The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection for pneumococcal disease. It contains all 13-valent pneumococcal conjugate vaccine (PCV13) components plus conjugates for 7 additional serotypes. Our primary objective with this study was to evaluate PCV20 tolerability and safety.
In this phase 3, multi-country, double-blind study, healthy infants born at ≥34 weeks’ gestation were randomly assigned 2:1 to receive PCV20 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety assessments included local reactions and systemic events within 7 days after each vaccination, adverse events (AEs) from dose 1 to 1 month after dose 3 and from dose 4 to 1 month after dose 4, and serious AEs and newly diagnosed chronic medical conditions from dose 1 through 6 months after the last dose.
Participants received PCV20 (N = 1000) or PCV13 (N = 504); 91.7% received all 4 doses. The frequencies of local reactions and systemic events were generally similar in PCV20 and PCV13 groups, with most reported as mild or moderate. The most common local reaction was injection site pain (PCV20, 24.7% to 40.5%; PCV13, 26.8% to 42.0%); irritability was the most common systemic event (PCV20, 54.8% to 68.2%; PCV13, 54.7% to 68.5%). AE frequencies were similar in both groups. No serious AEs were related to study vaccines. Few newly diagnosed chronic medical conditions were reported (2.8% in both groups). PCV20 was safe across multiple countries, in late preterm infants, and when administered with other vaccines.
A 4-dose series of PCV20 had a tolerability and safety profile similar to that of PCV13.
Pneumococcal disease remains a burden because of nonvaccine serotypes. PCV20 includes conjugates for 7 additional serotypes beyond those in PCV13. PVC20 was well-tolerated in previous phase 3 trials in infants and toddlers and is expected to expand protection against pneumococcal disease.
A PCV20 4-dose infant series had a tolerability and safety profile similar to that of PCV13. Local reaction, systemic event, and adverse event rates were generally similar in both groups; PCV20 was safe in late preterm and term infants and when administered with other vaccines.
The spectrum of diseases caused by Streptococcus pneumoniae ranges from localized conditions, such as acute otitis media, to more serious and potentially fatal diseases, such as pneumonia and meningitis.1,2 Pneumococcal lower respiratory infections are the leading global cause of morbidity and mortality in children <5 years of age and were associated with ∼3.5 million severe cases in 2015, and >340 000 deaths in 2016.3,4
The global burden of invasive pneumococcal disease (IPD) decreased substantially with the widespread implementation of safe and immunogenic pneumococcal conjugate vaccines (PCVs) in infant national immunization programs (NIPs).5 The 7-valent PCV, which targeted serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, was introduced for use in infants in 2000; 13-valent PCV (PCV13; which added conjugates for serotypes 1, 3, 5, 6A, 7F, and 19A) was introduced in 2010.6 PCV13 is included in many infant NIPs around the world as either a 3-dose or 4-dose series.7 In 2020, 148 of 194 World Health Organization member states had introduced PCV into their NIPs, and in 2022, the estimated global coverage of a complete PCV series was 60%.8,9 In children <5 years of age in the United States, IPD cases overall decreased by 93% between 1998 and 2019 after the implementation of PCV immunization programs.10 Globally, it is estimated that 175 million cases of pneumococcal disease and >620 000 associated deaths were averted in children <5 years of age in the 10 years after the initial introduction of PCV13.5
Other studies have also shown that the risk of IPD is higher among preterm infants (32 to <38 weeks’ gestational age) than among those born full-term.11–14 For instance, one study reported an ∼83% higher risk of IPD in the first 23 months of life among preterm infants,12 and another described an increased risk of hospitalizations for pneumococcal disease for up to 6 months after birth in preterm compared with full-term infants.14 In clinical trials of PCVs, immune responses, although generally lower among preterm infants compared with full-term infants, were expected to be protective.15,16 Nevertheless, the risk of IPD remains higher in preterm infants compared with those born at term. The authors of a study of IPD in infants <1 year of age in the United Kingdom from 2013 to 2016 reported that preterm infants were diagnosed with IPD almost 3 times more frequently than full-term infants; non-PCV13 serotypes accounted for 69% of these IPD cases.17
A substantial burden of pneumococcal disease from serotypes not covered by PCV13 remains, particularly serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F, which are also associated with severe disease and antibiotic resistance, are a frequent cause of IPD, and are estimated to cause 16% to 38% of IPD in young children around the world.7,18–22 Thus, there is a great unmet need to broaden protection against pneumococcal disease to include these important non-PCV13 serotypes.
