Dengvaxia

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 local replication and induction of a humoral and cellular immune response against the four dengue virus serotypes. Clinical efficacy The clinical efficacy of Qdenga was evaluated in DEN-301, a pivotal, double-blind, randomised, placebo-controlled phase 3 study conducted in 5 countries in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua, Panama) and 3 countries in Asia (Sri Lanka, Thailand, Philippines). A total of 20,099 children aged 4 to 16 years were randomised (2:1 ratio) to receive either Qdenga or placebo, regardless of prior dengue virus infection. Efficacy was evaluated through active surveillance throughout the study. Subjects with febrile illness (defined as fever ≥ 38 °C on any 2 of 3 consecutive days) were required to attend the study site for assessment of dengue fever by the investigator. Subjects/caregivers were reminded of this requirement at least once weekly to maximise detection of all symptomatic virologically-confirmed dengue (VCD) cases. Febrile episodes were confirmed by a validated quantitative dengue reverse transcription–polymerase chain reaction (RT-PCR) assay for detection of specific dengue virus serotypes. Clinical efficacy data in subjects aged 4 to 16 years Vaccine efficacy (VE) results for the primary endpoint (VCD fever occurring from 30 days to 12 months after the second vaccine dose) are presented in Table 2. The mean age of the per-protocol study population was 9.6 years (standard deviation 3.5 years), with 12.7% of subjects aged 4–5 years, 55.2% aged 6–11 years, and 32.1% aged 12–16 years. Of these, 46.5% were in Asia and 53.5% in Latin America; 49.5% were female and 50.5% male. Baseline dengue serostatus (before the first injection) was assessed in all subjects by microneutralisation assay (MNT50) to allow evaluation of VE by baseline serostatus. The baseline dengue seronegativity rate in 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 after the second dose in DEN-301 (per-protocol set)ᵃ Qdenga n = 12,700ᵇ; Placebo n = 6,316ᵇ VCD fever, n (%): 61 (0.5) vs 149 (2.4) Vaccine efficacy (95% CI) (%): 80.2 (73.3; 85.3) p-value < 0.001 CI: confidence interval; n: number of subjects with fever; VCD: virologically-confirmed dengue ᵃ The primary efficacy analysis was based on the per-protocol set, which included all randomised subjects who did not have any major protocol deviations, including failure to receive both doses of the correctly assigned Qdenga or placebo. ᵇ Number of subjects evaluated VE results for secondary endpoints—prevention of hospitalisation due to VCD fever, prevention of VCD fever by serostatus, by serotype, and prevention of severe VCD cases—are presented in Table 3. Two types of endpoints were considered for severe VCD cases: clinically severe VCD cases and VCD cases meeting the 1997 WHO criteria for dengue haemorrhagic fever (DHF). The criteria used in the DEN-301 trial for assessment of VCD severity by an independent Dengue Case severity Adjudication Committee (DCAC) were based on the 2009 WHO guidelines. The DCAC adjudicated all VCD hospitalisation cases against predefined criteria including assessment of bleeding abnormalities, plasma leakage, hepatic function, renal function, cardiac function, central nervous system involvement, and shock. In the DEN-301 trial, VCD cases meeting the 1997 WHO criteria for DHF were identified by a programmed algorithm, i.e. without application of clinical judgement. Broadly, the