Use of 15-Valent Pneumococcal Conjugate Vaccine Among U.S. Children…

Evidence

Pneumococcal Disease Incidence in Persons Aged <19 Years

Acute otitis media is one of the most common diagnoses associated with outpatient pediatric medical visits (8) and antibiotic prescribing (9). According to a recent analysis using administrative data, 20,800 all-cause acute otitis media episodes per 100,000 person-years occurred among U.S. persons aged <18 years during 2018, with a higher incidence in younger age groups (10). During 2015–2019, in a cohort of 319 U.S. children aged 6–36 months with clinically diagnosed acute otitis media, Streptococcus pneumoniae was detected in the middle ear fluid of 24% (11); 9% of these children were infected with a PCV13 serotype (including 6C), and 8% with one of the serotypes included in PCV15 but not in PCV13 (serotypes 22F and 33F) (11). Additional analysis using administrative data estimated that among persons aged <18 years, 1,280 to 3,990 episodes of health care utilization per 100,000 person-years occurred in 2014 for all-cause pneumonia (12), and that during 2018–2019, 87 to 680 hospitalizations per 100,000 population occurred for all-cause pneumonia (13). Using population-based surveillance data, S. pneumoniae was detected in 4% of persons aged <18 years who were hospitalized with community-acquired pneumonia; the attributable proportion of pneumococcus and serotype distribution among all-cause pneumonia in children and adolescents, however, has not been determined (14). According to U.S. multistate surveillance, the incidence of IPD^†† during 2018–2019 was 7.2 per 100,000 children aged <5 years and 1.5 per 100,000 persons aged 5–18 years. PCV13-serotypes accounted for 21% and 34% of IPD cases in children aged <5 years and persons aged 5–18 years, respectively; similarly, additional serotypes unique to PCV15^§§ caused 15% and 23% of IPD in children aged <5 years and persons aged 5–18 years, respectively (15).

PCV15 Immunogenicity

Phase II and III randomized controlled trials (RCTs) evaluated the immunogenicity of PCV15 compared with PCV13 in healthy infants and children (16–19), persons aged 5–17 years with sickle cell disease (20), and persons aged 6–17 years living with HIV infection (21). The following outcomes were measured 30 days after administration of ≥1 doses of PCV, as specified in the respective study protocols: serotype-specific immunoglobulin G (IgG) geometric mean concentration (GMC) (16–21), proportion of participants meeting the serotype-specific IgG value of ≥0.35 μg/mL (response rate) (16–19), and opsonophagocytic activity geometric mean titer in a subset of the study population (17,20,21). One of the phase III RCTs enrolled healthy children aged 42–90 days who received PCV13 or PCV15 at ages 2, 4, 6, and 12–15 months. Except for serotype 6A GMC ratio after dose 3, PCV15 met criteria for noninferiority^¶¶ to PCV13 for the 13 shared serotypes regarding the response rate after dose 3 and GMC ratio after dose 3 and after dose 4. PCV15 elicited statistically significantly higher immune response for serotype 3 than for PCV13 (17). PCV15 met the noninferiority criteria compared with PCV13 for the two unique serotypes 22F and 33F (17).

Another phase III RCT enrolled healthy children aged 42–90 days who were randomized to five different arms that received 0–4 doses of PCV15 in combination with PCV13 to complete their 4-dose PCV series, to assess interchangeable use of PCV13 and PCV15 (19). IgG GMCs for the 13 shared serotypes measured after dose 4 in children who received ≥1 dose of PCV15 were generally comparable to those in children who completed their PCV series with PCV13 only. Among PCV-naïve or partially vaccinated persons aged 7 months–17 years who received catch-up PCV doses, PCV15 elicited IgG GMCs comparable to PCV13 for the 13 shared serotypes (18). Among children with sickle cell disease, a dose of PCV15 elicited higher IgG GMC for six of 13 shared serotypes and for the two unique serotypes (20). Among children living with HIV infection, a dose of PCV15 elicited higher IgG GMC for eight of 13 shared serotypes and for the two unique serotypes, compared with a dose of PCV13; 1 dose of PCV15 followed by PPSV23 8 weeks later elicited higher IgG GMC for three of 13 shared serotypes compared with a dose of PCV13 followed by PPSV23, although IgG GMC for 22F and 33F were lower in those who received PCV15 followed by PPSV23 than in those who received PCV13 followed by PPSV23 (21).

