Serotypic heterogeneity in the response to pneumococcal vaccine

The assessment of pneumococcal vaccine response currently relies on a single IgG concentration threshold, identical for all serotypes, as recommended by the WHO and AAAAI. However, the recommended thresholds do not take the wide inter-serotype variability into account. The purpose of this study was to determine if the antibody threshold linked to a functional immune response varies according to serotype. We performed a retrospective analysis on 729 samples from adults at risk of invasive pneumococcal disease (IPD), sent between 2018 and 2024 to assess vaccine response. Specific IgG concentrations for seven vaccine serotypes were measured by ELISA and compared to opsonophagocytic assay (OPA) results, a functional test considered as the gold standard. For each serotype, we determined the most predictive IgG concentration (PIC) for a positive OPA result using ROC curves, Youdens index, and bootstrap analysis with 1,000 resamples. The resulting PIC were then compared using non-parametric tests (Kruskal-Wallis test followed by Dunns post-hoc test with Holms correction). The PIC varied considerably among serotypes, ranging from 0.84 to 4.74 {micro}g/mL. This variability was found to be statistically significant (p<0.0001). Areas Under the Curve (AUC), ranging from 0.73 to 0.87, demonstrate good diagnostic performance. Overall, the application of serotype-specific thresholds in patients significantly change the classification of vaccination status compared to a single threshold (Cochran, McNemar). These results indicate that the protective antibody threshold is not universal. A serotype-specific approach would allow a more precise and relevant assessment of the pneumococcal vaccine response. Author summaryThe introduction of the 7-valent pneumococcal conjugate vaccine (PCV-7) in the early 2000s significantly changed the epidemiology of invasive pneumococcal disease by modifying serotype distribution. However, vaccine-induced immunity varies across serotypes, and this heterogeneity remains incompletely understood. In this study, we first assessed differences in vaccine responses according to serotype. We then determined predictive serotype-specific immunoglobulin concentration for the seven routinely serotypes tested in our laboratory, defined as the minimal levels required to induce a positive opsonophagocytic activity (OPA) response. The results enable a more accurate assessment of serotype-specific vaccine immunity, supporting improved patient stratification and guiding booster vaccination in individuals with insufficient responses.