Summary of the characteristics of clinical trials included in the analysis.

<p>Summary of the characteristics of clinical trials included in the analysis.</p

Number of CYD-TDV (final formulation) injections received overall and by age group in main trials (CYD-TDV at D0 M6 and M12), and all trials (including those who received three doses of CYD-TDV at D0 M3.5/4 and M12) and number of placebo and active control injections.

<p>Number of CYD-TDV (final formulation) injections received overall and by age group in main trials (CYD-TDV at D0 M6 and M12), and all trials (including those who received three doses of CYD-TDV at D0 M3.5/4 and M12) and number of placebo and active control injections.</p

SAEs within 28 days after any dose of CYD-TDV vaccine or placebo in participants aged 9–60 years.

<p>None of the preferred term events affected ≥0.1% of the participants; n = number of participants with ≥1 of each SAE.</p

Overall safety profile of CYD-TDV and placebo.

<p>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.</p

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

<p>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.</p

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

<div><p>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.</p></div

Unsolicited non-serious adverse reactions affecting ≥0.1% of participants aged 9–60 years in the CYD-TDV and placebo groups.

<p>n = number of participants with ≥1 of each SAE.</p

Definitions and severity scales for solicited injection site and systemic reactions.

<p>Definitions and severity scales for solicited injection site and systemic reactions.</p

Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial

<div><p>Dengue incidence has increased globally, but empirical burden estimates are scarce. Prospective methods are best-able to capture all severities of disease. CYD14 was an observer-blinded dengue vaccine study conducted in children 2–14 years of age in Indonesia, Malaysia, Thailand, the Philippines, and Vietnam. The control group received no vaccine and resembled a prospective, observational study. We calculated the rates of dengue according to different laboratory or clinical criteria to make inferences about dengue burden, and compared with rates reported in the passive surveillance systems to calculate expansion factors which describe under-reporting. Over 6,933 person-years of observation in the control group there were 319 virologically confirmed dengue cases, a crude attack rate of 4.6%/year. Of these, 92 cases (28.8%) were clinically diagnosed as dengue fever or dengue hemorrhagic fever by investigators and 227 were not, indicating that most symptomatic disease fails to satisfy existing case definitions. When examining different case definitions, there was an inverse relationship between clinical severity and observed incidence rates. CYD14’s active surveillance system captured a greater proportion of symptomatic dengue than national passive surveillance systems, giving rise to expansion factors ranging from 0.5 to 31.7. This analysis showed substantial, unpredictable and variable under-reporting of symptomatic dengue, even within a controlled clinical trial environment, and emphasizes that burden estimates are highly sensitive to case definitions. These data will assist in generating disease burden estimates and have important policy implications when considering the introduction and health economics of dengue prevention and control interventions.</p></div

Expansion factors for VCD, cVCD, and CDD over the active phase of the CYD14 study.

<p>Expansion factors for VCD, cVCD, and CDD over the active phase of the CYD14 study.</p