Abstract
BackgroundTwo electrochemiluminescence (ECL) assays were developed which, together, can simultaneously measure serum antibodies against pneumococcal capsular polysaccharides (PnPS) for 17 serotypes. The assays were validated for the 13 PnPS included in the 13-valent pneumococcal conjugate vaccine (PCV13). As recommended by the World Health Organization (WHO), we compared the ECL assays with the WHO reference enzyme-linked immunosorbent assay (ELISA) and derived a threshold corresponding to the 0.35 µg/mL threshold established for the WHO reference ELISA for the non-inferiority comparison and licensure of new PCVs against invasive pneumococcal disease. MethodsA panel of 452 serum samples from children vaccinated with one of the three licensed PCVs was assessed with the ECL assays and the WHO reference ELISA. The ECL assay threshold for the aggregated seven PnPS included in the 7-valent PCV (PCV7) and serotype-specific thresholds were determined using a receiver operating characteristics (ROC) curve-based approach and Deming regression. To evaluate concordance between the ECL assays and the WHO reference ELISA, serostatus agreement rates between both assays and geometric means of the ratios (GMRs) of concentrations obtained with both assays were calculated. ResultsThe thresholds for the seven aggregated PCV7 serotypes obtained with the ROC curve-based approach and Deming regression approximated 0.35 µg/mL (0.38 and 0.34 µg/mL, respectively). Individual thresholds for the PCV13 serotypes ranged between 0.24 and 0.51 µg/mL across both approaches. Serostatus agreement rates using a 0.35 µg/mL threshold for both assays were ≥86.9% for all PCV13 serotypes. GMRs ranged between 0.85 and 1.25 for 11/13 serotypes and were <1.29 for the two remaining serotypes. ConclusionThe ECL assays were comparable to the WHO reference ELISA and offer a sensitive, time- and serum volume-saving method to quantify serotype-specific anti-PnPS antibodies in pediatric sera. A 0.35 µg/mL threshold will be used for each PCV13 serotype to assess PCV immunogenicity in clinical trials.
Highlights
Streptococcus pneumoniae causes invasive infections, such as meningitis and sepsis, and is a major bacterial cause of mucosal infections, including otitis media and pneumonia
To compare the different aggregate thresholds (0.35 mg/mL and those obtained with the receiver operating characteristics (ROC) curve-based approach and Deming regression for the aggregated 7-valent pneumococcal conjugate vaccine (PCV7) serotypes), we looked at how the different thresholds affected the contingency tables between the ECL assays and the World Health Organization (WHO) reference enzyme-linked immunosorbent assay (ELISA) in terms of the serostatus of the samples for the aggregated PCV7 serotypes
To evaluate whether an anti-pneumococcal capsular polysaccharides (PnPS) concentration of 0.35 mg/mL could be used as the aggregate threshold for the ECL assays, we evaluated how the three different thresholds (0.38 mg/mL, 0.34 mg/mL, and 0.35 mg/mL) impacted the contingency tables between the ECL assays and the WHO reference ELISA in terms of the serostatus of the samples for the aggregated PCV7 serotypes (Supplementary table 5)
Summary
Streptococcus pneumoniae causes invasive infections, such as meningitis and sepsis, and is a major bacterial cause of mucosal infections, including otitis media and pneumonia. A 7-valent PCV (PCV7, Pfizer Inc.) including PnPS of seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) was licensed based on efficacy results from several clinical trials [4,5,6]. The assays were validated for the 13 PnPS included in the 13-valent pneumococcal conjugate vaccine (PCV13). Methods: A panel of 452 serum samples from children vaccinated with one of the three licensed PCVs was assessed with the ECL assays and the WHO reference ELISA. The ECL assay threshold for the aggregated seven PnPS included in the 7-valent PCV (PCV7) and serotype-specific thresholds were determined using a receiver operating characteristics (ROC) curve-based approach and Deming regression.
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