Study Participants

A total of 3203 of the 4002 participants (80%) in the CYD23 trial who were between the ages of 4 and 11 years at enrollment were subsequently enrolled in the extension trial, CYD57 (2131 in the vaccine group and 1072 in the control group). A total of 10,165 of 10,275 participants (99%) in the CYD14 trial and 19,898 of 20,869 participants (95%) in the CYD15 trial who were between the ages of 2 and 16 years are being followed (6778 in the vaccine group and 3387 in the control group in the CYD14 trial and 13,268 and 6630, respectively, in the CYD15 trial). The vaccine and control groups were well balanced with respect to age and sex (Table S1 in the Supplementary Appendix). More participants in the CYD15 trial than in the CYD14 trial were seropositive for dengue at baseline, although the numbers were similar among those who were 9 years of age or older (Fig. S1 in the Supplementary Appendix).

Interim Long-Term Safety Analyses

All Participants

Table 1. Table 1. Annual Incidence of Hospitalization for Virologically Confirmed Dengue, According to Trial, Age Group, and Study Period.

During year 3, the annual incidence of hospitalization for virologically confirmed dengue was 0.4% (27 of 6778 participants) in the vaccine group and 0.4% (13 of 3387) in the control group in the CYD14 trial, 0.1% (16 of 13,268 participants) in the vaccine group and 0.2% (15 of 6630) in the control group in the CYD15 trial, and 1.1% (22 of 2131 participants) in the vaccine group and 1.1% (11 of 1072) in the control group in the CYD57 trial (Table 1). The relative risk of hospitalization for virologically confirmed dengue in the vaccine group as compared with the control group was 1.04 (95% confidence interval [CI], 0.52 to 2.19) in the CYD14 trial, 0.53 (95% CI, 0.25 to 1.16) in the CYD15 trial, and 1.01 (95% CI, 0.47 to 2.30) in the CYD23/57 trial (Table 1). The pooled relative risk for the three trials was 0.84 (95% CI, 0.56 to 1.24). The majority of patients had serotype 1 or 2 infection; serotype 4 was the least frequently identified serotype (Table 1).

The length of hospitalization, duration of fever, and clinical symptoms were similar in the three trials (Tables S2A, S2B, and S2C in the Supplementary Appendix). No clinically important differences in the frequencies of signs and symptoms were observed between the vaccine and control groups, suggesting that there were no vaccine-related changes in the clinical picture of hospitalized participants. Similar levels of viremia were observed among hospitalized participants in the vaccine group and the control group (Table S3 in the Supplementary Appendix).

Overall, during year 3, severe dengue, defined according to the criteria of the independent data monitoring committee, was reported in 18 of 22,177 participants in the vaccine group and in 6 of 11,089 in the control group (Table S4 in the Supplementary Appendix). In the CYD23/57 trial during year 4, severe dengue occurred in 1 participant in the vaccine group and in 2 participants in the control group. All the cases that were classified as severe according to the criteria of the independent data monitoring committee were classified as WHO grade I or II, except for the cases in 2 participants in the vaccine group during year 3 of the CYD23/57 trial, which were classified as grade III. All the participants who were hospitalized for virologically confirmed dengue during follow-up had a full recovery after receiving appropriate supportive treatment.

Long-Term Follow-up According to Age Group

In the CYD14 trial, prespecified age-specific analyses showed a clear trend toward a higher relative risk for hospitalization for virologically confirmed dengue among younger children, although the number of cases was low; the relative risks were 7.45 among children between the ages of 2 and 5 years, 0.63 among those between the ages of 6 and 11 years, and 0.25 among those between the ages of 12 and 14 years (Table 1). The prespecified age-specific analyses in the CYD23/57 trial showed a relative risk of 2.44 (95% CI, 0.27 to 115.34) among participants who were 4 or 5 years of age during year 3 (Table 1). In year 4 of the CYD23/57 trial, the relative risk among children who were 4 or 5 years of age was 0.81, but the upper boundary of the 95% confidence interval remained more than 1 (95% CI, 0.16 to 5.24). Further analyses in the CYD15 trial, in which participants between the ages of 9 and 16 years were enrolled, showed no trend according to age group among those who were between the ages of 9 and 11 years and those who were between the ages of 12 and 16 years.

