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Article

Randomized Phase 3 Trial Evaluating the Safety, Tolerability, and Immunogenicity of V114, a 15-Valent PCV, Followed by PPSV23 6 Months Later (PNEU-DAY): Subgroup Analysis in Adults 18–49 Years of Age Enrolled at Center for Indigenous Health Sites

by
Laura L. Hammitt
1,*,
Ulrike K. Buchwald
2,
Jennifer McCauley
2,
Tulin Shekar
2,
Wei Fu
2,
Kyeongmi Cheon
2,
Tina Sterling
2,
Gretchen Tamms
2,
Natalie Banniettis
2,
Luwy Musey
2,
Jason J. LeBlanc
3,4,
Robert Weatherholtz
1,
Dennie Parker Riley
1,
Estar Denny
1,
Carol Tso
1,
Kristen Roessler
1 and
Mathuram Santosham
1
1
Department of International Health, Center for Indigenous Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
2
Merck & Co., Inc., Rahway, NJ 07065, USA
3
Division of Microbiology, Department of Pathology and Laboratory Medicine, Nova Scotia Health, Halifax, NS B3H 1V8, Canada
4
Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada
*
Author to whom correspondence should be addressed.
Vaccines 2026, 14(1), 3; https://doi.org/10.3390/vaccines14010003
Submission received: 19 November 2025 / Revised: 15 December 2025 / Accepted: 17 December 2025 / Published: 19 December 2025
(This article belongs to the Section Vaccine Advancement, Efficacy and Safety)
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Abstract

Background/Objectives: American Indian/Alaska Native individuals exhibit a higher prevalence of carriage of Streptococcus pneumoniae and are at increased risk of invasive pneumococcal disease compared with the general US population, driven by persistent inequities in health determinants. Although the use of pneumococcal vaccines has reduced carriage of vaccine serotypes, the prevalence of carriage of non-vaccine serotypes has increased. Methods: This study was a descriptive subgroup analysis of the PNEU-DAY study (NCT03547167; EudraCT 2017-004915-38). Safety, tolerability, and immunogenicity of sequential administration of either V114, a 15-valent pneumococcal conjugate vaccine (PCV), or 13-valent PCV (PCV13), followed 6 months later by 23-valent pneumococcal polysaccharide vaccine (PPSV23), were evaluated in pneumococcal vaccine-naïve American Indian adults with or without pre-defined risk factors for pneumococcal disease. Polymerase chain reaction testing assessed nasopharyngeal/oropharyngeal carriage of S. pneumoniae. Results: Following administration of PCV and PPSV23, the proportions of participants with adverse events were generally comparable between vaccination groups. V114 and PCV13 were immunogenic for all respective vaccine serotypes, with V114 inducing robust immune responses to the two additional serotypes not included in PCV13 (22F and 33F), based on opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations at 30 days post-vaccination. Sequential administration with PPSV23 was immunogenic in both vaccination groups. Nasopharyngeal/oropharyngeal carriage of S. pneumoniae was observed in 16.7% to 22.6% of American Indian participants across the study timepoints. Conclusions: V114 was well tolerated and immunogenic for the 15 serotypes in V114 when administered either alone or followed by PPSV23. Use of V114 has the potential to expand serotype coverage and protect against pneumococcal disease resulting from serotypes absent in PCV13 among American Indian adults.

1. Introduction

Pneumococcal disease (PD) caused by Streptococcus pneumoniae is a significant cause of morbidity, hospitalization, and mortality across all ages [1,2,3]. American Indian/Alaska Native individuals, who comprise approximately 2.9% of the total population of the United States [4], have a higher prevalence of nasopharyngeal (NP) carriage of S. pneumoniae and experience a three-to-five-fold-higher risk of invasive PD (IPD) when compared with the overall population of the United States [5,6,7,8]. Disparities in socioeconomic conditions and access to healthcare, in addition to a high prevalence of chronic comorbidities, including diabetes mellitus, chronic heart disease, and asthma, contribute to the elevated burden of PD in American Indian/Alaska Native communities [1,6,9,10,11,12,13].
In the United States, two types of vaccine are recommended for pneumococcal immunization: pneumococcal conjugate vaccines (PCVs) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23) [14,15]. PPSV23 is a vaccine that has been recommended since the 1980s for older adults and individuals with certain underlying conditions that increase the risk of PD [14,16,17,18]. Until recently, 13-valent PCV (PCV13), which contains 13 serotypes, was recommended by the Advisory Committee on Immunization Practices (ACIP) in adults ≥65 years of age with or without chronic medical conditions based on shared clinical decision-making [19,20]; for adults ≥19 years of age with immunocompromising conditions, vaccination with PCV13 followed by PPSV23 was recommended [19]. While the use of pneumococcal vaccines among the American Indian/Alaska Native population has led to a substantial decrease in IPD caused by vaccine serotypes and vaccine-type carriage prevalence [5,21], the prevalence of non-vaccine serotype carriage has increased [21], highlighting the need for new PCVs with broader serotype coverage.
Three higher-valency PCVs were recently approved for use in adult populations [22,23,24]. V114 (VAXNEUVANCE™, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA [MSD]) is a 15-valent PCV that contains the 13 serotypes in PCV13 plus two epidemiologically important serotypes (22F and 33F) that cause IPD [20,25,26,27,28,29,30,31]. V114 is approved for use in the United States and globally for the prevention of PD in adults ≥18 years of age [25,32,33]. V116 (CAPVAXIVE™, MSD) is an adult-specific, 21-valent PCV containing the serotypes most often associated with IPD in adults from regions with established pediatric PCV programs; V116 is approved in multiple regions, including the United States, Canada, Australia, the European Union, and Japan, among others, for the prevention of IPD in individuals ≥18 years of age, and for the prevention of pneumonia in individuals ≥18 years of age in the United States and the European Union [22,34,35,36,37,38]. A 20-valent PCV (PCV20), which contains 20 serotypes, was also recently approved in adults ≥18 years of age [33,39]. In October 2024, the ACIP revised and expanded the adult pneumococcal immunization recommendations: for individuals ≥19 years of age with particular risk factors for PD and for all adults ≥50 years of age, vaccination is recommended with either a single dose of V116 or PCV20 or V114 followed by PPSV23 ≥1 year later [40,41].
PNEU-DAY was a descriptive Phase 3 study assessing the safety, tolerability, and immunogenicity of V114 or PCV13 administered on Day 1, as well as PPSV23 6 months later, among 1515 immunocompetent pneumococcal vaccine-naïve adults 18–49 years of age with or without pre-defined risk factors for PD [42]. In this descriptive subgroup analysis of PNEU-DAY, we evaluated the safety, tolerability, and immunogenicity of V114 in American Indian adults as compared with PCV13. In addition, NP/oropharyngeal (NP/OP) carriage of S. pneumoniae was assessed in this population.

2. Materials and Methods

2.1. Study Design and Participants

In the primary study conducted between July 2018 and July 2020 (Protocol V114-017; PNEU-DAY study; registered with Clinicaltrials.gov: NCT03547167 [trial registration date: 24 May 2018] and the European Union Clinical Trials Register: EudraCT 2017-004915-38 [trial registration date: 4 October 2018]; the full protocol and statistical analysis plan for the primary study are available online [43]), approximately 600 American Indian participants 18–49 years of age with and without risk factors for PD were recruited between October 2018 and June 2019 and enrolled at five sites of the Johns Hopkins Center for Indigenous Health (CIH; formerly the Center for American Indian Health) located in the southwest region of the United States (a list of sites and investigators is provided in Table S1). This descriptive subgroup analysis was conducted to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in this population, and to describe pneumococcal NP/OP carriage. Participants in this subgroup analysis met eligibility criteria for the PNEU-DAY study (Table S2) [43]. In brief, participants were eligible if they had not previously received a pneumococcal vaccine and were American Indian adults in good health or with any of the following risk conditions for PD: chronic heart disease, chronic liver disease, chronic lung disease, diabetes mellitus, and tobacco use. The sample size was selected to reach a sufficient number of participants across different age groups and risk factor categories with exposure to V114 [42].
Participants were randomized 3:1 to receive a single dose of either V114 or PCV13 on Day 1, and a subsequent single dose of PPSV23 administered at Month 6. Randomization was implemented using an interactive response technology system and was stratified based on enrollment site and type/number of pre-defined baseline risk factors [42,43]. The participants and investigators involved in clinical evaluation remained blinded to the group assignments. In addition, participants were all screened for alcohol misuse/abuse using the Alcohol Use Disorder Identification Test Alcohol-Consumption (AUDIT-C) test; potentially harmful alcohol use (scores of ≥5) counted as an additional risk factor for stratification purposes [42,44].

