Safety and Tolerability of V114 Pneumococcal Vaccine in Infants: A Phase 3 Study

This study was a multicenter, randomized, double-blind, active-controlled study to evaluate the safety and tolerability of V114 when administered in a 3 + 1 dosing regimen to healthy infants (protocol V114-031). It was conducted at 72 centers in 10 countries (United States, Australia, Canada, Finland, Germany, Israel, Malaysia, Peru, Taiwan, and Thailand) (Supplemental Table 4) from December 2018 to April 2021 (registered at clinicaltrials.gov as #NCT03692871 and with the European Union at EudraCT, #2018-003308-38).

The target participant enrollment was 2400, randomized in a 5:1 ratio to receive a 4-dose vaccination regimen of V114 (n = 2000) or PCV13 (n = 400) at ∼2, 4, 6, and 12 to 15 months of age. Premature (<37 weeks’ gestation) infants were also included in the study (target enrollment n = 50) and were randomized 1:1 to each vaccination group. Treatment allocation/randomization occurred centrally using an interactive response technology system. The study permitted the administration of routine childhood vaccines according to the local recommended pediatric vaccination schedule. Study procedures relating to the blinding and administration of study vaccines were performed as previously described.^18–20 

The study was approved by the appropriate regulatory agencies and institutional review boards and conducted according to the principles of Good Clinical Practice. Periodic safety reviews were conducted by an external data monitoring committee.

Participants were healthy infants, ∼2 months of age (42–90 days inclusive), at the time of informed consent. Consenting procedures and key exclusion criteria of this study were as previously described for the V114 pediatric program.^18–20 

V114 is a 15-valent PCV containing all serotypes in PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) as well as serotypes 22F and 33F. Study vaccines composition and storage are as previously described.^18–20  V114 (lot numbers WL00068289, WL00068571, WL00068572, and WL00068941) or PCV13 (lot numbers X32864, X24885, AA4507, AD5372, W11307, and AL3605) were administered in a 0.5 mL dose intramuscularly by needle. Participants were observed for 30 minutes postvaccination for any immediate reactions.

Each participant was provided an electronic vaccine report card to record safety data for 14 days after each PCV dose for nonserious adverse events (AEs), and from time of informed consent to 6 months after last PCV dose for serious AEs and deaths. AEs were considered serious if they were life-threatening, required hospitalization or extended an existing hospitalization, resulted in persistent or significant disability/incapacity, were a congenital anomaly/birth defect in an offspring of participant, or resulted in death. Additionally, solicited daily maximum body temperature measurements were collected via the electronic vaccine report card for 7 days after each study vaccination (and on days 8–14 after vaccination if fever was suspected). Solicited AEs in the study included injection-site (erythema, swelling, pain, and induration) and systemic (decreased appetite, irritability, somnolence, and urticaria) AEs; pyrexia, as determined by the investigator, was an unsolicited AE.

Study investigators reviewed all complaints and recorded events meeting protocol-defined AE criteria. They also assessed all complaints to determine relatedness to study vaccines, duration of event, and maximum size (solicited injection-site swelling, induration, and erythema) and intensity (solicited injection-site pain, irritability, somnolence, decreased appetite, and urticaria). In this report, solicited injection-site swelling, induration, and erythema were categorized as mild (measuring 0–≤1 in [2.5 cm]), moderate (>1–≤3 in [7.6 cm]), or severe (>3 in [7.6 cm]). Safety assessments were completed on the “all participants as treated” population, consisting of all randomized participants who received a study vaccine.

The primary endpoint was to evaluate the safety and tolerability of V114 with respect to the proportion of participants with AEs. Between-group differences in the proportion of participants with solicited AEs observed from day 1 to day 14 after any study vaccination were assessed for statistical significance with 95% confidence intervals and P values using the Miettinen and Nurminen method.²⁵  Differences in the proportion of participants with any AE, any vaccine-related AE, any serious AE, any vaccine-related serious AE, discontinuation because of an AE, death, and maximum body temperature measurements (rectal or rectal equivalent) were assessed with point estimates and 95% confidence intervals using the same method. Assuming all randomized participants are evaluable for safety analysis, the study sample size of 2000 randomized participants in the V114 group is sufficient to provide 97.5% confidence to detect a given serious AE with a frequency of at least 0.18% (1 in 543 participants).

All analyses were performed using SAS© software version 9.4, of the SAS System for Unix, copyright 2012 SAS Institute, Inc (Cary, NC).

This study enrolled a total of 2409 participants, randomized in a 5:1 ratio to receive a 3 + 1 dosing regimen of V114 or PCV13. Of the randomized participants, 2403 (99.8%) received the first study vaccination and 93.7% (V114 groups) and 91.5% (PCV13 group) of participants completed the study (Fig 1). The vaccination groups included participants with comparable demographic characteristics in terms of sex, age at enrollment, race, and ethnicity (Table 1). Reported medical history conditions were generally comparable between groups, with the most frequent conditions being jaundice (21%) and gastroesophageal reflux disease (5.1%).

For safety reporting, 93.6% (V114 group) and 93.3% (PCV13 group) of participants experienced 1 or more AEs after any PCV dose. The proportions of participants that experienced injection-site, systemic, vaccine-related, and serious AEs after any PCV dose were generally comparable between vaccination groups (Table 2). Similar results were observed after each dose of study vaccine (Supplemental Table 5). The most frequent AEs were those solicited in the trial, with >86% of participants experiencing 1 or more solicited AEs in both vaccination groups after any PCV dose; irritability and somnolence were reported most frequently (Table 2).

