http://orcid.org/0000-0003-1919-0302
ABSTRACT
Background: Pneumococcal disease remains a public health priority in adults. Safety and immunogenicity of 2 different formulations of 15-valent pneumococcal conjugate vaccine (PCV15) containing 13 serotypes included in 13-valent pneumococcal conjugate vaccine (PCV13) plus 2 additional serotypes (22F and 33F) were evaluated in adults ≥ 50 years (V114-006; NCT02547649).
Methods: A total of 690 subjects (230/arm) received a single dose of either PCV15 Formulation A, PCV15 Formulation B, or PCV13 and were followed for safety for 14 days postvaccination. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) and Immunoglobulin G (IgG) geometric mean concentrations (GMCs) were measured immediately prior and 30 days postvaccination.
Results: Both PCV15 formulations had generally comparable safety profiles to PCV13. Baseline IgG GMCs and OPA GMTs were comparable across vaccination groups. At 30 days postvaccination, both PCV15 formulations induced serotype specific antibodies to all 15 serotypes in the vaccine. IgG GMCs and OPA GMTs in recipients of either PCV15 formulation were non-inferior (≤ 2-fold margin) to those measured in recipients of PCV13 for shared serotypes and superior (> 1.0-fold difference) for serotypes unique to PCV15. Formulation B generally induced higher immune responses than Formulation A.
Conclusion: In healthy adults ≥ 50 years of age, both new formulations of PCV15 displayed acceptable safety profiles and induced serotype-specific immune responses comparable to PCV13.
Introduction
Pneumococcal disease (PD) is associated with significant morbidity and mortality worldwide. Children < 5 years of age, older adults ≥ 65 years of age, and individuals of any age with certain medical conditions (i.e., cancer, chronic heart disease, chronic lung disease, and diabetes mellitus) are at increased risk for pneumococcal disease.Citation1,Citation2 High incidence of disease in older adults is due to immune senescence and physiological changes in the respiratory system associated with aging.Citation3 Invasive pneumococcal disease (IPD) includes disease with high degree of invasiveness such as meningitis, bacteremia/sepsis, and bacteremic pneumonia. Non-invasive disease includes sinusitis, otitis media, and non-bacteremic pneumonia.Citation4 Incidence of pneumococcal pneumonia without bacteremia is difficult to estimate due to limited use in clinical practice of confirmatory laboratory test despite recent development of new urinary tests aimed at detecting all or serotype-specific cases of non-bacteremic pneumococcal pneumonia.Citation5–Citation7
Several pneumococcal polysaccharide vaccines (PPVs) containing capsular polysaccharides from 6 to 23 serotypes have been developed since the 1970s. Currently, only the 23-valent pneumococcal polysaccharide vaccine (PPV23) is licensed in many countries worldwide. Effectiveness of PPV23 against IPD in immunocompetent adults has generally ranged from 56-to-81%, but is lower in immunocompromised individuals.Citation8 Additionally, the vaccine was found to be ineffective in children < 2 years of age due to the immaturity of their immune system. Efficacy of PPV23 against pneumococcal pneumonia was demonstrated in several studies but rates varied between studies.Citation9–Citation14 Although underused, PPVs were shown to be efficacious and cost-effective against pneumococcal disease.Citation15–Citation17
In order to improve vaccine effectiveness in children, several pneumococcal conjugate vaccines (PCV7 [Prevnar™, Pfizer, Philadelphia], PCV10 [Synflorix™, GlaxoSmithKline, Rixensart, Belgium], and PCV13 [Prevnar 13™, Pfizer, Philadelphia, PA]) have been licensed since 2000. Efficacy of PCV7 against IPD was demonstrated in several pediatric clinical trialsCitation18-Citation20 and effectiveness of both PCV10 and PCV13 against IPD and otitis media has been observed in children < 5 years of age.Citation21–Citation24 Recently, a placebo-controlled study (CAPiTA) showed PCV13 to be 45.6% efficacious in preventing first episode of vaccine-type (VT) pneumococcal pneumonia and 75% against VT-IPD but did not improve overall survival of vaccinated adults ≥ 65 years of age compared to placebo.Citation7 Based on CAPiTA results, sequential dosing regimen of PCV13 followed by PPV23 administered 1 year later was adopted in the U.S. for adults ≥ 65 years of age but usage of PCV13 in adults remains undecided in most countries with established childhood PCV programs.
