An overview of the clinical development of the 20-valent pneumococcal conjugate vaccine in adults

Kathleen McElwee; Jelena Vojicic; Charulata Sabharwal; John Ginis; Yahong Peng; Gabriel Mircus; Wendy Watson; Annaliesa Anderson

doi:10.1080/21645515.2026.2616144

. 2026 Feb 9;22(1):2616144. doi: 10.1080/21645515.2026.2616144

An overview of the clinical development of the 20-valent pneumococcal conjugate vaccine in adults

Kathleen McElwee ^a,^✉,^*, Jelena Vojicic ^a,^*, Charulata Sabharwal ^b, John Ginis ^a, Yahong Peng ^a, Gabriel Mircus ^a, Wendy Watson ^a,^Ɨ, Annaliesa Anderson ^b

PMCID: PMC12893683 PMID: 41661647

ABSTRACT

The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection against vaccine-preventable disease caused by Streptococcus pneumoniae beyond the 13-valent pneumococcal conjugate vaccine (PCV13). This review summarizes the adult clinical development program of PCV20. Across studies, the safety profile of PCV20 was acceptable and similar to that of PCV13 and the 23-valent pneumococcal polysaccharide vaccine (PPSV23). Pivotal noninferiority comparisons of serotype-specific opsonophagocytic activity responses (PCV20 to PCV13 for the 13 matched serotypes; PCV20 to PPSV23 for the 7 additional serotypes) were conducted in pneumococcal vaccine‒naive ≥60-y-old adults to infer efficacy. Immunobridging of PCV20 responses to adults 60–64 y of age supports PCV20 use in adults 18 through 59 y of age, including those at increased risk of pneumococcal disease. Additionally, PCV20 elicited functional responses to all 20 vaccine serotypes in adults ≥65 y old who were previously vaccinated with PCV13 and/or PPSV23.

KEYWORDS: Adults, clinical trials, immunogenicity, safety, Streptococcus pneumoniae, 20-valent pneumococcal conjugate vaccine

Introduction

Streptococcus pneumoniae infections in adults are associated with noninvasive pneumococcal diseases, such as nonbacteremic community-acquired pneumonia (CAP) and sinusitis, as well as invasive pneumococcal disease (IPD; e.g., meningitis, bacteremia, or bacteremic pneumonia).¹ In 2019, S. pneumoniae was among the top five pathogens associated with worldwide infection-related mortality (>800,000 deaths), with the highest burden of disease in infants, young children, and older adults.² At least 100 S. pneumoniae serotypes have been identified and characterized by their capsular polysaccharides.³ Only a subset of these serotypes cause the majority of pneumococcal disease, of which critical serotypes are targeted by available pneumococcal vaccines.⁴

Initially approved in 1983, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) had long been the only available pneumococcal vaccine option for adults.⁵ PPSV23 contains unconjugated polysaccharides⁴ and is associated with T-cell – independent responses that lead to terminal differentiation of B cells into plasma cells, without establishment of immunologic memory.^6,7 PPSV23 protection against IPD is considered short-lived with substantial waning of protection within 5 y⁸; data on CAP effectiveness is equivocal, and revaccination may result in hyporesponsiveness.^6,9 Pneumococcal conjugate vaccines (PCVs) elicit T-cell – dependent immune responses, leading to robust functional antibody responses and establishment of immune memory.^6,10

The introduction of PCVs into childhood immunization programs led to considerable reductions of vaccine-type disease in both vaccinated, and, through indirect effects, unvaccinated populations.¹¹ However, the burden of disease in adults has remained, which, along with the limitations of PPSV23, prompted development and subsequent recommendations for PCVs in adults.^11–15 In 2011, the 13-valent PCV (PCV13) was the first PCV to be approved for use in adults. It was initially approved by the US Food and Drug Administration (FDA) for use in adults ≥50 y of age for protection against vaccine-type IPD based on immunologic noninferiority to PPSV23; the indication for vaccine-type CAP was granted by an accelerated approval pathway, requiring a confirmatory clinical outcome trial.¹⁵ Full approval was subsequently granted for individuals >18 y of age following the positive results from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), which demonstrated PCV13 efficacy against vaccine-type CAP and IPD.^16,17

The 20-valent PCV (PCV20) was developed using the same platform as PCV13, retaining the conjugates for all PCV13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) and adding conjugates for seven new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F).¹⁸ These seven additional serotypes were selected to expand PCV coverage based on associations with disease prevalence, disease severity, invasive potential, and resistance to antibiotics.^19–26 Some of these serotypes showed increasing prevalence after introduction of earlier PCVs, possibly due to serotype replacement.^27,28

PCV20 was licensed for use in adults in the United States in 2021¹⁸ and has subsequently been licensed in at least 75 additional countries for adult use.^29–31 This review summarizes the PCV20 clinical development program in adults, with a short overview of PCV13 data, focusing on safety, immunogenicity, and coadministration data from PCV20 adult clinical trials (sponsored by Pfizer Inc, New York, NY, USA).