Solicited AEs were each characterized by frequency, duration, and severity. After any PCV dose, a statistically significantly higher proportion of participants (P < .05) experienced solicited injection-site pain, injection-site erythema, decreased appetite, and irritability in the V114 group compared with the PCV13 group (Table 2 and Supplemental Fig 3); the between-group difference in frequency for each solicited AE was <8%. The severity of solicited AEs after any PCV dose was comparable between vaccination groups, with most AEs being reported as mild or moderate (Fig 2). Some differences were also observed for individual solicited AEs after each PCV dose (Fig 2). Of all participants with solicited AEs, the majority had events with a duration of 3 days or less (Supplemental Table 6).

Solicited daily body temperature measurements, collected for 7 days after any PCV dose, were also comparable between vaccination groups, with the majority of participants (62.6% in V114 group and 60.3% in PCV13 group) reporting a maximum body temperature <38.5°C (Table 3). One participant in each treatment group reported a temperature of ≥41.0°C; those participants concurrently reported AEs of acute otitis media (V114 group) and teething (PCV13 group). The proportion of participants with the unsolicited AE of pyrexia after any PCV dose as determined by the investigator was comparable between groups (39.5% for V114 group, 40.6% for PCV13 group). In addition, there were few reports of febrile convulsion after any PCV dose (0.2% for both V114 and PCV13 groups; time to onset for all events was >90 days after a study vaccination); none were determined by the investigator to be vaccine-related.

Throughout the study, the proportion of participants with serious AEs was comparable between vaccination groups (9.8% in V114 group and 10.4% in PCV13 group), with the majority of serious AEs being infections (Supplemental Table 7). In the V114 group, 2 participants had vaccine-related serious AEs of pyrexia (classified as serious because of hospitalization). The first was considered mild (temperature of 38.0°C), occurred after V114 dose 1, and resolved within 3 days. Concomitant vaccines administered included RotaTeq, Pentaxim, and Hiberix. The second was considered moderate (temperature of 39.4°C), occurred after V114 dose 3, and resolved within 3 days. Concomitant vaccines administered included Pentabio (containing whole-cell pertussis), and oral polio vaccine. Neither was associated with febrile convulsion.

There were 2 deaths that occurred during the study, 1 in each treatment group. The first was in the PCV13 group, occurred 25 days after dose 1, and was because of sudden unexplained infant death. The second was in the V114 group, occurred 110 days after dose 4, and was because of craniocerebral injury after a motor vehicle accident. Neither death was considered to be related to the study vaccines by the investigator. No participants discontinued the study because of an AE.

This dedicated safety study in the V114 development program demonstrates that V114 is well tolerated when administered in a 3 + 1 dosing regimen to healthy infants, with a safety profile that is generally comparable to PCV13. This is the largest completed study in the program, with ∼2400 participants from 10 countries globally, lending to a racially and ethnically diverse participant population. The results of the current study are consistent with other published studies in the V114 pediatric development program.^18–20,26  Although there were some differences in the frequency of individual solicited AEs between V114 and PCV13, the overall proportions of participants with solicited injection-site and systemic AEs, vaccine-related AEs, serious AEs, the unsolicited AE of pyrexia, and body temperature measurements were comparable between groups. Furthermore, no participant discontinued study vaccination because of an AE.

A statistically significantly higher proportion of participants experienced injection-site pain, injection-site erythema, decreased appetite, and irritability in the V114 group after any vaccine dose compared with PCV13. It is not anticipated that these findings are clinically meaningful for several reasons. First, none of these AEs were consistently statistically significantly higher after each vaccine dose. Second, the between-group differences were small, with all differences being <8%. Third, the severity of the AEs was comparable between groups, suggesting the increased reporting frequency was not accompanied by a change in the characterization of the AEs. Indeed, the majority of all solicited AEs were of mild or moderate severity and were of a short duration. Lastly, the most common AEs experienced by participants were the same in both vaccination groups, suggesting the pattern of experienced AEs in V114 recipients is similar to recipients of PCV13. The differences observed on the basis of statistical significance may be because of a large sample size and unadjusted multiple comparisons as appropriate for safety analyses.

An advantage of a large cohort study is to better evaluate less-frequent AEs that may occur after vaccination. No new or unexpected vaccine-related AEs or serious AEs were identified during the study. Additionally, out of nearly 2000 participants in the V114 group, there were only 2 vaccine-related serious AEs reported, both of which were pyrexia. The cases were of short duration, of mild-to-moderate intensity, and were further confounded by concomitantly administered licensed pediatric vaccines. These data further support the favorable safety profile of V114.

This study has some limitations. Although descriptive P values were provided for prespecified endpoints, the study was not designed to test a specific predefined hypothesis. The large sample size in the V114 group in this study was sufficient to evaluate most AEs; however, AEs of very low frequency would not be readily detected. Because this was a dedicated safety study, immunogenicity endpoints were only tested for preterm infants and are not included in this manuscript. Other studies in the V114 program, both published and in process, evaluate key immunogenicity endpoints.^18–20,26 

In conclusion, data from this trial suggest V114 has an acceptable safety profile and is well tolerated among healthy infants. Overall, findings support the use of V114 in pediatric vaccination programs.

The study was conducted ethically and in accordance with the principles of Good Clinical Practice and approved by the appropriate institutional review boards and regulatory agencies. An external data monitoring committee conducted periodic reviews of safety and tolerability data for the study.

We thank the participants and their families, study staff, and investigators in the V114-031 study group for their contributions. Richard McFetridge (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA) was an important contributor to this study through study planning and execution; however, he sadly died before development of this manuscript. Medical writing assistance was provided by Timothy J. Chapman and editorial assistance was provided by Karyn Davis (both of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA).

AE

adverse event

IPD

invasive pneumococcal disease

PCV

pneumococcal conjugate vaccine

PCV13

Prevnar 13

V114

VAXNEUVANCE