Widespread use of these vaccines has led to significant reduction in nasopharyngeal carriage, IPD, and pneumococcal pneumonia in the population targeted by vaccination but also in other age groups (herd protection). For all age groups, greater impact has been observed in disease caused by vaccine serotypes whereas cases of IPD caused by non-vaccine serotypes have increased over time.Citation25–Citation31 Interestingly, disease caused by serotypes not included in newly licensed vaccines, including 22F and 33F, also increased in recent years.Citation32–Citation34 Vaccine impact was observed for both IPD and pneumococcal pneumonia.Citation32–Citation38
A 15-valent pneumococcal conjugate vaccine (PCV15) comprised of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F has the potential to address important medical and public health needs by providing broader coverage for leading serotypes associated with pneumococcal disease worldwide.Citation39 In comparison to PCV13, the 2 serotypes unique to PCV15 (22F and 33F) are among leading serotypes causing IPD in children and adults following widespread use of PCV13 in children in many countries, likely due to their invasiveness capacity.Citation25,Citation28,Citation32–Citation34 By 2013 in the US, residual IPD caused by serotype 22F among children < 5 years and adults ≥ 18 years were 11% and 13%, respectively while serotype 33F caused 10% and 5% of residual IPD cases in children < 5 years and adults ≥ 18 years, respectively.Citation33 The current study (V114-006; NCT02547649) compared safety and immunogenicity of a single dose of 2 different formulations of PCV15 to PCV13 in pneumococcal vaccine-naïve adults ≥ 50 years of age. Both PCV15 formulations (PCV15-A and PCV15-B) contain 15 pneumococcal polysaccharides conjugated to a carrier protein (diphtheria CRM197 protein) and are formulated with aluminum phosphate adjuvant. PCV15-A utilizes the same conjugation process for all 15 glycoconjugates. PCV15-B utilizes the same conjugation as PCV15-A for 8 serotypes and a modified process for 7 serotypes. These modifications were aimed at improving overall stability of the investigational vaccine over its shelf-life as well as immune recognition of glycoconjugates in both adults and children.
Results
Study subjects
Of 689 vaccinated subjects, nearly all (98.4%) completed all study-required procedures and study visits (). Across the 3 vaccination groups, subjects were equally distributed with respect to age, gender, race/ethnicity, presence of key pre-existing medical conditions [i.e., chronic heart disease, chronic obstructive pulmonary disease (COPD), and diabetes mellitus], as well as prior and concomitant therapies (Supplemental ). In each vaccination group, subjects were equally distributed into protocol-specified age cohorts (50–64 years, 65–74 years, and ≥ 75 years) and approximately 50% of subjects were ≥ 65 year of age.
Table 1. Subjects reporting local and systemic adverse events within 14 days postvaccination.
Figure 1. Subject disposition.
Safety
Majority of subjects reported at least one injection-site or systemic adverse event (AE). Most of these AEs were those solicited in the vaccination report card (VRC) and included conditions commonly observed in older adults. Serious AEs (SAEs) were rarely reported and none was related to study vaccine. During the study period, no death was reported and no subject was discontinued due to an AE. Most commonly reported AEs were injection site pain/tenderness, swelling, and erythema, as well as systemic events of fatigue, myalgia, headache, and arthralgia (). Reporting rates of solicited events were generally comparable across vaccination groups and most events were transient (lasting 1-to-3 days), and mild-to-moderate in intensity. Rates of injection site AEs were higher in recipients of PCV15-A and PCV15-B than recipients of PCV13 and the observed differences were mainly due to higher frequencies of injection site pain/tenderness. No specific trends were observed when comparing reporting rates of other injection site AEs (swelling and erythema) or systemic AEs across vaccination groups. Although the reporting rates of overall injection site AEs and myalgia were statistically higher in recipients of PCV15-A than PCV13 (p-value < 0.05), these differences were not clinically significant (most of these AEs were transient, mild-to-moderate in intensity) and could be due to chance given the many AE comparisons analyzed. Elevated body temperature was rarely reported and no study subject reported body temperature ≥ 39.5ºC (oral) during the 5 days postvaccination ().