PCV13 experience in adults

As the first pneumococcal conjugate vaccine to be developed for use in adults, PCV13 was supported by an extensive development program. Key learnings are summarized in a recently published review that includes the clinical development program as well as additional studies of PCV13 in healthy adults; the review also addresses topics such as formulation development, dose assessment, safety, immunogenicity, repeat vaccination and sequencing with PPSV23, coadministration studies, and clinical efficacy.¹⁶

In 19 adult studies conducted, PCV13 had a favorable reactogenicity and safety profile; local reactions and systemic events were mostly mild to moderate and resolved within 6 d, and adverse events (AEs) were rare.¹⁶

Efficacy against IPD was inferred using a surrogate immunogenicity outcome, serotype-specific opsonophagocytic activity (OPA), by establishing immunobridging between PCV13 and PPSV23, a vaccine with established clinical efficacy against IPD.¹⁶ OPA assesses the ability of vaccine-induced antibodies to mediate pneumococcal killing through opsonophagocytosis, which is the immune system’s primary method of protection against pneumococcal disease.^32,33 As such, OPA is considered as a surrogate endpoint that can reasonably predict protection against pneumococcal disease.³⁴ Additionally, OPA use is preferred in older adults due to the need to assess antibody functionality (often diminished in aging individuals), which cannot be achieved by measuring ELISA IgG levels.³⁵ Ten clinical trials evaluated PCV13 immunogenicity, five of which compared PCV13 with PPSV23, including among PPSV23-naive and -experienced participants. PCV13 elicited robust immune responses to all 13 serotypes, with OPA geometric mean titers (GMTs) meeting noninferiority criteria for most of the serotypes in common with PPSV23.^16,36–40 Additionally, OPA GMTs were higher for PCV13 compared with PPSV23 for the majority of serotypes, and this trend was consistent in both PPSV23-naive and -experienced participants, as well as across evaluated age groups.^16,36–40 Previous vaccination with PPSV23 appeared to blunt the immune response of subsequent PCV13 administration, regardless of participant age, vaccination status, or time between vaccine doses; this finding supports administering PCV first if sequential administration of PCV and PPSV23 is considered.^16,36,37

PCV13 efficacy against clinical outcomes was established in CAPiTA, a randomized, placebo-controlled trial conducted in the Netherlands among ~84,000 pneumococcal vaccine–naive participants ≥65 y of age. Vaccine efficacy was 75% (95% CI, 41.4, 90.8) against the first episode of vaccine-type IPD and 45% (95% CI, 14.2, 65.3) against the first episode of vaccine-type CAP¹⁷ and was maintained over approximately 4 y of follow-up after vaccination.⁴¹

Nine studies evaluated concurrent administration of PCV13 with other adult vaccines, including the influenza vaccine, the tetanus-diphtheria and tetanus-diphtheria – acellular pertussis vaccines, the tetravalent meningococcal vaccine, and the recombinant herpes zoster vaccine.¹⁶ Across these studies, PCV13 elicited immune responses with concomitant vaccine administration.¹⁶

The clinical development program included studies in two special populations: adults infected with HIV and hematopoietic stem cell transplant (HSCT) recipients.^42,43 The findings supported the use of a single PCV13 dose in HIV-infected individuals and demonstrated immunogenicity of a 4-dose PCV13 regimen in HSCT recipients.^42,43

PCV13 has demonstrated effectiveness against vaccine-type IPD, vaccine-type pneumonia and all-cause pneumonia/lower respiratory tract infections in a real-world setting.^9,44,45

PCV20 clinical development studies

The adult clinical development program for PCV20 was generally modeled on the adult clinical development program for PCV13 while also taking into consideration the favorable safety profile established for PCV13, the scientific concepts established in that program, and the adult postmarketing experience since the initial licensure of PCV13 in 2011. The program supported indications for IPD and pneumonia in adults ≥18 y of age and generated safety and immunogenicity data in adults with and without previous pneumococcal vaccination.