2.2. Vaccines and Administration

V114 (VAXNEUVANCE™, MSD) contains pneumococcal capsular polysaccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 22F, and 33F [25,42].
PCV13 (Prevnar 13©, Wyeth LLC, marketed by Pfizer, New York, NY, USA) contains pneumococcal capsular polysaccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F [20,42].
PPSV23 (PNEUMOVAX® 23, MSD) contains pneumococcal capsular polysaccharides from serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F [16,42].
The three vaccines were supplied, stored, and administered per a previous report [42]. A 0.5 mL dose of V114 (lot number 00068290) or PCV13 (lot numbers 0000793304, 0000921112, and 0000814723) and PPSV23 (lot number 0000794346) were administered by study personnel who were unblinded and not otherwise involved in the conduct of the study.

2.3. Study Assessments and Analyses

2.3.1. Safety and Immunogenicity

Adverse events (AEs) occurring after each study vaccine were ascertained, including any unsolicited non-serious AEs within 14 days of vaccination and any serious AEs (SAEs) occurring from Day 1 through Month 7. Solicited injection-site events were collected from Days 1–5 following vaccination and were designated as vaccine-related. Solicited systemic events were collected from Days 1–14 following vaccination; vaccine-relatedness was determined by the investigators. Safety analyses for the subset of participants enrolled at CIH sites were conducted on the all-participants-as-treated population (i.e., participants who received the study vaccine for the timepoint of interest) and were reported as proportions.
To assess immune responses, blood samples were drawn pre-PCV vaccination (Day 1), 30 days post-PCV vaccination (Day 30), pre-PPSV23 vaccination (Month 6), and 30 days post-PPSV23 vaccination (Month 7), as previously described [42]. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) and serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) were assessed in the subset of participants enrolled at CIH sites who were among the per-protocol population, which included all randomized participants with no protocol deviations that could affect the immunogenicity results in a substantial way.
Safety and immunogenicity of study PCV followed by PPSV23 were also analyzed in subgroups based on age (18–29, 30–39, and 40–49 years of age) and number of baseline risk factors for PD (0 or ≥1 risk factors).

2.3.2. NP/OP Carriage of Vaccine-Preventable Serotypes

Approximately 300 American Indian participants who were part of the CIH cohort of the primary study were further included in a substudy to evaluate the relationship between NP/OP carriage of S. pneumoniae and pneumococcal vaccination on the performance of a serotype-specific urinary antigen detection (SSUAD) assay. The methodology and characteristics of the SSUAD assay have been included in a different manuscript; in this current analysis, overall pneumococcal NP/OP carriage data in this population and carriage of vaccine serotypes are further analyzed.

2.3.3. Detection and Serotyping of S. pneumoniae from NP/OP Analyses

NP/OP flocked swabs were collected immediately prior, to and up to, 30 days following each vaccination (on Days 3, 8, 15, and 30 following V114/PCV13; on Days 183, 188, 195, and Month 7 following PPSV23), using standard procedures [45,46]. Total nucleic acids were purified from NP/OP swab material, and detection and serotyping of S. pneumoniae in NP/OP swabs were performed using previously described methods [46,47,48]. In brief, sequential real-time polymerase chain reaction (PCR) was used to target autolysin (lytA), capsular polysaccharide synthesis gene A (cpsA), and the pneumococcal iron acquisition (piaA) gene. S. pneumoniae carriage positivity was determined if lytA PCR was positive, along with a positive result from cpsA or piaA; only these specimens were then subjected to triplex real-time multiplex PCRs spanning the 15 serotypes covered in V114 [46].

3. Results

3.1. Study Population

Between October 2018 and July 2020, a total of 587 randomized participants from CIH sites were included in this analysis (Figure 1). All randomized participants were vaccinated with V114 or PCV13 in a 3:1 ratio, with 439 receiving V114 and 148 receiving PCV13. Nearly all participants (90.3%) were vaccinated with PPSV23 in Month 6. Most participants (90.6%) completed the study. All intervention groups had similar discontinuation rates.
Across both vaccination groups, participant characteristics were generally comparable at baseline (Table 1). The mean age of the study participants was 32.6 years, and about 58% of participants were female. Approximately 65% of enrollees did not have protocol-defined risk factors for PD at screening.

3.2. Safety

3.2.1. Following Vaccination with PCV (Days 1–30)

Following administration of PCV, the proportions of participants with AEs, including solicited AEs, were generally comparable between the V114 and PCV13 groups (Table 2). No vaccine-related SAEs were reported in either group. Three deaths were reported across both vaccination groups (two in the V114 group and one in the PCV13 group), none of which were considered by the investigator to be related to the study vaccine. The most common solicited AE was injection-site pain (V114: 72.0%; PCV13: 64.9%). Fatigue was the most frequently reported solicited systemic AE in both groups (V114: 33.3%; PCV13: 37.8%). In both vaccination groups, most solicited AEs were mild (Figure 2; Table S3).
In a subgroup analysis by age (18–29, 30–39, and 40–49 years), V114 was well tolerated within each age group (Table S4). Following administration of V114, solicited AEs were observed in 79.3%, 73.3%, and 80.8% of participants in the 18–29, 30–39, and 40–49 years of age groups, respectively. The proportions of participants with solicited AEs within each age group were generally comparable between the V114 and PCV13 groups.
V114 was well tolerated, regardless of whether risk factors for PD (0 or ≥1) were present at baseline. The proportions of participants experiencing solicited AEs were generally comparable between participants with or without risk factors for PD (Table S5).

3.2.2. Following Vaccination with PPSV23 (Months 6–7)

Following administration of PPSV23, the majority of participants in both vaccine groups experienced at least one AE (Table 2). As with the Day 1 vaccination, pain was the most frequently reported solicited injection-site AE (V114: 55.0%; PCV13: 56.1%) and fatigue was the most frequently reported solicited systemic AE (V114: 24.9%; PCV13: 23.5%). The majority of solicited AEs were mild (Figure S1; Table S3).

3.3. Immunogenicity

3.3.1. Following Vaccination with PCV (Days 1–30)

V114 induced immune responses for all 15 V114 serotypes at 30 days post-vaccination, as assessed by OPA GMTs (Figure 3; Table S6) and IgG GMCs (Table S7). PCV13 was immunogenic for all 13 PCV13 serotypes at 30 days post-vaccination.
V114 induced immune responses for all 15 V114 serotypes, regardless of participant age or presence of risk factors for PD, as assessed by OPA GMTs at 30 days post-vaccination with PCV (Tables S8–S11). There was a suggestion of lower serotype-specific OPA GMTs in those 40–49 years of age compared with those 18–29 years of age (Figure 4). OPA GMTs were generally comparable between the vaccination groups for most of the shared serotypes within each age group and whether or not risk factors for PD were present.

3.3.2. Following Vaccination with PPSV23 (Months 6–7)

Vaccination with PPSV23 at 6 months after the V114 or PCV13 PCV vaccination induced immune responses. At 30 days after the PPSV23 vaccination (i.e., at Month 7), serotype-specific OPA GMTs (Figure 5; Table S6) and IgG GMCs (Table S7) in both vaccination groups were generally comparable for all 15 serotypes, including serotypes 22F and 33F. A consistent booster response was not observed following vaccination with PPSV23 across the serotypes shared between V114/PCV13 and PPSV23 (Figure 5).