Immunogenicity
At 1-month postvaccination, both PCV15-A and PCV15-B were non-inferior to PCV13 for all 13 shared serotypes, as lower bounds of 95% CIs for OPA GMT ratios (PCV15-A/PCV13 and PCV15-B/PCV13) were all > 0.33 (). Although not hypothesized in this trial, either formulations of PCV15 were also non-inferior to PCV13 if a more stringent criterion of 2-fold difference in OPA GMTs (lower bound of 95% confidence interval of serotype-specific OPA GMT ratios being ≥ 0.5) was tested. Both PCV15-A and PCV15-B were superior to PCV13 for the 2 serotypes unique to PCV15 (22F and 33F) as the lower bounds of two-sided 95% CI of GMT ratios (PCV15-A/PCV13 and PCV15-B/PCV13) were > 1.0. Comparisons of serotype-specific IgG GMC ratios based on 2-fold difference between recipients of either PCV15-A or PCV15-B and PCV13 mimicked those observed using OPA GMTs and confirmed that both formulations of PCV15 were non-inferior to PCV13 (). Although no formal comparison was performed between PCV15-A and PCV15-B, recipients of PCV15-B tended to have higher levels of OPA GMTs and IgG GMCs for serotypes manufactured with the modified conjugation process; however, improvement for these serotypes was associated with some reduction, albeit minimal, on antibody titers to serotypes using the same conjugation process in both formulations A and B (e.g., serotypes 9V and 14) (,). As geometric mean antibody concentrations or titers do not fully describe the overall performance of a given vaccine and potential differences across a range of antibody titers, we also analyzed reverse cumulative distribution curves (RCDCs) of serotype-specific IgG GMCs and opsonophagocytic killing activity (OPA) GMTs between recipients of PCV15-A, PCV15-B, and PCV13. RCDCs showed comparable performance of the 3 study vaccines for most shared serotypes and higher levels of serotype-specific OPA GMTs and IgG GMCs for serotypes 22F and 33F among recipients of either PCV15-A or PCV15-B than PCV13 (Supplementary Figures 1 and 2).
Figure 2. PCV15-A and PCV15-B versus PCV13 OPA GMT ratios at 1 month postvaccination.
Figure 3. PCV15-A and PCV15-B versus PCV13 IgG GMC ratios at 1 month postvaccination.
Baseline serotype-specific IgG GMCs and OPA GMTs were comparable across vaccination groups and significant increases were observed at 30 days postvaccination to all serotypes included in study vaccines. For shared serotypes between study vaccines, geometric mean fold-rises (GMFRs) and OPA GMTs varied by serotype and were generally comparable across the vaccination groups. OPA GMFR was lowest for serotype 3 and highest for serotype 6A or serotype 6B for all 3 vaccination groups, ranging from 11.26 (serotype 3) to 85.26 (serotype 6B) among recipients of PCV15-A, from 6.93 (serotype 3) to 123.84 (serotype 6A) among recipients of PCV15-B, and from 4.26 (serotype 3) to 77.52 (serotype 6A) among recipients of PCV13 (). IgG GMFRs for the shared serotypes varied by serotype and vaccination groups, ranging from 6.00 (serotype 3) to 15.34 (serotype 1) among recipients of PCV15-A, from 4.00 (serotype 3) to 20.68 (serotype 18C) among recipients of PCV15-B, and from 3.08 (serotype 3) to 15.14 (serotype 6A) among recipients of PCV13 ().
Table 2. Summary of OPA antibody responses – geometric mean fold rise (GMFR) (per protocol population).
Table 3. Summary of IgG antibody responses – GMFR (per protocol population).
Both serotypes 22F and 33F are included in PCV15 but not in PCV13. OPA GMFRs for serotypes 22F and 33F were 36.87 and 5.77, respectively for recipients of PCV15-A and 35.31 and 5.34, respectively for recipients of PCV15-B. As expected, no increase was observed for these serotypes following vaccination with PCV13 (). Similar trends were observed for IgG GMFRs for serotypes 22F and 33F across vaccination groups ().