As agreed with regulators, the pathway to licensure was based on immunologic comparisons to vaccines with established clinical efficacy, i.e., immunobridging. To infer efficacy against IPD and pneumonia for the 13 serotypes in-common, PCV20 was immunobridged to PCV13. For the seven additional serotypes, PCV20 was immunobridged to PPSV23 to infer efficacy against IPD only, as data on PPSV23 effectiveness against pneumonia is inconsistent. The indication of pneumonia was granted based on accelerated approval with a postlicensure commitment for a confirmatory effectiveness study; this study is ongoing (NCT05452941).

The program design was based on the following key aspects of pneumococcal vaccines in adults: (1) PCV13 has demonstrated both efficacy and effectiveness against vaccine-type IPD and pneumonia in adults; (2) PPSV23 has demonstrated efficacy against vaccine-type IPD, while the effectiveness data against pneumonia is limited and inconsistent; and (3), opsonophagocytic antibody response, measured by OPA assays, is the accepted marker for vaccine response, and (4) the known characteristics of a pneumococcal conjugate vaccine (e.g., the ability to induce immune memory, longevity of protection, ability for boosting) which contribute to the basis for protection.

Pivotal immunogenicity noninferiority comparisons were performed in pneumococcal vaccine−naive participants ≥60 y of age. Levels of response (OPA GMTs) induced by PCV20 were compared with those induced by PCV13 for the 13 matched serotypes, and with responses induced by PPSV23 for the 7 additional serotypes. Noninferiority for each of the 20 serotypes was declared if the lower bound of the 2-sided 95% CI for the serotype-specific geometric mean (titer) ratio was >0.5 (2-fold noninferiority criterion). As in the PCV13 clinical development program, OPA GMTs in PCV20 recipients <60 y of age were bridged to those of adults 60 to 64 y of age for all serotypes; this approach was considered more appropriate than administration of PPSV23 as a control to healthy younger adults due to potential hyporesponsiveness to subsequent pneumococcal vaccination following receipt of PPSV23.

Although there is no established threshold of OPA titer that predicts protection against pneumococcal disease in adults, when considering the known efficacy and real-world effectiveness of PCV13 against IPD and pneumonia and the established attributes of a conjugate vaccine, demonstration of noninferior immune responses by PCV20 would likely predict similar clinical efficacy. Additionally, missing the statistical criterion for noninferiority would not necessarily indicate that PCV20 does not have efficacy similar to the comparator vaccine (e.g., the titer in the comparator vaccine may be much higher than needed for clinical protection). Therefore, for serotypes that did not meet statistical noninferiority based on the ratio of OPA titers, the totality of data (including consideration of the margin by which the noninferiority is missed, the fold-rise in OPA titers, the proportion of study participants with ≥4-fold rise in OPA titers, the proportion of participants with OPA titers at or above the lower level of quantification after vaccination, and the reverse cumulative distribution curves of OPA titers) would be used to predict clinical efficacy as agreed with regulatory authorities. This approach was considered particularly relevant for serotypes that missed statistical noninferiority by a small margin and/or OPA results that showed a clear serotype-specific response with vaccination.

The core PCV20 clinical development program included five safety and immunogenicity trials of PCV20 in adults: a phase 1 trial in individuals 18 to 49 y of age,¹⁹ a phase 2 trial in those 60 to 64 y of age,⁴⁶ and three phase 3 trials (Table 1).^47–49 In the pivotal study, PCV13 was given to individuals <60 y of age for blinding and as a control for safety assessments, not for immunogenicity evaluation.⁴⁷ Study designs for the core phase 3 studies comprised a pivotal comparison study, a lot consistency study, and a study in pneumococcal vaccine-experienced adults (Figure 1). Additional studies were conducted to provide supplemental data to support PCV20 regional needs and concomitant use with other vaccines (Table 2). Immune responses in the subsets of individuals 18 to 64 y of age with factors increasing the risk for pneumococcal disease, as well as responses in individuals ≥65 y of age, were assessed post hoc and are also described in this review.

Table 1.

Study characteristics of core clinical trials in the PCV20 development program.