criteria included the 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 fever from 30 days to 18 months after the second injection in DEN-301 (per-protocol set) Qdenga n = 12,700ᵃ; Placebo n = 6,316ᵃ; VE (95% CI) VE in preventing hospitalisations for VCD feverᵇ, n (%): VCD-related hospitalisationᶜ 13 (0.1) vs 66 (1.0); 90.4 (82.6; 94.7)ᵈ VE in preventing VCD fever by dengue serotype, n (%): VCD caused by DENV-1: 38 (0.3) vs 62 (1.0); 69.8 (54.8; 79.9) VCD caused by DENV-2: 8 (< 0.1) vs 80 (1.3); 95.1 (89.9; 97.6) VCD caused by DENV-3: 63 (0.5) vs 60 (0.9); 48.9 (27.2; 64.1) VCD caused by DENV-4: 5 (< 0.1) vs 5 (< 0.1); 51.0 (-69.4; 85.8) VE in preventing VCD fever by baseline dengue serostatus, n (%): VCD in all subjects: 114 (0.9) vs 206 (3.3); 73.3 (66.5; 78.8) VCD in baseline seropositive subjects: 75 (0.8) vs 150 (3.3); 76.1 (68.5; 81.9) VCD in baseline seronegative subjects: 39 (1.1) vs 56 (3.2); 66.2 (49.1; 77.5) VE in preventing DHF caused by any dengue serotype, n (%): Overall: 2 (< 0.1) vs 7 (0.1); 85.9 (31.9; 97.1) VE in preventing severe dengue fever caused by any dengue serotype, n (%): Overall: 2 (< 0.1) vs 1 (< 0.1); 2.3 (-977.5; 91.1) 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 observed cases were caused by DENV-2 (0 cases in the Qdenga arm and 46 cases in the placebo arm) ᵈ p-value < 0.001 Early onset of protection was observed in an exploratory VE of 81.1% (95% CI: 64.1%; 90.0%) against VCD fever caused by any serotype, pooled from the first to the second injection. Long-term protection In DEN-301, a series of exploratory analyses were performed to estimate long-term protection from the first dose to 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 the first dose to 54 months after the second dose in DEN-301 (safety set) Qdenga n/N; Placebo n/N; VE (95% CI) for prevention of VCD feverᵃ; Qdenga n/N; Placebo n/N; VE (95% CI) for prevention of hospitalisation for VCD feverᵃ Overall: 442/13,380; 547/6,687; 61.2 (56.0; 65.8); 46/13,380; 142/6,687; 84.1 (77.8; 88.6) Baseline seronegative, N = 5,546 Any serotype: 147/3,714; 153/1,832; 53.5 (41.6; 62.9); 17/3,714; 41/1,832; 79.3 (63.5; 88.2) DENV-1: 89/3,714; 79/1,832; 45.4 (26.1; 59.7); 6/3,714; 14/1,832; 78.4 (43.9; 91.7) DENV-2: 14/3,714; 58/1,832; 88.1 (78.6; 93.3); 0/3,714; 23/1,832; 100 (88.5; 100)ᵇ DENV-3: 36/3,714; 16/1,832; -15.5 (-108.2; 35.9); 11/3,714; 3/1,832; -87.9 (-573.4; 47.6) DENV-4: 12/3,714; 3/1,832; -105.6 (-628.7; 42.0); 0/3,714; 1/1,832; NRᶜ Baseline seropositive, N = 14,517 Any serotype: 295/9,663; 394/4,854; 64.2 (58.4; 69.2); 29/9,663; 101/4,854; 85.9 (78.7; 90.7) DENV-1: 133/9,663; 151/4,854; 56.1 (44.6; 65.2); 16/9,663; 24/4,854; 66.8 (37.4; 82.3) DENV-2: 54/9,663; 135/4,854; 80.4 (73.1; 85.7); 5/9,663; 59/4,854; 95.8 (89.6; 98.3) DENV-3: 96/9,663; 97/4,854; 52.3 (36.7; 64.0); 8/9,663; 15/4,854; 74.0 (38.6; 89.0) DENV-4: 12/9,663; 20/4,854; 70.6 (39.9; 85.6); 0/9,663; 3/4,854; NRᶜ VE: vaccine efficacy; CI: confidence interval; VCD: virologically-confirmed dengue; n: number of subjects; N: number of subjects evaluated; NR: not reported ᵃ Exploratory analyses; the study was not powered or designed to demonstrate a difference between the vaccine and placebo groups ᵇ Estimated using one-sided 95% CI ᶜ VE estimate not reported because fewer than 6 cases were observed in both TDV and placebo In addition, VE in preventing DHF caused by any serotype was 70.0% (95% CI: 31.5%; 86.9%) and VE in preventing clinically severe VCD cases caused by any