Abstract

METHODS

Study Design and Participants

This phase 3, randomized, active-controlled, double-blind, multicenter study was conducted between December 2018 and December 2019 in the United States and Sweden (NCT03760146; Figure 1). The study population comprised ≥18-year-olds in 3 cohorts based on age at enrollment (≥60, 50–59, and 18–49 years). Additional details are in the Supplementary Appendix and the study protocol, available at ClinicalTrials.gov. Participants were to be generally healthy or with a stable underlying disease. Key exclusion criteria included previous vaccination with any pneumococcal vaccine, diagnosis of a serious unstable chronic disorder or immunocompromising condition, or treatment with immunosuppressive therapies (detailed in Supplementary Appendix).

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Figure 1.

Study design. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.

Participants aged ≥60 years were randomized 1:1 to receive a 0.5-mL dose of PCV20 or PCV13 at the first visit then a 0.5-mL dose of saline or PPSV23, respectively, 1 month later. The 1-month interval between control vaccines, while not a formally recommended schedule [30], provided a contemporaneous control for all 20 serotypes and was previously used in the phase 2 study [26]. Randomization was stratified by age subgroup; approximately one-third of participants aged ≥60 years were planned to be aged ≥65 years. Participants aged 18–49 or 50–59 years were randomized 3:1 to receive a 0.5-mL dose of PCV20 or PCV13 (Figure 1). The study was conducted in accordance with local ethical principles and guidelines (see Supplementary Appendix).

RESULTS

Participants

A total of 3009 participants aged ≥60 years were randomized; 2835 (94.2%) completed the study (Figure 2). Of 2997 participants receiving the first vaccination, 66.2% were aged 60–64, 31.4% aged 65–79, and 2.3% aged ≥80 years (Supplementary Table 1). Approximately 17% of participants aged ≥65 years were enrolled in Sweden; the remaining participants were from US sites. Of 445 and 448 participants aged 50–59 or 18–49 years, respectively, randomized to receive PCV20 or PCV13, 432 (97.1%) and 423 (94.4%) completed the study. Demographic characteristics in each age-specific cohort were relatively diverse and generally similar between vaccine groups (Supplementary Table 1).

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Figure 2.

Participant disposition. ^aEvaluable immunogenicity population for 13 matched serotypes. ^bEvaluable immunogenicity population for 7 additional serotypes. ^cEvaluable immunogenicity population for all 20 serotypes. See Supplementary Appendix for descriptions of evaluable populations. Abbreviations: AE, adverse event; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.

Immunogenicity

PCV20 Noninferiority in Participants Aged ≥60 Years

Noninferiority criteria were met for all 13 matched serotypes between PCV13 and PCV20 (Figure 3). Although OPA GMTs 1 month after vaccination were slightly lower in PCV20 than in PCV13 recipients for 13 matched serotypes, substantial increases in OPA GMTs from baseline to 1 month after vaccination were observed in both groups (Figure 4). Similar percentages of participants in PCV20 and PCV13 groups had ≥4-fold rises in OPA titers from before to 1 month after vaccination and OPA titers at or above the LLOQ 1 month after vaccination (Supplementary Figures 1 and 2).

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Figure 3.

Model-based opsonophagocytic activity (OPA) geometric mean ratios (GMRs) in participants aged ≥60 years for the 13 matched serotypes (20-valent pneumococcal conjugate vaccine [PCV20]/13-valent pneumococcal conjugate vaccine [PCV13]) (A) and 7 additional serotypes (PCV20/23-valent pneumococcal polysaccharide vaccine [PPSV23]) (B) 1 month after vaccination. Noninferiority was declared if the lower bound of the 2-sided 95% confidence interval (CI) for the GMR was >0.5 (2-fold criterion). Noninferiority criteria were met for all 13 matched serotypes between PCV13 and PCV20. Assay results below the lower limit of quantitation (LLOQ) were set to 0.5 × LLOQ in the analysis. GMRs (PCV20/control) and 2-sided CIs were calculated by exponentiating the difference in least-squares means and the corresponding CIs based on analysis of log-transformed OPA titers using a regression model including terms of vaccine group, age at vaccination in years (continuous), sex, smoking status, and baseline log-transformed OPA titers. The numbers of subjects with valid and determinate OPA titers for the specified serotype varied by serotype and were 1399–1430 for PCV20 and 1390–1419 for PCV13 for the 13 matched serotypes, and 1157–1374 for PCV20 and 1201–1319 for PPSV23 for the 7 additional serotypes.