Article	Description	Immunogenicity objective(s)	N*	Study arms or age stratification (number vaccinated)	Location
Thompson et al.¹⁹	Phase 1 FIH randomized study in pneumococcal vaccine‒naive adults 18–49 y old	To describe immune responses 1 month after vaccination	66	n = 33, PCV20 n = 33, Tdap (control)	USA
Hurley et al.⁴⁶	Phase 2 randomized trial in pneumococcal vaccine‒naive adults 60–64 y old	Secondary: To describe immune responses 1 month after vaccination	443	n = 221, PCV20/saline n = 222, PCV13/PPSV23	USA
Essink et al.⁴⁷	Pivotal phase 3 randomized trial in pneumococcal vaccine‒naive adults ≥18 y old	Primary: NI of PCV20-elicited immune responses to the 13 matched serotypes after PCV13 and 7 additional serotypes after PPSV23, based on serotype-specific OPA GMTs 1 month after vaccination in ≥60-y-olds	2997 445 447	≥60 y: n = 1507, PCV20; n = 1490, PCV13/PPSV23 50–59 y: n = 334, PCV20; n = 111, PCV13 18–49 y: n = 335, PCV20; n = 112, PCV13	Sweden, USA
Cannon et al.⁴⁸	Phase 3 open-label trial in pneumococcal vaccine-experienced adults ≥65 y old	To describe immune responses in adults ≥65 y old previously vaccinated with PPSV23, PCV13, or both 1 month after vaccination	873	Prior PPSV23 only: n = 253, PCV20; n = 122, PCV13 Prior PCV13 only: n = 246, PCV20; n = 127, PPSV23 Prior PCV13 and PPSV23: n = 125, PCV20	Sweden, USA
Klein et al.⁴⁹	Phase 3 randomized lot consistency trials in vaccine-naive adults 18–49 y old	NI of 3 lots of PCV20 based on OPA GMTs 1 month after vaccination	1708	n = 488, PCV20 lot 1; n = 489, PCV20 lot 2; n = 486, PCV20 lot 3; n = 245, PCV13	USA

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*Total number vaccinated during the study.

FIH, first-in-human; GMT, geometric mean titer; NI, noninferiority; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; Tdap, tetanus, diphtheria and pertussis vaccine.

Figure 1. — Study designs of phase 3 trials: the pivotal comparison study⁴⁷ (A), the lot consistency study⁴⁹ (B), and the study in adults with prior pneumococcal vaccine⁴⁸ (C).

PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.

Table 2.

Study characteristics of additional studies in the PCV20 development program.

Article	Description	Immunogenicity objective(s)	N*	Study arms or age stratification (number vaccinated)	Location
Fitz-Patrick et al.⁵⁰	Phase 1 randomized study in US-based pneumococcal vaccine–naive Japanese adults 18–49 y old	To describe immune responses 1 month after vaccination	103	n = 34, PCV20 n = 33, cPCV7 n = 34, PCV13	USA
Haranaka et al.,⁵²	Phase 3 trial in pneumococcal vaccine–naive adults ≥60 y old in East Asia	NI of PCV20 to PCV13 for the 13 matched serotypes and to PPSV23 for 7 additional serotypes based on serotype-specific OPA GMTs 1 month after each vaccination	1421	n = 711, PCV20/saline n = 710, PCV13/PPSV23	Japan, South Korea, Taiwan
Cannon et al.,⁵⁴	Phase 3 trial of coadministration with QIV in adults ≥65 y old	NI of PCV20 coadministered with QIV to PCV20 and QIV when given 1 month apart based on OPA GMTs and HAI GMTs elicited 1 month after the last vaccination	1791	n = 895, QIV+PCV20/saline n = 896, QIV+saline/PCV20	USA
Fitz-Patrick et al.,⁵⁵	Phase 3 trial of coadministration with booster dose of BNT162b2 in adults ≥65 y old	To describe immune responses to PCV20 and BNT162b2 COVID-19 vaccine when administered based on OPA GMTs and SARS-CoV-2 neutralizing titers 1 month after vaccination	559	n = 187, PCV20+BNT162b2 n = 187, PCV20+saline n = 185, BNT162b2+saline	USA
Giriappa et al.,⁵³	Phase 3 single-arm trial in pneumococcal vaccine–naive adults in India	To describe immune responses 1 month after vaccination in adults	400	18–49 y old: n = 200, PCV20 ≥50 y old: n = 200, PCV20	India

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*Total number vaccinated during the study.

cPCV7, complementary 7-valent pneumococcal conjugate vaccine; GMT, geometric mean titer; HAI, hemagglutination inhibition; NI, noninferiority; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; QIV, quadrivalent influenza vaccine.