3.4. NP/OP Carriage Results

The proportion of participants who were PCR-positive for pneumococcal NP/OP carriage at a given visit ranged from 16.7% to 22.6% (Table 3). Small differences in pneumococcal carriage were seen between the V114 and PCV13 vaccination groups; however, given the 3:1 randomization, these findings are to be interpreted with caution. The NP/OP carriage prevalence differed by timepoint and ranged between 17.3% at Day 183 and 22.6% at Day 1 in the combined vaccination groups. The serotype-specific NP/OP carriage prevalence of specific serotypes varied by serotype and over time (Table S12). Serotype-specific carriage prevalences for serotypes 1, 4, 5, 9V, and 33F were approximately 4–7% on Day 1. The highest carriage detection rates for the two additional serotypes in V114 in the total cohort were 2.7% at Day 1 for serotype 22F and 6.0% at Day 1 for serotype 33F; group-specific differences in colonization rates for these two serotypes should be interpreted with caution, given small sample numbers. Colonization with other vaccine serotypes of S. pneumoniae was very low or not detected.

4. Discussion

This subgroup analysis demonstrated that V114 followed by PPSV23 was immunogenic and generally well tolerated in American Indian adults 18–49 years of age. These results are consistent with those observed in the overall study population [42].
In this substudy, administration of V114 or PCV13 followed by PPSV23 was well tolerated by participants. No vaccine-related SAEs were reported in either group. Solicited events accounted for most of the AEs and vaccine-related AEs; the majority of solicited AEs were mild to moderate in severity. When stratified based on age and the number of risk factors for PD, V114 was well tolerated within each age and risk factor group. While a relatively lower percentage of participants experienced solicited injection-site AEs with PCV13 when compared with V114, it is not possible to make formal comparisons between the vaccination groups, as this study was not designed to evaluate differences between the V114 and PCV13 vaccination groups. Statistical comparisons between V114 and PCV13 in a pivotal Phase 3 study in adults found that solicited systemic AEs were comparable between groups and the majority were reported as mild [49].
V114 induced immune responses against the two additional serotypes in V114, 22F and 33F, which are among the most common serotypes that cause IPD globally and were collectively responsible for 6.3% and 0.9% of IPD cases during 2011–2019 among Navajo children and adults, respectively [26,27,50,51,52,53,54,55,56]. In addition, immune responses to the 13 serotypes in common for the two vaccines were generally comparable among recipients of PCV13 and V114. This is further supported by the results of a pivotal Phase 3 study comparing V114 with PCV13, in which V114 was non-inferior for the 13 shared serotypes and was superior for the two unique serotypes 22F and 33F, as well as for the shared serotype 3 [49]. Taken together, these results suggest that V114 has the potential to expand protection to these two additional serotypes while maintaining protection against the serotypes that V114 has in common with PCV13.
PPSV23 administered 6 months following V114 vaccination induced immune responses to all 15 serotypes included in V114; these immune responses were generally similar to those elicited with PPSV23 administered 6 months following PCV13 vaccination. Following vaccination with PPSV23, a consistent booster response was not observed for certain serotypes in the V114 group and the PCV13 group; however, this is unlikely to be of clinical significance, given that post-PPSV23 antibody GMCs and GMTs were high. Immunogenicity findings were similar between vaccination groups for serotype 3, as well as other serotypes, such as 33F. Results from the primary study reported that, in general for some shared serotypes, OPA and IgG responses following receipt of PPSV23 were lower than those measured post-PCV [42]. Taken together, these results suggest that the 6-month interval between administration of PCV and PPSV23 may not have been sufficient to generate a robust booster response to serotypes common between them. Similar findings were reported in a study among adults 60–64 years of age that evaluated PCV13 followed 1 year later by PPSV23 [57]. OPA and antibody responses to the serotypes that PCVs share with PPSV23 may be greater with a longer interval between vaccines [58].
The benefits of sequential vaccination with PCV followed by PPSV23 due to the broadening of serotype coverage have been reported with PCV13 [59,60,61]. A study evaluating PCV13 alone compared with PCV13 followed by PPSV23 2 months later demonstrated superiority of immune responses against serotypes unique to PPSV23 and non-inferiority of shared serotypes at 3 months post-PCV administration [59]. As V114 has demonstrated immunogenicity to the unique serotypes 22F and 33F [49], sequential vaccination using V114 plus PPSV23 could potentially further expand serotype coverage over PCV13 plus PPSV23 [62,63]. Additional studies on the correlates of protection, as well as head-to-head evaluations of differing interval lengths, would be helpful to assess the potential benefit of sequential vaccination with different time intervals [64].
V114 was immunogenic across age ranges, with a suggestion of lower immune responses in older age groups, which is consistent with previous results of PCVs in older adults and may be attributed to immunosenescence [65,66]. The presence of chronic medical conditions did not affect the immunogenicity of V114, as immune responses were generally similar between participants with or without risk factors.
This study also measured S. pneumoniae NP/OP carriage among American Indian participants. While the primary purpose of the NP/OP substudy was to assess any associations between pneumococcal carriage and/or pneumococcal vaccination and performance of a pneumococcal SSUAD assay (results to be published separately), this also afforded the opportunity to characterize NP/OP carriage in this population at increased risk of PD. Pneumococcal carriage is a prerequisite for PD and has been shown to be correlated with the transmission of S. pneumoniae in several studies [67,68]. Both NP and OP samples were analyzed to increase sensitivity [69]. The proportion of participants in the total population who were positive for pneumococcal NP/OP carriage at a given visit ranged from 16.7% to 22.6%. The carriage detected in this study is similar to that detected in previous studies among American Indian adults; however, differences in laboratory methods used to detect pneumococci preclude direct comparison. In 2010–2012, the prevalence of pneumococcal NP carriage among American Indian adults in the southwest United States was 12% using culture-based methods [7]. In 2015–2017, NP/OP pneumococcal carriage among American Indian adults in the southwest United States was 8% by culture; by PCR, NP carriage was 9.2% while OP carriage was 22.1% [70]. In this study, PCR detection of S. pneumoniae carriage in swabs varied across timepoints. The real-time PCR assays used in this study were qualitative and, therefore, did not allow quantitative assessments of density following vaccination with PCVs.
Of note, real-time PCR targeting lytA or serotype-specific genes alone on OP samples may give false-positive results due to the diversity of streptococci found in the oropharynx [47,71,72,73,74]. To reduce the potential for false-positive results, only samples with a positive PCR on two pneumococcal targets (i.e., lytA, cpsA, or piaA) underwent serotype-specific PCR testing; this approach may have missed the detection of vaccine serotype carriage for some individuals.
Serotypes 1, 4, 5, 9V, and 33F were the most common serotypes found in NP/OP samples. Of note, the prevalence of serotype 4 carriage was higher than reported in previous studies in this setting (0% by NP culture in 2010–2012, 1.6% by NP/OP PCR in 2015–2017, and 5.3–6.0% by NP/OP PCR across the study visits reported herein) [70]. This apparent increase in the carriage of serotype 4 among adults presaged an increase in serotype 4 IPD that has recently been reported in the Navajo Nation [75]. The two additional serotypes included in V114 but not in PCV13 (i.e., serotypes 22F and 33F) were carried by up to 10% of participants. These two serotypes were relatively less common in a similar carriage study carried out at CIH sites between 2015 and 2017 (33F in 1.8% and 22F in 0.7% of adult samples) [70]. However, it is uncertain whether these differences were real or potentially caused by differences in testing methods.
This analysis of safety and immunogenicity in American Indian adults was descriptive, thereby limiting direct comparison between the vaccination groups. The comparisons provided here refer to observed trends in immune responses but do not suggest clinically meaningful differences between the V114 and PCV13 vaccination groups. In addition, non-vaccine serotypes were not evaluated in this analysis.