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Figure 4.

Pneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) in participants aged ≥60 years for the 13 matched (A) and 7 additional (B) serotypes before and 1 month after vaccination. Substantial increases in OPA GMTs from baseline to 1 month after vaccination were observed in both groups. Assay results below the lower limit of quantitation (LLOQ) were set to 0.5 × LLOQ. The numbers of subjects with valid and determinate assay results for the specified serotypes varied by serotype and were 1360–1425 for 20-valent pneumococcal conjugate vaccine (PCV20) and 1294–1418 for 13-valent pneumococcal conjugate vaccine (PCV13) for the 13 matched serotypes and 973–1353 for PCV20 and 993–1293 for 23-valent pneumococcal polysaccharide vaccine (PPSV23) for the 7 additional serotypes.

Statistical noninferiority criteria were met for 6 of 7 additional serotypes between PCV20 and PPSV23 (Figure 3). Serotype 8 did not meet noninferiority, with an OPA GMR of 0.55 (95% CI, .49–.62). OPA GMTs for 6 of 7 additional serotypes were higher in the PCV20 group 1 month after vaccination, with robust increases in OPA GMTs for all 7 additional serotypes observed from baseline to 1 month after PCV20 (Figure 4).

There is no established minimum threshold of protection for OPA; nonetheless, OPA is used as a measure of response. In addition, OPA assays are uniquely optimized for individual serotypes, and it is therefore not appropriate to directly compare across vaccine-induced OPA GMTs. However, elements of relative response (eg, from baseline) to vaccine serotypes elicited by PCV13 can provide useful context. Additional assessments of immune response to serotype 8 after PCV20 showed robust responses within the range of those observed to 13 matched serotypes after PCV13, including OPA GMFR from before to 1 month after PCV20 of 22.1 (PCV13 range, 5.7–47.3) (Figure 4), with 77.8% of participants having ≥4-fold rises in OPA titers from baseline to 1 month after PCV20 (PCV13 range, 54.0%–84.0%; Supplementary Figure 1) and 92.9% having OPA titers at or above the LLOQ 1 month after PCV20 (PCV13 range, 76.0%–96.6%; Supplementary Figure 2).

PCV20 Noninferiority Comparison Between 18–59- and 60–64-Year-Old Participants

PCV20 also met the pivotal secondary immunogenicity objective, with OPA responses in participants aged 50–59 or 18–49 years showing noninferiority compared with those aged 60–64 years for all 20 serotypes 1 month after PCV20 (Supplementary Figure 3). The observed OPA GMTs for most serotypes were higher in younger participants, particularly those aged 18–49 years compared with those aged 60–64 years.

Safety

Local Reactions and Systemic Events

The frequency and severity of local reactions within 10 days after PCV20 or PCV13 were similar within each age group (Figure 5). Most local reactions were mild to moderate in intensity, and pain at the injection site was most frequent.

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Figure 5.

Prompted reactogenicity events in participants aged ≥18 years, including local reactions within 10 days of vaccination (A) and systemic events within 7 days of vaccination (B). The frequency and severity of local reactions within 10 days after 20-valent or 13-valent pneumococcal conjugate vaccine (PCV20 or PCV13) were similar within each cohort.