Safety and tolerability

Phase 1 and 2 trials

Overall, PCV20 was well tolerated with an acceptable safety profile for adults 18 to 49 in Phase 1, including laboratory assessment of hematology and assessment of hepatic, renal and cardiac organ systems.¹⁹ In Phase 2 with participants 60 to 64 y of age, PCV20 demonstrated a safety and tolerability profile similar to that of PCV13.^46,50 Laboratory testing in Phase 1 did not identify any subclinical safety concerns.¹⁹ These early safety data supported the continued evaluation of PCV20 in phase 3 clinical trials.

Phase 3 trials

Similar to PCV13, PCV20 had an acceptable safety profile in adults ≥18 y of age as measured by the percentage of participants reporting local reactions, systemic events, AEs, serious AEs (SAEs), and newly diagnosed chronic medical conditions.^47–49 AEs were reported at similar frequencies among PCV20 and PCV13 or other control vaccine recipients.

The proportions of participants reporting local reactions and systemic events after PCV20 were generally comparable to those after PCV13 or PPSV23. In pneumococcal vaccine–naive participants,^47,49 after PCV20, the most commonly reported local reaction was injection site pain (55–79% of participants), followed by injection site redness (7.3–8.2%) and swelling (7.5–9.1%). The frequency of local reactions tended to decrease with increasing age with 57%, 73%, and 80% of participants reporting any local reaction in PCV20 groups among individuals ≥60, 50 to 59, and 18 to 49 y of age, respectively. In pneumococcal vaccine–naive participants,^47,49 after PCV20, the most commonly reported systemic events were muscle pain (39–63%), fatigue (30–47%), and headache (22–37%); fever was reported in 0.9% to 1.5% of participants. As with local reactions, the frequency of systemic events tended to decrease with increasing age; the percentages of participants reporting any systemic event in the PCV20 group were 55%, 70%, and 77%, among participants ≥60, 50 to 59, and 18 to 49 y of age, respectively. After PCV20, muscle pain was reported by 39% of participants ≥60 y of age and by 63% of those 18 to 49 y of age; corresponding values were 30% versus 47% for fatigue and 22% versus 37% for headache. Decreased reactogenicity with increasing age is also observed with PCV13.⁵¹

PCV20 demonstrated an acceptable safety profile in adults ≥65 y of age who had previously been vaccinated with PCV13 and/or PPSV23.⁴⁸ The safety profile of PCV20 was acceptable across demographic subgroups of age, sex, and race. However, there was a trend of somewhat increased frequency of prompted systemic events reported by female participants.

PCV20 was also well tolerated, with a similar safety profile to that of PCV13, in a phase 3 study in participants ≥60 y of age from Japan, South Korea, and Taiwan. Local reactions and systemic events were reported at similar rates and frequencies between PCV20 and PCV13, and study withdrawal due to AEs and SAEs were infrequent in both vaccine groups; no SAEs were considered related to PCV20.⁵² In a single-arm study in adults ≥18 y of age in India, PCV20 was well tolerated with an acceptable safety profile.⁵³

The safety profile was similar whether PCV20 was coadministered with or administered after adjuvanted quadrivalent influenza vaccine.⁵⁴ PCV20 coadministered with mRNA COVID-19 vaccine (BNT162b2) had a safety profile similar to BNT162b2 administered alone.⁵⁵ No clinically significant tolerability issues were noted in either study.^54,55

Immunogenicity

Phase 1 and 2 trials

One month after vaccination, functional immune responses were elicited in the PCV20 group for all 20 vaccine serotypes in adults 18 to 49 and 60 to 64 y of age, supporting the continued development of PCV20.^19,46,50

Duration of immunity

In the phase 2 study, antibody levels were also measured 12 months after vaccination in adults 60 to 64 y of age.⁵⁶ At that time, OPA levels had declined from the levels reached at 1 month after vaccination but remained elevated above baseline levels. In PCV20 recipients, geometric mean fold rises (GMFRs) in OPA titers from baseline to 12 months after vaccination were 1.9 to 15.0 for the serotypes in common with PCV13 and 5.6 to 15.6 for the 7 additional serotypes.⁵⁶ This pattern of antibody decline was also observed in the CAPiTA study with PCV13⁵⁷; however, vaccine efficacy against vaccine-type disease persisted through approximately 4 y of follow-up.⁵⁸