5. Conclusions

In American Indian adults 18–49 years of age, V114 administered alone or sequentially with PPSV23 had an acceptable reactogenicity and safety profile and induced immune responses to all V114 serotypes. Among American Indian adults, who are at increased risk of PD, V114 may extend protection against IPD to two clinically important serotypes not included in PCV13.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/vaccines14010003/s1. Table S1. List of investigators at CIH sites; Table S2. Subgroup analysis inclusion and exclusion criteria; Table S3. Summary of AEs following vaccination with V114 or PCV13 by age group (Day 1–Month 6); Table S4. Summary of AEs following vaccination with V114 or PCV13 by number of baseline risk factors (Day 1–Month 6); Table S5. Summary of OPA GMTs; Table S6. Summary of IgG GMCs; Table S7. Summary of OPA GMTs at 30 days following vaccination with V114 or PCV13 in participants 18–29 years of age; Table S8. Summary of OPA GMTs at 30 days following vaccination with V114 or PCV13 in participants 30–39 years of age; Table S9. Summary of OPA GMTs at 30 days following vaccination with V114 or PCV13 in participants 40–49 years of age; Table S10. Summary of OPA GMTs at 30 days following vaccination with V114 or PCV13; Table S11. Pneumococcal NP/OP carriage prevalence for V114 vaccine serotypes in the per-protocol population; Table S12. Pneumococcal NP/OP carriage prevalence for V114 vaccine serotypes in the per-protocol population; Figure S1. Proportion of participants with solicited AEs following vaccination with PPSV23.

Author Contributions

Conceptualization, L.L.H., J.M., T.S., W.F., K.C., T.S. (Tina Sterling), G.T., L.M., J.J.L., R.W., N.B. and U.K.B.; methodology, L.L.H., J.M., T.S. (Tulin Shekar), W.F., K.C., T.S. (Tina Sterling), G.T., L.M., J.J.L., R.W., N.B. and U.K.B.; validation, W.F. and K.C.; formal analysis, L.L.H., J.M., T.S. (Tulin Shekar), W.F., K.C., T.S. (Tina Sterling), G.T., L.M., J.J.L., N.B. and U.K.B.; investigation, L.L.H., J.J.L. and R.W.; data curation, L.L.H., J.J.L., C.T., R.W., M.S., D.P.R., E.D. and K.R.; writing—original draft preparation, L.L.H., J.M., T.S. (Tulin Shekar), W.F., K.C., T.S. (Tina Sterling), G.T., L.M., J.J.L., N.B. and U.K.B.; writing—review and editing, all authors; supervision, L.L.H., R.W. and M.S.; funding acquisition, L.L.H. and M.S. All authors have read and agreed to the published version of the manuscript.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Institutional Review Board Statement

The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and Good Clinical Practice requirements. This study was approved by the Navajo Nation Human Research Review Board (NNR 18.307; approval date: 19 June 2018), the Phoenix Area Indian Health Service Institutional Review Board (PXR 18.08; approval date: 13 September 2018), and the Johns Hopkins School of Public Health Institutional Review Board (#00008782; approval date: 6 June 2018). The opinions expressed in the paper are those of the authors and do not necessarily reflect the views of the Indian Health Service.

Informed Consent Statement

Written informed consent was obtained from all participants involved in the study prior to any study procedure.

Data Availability Statement

The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), is available at https://engagezone.msd.com. Requests for access to the clinical study data can be submitted through the Engage Zone site or via email to dataaccess@msd.com. The data for this sub-analysis belong to the participating tribes. Data may be made available on request (contact lhammitt@jhu.edu), if use of data is consistent with the institutional review board-approved protocol and is approved by the participating tribes.

Acknowledgments

The authors thank the participants, their families, the Johns Hopkins Center for Indigenous Health staff, and all investigators involved in this study. Cindy Cheung and Ian Norton are employees of Scion (a division of Prime, London, UK), which was hired by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, to provide editorial/writing support for this manuscript according to Good Publication Practice guidelines: https://www.acpjournals.org/doi/10.7326/M15-0288.

Conflicts of Interest

L.L.H. reports research grants to her institution from Merck & Co., Inc., Rahway, NJ, USA and Pfizer. U.K.B., J.M., T.S. (Tulin Shekar), W.F., K.C., T.S. (Tina Sterling), G.T., and N.B. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may hold stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. L.M. is a former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who may hold stock or stock options in Merck & Co., Inc., Rahway, NJ, USA. J.J.L. reports investigator-initiated grants (Pfizer and GSK) and honoraria outside the submitted work (Pfizer, Janssen, and Sanofi), and a fee-for-service agreement from Merck & Co., Inc., Rahway, NJ, USA. R.W. reports grants from Merck & Co., Inc., Rahway, NJ, USA during the conduct of the study and grants from Pfizer outside the submitted work. D.P.R. reports grants from Merck & Co., Inc., Rahway, NJ, USA outside the submitted work. All other authors declare no conflicts of interest. Funding for the design of the study; the collection, analyses, and interpretation of data; and the writing of the manuscript was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Abbreviations

The following abbreviations are used in this manuscript:
ACIPAdvisory Committee on Immunization Practices
AEadverse event
AUDIT-CAlcohol Use Disorder Identification Test Alcohol Consumption
CIHJohns Hopkins Center for Indigenous Health
cpsAcapsular polysaccharide synthesis gene A
GMCgeometric mean concentrations
GMTgeometric mean titers
IgGimmunoglobulin G
IPDinvasive pneumococcal disease
lytAautolysin
MSDMerck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
NPnasopharyngeal
OPoropharyngeal
OPAopsonophagocytic activity
PCRpolymerase chain reaction
PCVpneumococcal conjugate vaccine
PCV1313-valent pneumococcal conjugate vaccine
PCV2020-valent pneumococcal conjugate vaccine
PDpneumococcal disease
piaApneumococcal iron acquisition
PPSV2323-valent pneumococcal polysaccharide vaccine
SAEserious adverse event
SSUADserotype-specific urinary antigen detection
V11415-valent pneumococcal conjugate vaccine

