Qdenga Mechanism of Action

Pharmacotherapeutic group: Vaccines, Viral vaccines. ATC code: J07BX04.
Pharmacology: Pharmacodynamics: 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, randomised, 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 randomised (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 maximise 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 1. 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%. (See Table 1.)

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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 2. 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. (See Table 2.)

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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 3). (See Table 3.)

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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%).
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 3).
A year-by-year analysis until four and a half years after the second dose was conducted (Table 4). (See Table 4.)

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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 as follows).
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 Geometric Mean Titres GMTs by baseline dengue serostatus in subjects 4 to 16 years of age in study DEN-301 are shown in Table 5. (See Table 5.)

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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 6. (See Table 6.)

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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 7). Protection against dengue disease is expected in adults although the actual magnitude of efficacy relative to that observed in children and adolescents is unknown. (See Table 7.)

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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.
Co-administration with HPV vaccine: In study DEN-308 involving approximately 300 subjects aged 9 to 14 years who received Qdenga concomitantly with a 9-valent HPV vaccine, there was no effect on the immune response to the HPV vaccine. The study only tested co-administration of the first doses of Qdenga and the 9-valent HPV vaccine. Non-inferiority of the Qdenga immune response, when Qdenga and the 9-valent HPV vaccine were co-administered, has not been directly assessed in the study. In the dengue seronegative study population, dengue antibody responses after co-administration were in the same range as those observed in the Phase 3 study (DEN-301) where efficacy against VCD and hospitalised VCD was shown.
Pharmacokinetics: No pharmacokinetic studies have been performed with Qdenga.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special hazard for humans based on conventional studies of single dose, local tolerance, repeated dose toxicity, and toxicity to reproduction and development. In a distribution and shedding study, there was no shedding of Qdenga RNA in faeces and urine, confirming a low risk for vaccine shedding to the environment or transmission from vaccinees. A neurovirulence study shows that Qdenga is not neurotoxic.
Although no relevant hazard was identified, the relevance of the reproductive toxicity studies is limited, since rabbits are not permissive for dengue virus infection.