Immunogenicity and safety of the 15-valent pneumococcal conjugate vaccine, a systematic review and meta-analysis

Literature search

Our literature search of databases and registries yielded 421 records. In addition, we identified 157 records through other methods. We included 22 publications12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 of 20 randomised controlled trials (RCTs) in our review, contributing data on immunogenicity and safety outcomes. We did not identify any non-randomised studies of interventions (NRSIs). Fig. 1 illustrates the flow diagram of the study selection process. Supplementary Table 1 lists the studies excluded by full-text assessment, with the corresponding reasons for exclusion.

Fig. 1: PRISMA flow diagram adapted from Page et al.43.figure 1

PRISMA flow diagram illustrating the study selection process. n number of records.

Characteristics of the included studies

Overall, the 20 identified phase 2 and 3 trials, published in 22 articles12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33, included 19,358 participants. Eight studies (10 publications) included only adults16,18,19,20,23,24,25,28,29,30, while 11 focused exclusively on infants, children, or adolescents12,13,14,15,17,21,22,26,27,31,32, and one study included both adults and children33. The study investigators randomised participants to either PCV15, PCV13, PPSV23, or a sequential combination of both PCV and PPSV23. None of the included studies compared PCV15 with PCV20, and none compared PCV15 with no vaccination or placebo. Most studies were multicentric studies conducted in countries across the world. All studies were funded by Merck Sharp & Dohme LLC.

Supplementary Table 3 provides details of the study and patient characteristics. Supplementary Table 4 summarizes primary and secondary outcomes, Supplementary Table 5 the results for safety outcomes and Supplementary Table 6 the subgroup results from individual studies. The COE is provided in Supplementary Tables 7 and 8.

Risk of bias in the included studies

For the immunogenicity and safety outcomes, we assessed the risk of bias as low for 10 trials12,13,14,22,25,27,28,29,31,32 and as some concerns for 10 trials15,16,17,18,21,23,24,26,30,33. Supplementary Fig. 1 shows the ratings for the individual domains for each RCT. The main reasons for rating the risk of bias with some concerns were inadequate reporting of the randomisation process and bias due to missing data.

Studies in infants, children, and adolescents

We identified 12 RCTs including 11,428 infants, children, or adolescents12,13,14,15,17,21,22,26,27,31,32,33, of which nine studies were on healthy infants, children, and adolescents12,13,14,15,17,21,22,26,31. Three studies included immunocompromised children27,32,33. Two studies were phase 2 trials17,26; the others were phase 3 trials12,13,14,15,21,22,27,31,32,33.

The number of participants in the included studies ranged from 14 to 2,409. The mean age of the trial participants at study entry ranged from 8.4 weeks to 12.7 years. The proportion of females ranged from 45.6% to 49.8%. The study populations included 2.8% to 88.3% non-white ethnic groups, depending on the countries where the study was conducted. The study by Suzuki et al. included only healthy Japanese infants31. Most studies were conducted in pneumococcal vaccine–naïve infants.

Six studies evaluated a 3 plus 1 vaccination schedule consisting of a primary infant series of 3 doses of PCV15 or PCV13 between the ages of 2 and 6 months, followed by a toddler dose at 12 to 15 months12,15,17,21,

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