Responses to vaccination were also analyzed by computing the proportion of study subjects achieving ≥ 4-fold increase in OPA GMTs and IgG GMCs from prevaccination to 30 days postvaccination. Overall, proportions of subjects with such increase in OPA response were comparable across vaccination groups for any given shared serotype, ranging from 61.6% (serotype 14) to 87.0% (serotype 6B) among recipients of PCV15-A, from 50.3% (serotype 14) to 87.3% (serotype 6B) among recipients of PCV15-B, from 44.1% (serotype 3) to 84.2% (serotype 6B) among recipients of PCV13 (). As expected, more recipients of either PCV15-A or PCV15-B than PCV13 achieved 4-fold increase in OPA GMTs from baseline to postvaccination for 22F and 33F (). The analyses of the proportion of subjects achieving 4-fold increase in serotype-specific IgG GMCs from baseline to postvaccination followed the same trends as OPA responses.
Table 4. Summary of OPA antibody responses – %≥ 4 fold rise (per protocol population).
We performed a subgroup analysis of vaccine-induced immune responses (OPA GMTs and IgG GMCs) by age stratum (50-to-64 years, 65-to-74 years, and ≥ 75 years). Responses varied by serotype but were comparable across the 3 vaccination groups. For the majority of shared serotypes, older subjects ≥ 75 years of age tended to have numerically lower OPA GMTs and IgG GMCs than those in younger age groups although antibody levels for a given serotype did overlap across the 3 age strata (A,B). Furthermore and within each vaccination group, levels of vaccine-induced antibodies varied between subjects with underlying chronic heart disease, chronic lung disease, diabetes mellitus or those not reporting any of these conditions; however, no differences were observed when comparing IgG GMCs and OPA GMTs among subjects with or without history of either chronic condition who received the same study vaccine (Supplementary Tables 2 and 3).
Figure 4. Serotype-specific OPA GMTs by age stratum [PCV15-A (left); PCV15-B (right)]
![Figure 4. Serotype-specific OPA GMTs by age stratum [PCV15-A (left); PCV15-B (right)]](/cms/asset/1b9c1495-0ec6-4c3b-9527-6d28e754bb99/khvi_a_1532249_f0004_b.gif)
Discussion
The significant reduction in the burden of pneumococcal disease in both children and adults worldwide over the last 2 decades underscores the public health value of infant immunization with PCVs. Widespread use of PCVs in children has significantly decreased nasopharyngeal colonization and IPD by serotypes included in the vaccine in other age groups not targeted by the vaccination program.Citation25 Notwithstanding, nonbacteremic pneumonia remains an important unmet medical need in older adults. It is therefore conceivable that direct immunization of older adults with PCVs could further reduce burden of nonbacteremic pneumococcal pneumonia.Citation7
Our study compared the tolerability, safety, and immunogenicity profiles of 2 new formulations of PCV15 in adults ≥ 50 years of age. Although these new PCV15 formulations differ in the processes used to manufacture glycoconjugates for some serotypes, the nature of the key vaccine ingredients are generally similar and comparable to an earlier formulation evaluated in children and adults.Citation40,Citation41 Study results showed that both PCV15-A and PCV15-B displayed tolerability and safety profiles comparable to PCV13 with regard to the nature, frequency, duration, and severity of AEs over the protocol-specified safety follow-up period. With the exception of higher rates of injection site pain/tenderness observed in recipients of both PCV15-A and PCV15-B than in PCV13, no specific trends were observed when comparing reporting rates of other injection-site or systemic AEs across vaccination groups.
Overall, baseline and postvaccination serotype-specific IgG GMCs and OPA GMTs, GMFRs as well as proportions of subjects with ≥ 4-fold increase in antibody titers from baseline varied by serotype but were generally comparable for each shared serotype across vaccination groups. Both PCV15-A and PCV15-B were non-inferior to PCV13 for all 13 shared serotypes, and superior to PCV13 for the 2 serotypes (22F and 33F) unique to PCV15. Of interest, both PCV15 formulations elicited higher OPA GMTs and IgG GMCs than PCV13 to serotype 3, a serotype that is still associated with a significant burden of pneumococcal disease in children and older adults despite high uptake of PCV13 in children in many countries for several years.Citation42–Citation44 Although serotype-specific OPA GMTs or IgG GMCs were observed to be numerically higher for a given study vaccine than the 2 other study vaccines, the clinical significance of such differences are unknown as no serotype-specific correlate of protection against pneumococcal disease has been established in adults. No clear underlying biological or chemical reasons were found and such differences could be due to chance alone given the number of comparisons tested between PCV15-A, PCV15-B and PCV13. Although the study was not aimed at comparing the immune responses between PCV15-A and PCV15-B, recipients of PCV15-B tended to have higher levels of OPA GMTs and IgG GMCs for most serotypes included in PCV15.
