Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
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, 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 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
Qdenga                  Placebo
N = 12,700b              N = 6316b
VCD fever, n (%)                                                       61 (0.5)                        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 analysis of efficacy data were based on the Per Protocol Set, which consisted of all randomised 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) Qdenga     Placebo
VE (95% CI)
N=12,700   a
N=6316a
VE in preventing hospitalisations due to VCD feverb, n (%)
Hospitalisations due to VCD feverc                   13 (0.1)   66 (1.0)    90.4 (82.6, 94.7)d VE in preventing VCD fever by dengue serotype, n (%)
VCD fever caused by DENV-1                           38 (0.3)   62 (1.0)    69.8 (54.8, 79.9) VCD fever caused by DENV-2                           8 (<0.1)   80 (1.3)    95.1 (89.9, 97.6) VCD fever caused by DENV-3                           63 (0.5)   60 (0.9)    48.9 (27.2, 64.1) VCD fever caused by DENV-4                       5 (<0.1)     5 (<0.1)                             51.0 (-69.4, 85.8) VE in preventing VCD fever by baseline dengue serostatus, n (%)
VCD fever in all subjects                       114 (0.9)     206 (3.3)                             73.3 (66.5, 78.8) VCD fever in baseline seropositive subjects                       75 (0.8)         150 (3.3)        76.1 (68.5, 81.9) VCD fever in baseline seronegative subjects                       39 (1.1)          56 (3.2)        66.2 (49.1, 77.5) VE in preventing DHF induced by any dengue serotype, n (%)
Overall                                        2 (<0.1)                             7 (0.1)         85.9 (31.9, 97.1) VE in preventing severe dengue induced by any dengue serotype, n (%)
Overall                                          2 (<0.1)    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 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 (95% CI) in                            VE (95% CI) in
Qdenga       Placebo    preventing VCD      Qdenga      Placebo preventing n/N         n/N            Fevera           n/N        n/N      Hospitalisation due to VCD Fevera
Overall    442/13380 547/6687        61.2 (56.0, 65.8)  46/13380 142/6687 84.1 (77.8, 88.6) Baseline Seronegative, N=5,546
Any         147/3714 153/1832        53.5 (41.6, 62.9)   17/3714 41/1832       79.3 (63.5, 88.2) serotype
DENV-1       89/3714     79/1832     45.4 (26.1, 59.7)    6/3714 14/1832       78.4 (43.9, 91.7) DENV-2       14/3714     58/1832     88.1 (78.6, 93.3)    0/3714 23/1832       100 (88.5, 100)b DENV-3                                     -15.5
36/3714     16/1832                         11/3714 3/1832        -87.9 (-573.4, 47.6) (-108.2, 35.9)
DENV-4                                    -105.6
12/3714      3/1832                          0/3714 1/1832        NPc (-628.7, 42.0)
Baseline Seropositive, N=14,517
Any         295/9663 394/4854        64.2 (58.4,69.2)    29/9663 101/4854 85.9 (78.7, 90.7) serotype
DENV-1      133/9663 151/4854        56.1 (44.6, 65.2)   16/9663 24/4854       66.8 (37.4, 82.3) DENV-2       54/9663 135/4854        80.4 (73.1, 85.7)    5/9663   59/4854     95.8 (89.6, 98.3) DENV-3          96/9663        97/4854         52.3 (36.7, 64.0)         8/9663      15/4854         74.0 (38.6, 89.0) DENV-4          12/9663        20/4854         70.6 (39.9, 85.6)         0/9663      3/4854          NPc 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%).

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 4).

A year-by-year analysis until four and a half years after the second dose was conducted (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 (95% CI) in preventing
VE (95% CI) in        Hospitalisation due preventing VCD Fever         to VCD Fever
N = 19,021 a
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) By baseline dengue serostatus
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) By baseline dengue serostatus
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) By baseline dengue serostatus
Seropositive                               64.1 (37.4, 79.4)               94.0 (52.2, 99.3) Seronegative                               60.2 (11.1, 82.1)                     NPf 
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 Geometric Mean Titres (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
Baseline Seropositive                    Baseline Seronegative
1 month                                  1 month
Pre-Vaccination        Post-Dose 2        Pre-Vaccination       Post-Dose 2 N=1816*               N=1621                N=702               N=641 DENV-1
GMT            411.3                2115.2                5.0                 184.2 95% CI       (366.0, 462.2)      (1957.0, 2286.3)          NE**            (168.6, 201.3) DENV-2
GMT            753.1                4897.4                5.0                1729.9 95% CI       (681.0, 832.8)      (4645.8, 5162.5)          NE**           (1613.7, 1854.6) DENV-3
GMT            357.7                1761.0                5.0                 228.0 95% CI       (321.3, 398.3)      (1645.9, 1884.1)          NE**            (211.6, 245.7) DENV-4
GMT            218.4                1129.4                5.0                 143.9 95% CI       (198.1, 240.8)      (1066.3, 1196.2)          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 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) Baseline Seropositive*                               Baseline Seronegative* 1 month                                             1 month
Pre-Vaccination               Post-Dose 2            Pre-Vaccination              Post-Dose 2 N=68                        N=67                    N=379                      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                     3098.0                        5.0                   2956.9 95% CI              (22.5, 44.8)            (2233.4, 4297.2)                 NE**               (2635.9, 3316.9) 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 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) GMT Ratio*               DENV-1                  DENV-2                DENV-3              DENV-4 (95% CI)
1m post-2nd dose         0.69 (0.58, 0.82)       0.59 (0.52, 0.66)     1.77 (1.53, 2.04)   1.05 (0.92, 1.20) 6m post-2nd dose         0.62 (0.51, 0.76)       0.66 (0.57, 0.76)     0.98 (0.84, 1.14)   1.01 (0.86, 1.18) 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.

Co-administration with HPV

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.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

No pharmacokinetic studies have been performed with Qdenga.