Use of the 15-valent pneumococcal conjugate vaccine in US children: updated recommendations from the Advisory Committee on Immunization Practices – United States, 2022

Evidence

Incidence of pneumococcal disease in people aged less than 19 years

Acute otitis media is one of the most common diagnoses associated with outpatient pediatric medical visits (8) and the prescription of antibiotics (9). According to a recent analysis using administrative data, 20,800 episodes of all-cause acute otitis media per 100,000 person-years occurred among Americans under the age of 18 in 2018, with a higher incidence in age groups. younger age (ten). From 2015 to 2019, in a cohort of 319 U.S. children aged 6 to 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 people younger than 18, 1,280 to 3,990 health care utilization episodes per 100,000 person-years occurred in 2014 for all-cause pneumonia. confused (12), and that in 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 people under the age of 18 who were hospitalized for community-acquired pneumonia; however, the attributable proportion of pneumococci and serotype distribution among all-cause pneumonia in children and adolescents have not been determined (14). According to the US Multistate Surveillance, the incidence of IPD†† in 2018-2019 was 7.2 per 100,000 children aged under 5 and 1.5 per 100,000 people aged 5-18. PCV13 serotypes accounted for 21% and 34% of IPD cases in children under 5 and people 5-18, respectively; likewise, additional serotypes unique to PCV15§§ caused 15% and 23% of IPDs in children under 5 years of age and people 5 to 18 years of age, respectively (15).

Immunogenicity of PCV15

Phase II and III randomized controlled trials (RCTs) have evaluated the immunogenicity of PCV15 versus PCV13 in healthy infants and children (1619), people aged 5 to 17 with sickle cell disease (20) and people aged 6 to 17 living with HIV (21). The following outcomes were measured 30 days after administration of ≥1 dose of PCV, as specified in the respective study protocols: geometric mean (GMC) concentration of serotype-specific immunoglobulin G (IgG) (16–21), proportion of participants achieving serotype-specific IgG value ≥0.35 µg/mL (response rate) (1619), and the geometric mean titer of opsonophagocyte activity in a subset of the study population (17,20,21). One of the phase III RCTs recruited healthy children aged 42 to 90 days who received PCV13 or PCV15 at 2, 4, 6, and 12 to 15 months of age. Except for the GMC serotype 6A report after dose 3, PCV15 met the criteria for non-inferiority¶¶ to PCV13 for the 13 serotypes shared regarding response rate after dose 3 and GMC ratio after dose 3 and after dose 4. PCV15 elicited a statistically significantly higher immune response for serotype 3 than for PCV13 (17). PCV15 met the criteria for non-inferiority to PCV13 for both single serotypes 22F and 33F (17).

Another phase III RCT recruited healthy children aged 42-90 days who were randomized to five different arms who received 0-4 doses of PCV15 in combination with PCV13 to complete their 4-dose PCV series , to assess the 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 individuals aged 7 months to 17 years who received catch-up doses of PCV, PCV15 induced IgG GMCs comparable to PCV13 for all 13 shared serotypes (18). In children with sickle cell disease, a dose of PCV15 elicited higher GMC IgG for six of 13 shared serotypes and for the two unique serotypes (20). In children living with HIV infection, one dose of PCV15 elicited higher GMC IgG for eight of 13 shared serotypes and for the two unique serotypes, compared to one dose of PCV13; 1 dose of PCV15 followed by PPSV23 8 weeks later elicited higher GMC IgG for three of 13 shared serotypes compared to 1 dose of PCV13 followed by PPSV23, although GMC IgG 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 Security

The safety of PCV15 was evaluated in seven RCTs with 4778 people aged 6 weeks to 17 years who received ≥ 1 dose of PCV15 (1623). Two of these RCTs involving children and adolescents with sickle cell disease or HIV infection were assessed separately. Of the remaining five studies in healthy children, four were also included in the immunogenicity assessment (1619). Three studies involved preterm infants born at less than 37 weeks’ gestation (17,19,23). In these five studies, four of the 4,540 children who received PCV15 developed serious adverse events*** that were considered vaccine-related, compared to one of the 2,655 children who received PCV13. The two RCTs in children with sickle cell disease or HIV infection were both included in the immunogenicity assessment (20,21). No serious adverse events considered to be vaccine-related were reported in either study.

Given the similarities between the target population and the vaccine schedule used, a detailed safety assessment was performed by combining data from three studies of healthy infants who received 4 doses of PCV15 (3,002) or PCV13 (1,467) at 2, 4, 6, and 12–15 months of age (17,19,22,23). The most frequently reported adverse events after any dose of PCV 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 seizures were reported in eight of 3002 (0.3%) children who received PCV15 and three of 1467 (0.2%) who received PCV13. Almost all febrile seizures (8 of 11, 73%) occurred ≥ 50 days after receiving PCV, and none were judged to be vaccine-related by study investigators. Adverse events considered 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 experienced serious adverse events that were considered vaccine-related; these two children were hospitalized for fever after the administration of the vaccine (after dose 1 and after dose 3). A maximum rectal temperature (or its rectal equivalent) of ≥104°F (40°C) within the first 7 days after vaccination was reported for 19 of 2772 (0.7%) children who received a fourth dose of PCV15 and three of 1,287 (0.2%) who received PCV13.

Profitability

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

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