To meet this need, a 20-valent PCV (PCV20) was developed containing PCV13 components and conjugates for 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F).23 PCV20 is licensed in several countries for pneumococcal pneumonia and IPD prevention among adults and also for pediatric use from 6 weeks of age in the United States, the European Union, Canada, Brazil, and Australia, with licensure in this population under review in other regions.23–29 In a phase 2 clinical trial in infants, PCV20 had a safety and tolerability profile similar to PCV13 and elicited robust immune responses to all 20 vaccine serotypes.30 The safety and immunogenicity of PCV20 were further established in phase 3 clinical trials in infants, toddlers, and children, in which PCV20 again induced robust immune responses and revealed a safety and tolerability profile similar to that of PCV13.31–33
Here, we describe the results of a phase 3, randomized, double-blind study of the safety of a 4-dose PCV20 series. This study expands the safety database for PCV20 through the inclusion of late preterm and full-term infants (≥34 weeks’ gestational age) across multiple countries and the use of concomitant licensed routine vaccines per local practice, with targeted subgroup analyses.
Methods
Study Design and Participants
This phase 3, randomized, multicenter, double-blind study (NCT04379713) was conducted at investigator sites in Argentina, Canada, Chile, the Czech Republic, Finland, Germany, Greece, Hungary, Spain, the United States, and Puerto Rico from May 21, 2020, to August 31, 2022. Healthy infants who were born at ≥34 weeks’ gestation and were ∼2 months of age (42 to 98 days) at the time of consent were eligible. The key exclusion criteria included a significant neurologic disorder or history of seizure, congenital malformation, known or suspected immunodeficiency or immunosuppression, immunosuppressive therapy within 28 days of enrollment through 1 month after dose 4, and a history of severe reaction to PCV13, PCV20, or any diphtheria toxoid-containing vaccine. Demographic data, including race and ethnicity (as reported by parents or guardians), were collected at enrollment; the collection of these data helps ensure diversity in clinical trials per US Food and Drug Administration guidance.34
The protocol was approved by an independent ethics committee or institutional review board before the study was initiated. This study was conducted in accordance with the protocol and the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, and all applicable national privacy laws. Participants’ parents or legal guardians were required to provide written informed consent before enrollment.
Study Intervention
Participants were randomly assigned using interactive response technology 2:1 to receive 4 doses of either PCV20 or PCV13, respectively, at ∼2, 4, 6, and 12 to 15 months of age (Fig 1). Each participant received the same vaccine for all 4 doses. A single 0.5 mL dose of PCV20 or PCV13 was administered intramuscularly into the left thigh at each time point. Although the study was conducted in multiple countries, some of which have different vaccination calendars, all study participants received the 4-dose PCV per the US schedule.23 This provides safety data expected to encompass a series with fewer doses administered. No non-study pneumococcal vaccine was permitted, but other routine pediatric vaccines were allowed per the local vaccination calendar and practice.
Study design. PCV13 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. PCV20 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F (13 matched serotypes) 8, 10A, 11A, 12F, 15B, 22F, and 33F (7 additional serotypes).
Study design. PCV13 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. PCV20 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F (13 matched serotypes) 8, 10A, 11A, 12F, 15B, 22F, and 33F (7 additional serotypes).
