are contained in PCV13). As observed for the serotypes in common with PCV7, nearly all recipients of either formulation of PCV15 achieved OPA GMT > 1:8 for the 8 serotypes unique to PCV15. Among the 15 serotypes tested in the study, IgG GMC to serotype 33F measured at 1 month postvaccination was the lowest in recipients of either formulation of PCV15 (0.9 and 1.1 µg/mL among recipients of adjuvanted and nonadjuvanted PCV15, respectively), but OPA GMTs were highest when comparing absolute titers across the 15 serotypes. Such observation has also been reported when comparing IgG and OPA responses to serotype 9V after infant primary series and toddler dose in recipients of PCV7 and PCV13.18 Baseline OPA GMTs to serotype 33F varied between the 3 vaccination groups and was highest among recipients of PCV7. However, no change in OPA GMTs was observed following vaccination among recipients of PCV7 as the serotype was not included in the vaccine, but 77.2-fold rise and 34.3-fold rise were observed in recipients of adjuvanted PCV15 and nonadjuvanted, respectively. The high OPA GMT observed among recipients of PCV7 (approximately 2600) was probably due to the 33F strain of S. pneumoniae and reagents used in MOPA-4. Consequently, a higher cutoff value than 1:8 that excludes the 95th percentile of the observed responses in recipients of PCV7 should be used when analyzing the proportion of responders to serotype 33F. Less than 5% of study subjects achieved OPA GMT greater than 8000 at baseline across the 3 vaccination groups and less than 5% achieved that threshold value among recipients of PCV7 at 1 month postvaccination. However, more than 95% of recipients of either formulation of PCV15 had OPA GMT above 8000 at 1 month postvaccination. The use of a higher threshold value OPA GMT (ie, 8000) is likely to yield a more specific result than the conventional threshold value of 1:8 for serotype 33F. Such observation is not surprising as previous studies comparing the immunogenicity of PCV7 and PCV13 have shown similar non-specific OPA results for serotype 7F.28,30 Overall, the 2 formulations of PCV15 induced serotype-specific IgG and OPA to all 15 serotypes included in the vaccine. Although several studies have demonstrated that nonadjuvanted pneumococcal conjugate formulations induced generally lower GMCs than adjuvanted formulations,33–35 a clear advantage of the adjuvanted formulation was not observed in this study; this outcome could be due to the fact that the study was not powered to compare between arms. A definitive comparison of the performance of the 2 formulations of PCV15 will need to be ascertained in future larger clinical studies, notably when administered as a priming series in infants and when boosting such infants.

Additionally, although not contained in PCV7 and PCV15, OPA response to serotype 6C was observed in recipients of both formulations of PCV15 but not in recipients of PCV7; the observed response is likely due to a combined cross-reactivity to serotypes 6A and 6B present in PCV15. Similar findings were observed with PCV13 which also contains serotypes 6A and 6B.36

In summary, PCV15 displays comparable safety and immunogenicity profiles to PCV7 when administered as a single dose to toddlers who were previously vaccinated with PCV7 during infancy. Larger studies will need to be conducted to evaluate the clinical performance of PCV15 when given as a 3-dose or 4-dose vaccination regimen in infants and toddlers. If successful, it is anticipated that PCV15 will provide expanded protection against vaccine-serotype pneumococcal disease, thereby addressing a global unmet medical need for increasing accessibility to pneumococcal conjugate vaccination that includes protection against the most common emerging serotypes causing IPD.

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ACKNOWLEDGMENTS

The authors thank all the subjects who participated in this study and their parents or legal guardian and The V114 P001 Toddler Cohort Study Investigators: Ahonen A, Lagerstrom P-M and Kuismanen K (Finland); Arrieta A, Cunha CA, Hollingsworth MA, Malacaman EA, Medford SO, Reisinger KS, Saunders MK, Senders SD and Shapiro SA (USA).

Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the sponsor. All co-authors approved the final version of the manuscript.

Author Contributions: T.V., E.A.M. and S.A.S. contributed to the enrollment of subjects and/or data collection, analysis and interpretation of data, and preparation of manuscript. P.A.H., R.M., J.E.S., J.H. and H.P. contributed to the analysis and interpretation of data, and preparation of manuscript. A.S.M., M.J.D., R.D.M., W.J.W. and L.K.M. contributed to the study concept and design, analysis and interpretation of data, and preparation of manuscript.

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Keywords:

pneumococcal conjugate vaccine; safety; immunogenicity

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