Overall, 100% (90/90) of randomized subjects were vaccinated, with 98.9% of subjects completing the study (Fig. 1). A single subject in the nonadjuvanted PCV15 group was lost to follow-up; this subject did not provide any safety follow-up information and is not included in the safety analyses. There were 3 subjects (3.3%) in the adjuvanted PCV15 group, 5 subjects (5.6%) in the non-adjuvanted PCV15 group and 4 subjects (4.4%) in the PCV7 control group that were excluded from the immunogenicity analyses due to protocol violations. Most of these protocol violations (9/12; 75%) were the result of postvaccination blood sample collection occurring outside the protocol-specified visit window.
Subjects across all vaccination groups were similar with respect to age and race (Table 1). A higher percentage of females (58.9%) were enrolled across all vaccination groups. Approximately 90% of the study population reported a medical condition prestudy that were equally distributed across the three vaccination groups. The most common medical conditions were otitis media (51.1%) and upper respiratory tract infection (35.6%). Only 23.3% of subjects received any prior medications, and these were similar across vaccination groups. The most common prior therapies were amoxicillin (7.8%) and acetaminophen (7.8%). Concomitant medications increased to 66.7% across vaccination groups, compared with the use of therapies prior to study start. This was largely due to the increase in use of ibuprofen (22.2%) and acetaminophen (48.9%). The percentage of subjects with any concomitant medication was comparable across vaccination groups.
Clinical AEs were reported by 89.9% of randomized subjects (Table 2). Although numerically higher proportions of injection-site and systemic AEs were reported among recipients of adjuvanted PCV15 (72.7% and 93.9%, respectively) and nonadjuvanted PCV15 (64.3% and 85.7%, respectively) than PCV7 (57.1% and 82.1%, respectively), these differences were not statistically significant. In the study, 65.2% of subjects reported a vaccine-related injection-site AE, whereas 68.5% reported a vaccine-related systemic AE. The majority of the reported AEs were transient and of mild to moderate intensity. A total of 3 subjects reported severe injection pain and were equally distributed across the 3 vaccination groups. No vaccine-related SAEs or discontinuations from the study due to AEs were reported.
The most common systemic AEs were fatigue, myalgia, pyrexia and irritability. These AEs were solicited during the study and recipients of either formulation of PCV15 tended to have higher frequencies of these AEs than recipients of PCV7. A higher observed percentage of recipients of adjuvanted PCV15 reported myalgia, irritability or pyrexia versus those who received either nonadjuvanted PCV15 or PCV7. In addition, 1 recipient of adjuvanted PCV15 reported an AE of febrile convulsion (day 10 postvaccination, lasting 2 minutes) that was deemed not related to the study vaccine by the investigator. Previous studies have indicated that the risk windows for febrile seizure following administration of PCV in infants and measles-containing vaccine in toddlers were 0–7 days and 5–12 days postvaccination, respectively. The indicated periods are consistent with the timing during which elevated body temperature is more frequently reported. On the basis of the timing of the febrile seizure, it was determined by the investigator that the event was likely related to the measles–mumps–rubella vaccine administered concomitantly with the study vaccine on day 1.
During the 7-day postvaccination safety follow-up period, body temperature of ≥38°C was reported by 40.6% (13/32) of PCV15 adjuvanted recipients, 46.4% (13/28) of PCV15 nonadjuvanted recipients and 39.3% (11/28) of PCV7 recipients. Five (15.6%) recipients of aluminum-adjuvanted PCV15 and 2 (7.2%) recipients of PCV7 reported elevated body temperature ≥39.0°C to <40.0°C, with all 7 subjects reporting either a concurrent infection or administration of other pediatric vaccines concomitantly with the study vaccine. All cases of elevated body temperature returned to normal level within 3 days.
From day 8 to day 14 postvaccination, body temperature was measured only if fever was suspected. A total of 4 (40%) recipients of aluminum-adjuvanted PCV15, 1 (25%) recipient of nonadjuvanted PCV15 and 2 (28.6%) recipients of PCV7 reported elevated body temperature ≥39.0°C to <40.0°C. For 6 of these 7 subjects, either a concurrent infection or administration of another pediatric vaccine concomitantly was reported. Five of the 7 subjects (follow-up was not obtained for 2 of them) returned to normal temperature level within 4 days.
Serotypes in Common Between PCV15 and PCV7 (4, 6B, 9V, 14, 18C, 19F and 23F). Baseline IgG GMCs were generally comparable across the 3 vaccination groups (Table 3). Following vaccination, the IgG GMCs were generally comparable between recipients of PCV15 and PCV7 for the serotypes in common (Table 3), as the analysis demonstrated overlapping 95% CIs for all comparisons except for serotype 19F. GMCs were numerically lower for recipients of adjuvanted PCV15 versus PCV7 for all serotypes except 6B. Additionally, GMCs were numerically lower for recipients of nonadjuvanted PCV15 versus PCV7 for all serotypes except 6B. The proportion of responders that met the IgG cutoff value of ≥1.0 μg/mL by Pn ECL assay varied by serotype and vaccine group at both baseline and postvaccination. With the exception of serotypes 4, 18C and 19F, the proportion of responders was comparable across the 3 vaccination groups at both time points. The observed differences were likely due to the small sample size in our study. In comparison to recipients of PCV7, the differences in the proportion of responders above the specified threshold value for these 3 serotypes were only seen for recipients of aluminum-adjuvanted PCV15 but not for recipients of nonadjuvanted PCV15 (Table 4).
The serotype-specific OPA GMTs were generally comparable among subjects who received adjuvanted PCV15, nonadjuvanted PCV15 and PCV7 although OPA GMT to serotype 23F was higher among recipients of PCV7 than recipients of either formulation of PCV15 (Table 5). Postvaccination GMTs were numerically lowest for serotype 19F in all groups (1136.4 adjuvanted PCV15, 1117.8 nonadjuvanted PCV15 and 2493.4 PCV7). The serotype with the highest postvaccination GMT was 23F for adjuvanted PCV15 (7058.5) and 6B for nonadjuvanted PCV15 (6673.5), while the serotype with the highest postvaccination GMT in the recipients of PCV7 was 23F (18352.1).
Additional Serotypes Only in PCV15 (1, 3, 5, 6A, 7F, 19A, 22F and 33F). Serotype-specific IgG GMCs measured at 1 month postvaccination were expectedly higher among recipients of either formulation of PCV15 than recipients of PCV7 for the serotypes unique to PCV15, except for serotypes 6A and 19A; the lack of difference in GMCs for these serotypes is likely due to cross-reactivity to serotypes 6B and 19F that are contained in PCV7. The postvaccination IgG GMCs for all of the serotypes contained in PCV15 that are not included in PCV7 were comparable among recipients of either PCV15 formulation (Table 3). The lowest postvaccination GMCs in both PCV15 groups were observed for serotype 33F (0.9 and 1.1 μg/mL, respectively), and the highest GMCs were observed for serotype 22F (12.5 and 8.8 μg/mL, respectively). The proportion of responders that met the Pn ECL IgG cutoff value of ≥1.0 μg/mL by Pn ECL assay for the serotypes unique to PCV15 was generally comparable between recipients of the 2 formulations of PCV15 (Table 4).
The OPA GMT responses demonstrate that both PCV15 formulations were immunogenic following vaccination for all additional serotypes (Table 5). In the group that received PCV7, a high GMT relative to the PCV15 formulations was observed for the cross-reacting serotype 6A (2435.8), even though this serotype is not contained in PCV7.