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J (ANTIINFECTIVES FOR SYSTEMIC USE) 07 (VACCINES) B (VIRAL VACCINES) X (Other viral vaccines).
Pharmacology: Pharmacodynamics: Mechanism of action: Dengvaxia 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 1800 subjects 12 through 45 years of age from endemic areas who received at least one dose of the final formulation of Dengvaxia according to the claimed vaccination schedule in 7 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies. Most of the subjects were 12 through 16 years of age (n= 1492).
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 dose of Dengvaxia.
GMT data on subjects 17 through 25 and 26 through 45 years of age included in Phase II safety and immunogenicity studies conducted in endemic areas (CYD22, CYD28 and CYD47) and on subjects 12 through 16 years of age included in the 2 large-scale Phase III efficacy studies, CYD14 and CYD15, and in CYD28 conducted in Singapore are presented by study and region in Table 2. (See Table 2.)
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 dose of Dengvaxia as compared to baseline, regardless of the region, i.e., Asia Pacific or Latin America.
Differences in GMTs 28 days after the third dose were observed depending on dengue immune statusa before the first dose, the age and the region. Overall: The higher the GMTs before the first dose, the higher the GMTs 28 days after the third dose; Dengue immune status before the first dose is a confounding factor of age: the older the subject, the higher the GMTs before the first dose and the higher the GMTs 28 days after the third dose.
Singaporean Population (data from CYD28 study): In CYD28, a clinical immunogenicity and safety study conducted in Singapore in individuals from 2 to 45 years of age, an immune response to the vaccine was observed in all age groups, with an increase of GMTs for each serotype 28 days after the third dose. Post-dose 3 GMTs in CYD28 study were lower than in the other studies conducted in highly endemic countries (see Table 2). Clinical efficacy studies have not been conducted in the Singaporean population.
Singaporean population with unknown previous history of dengue: Table 3 presents the immune response in CYD28 study, conducted in Singapore, by baseline dengue immune status. An increase in GMTs was observed 28 days after the third dose as compared to baseline in both dengue immune and non-immune subjects at baseline. GMTs 28 days after the third dose were higher in subjects who were dengue immune at baseline, as observed in the other clinical studies. Low GMTs were observed in dengue non-immune subjects at baseline. Post-dose 3 GMTs were also low in the out-of indication 2- to 5-year-old subjects included in the CYD14 Phase III study, for which the cumulative relative risk of hospitalized dengue illness was 2.108 95% CI (1.14; 4.21) within the 3 years of long-term follow-up that includes both hospital phase and partial surveillance expansion phase data (from 1 to 4 years after the third dose) and 1.360 95% CI (0.86; 2.22) within the first five years after the first dose.
In an exploratory analysis of up to 6 years of follow up from the first dose in three efficacy studies, an increased risk of hospitalization for dengue including clinically severe dengue (predominantly Dengue Hemorrhagic Fever grade 1 or 2 [WHO 1997]) has been observed in vaccinees with no previous dengue infection (see Precautions and Adverse Reactions). In Singapore, for individuals with unknown history of prior dengue exposure, serostatus testing if available may provide some additional information to inform the benefit/risk considerations following vaccination with Dengvaxia in these individuals. (See Table 3.)
a Dengue immune status at baseline (i.e. before the first dose) measured by PRNT is defined as: Subjects with quantified (≥ 10 [1/dil], the lower limit of quantitation) neutralizing antibodies against at least one dengue serotype in the baseline sample; Subjects without quantified (< the lower limit of quantitation) neutralizing antibodies against any of the 4 dengue serotypes in the baseline sample.
The terms "immune and non-immune" are used to describe the presence or not of antibodies at baseline. Immune is not used to imply that subjects are protected from dengue infection. (See Table 3.)
Click on icon to see table/diagram/imageAdult Population from 46 to 60 years of age: A study was conducted in adult subjects aged 18 to 60 years in Australia in non-endemic areas. This study included 241 subjects aged 46 through 60 years of age. A similar immune response was observed in 18 to 45 and 46 to 60-year-old subjects included in the trial against the 4 serotypes: in subjects aged 46 to 60 years, GMTs post-dose 3 were of 17.6 (1/dil) for serotype 1, 54.2 (1/dil) for serotype 2, 83.3 (1/dil) for serotype 3 and 144 (1/dil) for serotype 4.
Data on long-term persistence of antibodies: GMT data up to 4 years after the last dose are presented by age group and by study in Table 4 for serotype 1 and 2 and Table 5 for serotype 3 and 4.
Overall, in subjects 12 years of age and older in endemic areas, a decrease in the GMTs against all 4 serotypes was observed one year after the third dose 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 dose. Long-term GMTs for each serotype remained higher than GMTs before the first dose. (See Tables 4 and 5.)
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Click on icon to see table/diagram/imageEfficacy: The efficacy of Dengvaxia was assessed in 2 pivotal large-scale, randomized, observer-blinded, placebo-controlled 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 13,732 subjects 12 through 16 years of age who received at least one dose of the vaccine: 2329 subjects 12 through 14 years of age in CYD14 and the 11,400 subjects 12 through 16 years of age in CYD15. A time window of +/- 20 days was applied for the second and third dose. More than 70% of subjects were dengue immune at baseline.
In subjects 12 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 dose to the end of the active phase, i.e. over the 25-month period after the first dose.
The efficacy of Dengvaxia 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 in subjects 12 through 16 years of age are presented in Table 6 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. (See Table 6.)
Click on icon to see table/diagram/imageVaccine efficacy against VCD was demonstrated in dengue immune subjects at baseline (81.9%, 95% CI 67.2; 90.0) and dengue non-immune subjects at baseline (52.5%, 95% CI: 5.9; 76.1). This vaccine efficacy was measured over the 25-month period after the first dose and using PRNT 50 test in a subset of subjects aged aged 9 to 16 years.
Bridging of efficacy data to individuals 17 through 45 years of age in endemic areas: The 2 pivotal efficacy studies showed that higher post-dose 3 GMTs were associated with higher protection.
Based on immunogenicity data from Phase II studies conducted in Asia (CYD22 conducted in Vietnam in 180 subjects 2 through 45 years of age including 30 adults, and CYD47, conducted in India in 189 subjects 18 through 45 years of age), similar or higher neutralizing antibody levels after the third dose of Dengvaxia are anticipated in adults from endemic areas, and thus a similar or higher level of protection after the third dose of the vaccine is expected in individuals 17 through 45 years of age in endemic areas compared to the vaccine efficacy observed in the CYD14 and CYD15 studies.
Long-term follow-up data from Phase III studies in subjects aged 12 to 16 years: In CYD14 and CYD15, during the first 2 years of long-term follow-upa, 20 hospitalized VCD cases were reported in 8463 vaccinees versus 27 hospitalized VCD cases reported in 4229 subjects in the control group (with a 2:1 randomization ratio).
Overall, over 5 years after the first injection, 32 hospitalized VCD cases were reported in 8699 vaccinees versus 58 hospitalized VCD cases reported in 4343 subjects in the control group (with a 2:1 randomization ratio). Long-term follow-up data according to the baseline dengue immune status are provided in "Hospitalized and/or clinically severe dengue fever in long-term safety follow-up data" under Adverse Reactions.
Pharmacokinetics: No pharmacokinetic studies have been performed on Dengvaxia.
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.
aThe long-term follow-up period started at the end of the Active Phase, i.e. 25 months after the first injection.
