QDENGA Powder and solvent for solution for injection Ref.[50598] Active ingredients: Dengue vaccine

Pharmacotherapeutic group: Vaccines, Viral vaccines
ATC code: J07BX04

Mechanism of action

Qdenga contains live attenuated dengue viruses. The primary mechanism of action of Qdenga is to replicate locally and elicit humoral and cellular immune responses against the four dengue virus serotypes.

Clinical efficacy

The clinical efficacy of Qdenga was assessed in study DEN-301, a pivotal Phase 3, double-blind, randomized, placebo-controlled study conducted across 5 countries in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua, Panama) and 3 countries in Asia (Sri Lanka, Thailand, the Philippines). A total of 20,099 children aged between 4 and 16 years were randomized (2:1 ratio) to receive Qdenga or placebo, regardless of previous dengue infection.

Efficacy was assessed using active surveillance across the entire study duration. Any subject with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) was required to visit the study site for dengue fever evaluation by the investigator. Subjects/guardians were reminded of this requirement at least weekly to maximize the detection of all symptomatic virologically confirmed dengue (VCD) cases. Febrile episodes were confirmed by a validated, quantitative dengue RT-PCR to detect specific dengue serotypes.

Clinical efficacy data for subjects 4 to 16 years of age

The Vaccine Efficacy (VE) results, according to the primary endpoint (VCD fever occurring from 30 days to 12 months after the second vaccination) are shown in Table 2. The mean age of the per protocol trial population was 9.6 years (standard deviation of 3.5 years) with 12.7% subjects in the 4-5 years, 55.2% in the 6-11 years and 32.1% in the 12-16 years age-groups. Of these, 46.5% were in Asia and 53.5% were in Latin America, 49.5% were females and 50.5% were males. The dengue serostatus at baseline (before the first injection) was assessed in all subjects by microneutralisation test (MNT50) to allow Vaccine Efficacy (VE) assessment by baseline serostatus. The baseline dengue seronegativity rate for the overall per protocol population was 27.7%.

Table 2. Vaccine efficacy in preventing VCD fever caused by any serotype from 30 days to 12 months post second vaccination in study DEN-301 (Per Protocol Set)^a:

CI: confidence interval; n: number of subjects with fever; VCD: virologically confirmed dengue
^a The primary analysis of efficacy data were based on the Per Protocol Set, which consisted of all randomized subjects who did not have any major protocol violations, including not receiving both doses of the correct assignment of Qdenga or placebo
^b Number of subjects evaluated

VE results according to the secondary endpoints, preventing hospitalisation due to VCD fever, preventing VCD fever by serostatus, by serotype and preventing severe VCD fever are shown in Table 3. For severe VCD fever, two types of endpoints were considered: clinically severe VCD cases and VCD cases that met the 1997 WHO criteria for Dengue Haemorrhagic Fever (DHF). The criteria used in Trial DEN-301 for the assessment of VCD severity by an independent “Dengue Case severity Adjudication Committee” (DCAC) were based on the WHO 2009 guidelines. The DCAC assessed all cases of hospitalisation due to VCD utilizing predefined criteria which included an assessment of bleeding abnormality, plasma leakage, liver function, renal function, cardiac function, the central nervous system, and shock. In Trial DEN-301 VCD cases meeting the WHO 1997 criteria for DHF were identified using a programmed algorithm, i.e., without applying medical judgment. Broadly, the criteria included presence of fever lasting 2 to 7 days, haemorrhagic tendencies, thrombocytopenia, and evidence of plasma leakage.

Table 3. Vaccine efficacy in preventing hospitalisation due to VCD fever, VCD fever by dengue serotype, VCD fever by baseline dengue serostatus, and severe forms of dengue from 30 days to 18 months post second vaccination in study DEN-301 (Per Protocol Set):

VE: vaccine efficacy; CI: confidence interval; n: number of subjects; VCD: virologically confirmed dengue; DENV: dengue virus serotype
^a Number of subjects evaluated
^b key secondary endpoint
^c Most of the cases observed were due to DENV-2 (0 cases in Qdenga arm and 46 cases in Placebo arm)
^d p-value <0.001

Early onset of protection was seen with an exploratory VE of 81.1% (95% CI: 64.1%, 90.0%) against VCD fever caused by all serotypes combined from first vaccination until second vaccination.

Long term protection

In study DEN-301, a number of exploratory analyses were conducted to estimate long term protection from first dose up to 4.5 years after the second dose (Table 4).