PCV15 Safety

Safety of PCV15 was assessed in seven RCTs with 4,778 persons aged 6 weeks–17 years who received ≥1 dose of PCV15 (16–23). Two of these RCTs that enrolled children and adolescents with sickle cell disease or HIV infection were assessed separately. Of the remaining five studies that enrolled healthy children, four were also included in the immunogenicity assessment (16–19). Three studies included preterm infants born at <37 weeks gestation (17,19,23). Across these five studies, four of 4,540 children who received PCV15 developed serious adverse events*** that were considered to be vaccine-related, compared with one of 2,655 children who received PCV13. The two RCTs that enrolled children with sickle cell disease or HIV infection were both included in the immunogenicity assessment (20,21). No serious adverse events that were considered to be vaccine-related were reported in either study.

Given the similarities in the target population and the vaccine schedule used, a detailed safety assessment was performed combining data from three studies of healthy infants who received 4 doses of PCV15 (3,002) or PCV13 (1,467) at ages 2, 4, 6, and 12–15 months (17,19,22,23). The most commonly reported adverse events after any PCV dose included irritability (75.1% in the PCV15 group versus 72.7% in the PCV13 group), somnolence (56.7% versus 59.3%), injection site pain (45.1% versus.43.5%), and decreased appetite (39.1% versus 36.0%). Febrile convulsions were reported in eight of 3,002 (0.3%) children who received PCV15, and three of 1,467 (0.2%) who received PCV13. Nearly all (8 of 11, 73%) febrile convulsions occurred ≥50 days after PCV receipt, and none were deemed vaccine-related by study investigators. Adverse events that were considered to be vaccine-related were reported in 89.1% of children who received PCV15 and 86.4% of those in the PCV13 group. Two children (0.1%) who received PCV15 and none who received PCV13 had serious adverse events that were considered to be vaccine-related; both of these children were hospitalized for fever after vaccine administration (after dose 1 and after dose 3). A maximum rectal (or rectal equivalent) temperature of ≥104°F (40°C) within the first 7 days after vaccination was reported for 19 of 2,772 (0.7%) children who received a fourth dose of PCV15 and three of 1,287 (0.2%) who received PCV13.

Cost-Effectiveness

Two economic models (CDC model and Merck model) that assessed cost-effectiveness compared the use of PCV15 and PCV13 according to the currently recommended PCV13 4-dose series for children aged <2 years (24). PCV15 and PCV13 were assumed to have the same vaccine effectiveness against disease caused by the 13 serotypes contained in PCV13. For PCV15, the effectiveness against the two additional serotypes was assumed to be comparable to the overall effectiveness against disease caused by the serotypes contained in PCV13. In the CDC model, PCV15 effectiveness against IPD caused by the two additional serotypes was assumed to be 86% and the effectiveness against IPD caused by most of the other serotypes (excluding serotype 3 and 19F) was assumed to be 86%. Effectiveness against serotypes 3 and 19F disease was assumed to be lower than that against the other PCV serotypes (25). In the Merck model, PCV15 effectiveness against IPD caused by the two additional serotypes was assumed to be 86% and the effectiveness against the other serotypes was assumed to range from 80% to 100%. In both models, using PCV15 instead of PCV13 for routine vaccination of children was cost-saving^††† in all scenarios examined, including scenarios in which the PCV15 cost per dose^§§§ ranged from $4 less to $2 more than the PCV13 cost per dose.