Phase 3 trials

Pneumococcal vaccine‒naive adults

In the pivotal phase 3 trial in pneumococcal vaccine–naive adults ≥60 y of age, PCV20 elicited immune responses to the 13 matched serotypes and 6 of the 7 additional serotypes that were noninferior to responses elicited by PCV13 and PPSV23, respectively (Figure 2(A)).⁴⁷ Serotype 8 narrowly missed the statistical noninferiority criterion for the primary endpoint (lower bound of the 2-sided 95% CI for OPA GMR PCV20/PPSV23 of 0.49); however, based on the assessment of other parameters of immune response (i.e., totality of data, including the percentages of participants with ≥4-fold rises in OPA titers and with OPA titers at or above the lower limit of quantitation and GMFRs all being within the range of those observed for the 13 serotypes in the PCV13 group), the performance of PCV20 against this serotype is expected to be similar to the other vaccine serotypes. Post-implementation surveillance will be important to assess the impact of PCV20 on the seven additional serotypes, including serotype 8.

Figure 2. — Pneumococcal OPA geometric mean titers and geometric mean ratios (95% CIs) for the 20 vaccine serotypes 1 month after vaccination: (A) pivotal trial in participants ≥60 years of age and (B) post hoc analysis of participants ≥65 y of age.

GMR, geometric mean ratio; GMT, geometric mean titer, LS, least squares; OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine.

GMTs were calculated by exponentiating the LS means based on analysis of log-transformed OPA titers using a regression model with vaccine group, sex, smoking status, age at vaccination in years (continuous), and baseline log transformed OPA titers. GMRs (ratio of GMTs PCV20 to PCV13 [for the 13 matched serotypes] or PPSV23 [for the 7 additional serotypes]) and 2-sided CIs were calculated by exponentiating the difference of LS means and the corresponding CIs based on the same regression model.

PCV20 also elicited immune responses to all 20 vaccine serotypes in pneumococcal vaccine–naive adults 50 to 59 and 18 to 49 y of age that were noninferior to responses in pneumococcal vaccine–naive adults 60 to 64 y of age. In a subgroup analysis by age in the pivotal study, younger participants had higher antibody levels than the older group.

In a phase 3 study with a design similar to the pivotal trial conducted to generate regional data in Asia, PCV20 elicited robust immune responses to all 20 vaccine serotypes in pneumococcal vaccine–naive participants ≥60 y of age from Japan, South Korea, and Taiwan.⁵² The overall findings were consistent with the pivotal trial, relative to the PCV13 and PPSV23 control groups for the 13 matched and 7 additional serotypes.⁵²

Adults with previous pneumococcal vaccine experience

PCV20 elicited immune responses to all 20 vaccine serotypes in adults ≥65 y of age previously vaccinated with PCV13, PPSV23, or PCV13 followed by PPSV23.⁴⁸ Although caution must be taken when assessing responses across study arms due to differences in baseline OPA titers and the descriptive nature of the study, numerically higher responses following PCV20 vaccination were noted for all 20 serotypes in individuals who had previously received PCV13 only compared to those previously vaccinated with PPSV23 only or PCV13 followed by PPSV23. Immunogenicity data indicate that PCV20 is likely to perform well and similar to PCV13 in individuals previously vaccinated with a dose of PPSV23. In adults ≥65 y of age previously vaccinated with PCV13, immune responses to PCV20 were generally similar to those in the same age group in the pivotal trial in pneumococcal vaccine–naive adults. Based on these data, PCV20 is expected to provide the additional benefit of a conjugated vaccine with broad serotype coverage in older adults who were previously vaccinated with PCV13 or PPSV23.

Lot consistency

Lot consistency was demonstrated, with three unique lots of PCV20 eliciting similar (i.e., within the 2-fold equivalence margin) and robust immune responses at 1 month after vaccination for each of the 20 serotypes in pneumococcal vaccine–naive adults 18 to 49 y of age.