Table 4. Vaccine efficacy in preventing VCD fever and hospitalisation overall, by baseline dengue serostatus, and against individual serotypes by baseline serostatus from first dose to 54 months post second dose in study DEN-301 (Safety Set):

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, n: number of subjects, N: number of subjects evaluated, NP: not provided
^a Exploratory analyses; the study was neither powered nor designed to demonstrate a difference between the vaccine and the placebo group
^b Approximated using a one-sided 95% CI
^c VE estimate not provided since fewer than 6 cases, for both TDV and placebo, were observed

Additionally, VE in preventing DHF caused by any serotype was 70.0% (95% CI: 31.5%, 86.9%) and in preventing clinically severe VCD cases caused by any serotype was 70.2% (95% CI: -24.7%, 92.9%).

In year-by-year analysis until four and a half years after the second dose, VE in preventing VCD was shown for all four serotypes in baseline dengue seropositive subjects. In baseline seronegative subjects, VE was shown for DENV-1 and DENV-2, but not suggested for DENV-3 and could not be shown for DENV-4 due to lower incidence of cases (Table 5).

Table 5. Vaccine efficacy in preventing VCD fever and hospitalisation overall and by baseline dengue serostatus in yearly intervals 30 days post second dose in study DEN-301 (Per Protocol Set):

VE: vaccine efficacy, CI: confidence interval, VCD: virologically confirmed dengue, NP: not provided, N: total number of subjects in the per analysis set
^a number of subjects evaluated in each year is different.
^b Year 1 refers to 11 months starting 30 days after second dose.
^c Year 2 refers to 13 to 24 months after second dose.
^d Year 3 refers to 25 to 36 months after second dose.
^e Year 4 refers to 37 to 48 months after second dose.
^f VE estimate not provided since fewer than 6 cases, for both TDV and placebo, were observed.

Clinical efficacy for subjects from 17 years of age

No clinical efficacy study has been conducted in subjects from 17 years of age. The efficacy of Qdenga in subjects from 17 years of age is inferred from the clinical efficacy in 4 to 16 years of age by bridging of immunogenicity data (see below).

Immunogenicity

In the absence of correlates of protection for Dengue, the clinical relevance of immunogenicity data remains to be fully understood.

Immunogenicity data for subjects 4 to 16 years of age in endemic areas

The GMTs by baseline dengue serostatus in subjects 4 to 16 years of age in study DEN-301 are shown in Table 6.

Table 6. Immunogenicity by baseline dengue serostatus in study DEN-301 (Per Protocol Set for Immunogenicity)^a:

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: not estimated
^a The immunogenicity subset was a randomly selected subset of subjects, and the Per Protocol Set for Immunogenicity was the collection of subjects from that subset who also belong to the Per Protocol Set
^* For DENV-2 and DENV-3: N= 1815
^** All subjects had GMT values below LLOD (10), hence were reported as 5 with no CI values

Immunogenicity data for subjects 18 to 60 years of age in non-endemic areas

The immunogenicity of Qdenga in adults 18 to 60 years of age was assessed in DEN-304, a Phase 3 double-blind, randomized, placebo-controlled study in a non-endemic country (US). The post-dose 2 GMTs are shown in Table 7.

Table 7. GMTs of dengue neutralising antibodies in study DEN-304 (Per Protocol Set):

N: number of subjects evaluated; DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; NE: not estimated
^* Pooled data from Dengue tetravalent vaccine Lots 1, 2 and 3
^** All subjects had GMT values below LLOD (10), hence were reported as 5 with no CI values

The bridging of efficacy is based on immunogenicity data and results from a non-inferiority analysis, comparing post-vaccination GMTs in the baseline dengue seronegative populations of DEN-301 and DEN-304 (Table 8). Protection against dengue disease is expected in adults although the actual magnitude of efficacy relative to that observed in children and adolescents is unknown.

Table 8. GMT ratios between baseline dengue seronegative subjects in studies DEN-301 (4-16 years) and DEN-304 (18-60 years) (Per Protocol Set for Immunogenicity):

DENV: Dengue virus; GMT: Geometric Mean Titre; CI: confidence interval; m: month(s)
^* Non-inferiority: upper bound of the 95% CI less than 2.0.

Long-term persistence of antibodies

The long-term persistence of neutralising antibodies was shown in study DEN-301, with titres remaining well above the pre-vaccination levels for all four serotypes, up to 51 months after the first dose.