serotype was 70.2% (95% CI: -24.7%; 92.9%). VE in preventing VCD was demonstrated for all four serotypes in subjects with baseline dengue seropositivity. In subjects with baseline seronegativity, VE was demonstrated for DENV-1 and DENV-2 but was not suggested for DENV-3 and could not be demonstrated for DENV-4 owing to the lower number of cases (Table 4). A year-by-year analysis was performed up to four and a half years after the second dose (Table 5). Table 5: Vaccine efficacy in preventing VCD fever and hospitalisation overall and by baseline dengue serostatus at yearly intervals from 30 days after the second dose in DEN-301 (per-protocol set) VE (95% CI) for prevention of VCD fever, nᵃ = 19,021; VE (95% CI) for prevention of hospitalisation due to VCD fever, nᵃ = 19,021 Year 1ᵇ Overall: 80.2 (73.3; 85.3); 95.4 (88.4; 98.2) By baseline dengue serostatus — Seropositive: 82.2 (74.5; 87.6); 94.4 (84.4; 98.0). Seronegative: 74.9 (57.0; 85.4); 97.2 (79.1; 99.6) Year 2ᶜ Overall: 56.2 (42.3; 66.8); 76.2 (50.8; 88.4) Seropositive: 60.3 (44.7; 71.5); 85.2 (59.6; 94.6). Seronegative: 45.3 (9.9; 66.8); 51.4 (-50.7; 84.3) Year 3ᵈ Overall: 45.0 (32.9; 55.0); 70.8 (49.6; 83.0) Seropositive: 48.7 (34.8; 59.6); 78.4 (57.1; 89.1). Seronegative: 35.5 (7.4; 55.1); 45.0 (-42.6; 78.8) Year 4ᵉ Overall: 62.8 (41.4; 76.4); 96.4 (72.2; 99.5) Seropositive: 64.1 (37.4; 79.4); 94.0 (52.2; 99.3). Seronegative: 60.2 (11.1; 82.1); NR VE: vaccine efficacy; CI: confidence interval; VCD: virologically-confirmed dengue; NR: not reported; n: total number of subjects in a given analysis set ᵃ The number of subjects evaluated each year differs. ᵇ Year 1 covers 11 months beginning 30 days after the second dose. ᶜ Year 2 covers 13 to 24 months after the second dose. ᵈ Year 3 covers 25 to 36 months after the second dose. ᵉ Year 4 covers 37 to 48 months after the second dose. ᶠ VE estimate not reported because fewer than 6 cases were observed in both TDV and placebo. Clinical efficacy in subjects aged 17 years and older No clinical efficacy study has been conducted in subjects aged 17 years and older. The efficacy of Qdenga in subjects aged 17 years and older is inferred from clinical efficacy in subjects aged 4 to 16 years using bridging immunogenicity data (see below). Immunogenicity In the absence of an immunological correlate of protection against dengue virus, the clinical relevance of immunogenicity data is not yet fully established. Immunogenicity data in subjects aged 4 to 16 years in endemic areas Geometric mean titre (GMT) values by baseline dengue serostatus in subjects aged 4 to 16 years in DEN-301 are presented in Table 6. Table 6: Immunogenicity by baseline dengue serostatus in DEN-301 (per-protocol immunogenicity set)ᵃ Baseline seropositive — Pre-vaccination n = 1,816*; 1 month post dose 2 n = 1,621 Baseline seronegative — Pre-vaccination n = 702; 1 month post dose 2 n = 641 DENV-1: GMT 411.3 / 2,115.2 / 5.0 / 184.2; 95% CI (366.0; 462.2) / (1,957.0; 2,286.3) / NE** / (168.6; 201.3) DENV-2: GMT 753.1 / 4,897.4 / 5.0 / 1,729.9; 95% CI (681.0; 832.8) / (4,645.8; 5,162.5) / NE** / (1,613.7; 1,854.6) DENV-3: GMT 357.7 / 1,761.0 / 5.0 / 228.0; 95% CI (321.3; 398.3) / (1,645.9; 1,884.1) / NE** / (211.6; 245.7) DENV-4: GMT 218.4 / 1,129.4 / 5.0 / 143.9; 95% CI (198.1; 240.8) / (1,066.3; 1,196.2) / NE** / (133.6; 155.1) n: number of subjects evaluated; DENV: dengue virus; GMT: geometric mean titre; CI: confidence interval; NE: not estimated ᵃ The immunogenicity subgroup was a