Post hoc analysis in adults ≥65 y of age

In a previously unpublished post hoc analysis from the pivotal trial evaluating the subset of adults ≥65 y of age, model-based OPA GMRs (PCV20 to PCV13) for the 13 matched serotypes ranged from 0.76 (serotype 6A) to 1.03 (serotype 14) 1 month after vaccination (Figure 2(B)), applying the same pre-specified linear regression models used for the evaluation of OPA responses from the overall study population. Although the study was not powered to demonstrate noninferiority of PCV20 to PCV13 for any subgroup, OPA responses to all 13 matched vaccine serotypes induced by PCV20 would have demonstrated noninferiority compared to those induced by PCV13 for participants ≥65 y of age applying the same 2-fold noninferiority criterion (i.e., lower bounds of the 2-sided 95% CIs for the model-based OPA GMRs > 0.5) that was accepted by regulatory agencies for the evaluation of the overall Phase 3 pivotal study population. These post hoc analysis results for the 13 serotypes are consistent with the findings for the pivotal study primary objective in adults ≥60 y of age. OPA GMRs for the seven additional serotypes ranged from 0.63 (serotype 8) to 2.97 (serotype 15B) 1 month after vaccination (Figure 2(B)). OPA responses to the seven additional serotypes induced by PCV20 would have demonstrated noninferiority for all seven serotypes, including serotype 8, compared to those induced by PPSV23 for participants ≥65 y of age using the standard 2-fold noninferiority criterion. In the pivotal trial primary analysis, six of seven serotypes met the statistical NI criterion, with serotype 8 narrowly missing noninferiority.⁴⁷ Results from additional sensitivity analysis of the unadjusted OPA GMRs were generally consistent with the model-based OPA GMR results.

Post hoc analysis in participants with risk factors

PCV20 elicited robust immune responses to all 20 vaccine serotypes in a post hoc analysis of the subgroup of participants who were 18 to 64 y of age from two phase 3 trials (the pivotal study and the lot consistency study)^47,49 with chronic health conditions (e.g., asthma, diabetes mellitus, chronic heart or lung disease) or current smoking.⁵⁹ In this analysis, the immune responses to PCV20 compared with PCV13 for the matched 13 serotypes and PPSV23 for the 7 additional serotypes in the at-risk population were similar to the findings in the pivotal study, supporting PCV20 use in these individuals who may experience a particular benefit from pneumococcal vaccination compared with the general population.⁵⁹

Concomitant vaccine trials

Immune responses after coadministration of PCV20 and quadrivalent influenza vaccine (Fluad® Quadrivalent, Seqirus Inc., Holly Springs, NC, USA) were noninferior to separate administration of either vaccine in adults ≥65 y of age who were pneumococcal vaccine–naive or who had prior pneumococcal vaccination.⁵⁴ Although pneumococcal responses were noninferior, GMTs were modestly lower when coadministered with influenza vaccination; however, these findings were not expected to have been clinically significant.⁵⁴ Immune responses to PCV20 and a booster dose of the COVID-19 vaccine BNT162b2 were similar whether the vaccines were coadministered or each given alone in adults ≥65 y of age who were previously vaccinated with 2-doses of BNT162b2 ≥6 months before study vaccination.⁵⁵ In both studies, coadministration with PCV20 did not affect the immunogenicity of the concomitant vaccines.^54,55

Conclusions

The breadth and robustness of data generated with PCV13 in adults laid the foundations for PCV20 development in adults and enabled a focused clinical development plan.

PCV20 was well tolerated with an acceptable safety profile when administered as a single dose in adults ≥18 y of age who were naive to pneumococcal vaccine or had been previously vaccinated with PCV13 and/or PPSV23. Regardless of age or previous pneumococcal vaccination status, the safety profile of PCV20 was similar to that of PCV13, with no new safety concerns.

Immunogenicity analyses indicate that in adults ≥18 y of age, PCV20 is expected to perform similarly to PCV13 against pneumococcal disease caused by the 13 matched serotypes and provide protection against the 7 additional serotypes. Alongside the known efficacy of PCV13 against IPD and pneumonia and the known immunologic benefits of a conjugate vaccine, these immunogenicity data establish that PCV20 induces responses in primary and subgroup populations expected to help maintain protection against the matched 13 serotypes and extend it to the additional seven clinically and epidemiologically relevant serotypes.

Future directions

Although few adult PCV13 immunization programs were implemented around the world because the expectation that indirect (i.e., herd) effects from pediatric immunization programs would provide adequate protection in this population, epidemiological evidence suggests a rising burden of pneumococcal disease among adults, supporting the need for new generation vaccines.⁶⁰ This rising burden among adults is in part due to the persistence of certain serotypes (e.g., 3, 19A, 19F) as well as variably increasing incidence in recent years of previously suppressed serotypes (e.g., 4, 9V, 14).^61,62 With licensing of higher-valency PCVs (PCV15, PCV20, and a 21-valent pneumococcal conjugate vaccine, PCV21),⁶³ adult immunization programs are gaining momentum. While new-generation vaccines are expected to parallel the performance of PCV13, post-marketing studies will demonstrate their full public health benefit.