Within 7 days after PCV20 or PCV13, fever was reported by 0.9%–1.5% of PCV20 and 0.8%–1.8% of PCV13 recipients. The frequency and severity of systemic events after PCV20 and PCV13 were similar within each age group (Figure 5). Most systemic events were mild to moderate in intensity; muscle pain was most frequently reported.

AEs and SAEs

Frequencies of AEs within 1 month after PCV20 or PCV13 were similar for each age group (Supplementary Table 2). Less than 1.5% of reported AEs were considered by the investigator to be related to study vaccine. Immediate AEs were reported by <1.0% of participants. Severe AEs within 1 month after PCV20 or PCV13 were infrequent. One month after saline or PPSV23, 7.4% and 12.2% of participants reported AEs, respectively.

The SAEs collected through 6-month follow-up were infrequent and similar between vaccine groups in each age group; none were vaccine related (Supplementary Table 2). In all 3 age groups, ≤1% of participants reported a newly diagnosed chronic medical condition within 1 month after PCV20 or PCV13; through 6-month safety follow-up, newly diagnosed chronic medical conditions were reported by ≤ 2.3% of participants and were consistent with medical events that may be observed in the population. None of these conditions were considered vaccine related.

Eleven participants in the PCV20/saline group and 8 in the PCV13/PPSV23 group, all aged ≥60 years, discontinued the study owing to AEs. These were considered vaccine related by the investigator in 5 PCV20 recipients (redness or swelling with or without pruritis at the injection site in 3, palpitations and anxiety in 1, and feeling abnormal in 1) and 4 PCV13 recipients (injection site pain with muscle pain, injection site reaction, headache, and bronchial hypersensitivity 6 days after vaccination in 1 participant each). One death in the PCV20/saline group was due to a traumatic injury, unrelated to study vaccination.

DISCUSSION

Addressing the global pneumococcal disease burden remains a public health imperative. Introduction of PCVs, such as PCV13, into immunization programs worldwide led to striking decreases in pneumococcal disease [13, 14, 21]. However, certain serotypes not covered by available PCVs persistently cause disease and threaten at-risk populations, including adults aged ≥65 years [16–18]. The 7 additional serotypes targeted by PCV20 but not PCV13 annually cause an additional 82 722 cases of pneumonia and other serious disease among US adults at risk because of age or other factors [27]. Although PPSV23 also contains these serotypes [32], it induces T-cell–independent immune responses lacking immunological memory, which can significantly limit effectiveness compared with PCVs [1, 7, 33], and, unlike PCVs [11], may not prevent nonbacteremic pneumococcal pneumonia [8, 31, 34]. Thus, expanding coverage through conjugated vaccines without these limitations is necessary to further reduce the burden of this serious and potentially fatal disease [13, 16, 19, 20, 23, 24].

Here, we present findings from the pivotal phase 3 study in adults aged ≥18 years evaluating safety and immunogenicity of investigational PCV20. The study design was modeled from clinical studies supporting PCV13 licensure in adults, which involved first showing comparable or higher OPA responses to PPSV23 in adults aged ≥60 years, with bridging to adults aged 50–59 and 18–49 years [35, 36]. PCV13 efficacy against vaccine-type IPD and pneumococcal pneumonia was subsequently shown in the CAPiTA trial (Community-Acquired Pneumonia Immunization Trial in Adults) in adults aged ≥65 years [31, 37].

PCV20 elicited robust, functional immune responses as measured by OPA to all 20 vaccine serotypes 1 month after vaccination in participants aged ≥18 years. In those aged ≥60 years, PCV20 induced immune responses for 13 matched serotypes that were noninferior to those elicited by PCV13. Noninferiority was also shown for 6 of the 7 additional serotypes in both PCV20 and PPSV23. Although serotype 8 missed the statistical noninferiority criterion, additional ­immunogenicity analyses showed that PCV20 elicited robust responses against serotype 8 within the range of those observed for 13 matched serotypes after PCV13. Given the established efficacy and immunologic properties of PCVs, including PCV13 [1, 7, 31], PCV20 will likely provide similar protection against this and other vaccine serotypes. As adults aged <60 years may also be candidates for PCV20, this study also bridged PCV20-elicited immune responses in younger participants to those in adults aged 60–64 years.