randomly selected subset of subjects, and the per-protocol immunogenicity set comprised subjects from this subgroup who also belonged to the per-protocol set. * For DENV-2 and DENV-3: n = 1,815 ** All subjects had GMT values below the lower limit of detection (LLOD) (10) and were therefore reported as 5 without CI values Immunogenicity data in subjects aged 18 to 60 years in non-endemic areas The immunogenicity of Qdenga in adults aged 18 to 60 years was evaluated in DEN-304, a double-blind, randomised, placebo-controlled phase 3 study conducted in a non-endemic country (USA). GMT values after the second dose are presented in Table 7. Table 7: GMTs for dengue virus neutralising antibodies in DEN-304 (per-protocol set) Baseline seropositive* — Pre-vaccination n = 68; 1 month post dose 2 n = 67 Baseline seronegative* — Pre-vaccination n = 379; 1 month post dose 2 n = 367 DENV-1: GMT 13.9 / 365.1 / 5.0 / 268.1; 95% CI (9.5; 20.4) / (233.0; 572.1) / NE** / (226.3; 317.8) DENV-2: GMT 31.8 / 3,098.0 / 5.0 / 2,956.9; 95% CI (22.5; 44.8) / (2,233.4; 4,297.2) / NE** / (2,635.9; 3,316.9) DENV-3: GMT 7.4 / 185.7 / 5.0 / 128.9; 95% CI (5.7; 9.6) / (129.0; 267.1) / NE** / (112.4; 147.8) DENV-4: GMT 7.4 / 229.6 / 5.0 / 137.4; 95% CI (5.5; 9.9) / (150.0; 351.3) / NE** / (121.9; 155.0) n: number of subjects evaluated; DENV: dengue virus; GMT: geometric mean titre; CI: confidence interval; NE: not estimated * Pooled data for lots 1, 2, and 3 of the tetravalent dengue vaccine ** All subjects had GMT values below the LLOD (10) and were therefore reported as 5 without CI values Bridging of efficacy is based on immunogenicity data and the results of a non-inferiority analysis comparing post-vaccination GMTs in baseline dengue seronegative populations from DEN-301 and DEN-304 (Table 8). Protection against dengue disease is expected in adults, although the actual extent of efficacy relative to that observed in children and adolescents is not known. Table 8: GMT ratios between baseline dengue seronegative subjects in DEN-301 (4–16 years) and DEN-304 (18–60 years) (per-protocol immunogenicity set) GMT ratio* (95% CI) 1 month post dose 2: DENV-1 0.69 (0.58; 0.82); DENV-2 0.59 (0.52; 0.66); DENV-3 1.77 (1.53; 2.04); DENV-4 1.05 (0.92; 1.20) 6 months post dose 2: DENV-1 0.62 (0.51; 0.76); DENV-2 0.66 (0.57; 0.76); DENV-3 0.98 (0.84; 1.14); DENV-4 1.01 (0.86; 1.18) DENV: dengue virus; GMT: geometric mean titre; CI: confidence interval; m: month(s) * Non-inferiority: upper limit of the 95% CI below 2.0. Long-term antibody persistence Long-term persistence of neutralising antibodies was demonstrated in DEN-301, with titres remaining above pre-vaccination levels for all four serotypes up to 51 months after the first dose. Concomitant administration with HPV vaccine In DEN-308, involving approximately 300 patients aged 9 to 14 years who received Qdenga concomitantly with the 9-valent HPV vaccine, no effect on the immune response to the HPV vaccine was observed. The study examined only concomitant administration of the first doses of Qdenga and the 9-valent HPV vaccine. Non-inferiority of the immune response to Qdenga when co-administered with the 9-valent HPV vaccine was not directly assessed in the study. In the study population seronegative for dengue virus, antibody formation against dengue fever following concomitant administration was of the same magnitude as observed in the phase 3 study (DEN-301), which demonstrated efficacy against VCD and VCD leading to hospitalisation.