Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials

Abstract

Background: We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments.

Methods: We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples.

Results: There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline.

Conclusions: Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries.

Clinical trials registration: NCT01373281 and NCT01374516.

Figure 1.

Proportion of immunoglobulin M–positive (acute or convalescent) participants in virologically confirmed dengue (VCD) cases and other febrile cases without virological evidence of dengue according to baseline dengue serostatus, seropositive/immune (A) or seronegative/nonimmune (B) at baseline, and proportion of acute immunoglobulin G–positive participants according to baseline dengue serostatus, seropositive/immune (C) and seronegative/nonimmune (D) at baseline. VCD episodes were defined with a positive test for dengue nonstructural protein 1 (NS1) antigen or dengue polymerase chain reaction. Baseline dengue serostatus was defined by plaque reduction neutralization test (PRNT₅₀); seropositive was defined as a titer ≥10 1/dil for at least 1 serotype and seronegative as a titer <10 1/dil for any serotype.

Figure 2.

Change in relative immunoglobulin M (A) and immunoglobulin G (B) levels between acute (blue circle) and convalescent (red line) samples in virologically confirmed dengue (VCD) episodes and other febrile episodes without virological evidence of dengue, according to the dengue baseline serostatus (immune or nonimmune) and the treatment received (CYD-TDV or placebo control). VCD episodes were defined with a positive test for dengue nonstructural protein 1 (NS1) antigen or dengue polymerase chain reaction. Abbreviations: ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IgM, immunoglobulin M; VCD, virologically confirmed dengue.

Figure 3.

Immunoglobulin M (IgM)/immunoglobulin G (IgG) ratio distribution (on convalescent samples) in participants with virologically confirmed dengue (VCD) according to the treatment received and the baseline dengue serostatus: seropositive/immune (A) and seronegative/nonimmune (B). VCD episodes were defined with a positive test for dengue nonstructural protein 1 (NS1) antigen or dengue polymerase chain reaction. Baseline dengue serostatus was defined by plaque reduction neutralization test (PRNT₅₀); seropositive was defined as a titer ≥10 1/dil for at least 1 serotype and seronegative as a titer <10 1/dil for any serotype.

Figure 4.

Immunoglobulin M (IgM)/immunoglobulin G (IgG) ratio distribution (on convalescent samples) in participants with other febrile episodes (no virological evidence of dengue) according to the treatment received and the baseline dengue serostatus: seropositive/immune (A) and seronegative/nonimmune (B). Baseline dengue serostatus was defined by plaque reduction neutralization test (PRNT₅₀) assay; seropositive was defined as a titer ≥10 1/dil for at least 1 serotype and seronegative as a titer <10 1/dil for any serotype.