PCV20 was well tolerated, with a safety profile comparable to that of PCV13. Rates of prompted local reactions and systemic events were similar between vaccines; most were mild or moderate. No safety concerns were identified, and SAEs within 6 months after PCV20 or PCV13 were similarly infrequent.

Potential study limitations include that participants aged <65 years were enrolled from US sites, while those aged ≥65 years were also enrolled from Sweden to expand the population of pneumococcal vaccine-naive participants. While this could limit generalizability to global populations, based on efficacy and postmarketing effectiveness experience with PCV13 in adults [12, 31], PCV20 is likely to have similar effectiveness across regions. In addition, for most serotypes, immune responses to PCV20 relative to PCV13 or PPSV23 in participants aged ≥65 years had a trend generally similar to responses in those aged ≥60 years.

As in previous pivotal immunogenicity studies, immunocompromised or immunosuppressed individuals were excluded to support stringent noninferiority comparisons of PCV20 to licensed vaccines. Data from PCV studies, including PCV13, showed similar safety profiles in immunocompromised, immunosuppressed, and general populations and immune responses that may confer benefit against pneumococcal disease in high-risk populations [12, 38, 39]. Therefore, as PCV20 showed safety and immunogenicity comparable to PCV13 in this large study, PCV20 is anticipated to perform similarly to PCV13 in high-risk populations. In addition, only pneumococcal vaccine–naive adults participated, potentially limiting generalizability to populations with prior pneumococcal vaccination. Previous PCV13 studies showed that noninferiority to PPSV23 was met for both pneumococcal vaccine–naive and previously vaccinated populations, indicating expected applicability of these results regardless of prior vaccination [40].

In conclusion, in adults aged ≥18 years, PCV20 had a tolerability and safety profile similar to PCV13. PCV20 elicited functional immune responses in older adults that were noninferior to PCV13 responses for all 13 matched serotypes and to PPSV23 responses for 6 of 7 additional serotypes, with serotype 8 missing the statistical noninferiority criterion. The totality of immunogenicity data show that PCV20 elicits a robust response to serotype 8. Immune responses to PCV20 in adults aged 18–59 years were noninferior to those in adults aged 60–64 years. These data support potential PCV20 effectiveness against pneumococcal disease caused by these 20 serotypes.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. Editorial/medical writing support was provided by Emily Stackpole, PhD, of ICON (North Wales, Pennsylvania), and was funded by Pfizer Inc.

Financial support. This work was supported by Pfizer Inc.

Data availability. On request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual deidentified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the United States and/or the European Union or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Presented in part: IDWeek 2020, Oct 21–25, 2020.

Contributor Information

Brandon Essink, Meridian Clinical Research, Omaha, Nebraska, USA.

Charu Sabharwal, Vaccine Research and Development, Pfizer Inc, Pearl River, New York, USA.

Kevin Cannon, PMG Research of Wilmington, Wilmington, North Carolina, USA.

Robert Frenck, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA.

Himal Lal, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

Xia Xu, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

Vani Sundaraiyer, Syneos Health, Somerset, New Jersey, USA.

Yahong Peng, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

Lisa Moyer, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

Michael W Pride, Vaccine Research and Development, Pfizer Inc, Pearl River, New York, USA.

Ingrid L Scully, Vaccine Research and Development, Pfizer Inc, Pearl River, New York, USA.

Kathrin U Jansen, Vaccine Research and Development, Pfizer Inc, Pearl River, New York, USA.

William C Gruber, Vaccine Research and Development, Pfizer Inc, Pearl River, New York, USA.

Daniel A Scott, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

Wendy Watson, Vaccine Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA.

References