Objectives and Assessments
The primary objective of this study was to describe the safety profile of PCV20. Safety assessments included local reactions (redness, swelling, and injection site pain) and systemic events (fever, decreased appetite, drowsiness or increased sleep, and irritability) occurring within 7 days after each dose. Local reactions and systemic events were collected daily by parents or legal guardians using an electronic diary for 7 days after each vaccination. A severity grading scale for local reactions and systemic events is provided in Supplemental Table 2. Adverse events (AEs) were collected from dose 1 through 1 month after dose 3 and from dose 4 through 1 month after dose 4. An AE was defined as any untoward medical occurrence in a clinical study participant temporally associated with the use of study intervention, whether considered related to the study intervention or not.35 Serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) were collected from dose 1 through 6 months after dose 4. An SAE was defined as an AE resulting in death or that was life-threatening, required hospitalization (or prolonged existing hospitalization), or resulted in persistent disability or incapacity.35 An NDCMC was defined as a disease or medical condition not previously identified that is expected to be persistent or is otherwise long-lasting in its effects. The investigator assessed each AE or SAE and used clinical judgment to determine any potential relationship between study intervention and the event.
Statistical Analyses
The safety analyses were conducted in the safety population, which included all participants who received ≥1 dose of pneumococcal vaccine (PCV20 or PCV13), with safety follow-up after any dose. Descriptive summary statistics of each vaccine group were provided for the safety endpoints of the overall study populations, as well as for subgroups defined by sex, geographic region (United States/Puerto Rico and non-United States/Puerto Rico), and gestational age (34 to <37 weeks [late preterm] and ≥37 weeks [full-term]). Two-sided 95% confidence intervals for percentages were calculated using the Clopper and Pearson method.
Results
Overall, 1511 participants were randomly assigned, 1504 were vaccinated (PCV20, N = 1000; PCV13, N = 504), and 1357 (89.8%) completed the study (Supplemental Fig 5). After 1 participant was excluded from the PCV13 group because of receiving PCV20 at dose 1, the safety population was composed of 1503 participants (PCV20, N = 1000; PCV13, N = 503), of which 49.4% were female, 87.4% were white, and 37.3% were Hispanic or Latino (Supplemental Table 3). Demographic and baseline characteristics were similar in the vaccine groups. During the study, 85.9% (dose 1), 85.7% (dose 2), 50.8% (dose 3), and 62.0% (dose 4) of participants received ≥1 concomitant non-study routine childhood vaccine with the study vaccine (Supplemental Table 4).
Local Reactions and Systemic Events
Most local reactions were mild or moderate in severity. Local reactions within 7 days after doses 1 to 4 occurred in 38.6% to 53.6% of participants, with similar rates in the PCV20 and PCV13 groups (Fig 2A). The most frequent local reaction was injection site pain, which was reported by 24.7% to 40.5% of participants in the PCV20 group and 26.8% to 42.0% of participants in the PCV13 group. The median day of onset for local reactions and systemic events was between day 1 (day of vaccination) and day 2, whereas the median duration was 1 to 2 days.
Percentage of participants reporting (A) local reactions and (B) systemic events in the safety population within 7 days after administration of each dose of PCV20 or PCV13. Dose 1 (PCV20, N = 992/PCV13, N = 498), dose 2 (PCV20, N = 952/PCV13, N = 485), dose 3 (PCV20, N = 940/PCV13, N = 477), and dose 4 (PCV20, N = 892/PCV13, N = 454).
Percentage of participants reporting (A) local reactions and (B) systemic events in the safety population within 7 days after administration of each dose of PCV20 or PCV13. Dose 1 (PCV20, N = 992/PCV13, N = 498), dose 2 (PCV20, N = 952/PCV13, N = 485), dose 3 (PCV20, N = 940/PCV13, N = 477), and dose 4 (PCV20, N = 892/PCV13, N = 454).
Most systemic events were mild or moderate in severity, with similar rates in the PCV20 and PCV13 groups. The most frequent systemic events were irritability (54.8% to 68.2% in the PCV20 group and 54.7% to 68.5% in the PCV13 group) and drowsiness (35.3% to 64.8% in the PCV20 group and 35.9% to 62.2% in the PCV13 group; Fig 2B). Reports of fever were similar between vaccine groups (PCV20, 9.3% to 18.0%; PCV13, 9.8% to 17.0%), with few high fevers (≥38.9 °C) reported (≤1.4% in any group after doses 1–3, and ≤3.7% in any group after dose 4). Antipyretic or pain medication use was similar between groups (25.9% to 37.1% of participants in the PCV20 group and 27.7% to 34.8% of those in the PCV13 group).
