After more than a decade of 13 valent pneumococcal conjugate vaccine (PCV13) use, invasive pneumococcal disease (IPD) remains a significant public health challenge, particularly for children with underlying medical conditions 1. While these vaccines have been successful in reducing the incidence of vaccine-type IPD, serotype replacement remains an issue 2. Despite high vaccine coverage through national immunisation programs, vulnerable populations such as those with underlying conditions continue to experience disproportionately high IPD rates 1, 3. In France, children suffering from underlying conditions increasing the risk of IPD should receive a 3 + 1 schedule (2, 3, 4 and 11 months) of PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F and 23F) or PCV15 (PCV13 + serotypes 22F and 33F) followed by 1 dose of PPSV23 (serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9 N, 9 V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F) at 24 months. The introduction of extended-valency PCV raises the question of whether vaccine formule including a greater number of serotypes will improve protection in this vulnerable population. This study aims to evaluate the potential benefit of extended-valency PCVs among French children according to the presence of underlying conditions. From 2011 to 2024, 128 French paediatric wards prospectively reported IPD in children aged between 1 day and 15 years. IPD was defined as Streptococcus pneumoniae isolated in a normally sterile body site (blood, cerebrospinal fluid, joint fluid or pleural fluid). Demographics and clinical data, underlying conditions increasing the risk of IPD (immunosuppression, sickle cell disease, asplenia, splenectomy, cerebrospinal fluid (CSF) leakage, cochlear implant, cardiopathy, chronic lung disease, diabetes and recurrent meningitis without recognised aetiology), and outcome were collected. Pneumococcal strains were isolated according to standard methods of each laboratory and sent to the National Reference Center for pneumococci for serotyping as previously described 1. Serotype coverage was analysed relative to PCV13, PCV15, PCV20 (PCV15 + serotypes 8, 10A, 11A, 12F and 15B), or to PCV21 (3, 6A, 7F, 8, 9 N, 10A, 11A, 12F, 15A, 15B/C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F and 35B). Data were entered with use of 4D v6.4 and analysed by using Stata/SE version 18 software (StataCorp. 2023, College Station, TX, USA). Quantitative data were compared by Student t-test and categorical data by chi-squared or Fisher exact test. All tests were two-sided, and results were considered significant at p < 0.05. French legislation does not require any informed consent for this type of study; a mandatory information form validated by the ethics committee was given to all parents' participants. All data were analysed unless parents told the paediatrician that they refused to participate. This study was approved by the Créteil hospital ethics committee and the French National Data Protection Commission (no. 1413137) and was registered at ClinicalTrials.gov (NCT04664556). Among 2322 IPD (median age 22.4 months), 499 (21.5%) had an underlying condition (median age 43.8 months). The most frequent underlying conditions were immunosuppression (n = 168, 7.2%), asplenia/sickle cell disease (n = 92, 4.0%), and CSF leakage (n = 85, 3.7%, including n = 11 cochlear implant). The other underlying conditions accounted for 154 cases (6.6%), most often involving chronic pulmonary diseases (n = 48), cardiopathy (n = 36), neurological disorders (n = 34) and others (n = 36). The frequency of severe cases was significantly higher among children with underlying conditions (40.6% vs. 34.2%, p = 0.007) (Table S1). Similarly, the case fatality rate was 7.9% in children with comorbidities and 4.8% in those without (p = 0.007). PCV13 serotypes were significantly less frequent in children with underlying condition (16.8% vs. 26.0%, p < 0.001) and this difference was only observed in children older than 24 months (19% vs. 39.2%, p < 0.001) (Table 1 and Table S2). Overall, the potential coverage of PCV20 non-PCV13 serotypes accounted for 32.9% and was similar for children with or without underlying condition (33.7% vs. 32.7%). Non-PCV20 serotypes were significantly more common in children with underlying diseases (49.5% vs. 41.3%, p < 0.001) and this difference was only observed in children older than 24 months (53.2% vs. 32.6%, p < 0.001) (Table 1 and Table S2). The Figure S1 shows annual curves by underlying condition and serotype group. The main serotypes implicated in children with underlying condition were: 24F (n = 63, 12.6%), 15 bc (n = 51, 10.2%), 23B (n = 42 8.4%), 15A (n = 38, 7.6%) and 10A (n = 31, 6.2%). The main serotypes implicated in children without underlying condition were: 24F (n = 256, 14%), 10A (n = 128, 7.0%), 12F (n = 126, 6.9%), 19A (n = 117, 6.4%) and 15 bc (n = 116, 6.4%). The Table S3 showed the serotype distribution according to the presence of the different underlying conditions. Most of the serotype distribution differences with children without underlying condition appear attributable to two specific high-risk groups: sickle cell children and immunocompromised. Those children were more frequently infected