Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials

Abstract

A recombinant live attenuated tetravalent dengue vaccine (CYD-TDV) has been shown to be efficacious in preventing virologically-confirmed dengue disease, severe dengue disease and dengue hospitalization in children aged 2-16 years in Asia and Latin America. We analyzed pooled safety data from 18 phase I, II and III clinical trials in which the dengue vaccine was administered to participants aged 2-60 years, including long-term safety follow-up in three efficacy trials. The participants were analyzed according to their age at enrollment. The percentage of participants aged 2-60 years reporting ≥1 solicited injection-site or systemic reactions was slightly higher in the CYD-TDV group than in the placebo group. The most common solicited injection-site reactions were pain. Headache and malaise were the most common solicited systemic reactions. In both groups 0.3% of participants discontinued for safety reasons. The most common unsolicited adverse events were injection-site reactions, gastrointestinal disorders, and infections. Reactogenicity did not increase with successive doses of CYD-TDV. The frequency and nature of SAEs occurring within 28 days of any dose were similar in the CYD-TDV and placebo groups and were common medical conditions that could be expected as a function of age. Baseline dengue virus serostatus did not appear to influence the safety profile. No vaccine-related anaphylactic reactions, neurotropic events or viscerotropic events were reported. In year 3 after dose 1, an imbalance for dengue hospitalization, including for severe dengue, observed in participants aged <9 years in the CYD-TDV group compared with the placebo group was not observed for participants aged ≥9 years. In Year 4, this imbalance in participants aged <9 years was less marked, giving an overall lower risk of dengue hospitalization or severe dengue from dose 1 to Year 4 in the CYD-TDV group. These results have contributed to the definition of the target population for vaccination (≥9 years old) for which CYD-TDV has a satisfactory safety profile. Long-term safety will continue to be monitored in the ongoing follow-up of efficacy trials. Safety and effectiveness in real-life settings will be assessed through post-licensure studies.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: all authors were employees of Sanofi Pasteur at the time the study was conducted and the manuscript was written. This does not alter their adherence to all PLOS policies on sharing data and materials. All authors hold Sanofi Pasteur shares/stock options.

Figures

Fig 1. Overall safety profile of CYD-TDV and placebo.

Percentages and 95% confidence intervals for participants those who received at least one dose of CYD-TDV (left) or placebo (right) reporting solicited injection-site reactions within 7 days of any dose, solicited systemic reactions within 14 days of any dose, unsolicited AEs and SAEs within 28 days of any dose, by age group.

Fig 2. Safety profile after each dose of CYD-TDV.

Percentages and 95% confidence intervals for participants those who received at least one dose of CYD-TDV reporting solicited injection-site reactions within 7 days after each dose, solicited systemic reactions within 14 days after each dose, unsolicited AEs and SAEs within 28 days after each dose, by age group children (2–8 years), adolescents (9–17 years) and adults (≥18 years).

Fig 3. Effect of dengue sero-status at baseline on CYD-TDV safety profile by age.

The percentages and 95% confidence intervals for participants who had received at ≥1 dose of CYD-TDV who reported solicited injection-site reactions, solicited systemic reactions, unsolicited non-serious adverse events (AEs) and serious adverse events (SAEs) within 28 days of any dose by age (2–8 years and 9–60 years) and baseline dengue sero-status: sero-negative (left); sero-positive (right)

Fig 4. Relative risk (solid line) and 95% confidence interval (dotted lines) against hospitalized or severe dengue due to any serotype by age at enrollment.

The Epanechnikov kernel method (with h = 2.0) was used to provide a smooth curve. Data were combined from post-dose 1 up to year 3 in the phase III trial in Latin America and up to year 4 in the phase IIb and phase III trial in Asia.