Subgroup Analyses of Local Reactions and Systemic Events
Local reactions and systemic events were also summarized for subgroups defined by sex, geographic region, and gestational age (Fig 3). Regardless of the vaccine group, slightly more local reactions were reported in female participants than in male participants. Local reactions were also generally reported more frequently in the US/Puerto Rico subgroup than in the non-US/Puerto Rico subgroup. The rates of local reactions were similar in late preterm and full-term subgroups. The rates of systemic events were generally similar across subgroups, although the rates of fever ≥38.0 °C after dose 1 and dose 4 were somewhat lower in the US/Puerto Rico subgroup compared with the non-US/Puerto Rico subgroup (dose 1, 3.8% to 4.9% vs 11.5% to 12.7%; dose 4, 6.1% to 9.8% vs 21.4% to 21.5%).
Percentage of participants reporting any local reactions or systemic events by (A) sex, (B) region, and (C) gestational age. The bars reveal the percentages reporting any local reactions (redness, swelling, injection site pain) and systemic events (fever, decreased appetite, drowsiness, irritability). a Argentina, Canada, Chile, Czech Republic, Finland, Germany, Greece, Hungary, and Spain. US/PR, United States/Puerto Rico.
Percentage of participants reporting any local reactions or systemic events by (A) sex, (B) region, and (C) gestational age. The bars reveal the percentages reporting any local reactions (redness, swelling, injection site pain) and systemic events (fever, decreased appetite, drowsiness, irritability). a Argentina, Canada, Chile, Czech Republic, Finland, Germany, Greece, Hungary, and Spain. US/PR, United States/Puerto Rico.
Adverse Events, Serious Adverse Events, and Newly Diagnosed Chronic Medical Conditions
Overall, similar percentages of AEs, SAEs, and NDCMCs were reported in the vaccine groups (Table 1). From dose 1 to 1 month after dose 3, ≥1 AE was reported in 29.6% of participants in the PCV20 group and 27.6% of participants in the PCV13 group. AEs were most commonly reported in the infections and infestations system organ class (Fig 4A,; PCV20, 18.2%; PCV13, 15.9%). From dose 4 to 1 month after dose 4, ≥1 AE was reported in 15.1% of participants in the PCV20 group and 15.8% of participants in the PCV13 group, and AEs were most commonly reported in the infections and infestations system organ class (Fig 4B ; PCV20, 11.6%; PCV13, 13.4%). Vaccine-related AE rates were low (PCV20, ≤0.4%; PCV13, ≤1.0%), similar between the 2 groups, and most frequently reported in the system organ class of general disorders and administration site conditions and gastrointestinal disorders. There were no immediate or serious allergic reactions considered to be related to PCV20. One case of atopic dermatitis was considered to be PCV20-related by the investigator.
