Accuracy, efficacy and safety of dengue CYD-TDV pre-vaccination screening with 5 existing IgG serotests: Retrospective analysis of phase III trials

Abstract

Background: Post-hoc analyses of CYD-TDV vaccine efficacy trials indicated that dengue seropositive vaccinees experienced protection against dengue hospitalization and severe dengue, while seronegative vaccinees were at increased risk for these outcomes. Pre-vaccination screening has been recommended by WHO to identify those with prior dengue infection (PDI) who would benefit from vaccination. We retrospectively assessed the concept of pre-vaccination screening by estimating vaccine efficacy (VE) in test-positive individuals using five marketed serotests. Methods and materials: Pre-vaccination sera obtained from subjects in the immunogenicity subsets of CYD14 and CYD15 (n ≥ 3841) were tested by two ELISAs and three rapid diagnostic tests (RDT). Reference serostatus was determined using measured dengue PRNT90, PRNT50 and NS1 IgG ELISA pre-vaccination, enabling estimation of serotest performance. VE against symptomatic virologically-confirmed dengue (VCD) over 25 months and dengue hospitalization over 6 years from first injection was assessed in test+ subjects using a Cox regression model. Pooled VE [(1 − Hazard Ratio) × 100] across all ages (2–16 years) is presented. Results: Assay specificity was high for all tests: Euroimmun-IgG-ELISA, 98.8% (95% CI: 97.9–99.3); Panbio-Indirect-IgG-ELISA, 99.2% (98.5–99.6); Biocan-RDT, 99.0%(98.3–9.5); SDBioline-RDT, 96.0% (94.8–97.1); and CTK-RDT, 99.5% (98.9–99.8). Sensitivity of the Euroimmun-ELISA (89.2%[87.9–90.3]) and Panbio-ELISA (92.5% [91.4–93.5]) were substantially higher than that of the SDBioline-RDT (71.1% [69.3–72.8]), Biocan-RDT (52.5% [50.6–54.4]) and CTK-RDT (47.6% [45.7–49.5]). For each serotest, vaccination of test+ subjects was associated with high VE against VCD (Table 1). Significant protection against hospitalized VCD was evident for test+ subjects with each serotest except CTK-RDT, for which the estimate was favorable, but the lower 95% CI crossed the null.Table 1VE against VCD and dengue hospitalization in test+ subjects.EndpointImmunoassayaIgG readout only.IncidencebCases/100 person-years. (95% CI)VE (95% CI)CYD-TDVPlaceboVCD (25 months)ELISA-Euroimmun0.4 (0.2–0.6)3.0 (2.2–4.0)88.3 (77.4–93.9)ELISA-Panbio0.4 (0.2–0.6)3.0 (2.2–3.9)87.6 (76.7–93.4)RDT-Biocan0.2 (0.1–0.6)2.0 (1.2–3.0)88.8 (66.9–96.2)RDT-SDBioline0.5 (0.2–0.8)2.7 (1.9–3.8)82.8 (66.9–91.1)RDT-CTK0.2 (0.0–0.5)1.7 (1.0–2.8)89.7 (64.6–97.0)Hospitalized VCD (6 years)ELISA-Euroimmun0.1 (0.0–0.2)0.4 (0.2–0.6)72.8 (38.9–87.9)ELISA-Panbio0.1 (0.1–0.2)0.5 (0.3–0.7)77.5 (52.8–89.3)RDT-Biocan<0.1 (0.0–0.1)0.3 (0.1–0.5)92.4 (37.8–99.1)RDT-SDBioline<0.1 (0.0–0.1)0.3 (0.2–0.6)87.2 (54.5–96.4)RDT-CTK<0.1 (0.0–0.2)0.2 (0.1–0.5)73.7 (−5.1 to 93.4)a IgG readout only.b Cases/100 person-years. Open table in a new tab Conclusion: Using five dengue IgG immunoassays, vaccination of test+ subjects is evidently safe and efficacious. The more sensitive ELISAs offer the distinct advantage of identifying a larger proportion of individuals who would benefit from vaccination.