Despite the advantages of broader serotype coverage, an important challenge for pneumococcal vaccines remains: protection against the biologically unique serotype 3.^44,64,65 Although PCV13 demonstrated efficacy and effectiveness against this serotype, the protection waned more rapidly compared with other serotypes.^44,64 Additionally, the effect on carriage is modest, resulting in a lack of appreciable herd effect.⁶⁶ In many countries, serotype 3 has become the leading disease-causing serotype in adults.⁶⁷ Although broader use of recently licensed higher-valency PCVs may have an impact on serotype 3 epidemiology, this may be challenging given that serotype 3 is biologically different from other serotypes, harboring a thick capsule that makes it more resistant to opsonophagocytosis.⁶⁵ Thus, a highly efficacious vaccine with durable protection against this serotype is a key priority for new vaccine development, with potential for a significant public health impact.

As the epidemiology of pneumococcal disease evolves, there will be a need for further expansion of serotype coverage. Several novel approaches to vaccine development are being pursued, including removing low prevalence serotypes in exchange for emerging ones; changing conjugation technology; and using new or multiple carriers, protein antigens, or new adjuvants.^68–70 A number of pneumococcal vaccines are currently under development, covering different sets of serotypes and employing novel technologies to improve immune responses.^27,68 Because these vaccines will also be licensed based on immunobridging,⁷¹ understanding potential differences in their clinical performance will be necessary to optimize their use. This information will not be available at the time of licensing, and with the increasing number of available vaccines, assessment of their individual clinical effectiveness may become challenging even after introduction. Moreover, serotype-agnostic vaccines, either whole-cell or those based on subcapsular proteins common to all pneumococci, are also being pursued^27,70,72 but are challenged by the lack of proof-of-concept and an established licensing pathway. Thus, alternative approaches to assessing vaccine effectiveness, such as using human challenge models, may become more important in the future.

In conclusion, the pneumococcal vaccination environment is rapidly changing with the introduction of new vaccines and the adoption of adult vaccination programs in many countries. Close monitoring of evolving epidemiology, as well as the effectiveness and impact of the new vaccines will be important for ensuring continued protection among different populations.

Acknowledgments

Editorial support was provided by Sheena Hunt, PhD, of ICON (Blue Bell, PA, USA) and was funded by Pfizer Inc.

Biographies

Kathleen McElwee, MD, MPH is the PCV20 Global Clinical Program Lead in Vaccine Clinical Research and Development at Pfizer. She has previously worked on both pediatric and adult studies within the PCV20 program. Dr McElwee completed her undergraduate degree in biology at Saint Joseph’s University, Medical School at Temple University, and both internal medicine residency and infectious disease fellowship at the University of Illinois Chicago Medical Center. She holds a Master of Public Health from the University of Illinois Chicago in Public Health Informatics. Previously, she worked as an Infectious Disease Consultant at Reading Hospital in Pennsylvania and served as the medical director of the Ryan White HIV clinic in West Reading, PA.

Jelena Vojicic, MD completed her undergraduate degree in biology and obtained her medical degree from the Faculty of Medicine at the University of Novi Sad, Serbia. She worked in Clinical Research at Sanofi-Aventis and Medical Affairs at Boehringer-Ingelheim covering various therapeutic areas before joining Pfizer to focus on anti-infectives and vaccines. She currently serves as the Global Adult Pneumococcal Vaccines Medical Affairs Team Lead at Pfizer.

Funding Statement

This study was sponsored by Pfizer Inc.

Disclosure statement

All authors are current or former Pfizer employees and may hold stock and/or stock options.

Data availability statement

Upon request, and subject to review, Pfizer will provide the data that support the findings of this review. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

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Data Availability Statement

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PERMALINK

An overview of the clinical development of the 20-valent pneumococcal conjugate vaccine in adults

Kathleen McElwee

Jelena Vojicic

Charulata Sabharwal

John Ginis

Yahong Peng

Gabriel Mircus

Wendy Watson

Annaliesa Anderson

Roles

ABSTRACT

Introduction

PCV13 experience in adults

PCV20 clinical development studies

Table 1.

Figure 1.

Table 2.

Safety and tolerability

Phase 1 and 2 trials

Phase 3 trials

Immunogenicity

Phase 1 and 2 trials

Duration of immunity

Phase 3 trials

Pneumococcal vaccine‒naive adults

Figure 2.

Adults with previous pneumococcal vaccine experience

Lot consistency

Post hoc analysis in adults ≥65 y of age

Post hoc analysis in participants with risk factors

Concomitant vaccine trials

Conclusions

Future directions

Acknowledgments

Biographies

Funding Statement

Disclosure statement

Data availability statement

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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