References

  1. GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 2018, 18, 1191–1210. [Google Scholar] [CrossRef] [PubMed]
  2. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016, 388, 1459–1544. [Google Scholar] [CrossRef] [PubMed]
  3. Drijkoningen, J.J.; Rohde, G.G. Pneumococcal infection in adults: Burden of disease. Clin. Microbiol. Infect. 2014, 20, 45–51. [Google Scholar] [CrossRef] [PubMed]
  4. US Department of Health and Human Services Office of Minority Health. American Indian/Alaska Native Health Population Health Data. Available online: https://minorityhealth.hhs.gov/american-indianalaska-native-health (accessed on 4 November 2024).
  5. Weatherholtz, R.; Millar, E.V.; Moulton, L.H.; Reid, R.; Rudolph, K.; Santosham, M.; O’Brien, K.L. Invasive pneumococcal disease a decade after pneumococcal conjugate vaccine use in an American Indian population at high risk for disease. Clin. Infect. Dis. 2010, 50, 1238–1246. [Google Scholar] [CrossRef]
  6. Watt, J.P.; O’Brien, K.L.; Benin, A.L.; McCoy, S.I.; Donaldson, C.M.; Reid, R.; Schuchat, A.; Zell, E.R.; Hochman, M.; Santosham, M.; et al. Risk factors for invasive pneumococcal disease among Navajo adults. Am. J. Epidemiol. 2007, 166, 1080–1087. [Google Scholar] [CrossRef]
  7. Grant, L.R.; Hammitt, L.L.; O’Brien, S.E.; Jacobs, M.R.; Donaldson, C.; Weatherholtz, R.C.; Reid, R.; Santosham, M.; O’Brien, K.L. Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage Among American Indians. Pediatr. Infect. Dis. J. 2016, 35, 907–914. [Google Scholar] [CrossRef]
  8. Neal, E.F.G.; Chan, J.; Nguyen, C.D.; Russell, F.M. Factors associated with pneumococcal nasopharyngeal carriage: A systematic review. PLoS Glob. Public Health 2022, 2, e0000327. [Google Scholar] [CrossRef]
  9. Moulton, P.; McDonald, L.; Muus, K.; Knudson, A.; Wakefield, M.; Ludtke, R. Prevalence of Chronic Disease Among American Indian and Alaska Native Elders. Available online: https://www.nrcnaa.org/assets/6200-29399/chronic-disease-among-elders.pdf (accessed on 4 November 2024).
  10. Centers for Disease Control and Prevention (CDC). CDC and Indian Country Working Together. Available online: https://stacks.cdc.gov/view/cdc/44668/cdc_44668_DS1.pdf (accessed on 4 November 2024).
  11. Groom, A.V.; Hennessy, T.W.; Singleton, R.J.; Butler, J.C.; Holve, S.; Cheek, J.E. Pneumonia and influenza mortality among American Indian and Alaska Native people, 1990–2009. Am. J. Public Health 2014, 104, S460–S469. [Google Scholar] [CrossRef]
  12. Bruce, M.G.; Bressler, S.S.; Apostolou, A.; Singleton, R.J. Lower respiratory tract infection hospitalizations among American Indian/Alaska Native adults, Indian Health Service and Alaska Region, 1998–2014. Int. J. Infect. Dis. 2021, 111, 130–137. [Google Scholar] [CrossRef]
  13. Holman, R.C.; Curns, A.T.; Singleton, R.J.; Sejvar, J.J.; Butler, J.C.; Paisano, E.L.; Schonberger, L.B.; Cheek, J.E. Infectious disease hospitalizations among older American Indian and Alaska Native adults. Public Health Rep. 2006, 121, 674–683. [Google Scholar] [CrossRef]
  14. Niederman, M.S.; Folaranmi, T.; Buchwald, U.K.; Musey, L.; Cripps, A.W.; Johnson, K.D. Efficacy and effectiveness of a 23-valent polysaccharide vaccine against invasive and noninvasive pneumococcal disease and related outcomes: A review of available evidence. Expert. Rev. Vaccines 2021, 20, 243–256. [Google Scholar] [CrossRef] [PubMed]
  15. Kobayashi, M.; Leidner, A.J.; Gierke, R.; Farrar, J.L.; Morgan, R.L.; Campos-Outcalt, D.; Schechter, R.; Poehling, K.A.; Long, S.S.; Loehr, J.; et al. Use of 21-Valent Pneumococcal Conjugate Vaccine Among U.S. Adults: Recommendations of the Advisory Committee on Immunization Practices—United States, 2024. MMWR Morb. Mortal. Wkly. Rep. 2024, 73, 793–798. [Google Scholar] [CrossRef] [PubMed]
  16. United States Food and Drug Administration. PNEUMOVAX 23 Prescribing Information. Available online: https://www.fda.gov/media/80547/download (accessed on 4 December 2024).
  17. World Health Organization. Vaccination Schedule for Pneumococcal Disease. Available online: https://immunizationdata.who.int/global/wiise-detail-page/vaccination-schedule-for-pneumococcal-disease?ISO_3_CODE=&TARGETPOP_GENERAL= (accessed on 4 November 2024).
  18. Maeda, H.; Morimoto, K. Global distribution and characteristics of pneumococcal serotypes in adults. Hum. Vaccines Immunother. 2025, 21, 2469424. [Google Scholar] [CrossRef] [PubMed]
  19. Matanock, A.; Lee, G.; Gierke, R.; Kobayashi, M.; Leidner, A.; Pilishvili, T. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged >/=65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb. Mortal. Wkly. Rep. 2019, 68, 1069–1075. [Google Scholar] [CrossRef]
  20. United States Food and Drug Administration. PREVNAR 13 (Pneumococcal 13-Valent Conjugate Vaccine [Diphtheria CRM197 Protein]) Prescribing Information. Available online: https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM574852.pdf (accessed on 11 November 2024).
  21. Scott, J.R.; Millar, E.V.; Lipsitch, M.; Moulton, L.H.; Weatherholtz, R.; Perilla, M.J.; Jackson, D.M.; Beall, B.; Craig, M.J.; Reid, R.; et al. Impact of more than a decade of pneumococcal conjugate vaccine use on carriage and invasive potential in Native American communities. J. Infect. Dis. 2012, 205, 280–288. [Google Scholar] [CrossRef]
  22. Chen, C.H.; Chen, C.L.; Su, L.H.; Chen, C.J.; Tsai, M.H.; Chiu, C.H. The microbiological characteristics and diagnosis of Streptococcus pneumoniae infection in the conjugate vaccine era. Hum. Vaccines Immunother. 2025, 21, 2497611. [Google Scholar] [CrossRef]
  23. Ozisik, L. The New Era of Pneumococcal Vaccination in Adults: What Is Next? Vaccines 2025, 13, 498. [Google Scholar] [CrossRef]
  24. Morimoto, K.; Masuda, S. Pneumococcal vaccines for prevention of adult pneumonia. Respir. Investig. 2025, 63, 96–101. [Google Scholar] [CrossRef]
  25. United States Food and Drug Administration. VAXNEUVANCE™ (Pneumococcal 15-valent Conjugate Vaccine) Prescribing Information. Available online: https://www.fda.gov/vaccines-blood-biologics/vaccines/vaxneuvance (accessed on 10 August 2022).
  26. Moore, M.R.; Link-Gelles, R.; Schaffner, W.; Lynfield, R.; Lexau, C.; Bennett, N.M.; Petit, S.; Zansky, S.M.; Harrison, L.H.; Reingold, A.; et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: Analysis of multisite, population-based surveillance. Lancet Infect. Dis. 2015, 15, 301–309. [Google Scholar] [CrossRef]
  27. Waight, P.A.; Andrews, N.J.; Ladhani, S.N.; Sheppard, C.L.; Slack, M.P.; Miller, E. Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: An observational cohort study. Lancet Infect. Dis. 2015, 15, 535–543. [Google Scholar] [CrossRef]
  28. Tin Tin Htar, M.; Morato Martinez, J.; Theilacker, C.; Schmitt, H.J.; Swerdlow, D. Serotype evolution in Western Europe: Perspectives on invasive pneumococcal diseases (IPD). Expert. Rev. Vaccines 2019, 18, 1145–1155. [Google Scholar] [CrossRef]
  29. Deng, X.; Memari, N.; Teatero, S.; Athey, T.; Isabel, M.; Mazzulli, T.; Fittipaldi, N.; Gubbay, J.B. Whole-genome sequencing for surveillance of invasive pneumococcal diseases in Ontario, Canada: Rapid prediction of genotype, antibiotic resistance and characterization of emerging serotype 22F. Front. Microbiol. 2016, 7, 2099. [Google Scholar] [CrossRef] [PubMed]
  30. Golden, A.R.; Adam, H.J.; Gilmour, M.W.; Baxter, M.R.; Martin, I.; Nichol, K.A.; Demczuk, W.H.; Hoban, D.J.; Zhanel, G.G. Assessment of multidrug resistance, clonality and virulence in non-PCV-13 Streptococcus pneumoniae serotypes in Canada, 2011–2013. J. Antimicrob. Chemother. 2015, 70, 1960–1964. [Google Scholar] [CrossRef] [PubMed]
  31. Lo, S.W.; Gladstone, R.A.; van Tonder, A.J.; Lees, J.A.; du Plessis, M.; Benisty, R.; Givon-Lavi, N.; Hawkins, P.A.; Cornick, J.E.; Kwambana-Adams, B.; et al. Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: An international whole-genome sequencing study. Lancet Infect. Dis. 2019, 19, 759–769. [Google Scholar] [CrossRef] [PubMed]
  32. European Medicines Agency. Vaxneuvance: Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/product-information/vaxneuvance-epar-product-information_en.pdf (accessed on 29 November 2022).
  33. Government of Canada. Pneumococcal Vaccine: Canadian Immunization Guide. Available online: https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-16-pneumococcal-vaccine.html#a4 (accessed on 4 November 2024).
  34. Food and Drug Administration. CAPVAXIVE. Available online: https://www.fda.gov/vaccines-blood-biologics/capvaxive (accessed on 26 November 2024).
  35. Health Canada. CAPVAXIVE® (Pneumococcal 21-Valent Conjugate Vaccine) Injection, for Intramuscular Use, Product Monograph. Available online: https://pdf.hres.ca/dpd_pm/00076331.PDF (accessed on 4 December 2024).
  36. PMDA; Pharmaceuticals and Medical Devices Agency. Capvaxive Intramuscular Syringe. Available online: https://www.pmda.go.jp/drugs/2025/P20250828001/170050000_30700AMX00129000_B100_1.pdf (accessed on 5 November 2025).
  37. Government of Canada. CAPVAXIVE. Available online: https://dhpp.hpfb-dgpsa.ca/dhpp/resource/103871 (accessed on 1 January 2025).
  38. Therapeutic Goods Administration. CAPVAXIVE Pneumococcal 21-Valent Conjugate Vaccine 0.5mL Solution for Pre-filled Syringe. Available online: http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=429290&agid=%28PrintDetailsPublic%29&actionid=1 (accessed on 10 November 2025).
