Accounting for serotypic heterogeneity improves the interpretation of pneumococcal vaccine response using serotype-specific ELISA IgG concentrations

ABSTRACT Assessment of pneumococcal vaccine response by enzyme-linked immunosorbent assay (ELISA) currently relies on a single IgG concentration threshold applied to all serotypes. This approach does not account for the marked serotype variability in the relationship between IgG concentration and functional antibody activity. We investigated whether accounting for serotypic heterogeneity improves the interpretation of pneumococcal vaccine response by establishing serotype-specific IgG concentrations predictive of a positive OPA response (PIC). We analyzed 729 samples from adults referred for assessment of pneumococcal vaccine response. For seven vaccine serotypes, IgG concentrations were measured by ELISA and functional activity of antibodies was assessed by opsonophagocytic assay (OPA). IgG concentrations differed significantly according to both serotype and OPA status. Quantitative analyses demonstrated significant correlations between IgG concentrations and OPA titers for all serotypes (Spearman’s ρ = 0.45–0.76; all P < 0.0001). For each serotype, PIC was determined using receiver operating characteristic (ROC) curve analysis, Youden’s index, and bootstrap validation. PIC values ranged from 0.84 to 4.74 µg/mL and differed significantly between serotypes ( P < 0.0001). Diagnostic performance is good, with areas under the curve ranging from 0.73 to 0.87. Application of serotype-specific PICs significantly modified vaccine response classification compared with the use of a single universal threshold (Cochran’s Q and McNemar’s tests, P < 0.0001). Accounting for serotypic heterogeneity improves the interpretation of pneumococcal ELISA results by providing PIC that more closely reflect functional OPA responses. Although validation in clinically well-characterized patient cohorts remains necessary, this approach may facilitate interpretation of vaccine responses when OPA is not feasible. IMPORTANCE In routine clinical practice, pneumococcal vaccine responses are frequently assessed using serotype-specific IgG concentrations measured by enzyme-linked immunosorbent assay (ELISA), commonly interpreted with a single IgG cut-off applied uniformly across serotypes. However, this approach does not account for serotypic variability. Furthermore, it assumes that identical IgG concentrations reflect comparable functional antibody activity across serotypes. Opsonophagocytosis testing can determine antibody functionality, but these tests are difficult to implement routinely in clinical laboratories. Considering, on the one hand, the heterogeneity of the vaccine response and, on the other hand, the relationship between antibody concentration and functionality could help in evaluating the vaccine response in patients at risk of invasive pneumococcal disease.