Our study has several limitations. Study population only included subjects with stable underlying medical conditions and vaccine performance in those with immunocompromising conditions was therefore not demonstrated. The lack of immune correlates of protection against pneumococcal disease in adults did not allow for use of a clinically relevant biomarker to assess potential efficacy of PCV15. The study was not powered to evaluate the impact of either study vaccine on pneumococcal disease. As we only measured immune responses at baseline and 30 days postvaccination, no information can be provided about long-term persistence of vaccine-induced immune responses in recipients of either formulation of PCV15. Furthermore, our study was not powered to statistically compare the safety and immunogenicity profiles between PCV15-A and PCV15-B. Finally and given the small number of subjects with each of the medical comorbid conditions or within each age stratum among recipients of either PCV15 formulation or PCV13, no statistical analysis was performed to compare the impact of age or comorbid condition on the safety and immunogenicity of PCV15-A or PCV15-B and PCV13, nor the impact of age or comorbid condition on the safety and immunogenicity within each vaccination group.
Overall, both formulations of PCV15 are highly immunogenic and induce both OPA and IgG antibodies to all 15 serotypes included in the vaccine at levels comparable to PCV13 for shared serotypes. An important benefit afforded by PCV15 in comparison to PCV13 is the induction of high levels of antibodies to serotypes 22F and 33F which have emerged as leading causes of IPD in both children and older adults following widespread use of PCVs in many countries worldwide. Although both PCV15 formulations elicited higher OPA GMT and IgG GMC to serotype 3 than PCV13, it remains to be seen whether such trends in antibody responses could translate into greater effectiveness against disease caused by serotype 3. Taken together, the demonstrated acceptable safety and immunogenicity profiles of PCV15 in our study supports further development of PCV15. If licensed, PCV15 will increase availability of more PCVs and help in the worldwide effort to end preventable child and adult deaths from pneumococcal disease.
Methods
Participants and study design
This phase 2 randomized, double-blind trial was conducted at 23 clinical sites in the United States to compare the safety, tolerability and immunogenicity of a single dose of 2 different formulations of PCV15 (PCV15-A and PCV15-B) to PCV13 in pneumococcal vaccine-naïve adults ≥ 50 years of age. Key eligibility criteria were no previous pneumococcal vaccination, stable underlying medical condition, and absence of protocol-defined known or suspected immunocompromising conditions (e.g., HIV infection, generalized malignancy). The protocol was approved by ethical review committees of each site and conducted in conformance with applicable country or local requirements. Written informed consent was obtained from each subject prior to the performance of any study procedure.
A total of 689 community-dwelling adults were randomly given a single dose of PCV15-A, PCV15-B, or PCV13. All subjects were followed for AEs for 14 days postvaccination. Solicited injection-site AEs included redness, swelling, and pain/tenderness; and solicited systemic AEs included muscle pain (myalgia), joint pain (arthralgia), headache, and fatigue. SAEs were collected through 30 days postvaccination and/or completion of subject’s participation in study. Daily oral temperature was collected for first 5 days postvaccination.
Blood samples were collected prior and 30 days postvaccination and sera were used to measure serotype-specific OPA and Immunoglobulin G (IgG) antibodies to all 15 vaccine serotypes included in PCV15. Functional opsonophagocytic activity was measured using multiplex OPA (MOPA) assay (Prof. David Goldblatt, Institute of Child Health, London, UK)Citation45. Serotype-specific IgG was measured using pneumococcal electrochemiluminescence (ECL) assay (Meso Scale Diagnostics, Gaithersburg, MD) at PPD Laboratories’ bioanalytical lab (Richmond, VA)Citation46.