  39. United States Food and Drug Administration. Prevnar 20 Package Insert. Available online: https://www.fda.gov/vaccines-blood-biologics/vaccines/prevnar-20 (accessed on 8 April 2024).
  40. Centers for Disease Control and Prevention (CDC). Pneumococcal Vaccine Recommendations. Available online: https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/index.html (accessed on 23 January 2025).
  41. Advisory Committee on Immunization Practices. ACIP Recommendations. Available online: https://www.cdc.gov/acip/vaccine-recommendations/index.html (accessed on 20 November 2024).
  42. Hammitt, L.L.; Quinn, D.; Janczewska, E.; Pasquel, F.J.; Tytus, R.; Rajender Reddy, K.; Abarca, K.; Khaertynova, I.M.; Dagan, R.; McCauley, J.; et al. Immunogenicity, safety, and tolerability of V114, a 15-valent pneumococcal conjugate vaccine, in immunocompetent adults aged 18–49 years with or without risk factors for pneumococcal disease: A randomized phase 3 trial (PNEU-DAY). Open Forum Infect. Dis. 2022, 9, ofab605. [Google Scholar] [CrossRef]
  43. Clinicaltrials.gov. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults at Increased Risk for Pneumococcal Disease (V114-017/PNEU-DAY). Available online: https://clinicaltrials.gov/study/NCT03547167 (accessed on 22 January 2025).
  44. Rumpf, H.J.; Hapke, U.; Meyer, C.; John, U. Screening for alcohol use disorders and at-risk drinking in the general population: Psychometric performance of three questionnaires. Alcohol Alcohol. 2002, 37, 261–268. [Google Scholar] [CrossRef]
  45. Rajam, G.; Zhang, Y.; Antonello, J.M.; Grant-Klein, R.J.; Cook, L.; Panemangalore, R.; Pham, H.; Cooper, S.; Steinmetz, T.D.; Nguyen, J.; et al. Development and validation of a sensitive and robust multiplex antigen capture assay to quantify Streptococcus pneumoniae serotype-specific capsular polysaccharides in urine. mSphere 2022, 7, e0011422. [Google Scholar] [CrossRef]
  46. Cheon, K.; Buchwald, U.K.; Hammitt, L.L.; LeBlanc, J.J.; Tso, C.; Riley, D.P.; VanDeRiet, D.; Weatherholtz, R.; Musey, L.; Shekar, T.; et al. The impact of pneumococcal vaccination and nasopharyngeal colonization on the performance of a serotype-specific urine antigen detection (SSUAD) assay. Vaccine 2025, 62, 127453. [Google Scholar] [CrossRef]
  47. Centers for Disease Control and Prevention. Streptococcus pneumoniae Detection and Serotyping Using PCR. Available online: https://www.cdc.gov/strep-lab/php/pneumococcus/serotyping-using-pcr.html?CDC_AAref_Val=https://www.cdc.gov/streplab/pneumococcus/resources.html (accessed on 11 November 2024).
  48. Trzcinski, K.; Bogaert, D.; Wyllie, A.; Chu, M.L.; van der Ende, A.; Bruin, J.P.; van den Dobbelsteen, G.; Veenhoven, R.H.; Sanders, E.A. Superiority of trans-oral over trans-nasal sampling in detecting Streptococcus pneumoniae colonization in adults. PLoS ONE 2013, 8, e60520. [Google Scholar] [CrossRef]
  49. Platt, H.L.; Cardona, J.F.; Haranaka, M.; Schwartz, H.I.; Narejos Perez, S.; Dowell, A.; Chang, C.J.; Dagan, R.; Tamms, G.M.; Sterling, T.; et al. A phase 3 trial of safety, tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine, compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE). Vaccine 2022, 40, 162–172. [Google Scholar] [CrossRef]
  50. European Centre for Disease Prevention and Control. Invasive Pneumococcal Disease. Annual Epidemiological Report for 2018. Available online: https://www.ecdc.europa.eu/sites/default/files/documents/AER_for_2018_IPD.pdf (accessed on 30 September 2022).
  51. Owusu-Edusei, K.; Deb, A.; Johnson, K.D. Estimates of the health and economic burden of pneumococcal infections attributable to the 15-valent pneumococcal conjugate vaccine serotypes in the USA. Infect. Dis. Ther. 2022, 11, 987–999. [Google Scholar] [CrossRef] [PubMed]
  52. Sutcliffe, C.; Littlepage, S.; Yazzie, D.; Brasinikas, G.; Christensen, L.; Damon, S.; Denny, E.; Dixon , S.L.; Grant , L.R.; Harker-Jones., M.; et al. Impact of the COVID-19 pandemic on invasive pneumococcal disease in American Indian communities in the Southwest US. J. Med. Microbiol. 2025, 74, 001983. [Google Scholar]
  53. Ul Haq, M.Z.; Irfan, H.; Shah, M.S.U.; Sumbal, A.; Mughal, S.; Ashraf, S.; Basaria, A.A.A.; Abdullah; Chacho, M.A.; Ayalew, B.D. Immunogenicity, safety and tolerability of 15-valent pneumococcal conjugate vaccine (V114) compared to 13-valent pneumococcal conjugate vaccine (PCV-13) in healthy infants: A systematic review and meta-analysis. Vaccine X 2025, 24, 100654. [Google Scholar] [CrossRef]
  54. Balsells, E.; Guillot, L.; Nair, H.; Kyaw, M.H. Serotype distribution of Streptococcus pneumoniae causing invasive disease in children in the post-PCV era: A systematic review and meta-analysis. PLoS ONE 2017, 12, e0177113. [Google Scholar] [CrossRef]
  55. Golden, A.R.; Fear, T.; Baxter, M.; Adam, H.J.; Martin, I.; Demczuk, W.; Karlowsky, J.A.; Zhanel, G.G. Canadian Antimicrobial Resistance Alliance. Invasive pneumococcal disease caused by serotypes 22F and 33F in Canada: The SAVE study 2011–2018. Diagn. Microbiol. Infect. Dis. 2021, 101, 115447. [Google Scholar] [CrossRef]
  56. Sempere, J.; de Miguel, S.; Gonzalez-Camacho, F.; Yuste, J.; Domenech, M. Clinical Relevance and Molecular Pathogenesis of the Emerging Serotypes 22F and 33F of Streptococcus pneumoniae in Spain. Front. Microbiol. 2020, 11, 309. [Google Scholar] [CrossRef]
  57. Greenberg, R.N.; Gurtman, A.; Frenck, R.W.; Strout, C.; Jansen, K.U.; Trammel, J.; Scott, D.A.; Emini, E.A.; Gruber, W.C.; Schmoele-Thoma, B. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults 60–64 years of age. Vaccine 2014, 32, 2364–2374. [Google Scholar] [CrossRef]
  58. Jackson, L.A.; Gurtman, A.; van Cleeff, M.; Frenck, R.W.; Treanor, J.; Jansen, K.U.; Scott, D.A.; Emini, E.A.; Gruber, W.C.; Schmoele-Thoma, B. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine 2013, 31, 3594–3602. [Google Scholar] [CrossRef]
  59. Buchwald, U.K.; Andrews, C.P.; Ervin, J.; Peterson, J.T.; Tamms, G.M.; Krupa, D.; Ajiboye, P.; Roalfe, L.; Krick, A.L.; Sterling, T.M.; et al. Sequential administration of Prevnar 13 and PNEUMOVAX 23 in healthy participants 50 years of age and older. Hum. Vaccines Immunother. 2021, 17, 2678–2690. [Google Scholar] [CrossRef]
  60. Farrar, J.L.; Childs, L.; Ouattara, M.; Akhter, F.; Britton, A.; Pilishvili, T.; Kobayashi, M. Systematic review and meta-analysis of the efficacy and effectiveness of pneumococcal vaccines in adults. Pathogens 2023, 12, 732. [Google Scholar] [CrossRef]
  61. Arya, S.; Norton, N.; Kaushik, P.; Brandtmuller, A.; Tsoumani, E. Recent changes to adult national immunization programs for pneumococcal vaccination in Europe and how they impact coverage: A systematic review of published and grey literature. Hum. Vaccines Immunother. 2023, 19, 2279394. [Google Scholar] [CrossRef]
  62. Ngamprasertchai, T.; Ruenroengbun, N.; Kajeekul, R. Immunogenicity and safety of the higher-valent pneumococcal conjugate vaccine vs the 13-valent pneumococcal conjugate vaccine in older adults: A systematic review and meta-analysis of randomized controlled trials. Open Forum Infect. Dis. 2025, 12, ofaf069. [Google Scholar] [CrossRef] [PubMed]
  63. Schellenberg, J.J.; Adam, H.J.; Baxter, M.R.; Karlowsky, J.A.; Golden, A.R.; Martin, I.; Demczuk, W.; Mulvey, M.R.; Zhanel, G.G. Comparison of PCV10, PCV13, PCV15, PCV20 and PPSV23 vaccine coverage of invasive Streptococcus pneumoniae isolate serotypes in Canada: The SAVE study, 2011–2020. J. Antimicrob. Chemother. 2023, 78, i37–i47. [Google Scholar] [CrossRef]
  64. Kobayashi, M.; Bennett, N.M.; Gierke, R.; Almendares, O.; Moore, M.R.; Whitney, C.G.; Pilishvili, T. Intervals between PCV13 and PPSV23 vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb. Mortal. Wkly. Rep. 2015, 64, 944–947. [Google Scholar] [CrossRef] [PubMed]
  65. Pera, A.; Campos, C.; Lopez, N.; Hassouneh, F.; Alonso, C.; Tarazona, R.; Solana, R. Immunosenescence: Implications for response to infection and vaccination in older people. Maturitas 2015, 82, 50–55. [Google Scholar] [CrossRef] [PubMed]
  66. Nikolich-Zugich, J. The twilight of immunity: Emerging concepts in aging of the immune system. Nat. Immunol. 2018, 19, 10–19. [Google Scholar] [CrossRef]
  67. Simell, B.; Auranen, K.; Kayhty, H.; Goldblatt, D.; Dagan, R.; O’Brien, K.L. Pneumococcal Carriage Group. The fundamental link between pneumococcal carriage and disease. Expert. Rev. Vaccines 2012, 11, 841–855. [Google Scholar] [CrossRef]
  68. Wolter, N.; Tempia, S.; Cohen, C.; Madhi, S.A.; Venter, M.; Moyes, J.; Walaza, S.; Malope-Kgokong, B.; Groome, M.; du Plessis, M.; et al. High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia. J. Infect. Dis. 2014, 210, 1649–1657. [Google Scholar] [CrossRef]
  69. Miellet, W.R.; Almeida, S.T.; Trzcinski, K.; Sa-Leao, R. Streptococcus pneumoniae carriage studies in adults: Importance, challenges, and key issues to consider when using quantitative PCR-based approaches. Front. Microbiol. 2023, 14, 1122276. [Google Scholar] [CrossRef]
  70. Littlepage, S.J.; Grant, L.R.; Vidal, J.E.; Jacobs, M.R.; Weatherholtz, R.C.; Alexander-Parrish, R.; Colelay, J.; Charley, M.; Cutler, M.; Good, C.E.; et al. Differences in pneumococcal carriage prevalence by testing method and specimen type among Native American individuals during routine use of 13-valent pneumococcal conjugate vaccine (PCV13). Poster #117. In Proceedings of the 12th International Symposium on Pneumococci & Pneumococcal Diseases (ISPPD-12), Toronto, ON, Canada, 19–23 June 2022. [Google Scholar]