Participants in Each Study Group Reporting Any AEs, SAEs, or NDCMCs Within the Specified Time Period
| Reports of AEs, SAEs, or NDCMCs | PCV20, na (%), (95% CI)b | PCV13, na (%), (95% CI)b |
|---|---|---|
| From dose 1–1 mo after dose 3 | N = 1000c | N = 503c |
| Any AE | 296 (29.6) (26.8–32.5) | 139 (27.6) (23.8–31.8) |
| Related AE | 4 (0.4) (0.1–1.0) | 5 (1.0) (0.3–2.3) |
| Severe AE | 5 (0.5) (0.2–1.2) | 5 (1.0) (0.3–2.3) |
| From dose 4–1 mo after dose 4 | N = 923d | N = 461d |
| Any AE | 139 (15.1) (12.8–17.5) | 73 (15.8) (12.6–19.5) |
| Related AE | 2 (0.2) (0.0–0.8) | 1 (0.2) (0.0–1.2) |
| Severe AE | 5 (0.5) (0.2–1.3) | 3 (0.7) (0.1–1.9) |
| Throughout the study | N = 1000c | N = 503c |
| SAE | 44 (4.4) (3.2–5.9) | 28 (5.6) (3.7–7.9) |
| NDCMC | 28 (2.8) (1.9–4.0) | 14 (2.8) (1.5–4.6) |
| Reports of AEs, SAEs, or NDCMCs | PCV20, na (%), (95% CI)b | PCV13, na (%), (95% CI)b |
|---|---|---|
| From dose 1–1 mo after dose 3 | N = 1000c | N = 503c |
| Any AE | 296 (29.6) (26.8–32.5) | 139 (27.6) (23.8–31.8) |
| Related AE | 4 (0.4) (0.1–1.0) | 5 (1.0) (0.3–2.3) |
| Severe AE | 5 (0.5) (0.2–1.2) | 5 (1.0) (0.3–2.3) |
| From dose 4–1 mo after dose 4 | N = 923d | N = 461d |
| Any AE | 139 (15.1) (12.8–17.5) | 73 (15.8) (12.6–19.5) |
| Related AE | 2 (0.2) (0.0–0.8) | 1 (0.2) (0.0–1.2) |
| Severe AE | 5 (0.5) (0.2–1.3) | 3 (0.7) (0.1–1.9) |
| Throughout the study | N = 1000c | N = 503c |
| SAE | 44 (4.4) (3.2–5.9) | 28 (5.6) (3.7–7.9) |
| NDCMC | 28 (2.8) (1.9–4.0) | 14 (2.8) (1.5–4.6) |
CI, confidence interval.
a Number of participants reporting at least 1 occurrence of the event.
b Exact 2-sided confidence interval, based on the Clopper and Pearson method.
c Number of participants in the safety population, excluding 1 PCV13 participant, who incorrectly received PCV20.
d Number of participants who received dose 4 with safety follow-up, excluding 1 PCV13 participant, who incorrectly received PCV20.
Percentage of participants with AEs (A) from dose 1 to 1 month after dose 3 (B) from dose 4 to 1 month after dose 4 by system organ classa (≥1% of participants in any group). The numbers beside the bars are the percentage of participants with that event. a MedDRA (v25.0).
Percentage of participants with AEs (A) from dose 1 to 1 month after dose 3 (B) from dose 4 to 1 month after dose 4 by system organ classa (≥1% of participants in any group). The numbers beside the bars are the percentage of participants with that event. a MedDRA (v25.0).
Occurrences of SAEs were reported at similar rates in each vaccine group (PCV20, 4.4%; PCV13, 5.6%). No SAEs were considered to be vaccine-related. One febrile seizure was reported 14 days after dose 4 of PCV20; the seizure was considered not related to PCV20, but possibly related to the measles, mumps, and rubella or varicella vaccine. Few NDCMCs were reported throughout the study (2.8% in both the PCV20 and PCV13 groups), the majority of which were dermatitis, eczema, or food or milk allergies. Three participants in the PCV20 group withdrew due to AEs (2 unrelated SAEs and 1 unrelated AE). No deaths were reported during the study. In the subgroup analyses, the percentages of participants with AEs were similar between the PCV20 and PCV13 groups across sex, geographical region, and gestational age subgroups (Supplemental Table 5).
Discussion
A substantial amount of pediatric IPD is due to non-PCV13 serotypes,18–22 so the need for PCV20 is high.
