Dengue serostatus impacts vaccine safety

1. Among dengue-seronegative individuals 2 to 16 years of age, there was a significantly increased risk of hospitalization and severe virologically confirmed dengue (VCD) after vaccination with the tetravalent dengue vaccine (CYD-TDV) compared to dengue-seropositive vaccine recipients and unvaccinated control patients.

2. Vaccination conferred a significantly decreased risk of hospitalization and severe VCD in dengue-seropositive individuals 2 to 16 years of age.

Evidence Rating Level: 2 (Good)           

Study Rundown: In the original CYD-TDV trials, some recipients 2 to 5 years of age developed severe VCD and increased hospitalizations following vaccination. However, risk estimates based on dengue-serostatus could not be assessed due to limited baseline sample collection. Investigators of the present study developed an assay to retrospectively determine the prevaccination dengue-serostatus of recipients and compare the incidence of dengue-related hospitalizations and severe VCD between patients exposed or not exposed to dengue prior to vaccination. The primary outcome, hospitalization for VCD in recipients 9 to 16 years of age, demonstrated a trend towards increased risk of adverse outcomes in seronegative vaccine recipients compared to seronegative nonvaccinated control patients. Among secondary outcomes, there was a significantly increased risk of hospitalization and severe VCD in seronegative recipients 2 to 8 years of age and 2 to 16 years of age compared to controls. In seropositive vaccine recipients of all prespecified age groups, the results demonstrated a decreased risk of hospitalization and severe VCD compared to nonvaccinated controls. These results suggest the decision of whether to vaccinate against dengue may depend on serostatus and highlights the need for a rapid, reliable test for previous dengue exposure.

This was a retrospective cohort study that reassessed all cases of VCD, hospitalization for VCD, and severe VCD based on prevaccination dengue-serostatus. The main strength of the study was the use of a new assay of antibodies to a nonstructural virus protein (anti-NS1) not present in the vaccine. Although unverifiable methods for obtaining serostatus were also used, all analytic methods have well established accuracy and were generally consistent. Limitations include that the assay used to determine serostatus has not yet been validated and that power was predetermined, given the study was performed post hoc.

Click to read the study in NEJM

Relevant Reading: Efficacy and long-term safety of a dengue vaccine in regions of endemic disease

In-Depth [retrospective cohort]: This was a retrospective, case-cohort study that reassessed the dengue-serostatus of 3578 patients (2384 in the vaccine group and 1194 in the unvaccinated control group) from three CYD-TDV efficacy trials (CYD14 in the Asia-Pacific region, CYD15 in Latin America, and CYD23 in Thailand). Baseline serostatus was determined based on 50% plaque-reduction neutralization test in the original study (when available) or imputed using either logistic regression or super learner. Month 13 anti-NS1 were measured in all participants for whom samples were available and were used as a continuous variable in baseline serostatus imputation. The primary endpoint was hospitalization for VCD in seronegative vaccine recipients who were 9 years of age or older. Secondary endpoints included risk of hospitalization and risk of severe VCD in recipients 2 to 8 years of age, and risk in those 2 to 16 years of age. Assessment of efficacy up to month 25 in seronegative participants was also a secondary endpoint.

The cumulative incidence of hospitalization among seronegative participants aged 9 to 16 was 1.57% for vaccine recipients and 1.09% for controls, with a hazard ratio of 1.41 (95% confidence interval [CI], 0.74 to 2.68). Among dengue-seronegative patients 2 to 16 years of age, the cumulative 5-year incidence of hospitalization for VCD was 3.06% in the vaccine group and 1.87% in controls, with a hazard ratio of 1.75 (95% CI, 1.14 to 2.70). Similar trends were reported for severe VCD, with seronegative recipients experiencing higher risk than compared to controls. Among seropositive patients 2 to 16 years of age and patients 9 to 16 years of age, the cumulative incidence of hospitalization for VCD in vaccine recipients was 0.75% and 0.38%, respectively, and 2.47% and 1.88% in controls, with hazard ratios of 0.32 (95% CI, 0.23 to 0.45) and 0.21 (95% CI, 0.14 to 0.31), respectively. There was also a lower risk of severe VCD in seropositive vaccine recipients compared to seropositive controls.

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