  71. Simoes, A.S.; Tavares, D.A.; Rolo, D.; Ardanuy, C.; Goossens, H.; Henriques-Normark, B.; Linares, J.; de Lencastre, H.; Sa-Leao, R. lytA-based identification methods can misidentify Streptococcus pneumoniae. Diagn. Microbiol. Infect. Dis. 2016, 85, 141–148. [Google Scholar] [CrossRef]
  72. Dewhirst, F.E.; Chen, T.; Izard, J.; Paster, B.J.; Tanner, A.C.; Yu, W.H.; Lakshmanan, A.; Wade, W.G. The human oral microbiome. J. Bacteriol. 2010, 192, 5002–5017. [Google Scholar] [CrossRef]
  73. Abranches, J.; Zeng, L.; Kajfasz, J.K.; Palmer, S.R.; Chakraborty, B.; Wen, Z.T.; Richards, V.P.; Brady, L.J.; Lemos, J.A. Biology of oral streptococci. Microbiol. Spectr. 2018, 6, 10–1128. [Google Scholar] [CrossRef]
  74. Bryskier, A. Viridans group streptococci: A reservoir of resistant bacteria in oral cavities. Clin. Microbiol. Infect. 2002, 8, 65–69. [Google Scholar] [CrossRef]
  75. Navajo Epidemiology Center. Serotype 4 Invasive Pneumococcal Disease (IPD) Information for Providers. Active Bacterial Surveillance Alert—March 2024. Available online: https://nec.navajo-nsn.gov/Portals/0/Reports/ST4%20alert%20for%20NN%20providers_2024.0312.pdf (accessed on 1 April 2025).
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Figure 1. Participant flow chart. Data are for participants enrolled at Center for Indigenous Health sites. The denominator for calculations is based on the number randomized. The “completed trial” classification may include participants who missed PPSV23 administration. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; V114, 15-valent pneumococcal conjugate vaccine.
Figure 1. Participant flow chart. Data are for participants enrolled at Center for Indigenous Health sites. The denominator for calculations is based on the number randomized. The “completed trial” classification may include participants who missed PPSV23 administration. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; V114, 15-valent pneumococcal conjugate vaccine.
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Figure 2. Post-vaccination solicited AEs, by study group. Data are for participants enrolled at Center for Indigenous Health sites. Injection-site events were solicited from Days 1–5 following vaccination. Systemic events were solicited from Days 1–14 following vaccination. a For solicited injection-site swelling and injection-site erythema, mild events measured >0–≤5 cm, moderate events measured >5–≤10 cm, and severe events measured >10 cm. Abbreviations: AE, adverse event; PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
Figure 2. Post-vaccination solicited AEs, by study group. Data are for participants enrolled at Center for Indigenous Health sites. Injection-site events were solicited from Days 1–5 following vaccination. Systemic events were solicited from Days 1–14 following vaccination. a For solicited injection-site swelling and injection-site erythema, mild events measured >0–≤5 cm, moderate events measured >5–≤10 cm, and severe events measured >10 cm. Abbreviations: AE, adverse event; PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
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Figure 3. Serotype-specific OPA GMTs by timepoint and study group. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
Figure 3. Serotype-specific OPA GMTs by timepoint and study group. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
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Figure 4. Serotype-specific OPA GMTs at 30 days post-vaccination (Day 30) with V114, by age. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; V114, 15-valent pneumococcal conjugate vaccine.
Figure 4. Serotype-specific OPA GMTs at 30 days post-vaccination (Day 30) with V114, by age. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; V114, 15-valent pneumococcal conjugate vaccine.
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Figure 5. Serotype-specific OPA GMTs before and 30 days after PPSV23 vaccination. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; V114, 15-valent pneumococcal conjugate vaccine.
Figure 5. Serotype-specific OPA GMTs before and 30 days after PPSV23 vaccination. Data are for participants enrolled at Center for Indigenous Health sites. The within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. a Additional serotypes in V114. Abbreviations: CI, confidence interval; GMT, geometric mean titer (1/dilution); OPA, opsonophagocytic activity; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; V114, 15-valent pneumococcal conjugate vaccine.
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Table 1. Baseline Characteristics for Vaccinated Participants.
Table 1. Baseline Characteristics for Vaccinated Participants.
n (%)V114PCV13Total
Vaccinated participants439 (100)148 (100)587 (100)
Sex   
Female258 (58.8)81 (54.7)339 (57.8)
Male181 (41.2)67 (45.3)248 (42.2)
Age, years   
18–29179 (40.8)64 (43.2)243 (41.4)
30–39161 (36.7)48 (32.4)209 (35.6)
40–4999 (22.6)36 (24.3)135 (23.0)
Mean32.732.132.6
Range19–4918–4918–49
Race   
American Indian439 (100)148 (100)587 (100)
Ethnicity   
Not Hispanic/Latino422 (96.1)137 (92.6)559 (95.2)
Hispanic/Latino17 (3.9)11 (7.4)28 (4.8)
Participants by risk factors a   
No risk factors285 (64.9)96 (64.9)381 (64.9)
with ≥1 risk factors154 (35.1)52 (35.1)206 (35.1)
Data are for participants enrolled at Center for Indigenous Health sites. a Pre-defined risk factors include diabetes mellitus, chronic lung, liver, and heart disease, alcohol consumption, and tobacco use. Abbreviations: PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
Table 2. Summary of AEs Following Vaccination With V114/PCV13 and PPSV23.
Table 2. Summary of AEs Following Vaccination With V114/PCV13 and PPSV23.
n (%)Following Vaccination
with V114/PCV13
(Day 1–Month 6)		Following Vaccination
with PPSV23
(Month 6–Month 7)
V114
n = 439		PCV13
n = 148		V114
n = 398		PCV13
n = 132
Unsolicited or solicited AEs    
Any AE356 (81.1)114 (77.0)250 (62.8)85 (64.4)
Injection-site a324 (73.8)98 (66.2)225 (56.5)78 (59.1)
Systemic246 (56.0)91 (61.5)157 (39.4)54 (40.9)
Any vaccine-related AE b335 (76.3)105 (70.9)237 (59.5)80 (60.6)
Systemic193 (44.0)65 (43.9)125 (31.4)45 (34.1)
Any SAE25 (5.7)8 (5.4)1 (0.3)1 (0.8)
Any vaccine-related SAE b0 (0.0)0 (0.0)0 (0.0)0 (0.0)
Deaths2 (0.5)1 (0.7)0 (0.0)0 (0.0)
Solicited AEs    
Solicited injection-site AEs c323 (73.6)98 (66.2)225 (56.5)78 (59.1)
Injection-site pain316 (72.0)96 (64.9)219 (55.0)74 (56.1)
Injection-site swelling102 (23.2)31 (20.9)71 (17.8)25 (18.9)
Injection-site erythema60 (13.7)17 (11.5)53 (13.3)22 (16.7)
Solicited systemic AEs d212 (48.3)77 (52.0)141 (35.4)50 (37.9)
Fatigue146 (33.3)56 (37.8)99 (24.9)31 (23.5)
Headache105 (23.9)40 (27.0)68 (17.1)26 (19.7)
Myalgia111 (25.3)38 (25.7)56 (14.1)20 (15.2)
Arthralgia69 (15.7)20 (13.5)44 (11.1)17 (12.9)
Data are for participants enrolled at Center for Indigenous Health sites. Non-serious AEs reported between Days 1–14 following vaccination and SAEs reported between Day 1–Month 6 are included. a All injection-site AEs were considered vaccine-related by the investigator. b Relatedness determined by the investigator. c Solicited injection-site events were collected from Days 1–5 following vaccination. d Solicited systemic events were collected from Days 1–14 following vaccination. Abbreviations: AE, adverse event; PCV13, 13-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneumococcal polysaccharide vaccine; SAE, serious adverse event; V114, 15-valent pneumococcal conjugate vaccine.
Table 3. Pneumococcal NP/OP Carriage Prevalence by PCR in the Per-Protocol Population.
Table 3. Pneumococcal NP/OP Carriage Prevalence by PCR in the Per-Protocol Population.
Pneumococcal Carriage Prevalence, % (n/N)
VisitV114PCV13Total
Day 123.9 (54/226)18.7 (14/75)22.6 (68/301)
Day 322.4 (47/210)15.5 (11/71)20.6 (58/281)
Day 820.7 (42/203)16.7 (11/66)19.7 (53/269)
Day 1520.2 (42/208)9.0 (6/67)17.5 (48/275)
Day 3018.6 (41/220)10.3 (7/68)16.7 (48/288)
Month 618.6 (37/199)20.3 (13/64)19.0 (50/263)
Day 18318.0 (34/189)15.3 (9/59)17.3 (43/248)
Day 18817.8 (33/185)19.3 (11/57)18.2 (44/242)
Day 19520.4 (39/191)10.9 (6/55)18.3 (45/246)
Month 720.7 (42/203)11.3 (7/62)18.5 (49/265)
Data are for participants enrolled at Center for Indigenous Health sites. Carriage defined as detection of at least two pneumococcal genes by PCR: lytA and cpsA and/or piaA. N is the number of participants randomized and vaccinated in the substudy; n is the number of participants contributing to the analysis. Abbreviations: NP, nasopharyngeal; OP, oropharyngeal; PCV13, 13-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.
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Hammitt, L.L.; Buchwald, U.K.; McCauley, J.; Shekar, T.; Fu, W.; Cheon, K.; Sterling, T.; Tamms, G.; Banniettis, N.; Musey, L.; et al. Randomized Phase 3 Trial Evaluating the Safety, Tolerability, and Immunogenicity of V114, a 15-Valent PCV, Followed by PPSV23 6 Months Later (PNEU-DAY): Subgroup Analysis in Adults 18–49 Years of Age Enrolled at Center for Indigenous Health Sites. Vaccines 2026, 14, 3. https://doi.org/10.3390/vaccines14010003