In this phase 3 safety study of PCV20 in infants, most local reactions and systemic events were mild or moderate in severity, transient, and similar between the PCV20 and PCV13 groups. Injection site pain was the most frequently reported local reaction, whereas irritability and drowsiness were the most commonly reported systemic events. Reports of high fever (≥38.9 °C) were infrequent and similar between the PCV20 and PCV13 groups. These overall reactogenicity results are consistent with those reported in previous phase 3 infant trials of PCV20, in which injection site pain (along with redness after dose 2 in 1 study) was the most commonly reported local reaction, drowsiness and irritability were the most common systemic events, and reports of high fever were low.32,33
In the present study, female participants and those from the US/Puerto Rico subgroup tended to experience slightly more frequent local reactions than male participants and the non-US/Puerto Rico subgroup, respectively. Rates of systemic events were generally similar across sex and geographic region subgroups, apart from fever ≥38.0 °C, which was reported less frequently in the US/Puerto Rico subgroup compared with the non-US/Puerto Rico subgroup; this may be attributed to the observed differences in the use of antipyretic medications after some doses and the type of concomitant routine childhood vaccines administered on the same day as PCV20. The rates of both local reactions and systemic events were similar in the late preterm and full-term subgroups.
The percentages of participants reporting AEs, SAEs, and NDCMCs were similar in the PCV20 and PCV13 groups, and no SAEs or NDCMCs were considered related to study vaccinations. AEs were most commonly reported in the infections and infestations system organ class, which is consistent with illnesses expected in this age group. Study vaccine-related AEs were infrequent and reported at similar rates in the PCV20 and PCV13 groups. Overall, the type and frequency of AEs in this study are consistent with results from other phase 3 PCV20 trials in which AEs were also most commonly reported in the infections and infestations system organ class, and vaccine-related AEs were infrequent.32,33 In the present study, the rates of AEs were similar in the PCV20 and PCV13 groups across sex, geographic region, and gestational age subgroups.
The fact that PCV20 was well-tolerated in the late preterm infant subgroup is particularly important given that preterm infants are at high risk of IPD.11–14 Although preterm infants have benefited from the introduction of PCVs, including PCV13, they remain at risk from IPD due to non-PCV13 serotypes.17 Importantly, the safety profile of PCV20 was similar to that of PCV13 in preterm infants. We therefore expect that PCV20 may provide additional and safe protection against IPD to this vulnerable group.
The strengths of the study include the large population size, assessments of safety in a variety of settings and countries, and the inclusion of late preterm infants, all of which contributed to the generalizability of our findings. Another strength is that concomitant childhood vaccines were permitted, replicating the heavily overlapped scheduling of infant and child immunization programs common in real-world clinical practice. A limitation of the study is that the inclusion of concomitant vaccines potentially reduced our ability to differentiate safety signals related specifically to PCV20. Although we investigated a 4-dose (3 infant plus 1 toddler) series, we expect that a 3-dose series, as recommended in some regions, would have a similar or better safety profile.
Conclusions
In this study of a 4-dose immunization series, PCV20 had a tolerability and safety profile similar to that of PCV13. The favorable safety profile was observed across multiple countries, with a variety of concomitant vaccines administered, with diverse demographic factors, and in late preterm infants.
Acknowledgments
The authors thank the children who participated in this study, their parents and legal guardians, and the investigators and study site staff. Editorial and medical writing support was provided by Sheena Hunt, PhD, and Andrew Ray, PhD, of ICON (Blue Bell, PA, USA) and was funded by Pfizer Inc.
Drs Hajdu and Hughes coordinated and supervised data collection; Drs Ouedraogo, Parikh, and Lee analyzed and interpreted the data; Drs Flint and Young interpreted the data; Drs Peng and Watson conceptualized and designed the study, analyzed data, and interpreted the data; Drs Gruber and Scott conceptualized and designed the study and interpreted the data; and all the authors critically revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
This trial has been registered at www.clinicaltrials.gov (identifier NCT04379713).
On request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. The study protocol is available at https://clinicaltrials.gov/study/NCT04379713.
FUNDING: This study was funded by Pfizer Inc. Pfizer was responsible for study design and conduct, data collection, analysis and interpretation, and manuscript writing.
CONFLICT OF INTEREST DISCLOSURES: Drs Hajdu and Hughes have indicated they have no potential conflicts of interest relevant to this article to disclose. All other authors are employees or former employees of Pfizer and may hold stock or stock options.
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