In year 3, the relative risks among participants younger than 9 years of age were similar in the CYD14 and CYD23/57 trials, with a pooled estimated relative risk of 1.58 (95% CI, 0.83 to 3.02), which suggests an overall trend to increased risk in the vaccine group, although the lower boundary of the 95% confidence interval was less than 1 (Table 1). The relative risk among those who were 9 years of age or older was 0.57 (95% CI, 0.18 to 1.86) in the CYD14 trial and 0.31 (95% CI, 0.05 to 1.58) in the CYD23/57 trial, findings that were similar to the results in the CYD15 trial, in which all the participants were 9 years of age or older (relative risk, 0.53; 95% CI, 0.25 to 1.16). The pooled relative risk among participants who were 9 years of age or older was 0.50 (95% CI, 0.29 to 0.86). An exploratory analysis in the CYD14 trial showed that among participants between the ages of 9 and 11 years, the relative risk was 1.01 (95% CI, 0.22 to 6.23), as compared with a relative risk of 0.25 (95% CI, 0.02 to 1.74) among those between the ages of 12 and 14 years. This trend was not observed in the CYD15 trial (Table 1). In year 4 in the CYD57 trial, the relative risk among participants who were 9 years of age or older was similar to that in year 3 (relative risk, 0.31; 95% CI, 0.05 to 1.58), whereas the relative risk among the younger participants had decreased to 0.54 (95% CI, 0.23 to 1.29) (Table 1).

In the CYD14 trial, among participants younger than 9 years of age who were hospitalized for dengue, severe disease (according to the criteria of the independent data monitoring committee) occurred in 8 of 19 participants in the vaccine group and in none of 6 participants in the placebo group (relative risk could not be calculated). Among those who were 9 years of age or older, severe disease occurred in 3 of 8 participants in the vaccine group and in 1 of 7 participants in the control group (relative risk, 1.50; 95% CI, 0.12 to 78.9). The three cases in the vaccine group occurred in participants who were between the ages of 9 and 11 years at enrollment. In the CYD23/57 trial, all the severe cases occurred in participants who were younger than 9 years of age. In year 3, the two participants in the vaccine group in whom the illness was classified as grade III dengue hemorrhagic fever according to the WHO criteria had clinical shock.

For year 3, the overall pooled estimate of the relative risk of hospitalization for severe dengue was 1.50 (95% CI, 0.60 to 3.79) for all the participants, as compared with 0.50 (95% CI, 0.16 to 1.55) for participants who were 9 years of age or older. Among participants under the age of 9 years, there were 12 cases of severe dengue (8 in the CYD14 trial and 4 in the CYD23/57 trial) in the vaccine group and none in the control group; consequently, the relative risk for this analysis could not be calculated. The pooled relative risk was driven mainly by the cases occurring in participants younger than 9 years of age.

Hospitalization since Vaccination

Although the relative risk of hospitalization for dengue varied in the three studies, within-trial estimates showed reductions in risk in the vaccine group during years 1 and 2 of the efficacy surveillance phase. With the exception of year 1 in the CYD23/57 trial, the upper boundaries of the 95% confidence intervals were all less than 1 (Table S5 in the Supplementary Appendix). Cumulative relative risks for hospitalizations that occurred more than 3 years after vaccination were 0.46 (95% CI, 0.32 to 0.65) in the CYD14 trial, 0.28 (95% CI, 0.18 to 0.44) in the CYD15 trial, and 0.66 (95% CI, 0.43 to 1.02) in the CYD23/57 trial (Table S5 in the Supplementary Appendix). Cumulative relative risks during this period in the CYD14 trial were 0.61 (95% CI, 0.39 to 0.95) among participants younger than 9 years of age and 0.27 (95% CI, 0.14 to 0.48) among those who were 9 years of age or older. A Kaplan–Meier plot showed that there was greater protection among participants who were 9 years of age or older than among those who were under the age of 9 years, and the incidence appeared to be stable (Fig. S2 in the Supplementary Appendix). Cases occurred throughout the follow-up, with similar accrual patterns over time.

The length of hospitalization and duration of fever and clinical symptoms were similar for those hospitalized during the efficacy surveillance phase and the long-term follow-up phase in all three trials (Tables S2A, S2B, and S2C in the Supplementary Appendix). No clinically important differences in the frequencies of various signs and symptoms in the hospitalized participants were seen between the efficacy surveillance phase and the long-term follow-up phase in any of the studies or between the vaccine and control groups, which suggests there were no changes in the clinical picture of hospitalized cases during long-term follow-up. The levels of viremia were similar to those in the efficacy surveillance phase and similar between groups (Table S3 in the Supplementary Appendix).