AMA Style

Hammitt LL, Buchwald UK, McCauley J, Shekar T, Fu W, Cheon K, Sterling T, Tamms G, Banniettis N, Musey L, et al. Randomized Phase 3 Trial Evaluating the Safety, Tolerability, and Immunogenicity of V114, a 15-Valent PCV, Followed by PPSV23 6 Months Later (PNEU-DAY): Subgroup Analysis in Adults 18–49 Years of Age Enrolled at Center for Indigenous Health Sites. Vaccines. 2026; 14(1):3. https://doi.org/10.3390/vaccines14010003

Chicago/Turabian Style

Hammitt, Laura L., Ulrike K. Buchwald, Jennifer McCauley, Tulin Shekar, Wei Fu, Kyeongmi Cheon, Tina Sterling, Gretchen Tamms, Natalie Banniettis, Luwy Musey, and et al. 2026. "Randomized Phase 3 Trial Evaluating the Safety, Tolerability, and Immunogenicity of V114, a 15-Valent PCV, Followed by PPSV23 6 Months Later (PNEU-DAY): Subgroup Analysis in Adults 18–49 Years of Age Enrolled at Center for Indigenous Health Sites" Vaccines 14, no. 1: 3. https://doi.org/10.3390/vaccines14010003

APA Style

Hammitt, L. L., Buchwald, U. K., McCauley, J., Shekar, T., Fu, W., Cheon, K., Sterling, T., Tamms, G., Banniettis, N., Musey, L., LeBlanc, J. J., Weatherholtz, R., Riley, D. P., Denny, E., Tso, C., Roessler, K., & Santosham, M. (2026). Randomized Phase 3 Trial Evaluating the Safety, Tolerability, and Immunogenicity of V114, a 15-Valent PCV, Followed by PPSV23 6 Months Later (PNEU-DAY): Subgroup Analysis in Adults 18–49 Years of Age Enrolled at Center for Indigenous Health Sites. Vaccines, 14(1), 3. https://doi.org/10.3390/vaccines14010003

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