by serotype 24F, 15 bc, 15A and 23B. In contrast, children with CSF leakage were infected with serotype 23B, and rarely with serotype 24F. To the best of our knowledge, this is the largest published series to date, several years after PCV13 implementation that raises the question of whether vaccine formule including greater number of serotypes in extended-valency pneumococcal conjugate vaccines (PCVs) will enhance protection in vulnerable populations. This large cohort of children with IPD (n = 2322) confirmed in the late PCV13 era, that a significant proportion of IPD (21.5%) occurred in children with underlying conditions. Although, our data showed that PCV13 serotypes still accounted for 24% of overall IPD cases, they were significantly less frequent in children with underlying conditions (16.8%) and particularly low for children with sickle cell disease (7.6%). Moreover, our data suggest that focused immunisation programs, such as those for sickle cell disease, seems highly effective 4, 5. Indeed, In France, most children with sickle cell disease are managed in National Reference Centers or Regional Competence Centers, where dedicated teams closely monitor compliance with the specific vaccination schedules (including booster doses) recommended for these patients. It is worth emphasising that serotypes not covered by PCV13 or PCV15, and considered to have low invasive disease potential (including 15 bc, 15A, 23B, 23A, 35F, 35B and 11A), are nearly twice as prevalent in patients with underlying comorbidities. Our data suggest that PCV20 non-PCV13 offers a theoretical benefit to both healthy and at-risk children. However, despite similar potential PCV20 non-PCV13 coverage, differences in circulating serotypes between children with and without underlying conditions call for continued surveillance and possible adaptation of immunisation schedules, including consideration of PCV20 in booster strategies. In at-risk children, replacement serotypes, many with lower invasive potential, were more common (15 bc) reflecting the dynamic impact of herd immunity and individual-level vaccine protection. Therefore, our findings underscore the need for further data on PCV20 performance in booster schedules, particularly given that France still uses PCV13 or PCV15 or PPSV23 for at-risk children. Non-PCV20 serotypes were significantly more prominent in children with comorbidities (49.5% vs. 41.3%) with serotype 24F (included in PCV21) being the most common in both groups, except in children with CSF leakage where it was rare, with only two cases reported. Children with other comorbidities, including immunosuppression, continue to experience a broader range of serotypes, including some with lower invasive potential, which nevertheless caused significant disease in this vulnerable population. It is interesting to note that most of the serotype distribution differences with children without underlying condition appear attributable to two specific high-risk groups: sickle cell children and immunocompromised. Children with sickle cell disease could be infected both with serotypes with high disease potential, such as serotype 24F (20.7%), but also with serotypes with low disease potential, such as 15 bc (20.7%), 15A (9.8%), or 23B (8.7%). A similar distribution was also observed among immunocompromised children. In contrast, children with CSF leakage were infected exclusively with nasopharyngeal carriage serotypes with low disease potential, such as serotype 23B (15.3%). The main limitation of our study was the lack of exhaustive data, as only cases with complete serotype and clinical data were included. However, this analysis only focused on IPD in children with underlying conditions which did not require exhaustive data. Robert Cohen and Corinne Levy designed the study and wrote the article. Corinne Levy, Robert Cohen, Emmanuelle Varon, Aude Estivaux, Stéphane Béchet, Isabelle Hau, and Naim Ouldali analysed and interpreted the data and drafted the article. Corinne Levy and Stéphane Béchet performed the statistical analysis. All authors revised and approved the manuscript. We thank the team of ACTIV for technical assistance (Association Clinique et Thérapeutique Infantile du Val-de-Marne, Créteil, France) and the team of the NRCP for technical assistance (Laboratory of Medical Biology and National Reference Centre for Pneumococci, Intercommunal Hospital of Créteil, Créteil, France). Open access publication funding provided by COUPERIN CY26. The IPD study was supported by PFIZER. Robert Cohen reports personal fees and non-financial support from Pfizer and personal fees from GSK, Merck, Pfizer, and Sanofi outside the submitted work. Corinne Levy reports personal fees and non-financial support from Pfizer and personal fees from MSD outside the submitted work. Emmanuelle Varon reports travel grants from Pfizer and Merck, outside the submitted work. Naim Ouldali reports travel grants from Pfizer, Sanofi, and GSK outside the submitted work. All other authors declare no competing interests for this study. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1: Supporting Information. Appendix S1: IPD Study Group. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Cohen et al. (Fri,) studied this question.