Pooled Analyses for Vaccine Efficacy

Figure 2. Figure 2. Vaccine Efficacy, According to Serotype and Age Group. Panel A shows a forest plot indicating vaccine efficacy against virologically confirmed dengue according to serotype and serostatus at baseline among participants who were 9 years of age or older at baseline in the CYD14 trial (which enrolled children between the ages of 2 and 14 years), the CYD15 trial (which enrolled children between the ages of 9 and 16 years), and the meta-analysis of these trials. There was no significant interaction between the vaccine group and the trial. Panel B shows vaccine efficacy among participants who were under the age of 9 years in the CYD14 trial.

Vaccine efficacies for dengue caused by any and each serotype were generally consistent in the per-protocol and intention-to-treat analyses in the individual trials and in the pooled analyses for all outcomes, but multivariate analyses including age as a categorical variable (age group) or as a continuous variable showed significant interaction between age and vaccine group (Fig. S3 through S6 in the Supplementary Appendix). As compared with vaccine efficacies among all participants, for all outcomes, efficacies were higher among participants who were 9 years of age or older and lower among participants who were under 9 years of age. Vaccine efficacies against dengue in participants who were 9 years of age or older were similar in the individual trials, with a pooled estimate of 65.6% (95% CI, 60.7 to 69.9) (Figure 2A), as compared with 44.6% (95% CI, 31.6 to 55.0) among participants under the age of 9 years (Figure 2B).

The pooled serotype-specific vaccine efficacies for this outcome ranged from 47.1% (95% CI, 31.3 to 59.2) for serotype 2 to 83.2% (95% CI, 76.2 to 88.2) for serotype 4 among participants who were 9 years of age or older (Figure 2A). Among those under the age of 9 years, the range was from 33.6% (95% CI, 1.3 to 55.0) for serotype 2 to 62.1% (95% CI, 28.4 to 80.3) for serotype 3 (Figure 2B).

Approximately 80% of the participants 9 years of age or older in the immunogenicity subgroup in the CYD14 and CYD15 trials were seropositive for dengue at baseline (Fig. S1 in the Supplementary Appendix). Pooled vaccine efficacy among seropositive participants was 81.9% (95% CI, 67.2 to 90.0) among those who were 9 years of age or older (Figure 2A), as compared with 70.1% (95% CI, 32.3 to 87.3) among those who were younger than 9 years of age (Figure 2B). In each study, vaccine efficacies were lower among seronegative participants who were 9 years of age or older than among seropositive participants in the same age group, and the lower boundaries of the 95% confidence intervals were less than 0. However, the pooled vaccine efficacy in this age group was 52.5%, with a lower boundary of the 95% confidence interval of more than 0 (Figure 2A), as compared with a vaccine efficacy of 14.4% (95% CI, −111.0 to 63.5) among participants under the age of 9 years (Figure 2B).

Figure 3. Figure 3. Vaccine Efficacy, According to Group Criteria and Trial. Panel A shows a forest plot indicating vaccine efficacy among children who were 9 years of age or older at baseline according to rates of hospitalization for dengue in the intention-to-treat population; rates of severe dengue, as defined according to the criteria of the independent data monitoring committee (IDMC); and rates of dengue hemorrhagic fever (DHF), as defined according to the 1997 criteria of the World Health Organization (WHO). Shown are data for the CYD14 trial (which enrolled children between the ages of 2 and 14 years), the CYD15 trial (which enrolled children between the ages of 9 and 16), and the meta-analysis of these trials. There was no significant interaction between the vaccine group and the trial. Panel B shows the same results for children under the age of 9 years in the CYD14 trial.

Vaccine efficacies against hospitalization for dengue were more than 80% in the individual trials among participants who were 9 years of age or older, with a pooled vaccine efficacy of 80.8% (95% CI, 70.1 to 87.7) (Figure 3A), as compared with 56.1% (95% CI, 26.2 to 74.1) among participants under the age of 9 years (Figure 3B). Pooled vaccine efficacies for severe dengue, as defined according to the criteria of the independent data monitoring committee, were 93.2% (95% CI, 77.3 to 98.0) among participants who were 9 years of age or older and 44.5 (95% CI, −54.4 to 79.7) among those under the age of 9 years. The vaccine efficacies against dengue hemorrhagic fever, as defined according to the WHO criteria, were 92.9% (95% CI, 76.1 to 97.9) and 66.7% (95% CI, −4.7 to 90.2) in the two groups, respectively (Figure 3A and 3B).