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Pharmacology: Pharmacodynamics: Mechanism of action: The vaccine contains live attenuated viruses. Following administration, the viruses replicate locally and elicit neutralizing antibodies and cell-mediated immune responses against the four dengue virus serotypes.
Immunogenicity: Immunogenicity data were collected in a total of approximately 3104 subjects 9 through 45 years of age from endemic areas who received at least one injection of the final formulation of the vaccine according to the claimed vaccination schedule in 10 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies. Most of the subjects were 9 through 17 years of age (n= 2810).
The immunogenicity data presented correspond to the neutralizing antibody titers for each serotype as measured with the plaque reduction neutralization test (PRNT). The results are presented as geometric mean titers (GMTs), expressed in reciprocal dilutions (1/dil), measured at baseline and 28 days after the third injection of the vaccine.
GMT data on subjects 18 through 45 years of age included in Phase II safety and immunogenicity studies conducted in endemic areas (CYD22, CYD28 and CYD47) and on subjects 9 through 17 years of age included in the 3 efficacy studies (Phase IIb efficacy study, CYD23, and the two large-scale Phase III efficacy studies, CYD14 and CYD15) are presented by study and region in the Dengue Group and in the Placebo Group in Table 1 (serotypes 1 and 2) and Table 2 (serotypes 3 and 4). (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageIn all age groups in all studies, an increase in GMTs was observed for each of the 4 serotypes 28 days after the third injection as compared to baseline, regardless of the region, i.e., Asia Pacific or Latin America.
Differences in GMTs 28 days after the third injection were observed depending on dengue immune status before the first injection, the age and the region. Overall: The higher the GMTs before the first injection, the higher the GMTs 28 days after the third injection; GMTs 28 days after the third injection were higher in subjects with neutralizing antibodies against dengue virus before the first injection compared to subjects with no detectable neutralizing antibodies against dengue virus before the first injection; Dengue immune status before the first injection is a confounding factor of age: the older the subject, the higher the GMTs before the first injection and the higher the GMTs 28 days after the third injection, i.e., the immune response in terms of GMTs 28 days after the third injection increases with age.
Data on long-term persistence of antibodies: In subjects 9 years of age and older in endemic areas, a decrease in the GMTs against all 4 serotypes was observed one year after the third injection and then a trend toward stabilization was observed in the subsequent years. The decrease in GMTs was variable depending on age and the dengue immune status of subjects before the first injection. Long-term GMTs for each serotype remained higher than GMTs before the first injection.
Efficacy: The efficacy of the vaccine was assessed in 3 randomized, observer-blinded, placebo-controlled efficacy studies: one supportive Phase IIb efficacy study (CYD23), and 2 pivotal large-scale Phase III efficacy studies conducted in 5 countries each, CYD14 in Asia and CYD15 in Latin America.
In the 2 pivotal Phase III studies, efficacy was assessed in a total of 17,230 subjects 9 through 16 years of age who received at least one injection of the vaccine: 3316 subjects 9 through 14 years of age in CYD14 and the entire study population in CYD15, i.e., 13,914 subjects 9 through 16 years of age. A time window of +/- 20 days was applied for the second and third injections. More than 70% of subjects were dengue immune at baseline.
In subjects 9 through 16 years of age, the efficacy of the vaccine against symptomatic virologically confirmed dengue (VCD) cases due to any and each of the 4 serotypes was demonstrated in both studies, CYD14 and CYD15, and in the meta-analysis. The assessment period extended from the first injection to the end of the active phase, i.e. over the 25-month period after the first injection.
The efficacy of the vaccine against severe VCD cases and against hospitalized VCD cases (i.e., hospital admission due to dengue, whatever the severity) were also evaluated. For severe VCD cases, two types of endpoints were considered: clinically severe VCD cases and VCD cases that met WHO criteria for Dengue Hemorrhagic Fever (DHF). Vaccine efficacy was demonstrated for these three endpoints in both studies and in the meta-analysis.
The efficacy results were also analyzed according to covariates, i.e., age at the time of the first injection and dengue immune status before the first injection. In subjects 9 through 16 years of age, no significant effect of age on vaccine efficacy was observed, while a higher efficacy against VCD (any serotype and any severity) was observed in subjects with prior dengue infection (i.e subjects with neutralizing antibodies against any of the 4 dengue serotypes prior vaccination) (81.9%; 95% CI: 67.2; 90.0) compared to the overall population (65.6%; 95% CI: 60.7; 69.9) (see Table 3).
The efficacy results in subjects 9 through 16 years of age are presented in Table 3 for each of the two phase III efficacy studies and in the meta-analysis. The results are presented for the entire active phase of 25 months.
Dengue immune status at baseline (i.e before the first injection) measured by PRNT is defined as: Subject with qualified (≥ 10 [1/dil], the lower limit of quantitation) neutralizing antibodies against at least one dengue serotype in the baseline sample; Subject without qualified (< the lower limit of quantitation) neutralizing antibodies against any of the 4 dengue serotype in the baseline sample. (See Table 3.)
Click on icon to see table/diagram/imagePharmacokinetics: No pharmacokinetic studies have been performed on the vaccine.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special risks for humans based on a repeated-dose toxicity and local tolerance study, a distribution and shedding study, a neurovirulence study and a developmental and reproductive toxicology program.