Vaccines
Each dose of PCV15 contains 2μg of pneumococcal capsular polysaccharide from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F and 4μg of serotype 6B conjugated with 32μg of CRM197 and formulated with 125μg of aluminum phosphate adjuvant per 0.5mL dose. PCV15-A used the same conjugation process for all 15 serotypes. In PCV15-B, a modified conjugation process was implemented for 7 out of the 15 serotypes (6A, 6B, 7F, 18C, 19A, 19F, and 23F). Both PCV15 formulations contain a surfactant: Poloxamer 188 in PCV15-A and Polysorbate 20 in PCV15-B. PCV13 contains 2.2μg of polysaccharides from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F and 4.4μg of serotype 6B conjugated to 34μg of CRM197 and formulated with 125μg of aluminum phosphate adjuvant.
Statistical methods
Proportions of subjects reporting AE following vaccination were compared between PCV15 groups and PCV13. Study primary immunogenicity objective was to demonstrate that PCV15-A or PCV15-B were non-inferior to PCV13 for 13 shared serotypes and superior to PCV13 for the 2 non-shared serotypes (22F and 33F) at 1-month postvaccination. Non-inferiority was declared if lower bound of two-sided 95% CI of the OPA GMT ratios (PCV15/PCV13) for each shared serotype was > 0.33 (3-fold non-inferiority margin). Superiority was declared if lower bound of the two-sided 95% CI of the OPA GMT ratio (PCV15/PCV13) was > 1.0 for both 22F and 33F. A secondary non-inferiority immunogenicity hypothesis assessed PCV15 and PCV13 with respect to IgG GMCs for 13 shared serotypes and superiority for 2 unique serotypes. Non-inferiority was declared if lower bound of two-sided 95% CI of IgG GMC ratios (PCV15/PCV13) for each shared serotype was > 0.5 (2-fold non-inferiority margin). Superiority was declared if lower bound of the two-sided 95% CI of the GMC ratio (PCV15/PCV13) was > 1.0 for both 22F and 33F. GMC/GMT ratio estimation, 95% CI, and hypothesis test (1-sided p-value) were calculated using constrained longitudinal data analysis methodCitation47. Additional secondary objectives included summaries of geometric mean fold-rises, proportion of subjects with ≥ 4-fold rise from baseline in recipients of PCV15-A, PCV15-B, and PCV13 for all 15 serotypes contained in PCV15. The sample size was determined through simulations based on results from prior Phase 2 studies under the assumption that the natural logarithm of the Day 1 and Day 30 OPA responses follow a bivariate normal distribution for each serotype. A sample size of ~ 230 adults per vaccination group provided at least 90% power to demonstrate non-inferiority and superiority for at least one of the PCV15 formulations based on OPA. The success of either PCV15-A or PCV15-B required success on both non-inferiority to PCV13 for the 13 shared serotypes and superiority to PCV13 for the 2 unique serotypes.
Disclosure of potential conflicts of interest
HL Stacey, J Rosen, and JT Peterson were investigators for the sponsor supported by research grants.
A Williams-Diaz, V Gakhar, TM Sterling, CJ Acosta, K Nolan, J Li, A Pedley, P Benner, C Abeygunawardana, M Mosinski, WJ Smith, H Pujar, and LK Musey are employees of the sponsors and may hold stock and/or stock options from the sponsors.
Financial Disclosures
No author was paid for their work on this manuscript.
Author Contributions
HL Stacey, J Rosen, and JT Peterson: enrollment of subjects and/or data collection, review of the manuscript.
V Gakhar, TM Sterling, CJ Acosta, K Nolan, J Li, P Benner, C Abeygunawardana, M Mosinski, WJ Smith, and H Pujar: analysis and interpretation of data, and preparation of manuscript.
A Williams-Diaz, A Pedley, and LK Musey: study concept and design, analysis and interpretation of data, and preparation of manuscript.
Supplemental Material
Download Zip (665.1 KB)Acknowledgments
Jon E. Stek (Merck & Co., Inc.) assisted the authors with various administrative activities related to the submission of the manuscript and provided editorial assistance.
Supplemental material
Supplemental data can be accessed here.
Additional information
Funding
References
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