Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmaco-therapeutic group: rotavirus diarrhoea vaccines, ATC code: J07BH01 
Protective efficacy of the lyophilised formulation

In clinical trials, efficacy was demonstrated against gastro-enteritis due to rotavirus of the most common genotypes G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. In addition, efficacy against uncommon rotavirus genotypes G8P[4] (severe gastro-enteritis) and G12P[6] (any gastro-enteritis) has been demonstrated. These strains are circulating worldwide.

Clinical studies have been conducted in Europe, Latin America, Africa and Asia to evaluate the protective efficacy of Rotarix against any and severe rotavirus gastro-enteritis.

Severity of gastro-enteritis was defined according to two different criteria: - the Vesikari 20-point scale, which evaluates the full clinical picture of rotavirus gastro- enteritis by taking into account the severity and duration of diarrhoea and vomiting, the severity of fever and dehydration as well as the need for treatment or
- the clinical case definition based on World Health Organization (WHO) criteria 
Clinical protection was assessed in the ATP cohort for efficacy, which includes all subjects from the ATP cohort for safety who entered into the concerned efficacy follow-up period.

Protective efficacy in Europe

A clinical study performed in Europe evaluated Rotarix given according to different European schedules (2, 3 months; 2, 4 months; 3, 4 months; 3, 5 months) in 4,000 subjects.

After two doses of Rotarix, the protective vaccine efficacy observed during the first and second year of life is presented in the following table:

1st year of life                2nd year of life
Rotarix N=2,572                 Rotarix N=2,554
Placebo N=1,302                 Placebo N=1,294
Vaccine efficacy (%) against any and severe rotavirus gastro-enteritis [95% CI]
Genotype            Any severity Severe†            Any severity      Severe† G1P[8]              95.6             96.4           82.7              96.5 87.9;98.8      85.7;99.6    67.8;91.3       86.2;99.6 G2P[4]              62.0*            74.7*          57.1              89.9 <0.0;94.4      <0.0;99.6    <0.0;82.6       9.4;99.8 G3P[8]              89.9             100            79.7              83.1* 9.5;99.8       44.8;100     <0.0;98.1       <0.0;99.7 G4P[8]                  88.3             100              69.6*              87.3 57.5;97.9      64.9;100       <0.0;95.3        <0.0;99.7 G9P[8]                  75.6             94.7             70.5               76.8 51.1;88.5      77.9;99.4      50.7;82.8        50.8;89.7 Strains with P[8]       88.2             96.5             75.7               87.5 genotype                80.8;93.0      90.6;99.1      65.0;83.4        77.8;93.4 Circulating             87.1             95.8             71.9               85.6 rotavirus strains       79.6;92.1      89.6;98.7      61.2;79.8        75.8;91.9 Vaccine efficacy (%) against rotavirus gastro-enteritis requiring medical attention
[95% CI]
Circulating             91.8                              76.2 rotavirus strains       84;96.3                         63.0;85.0 Vaccine efficacy (%) against hospitalisation due to rotavirus gastro-enteritis [95% CI]
Circulating             100                               92.2 rotavirus strains       81.8;100                        65.6;99.1 †
Severe gastro-enteritis was defined as a score 11 on the Vesikari scale * Not statistically significant (p > 0.05). These data should be interpreted with caution 
Vaccine efficacy during the first year of life progressively increased with increasing disease severity, reaching 100% (95% CI: 84.7;100) for Vesikari scores 17.

Protective efficacy in Latin America

A clinical study performed in Latin America evaluated Rotarix in more than 20,000 subjects.
Severity of gastro-enteritis (GE) was defined according to WHO criteria. The protective vaccine efficacy against severe rotavirus (RV) gastro-enteritis requiring hospitalisation and/or rehydration therapy in a medical facility and the genotype specific vaccine efficacy after two doses of Rotarix are presented in the table below:


Genotype              Severe rotavirus gastro-           Severe rotavirus gastro- enteritis† (1st year of life)      enteritis† (2nd year of life)
Rotarix N=9,009                    Rotarix N=7,175
Placebo N=8,858                    Placebo N=7,062
Efficacy (%)                       Efficacy (%)
95% CI                           95% CI 
All RVGE              84.7                               79.0
71.7;92.4                        66.4;87.4
G1P[8]                91.8                               72.4
74.1;98.4                        34.5;89.9
G3P[8]                87.7                               71.9*
8.3;99.7                         <0.0;97.1
G4P[8]                50.8#*                             63.1
<0.0;99.2                        0.7;88.2
G9P[8]                90.6                               87.7
61.7;98.9                        72.9;95.3
Strains with P[8] 90.9                                   79.5 genotype              79.2;96.8                        67.0;87.9 † Severe rotavirus gastro-enteritis was defined as an episode of diarrhoea with or without vomiting that required hospitalization and/or re-hydration therapy in a medical facility (WHO criteria)
* Not statistically significant (p  0.05). These data should be interpreted with caution # The numbers of cases, on which the estimates of efficacy against G4P[8] were based, were very small (1 case in the Rotarix group and 2 cases in the placebo group) 


A pooled analysis of five efficacy studies* showed a 71.4% (95% CI: 20.1; 91.1) efficacy against severe rotavirus gastro-enteritis (Vesikari score 11) caused by rotavirus G2P[4] genotype during the first year of life.
* In these studies, the point estimates and confidence intervals were respectively: 100% (95% CI: -1,858.0;100), 100% (95% CI: 21.1;100), 45.4% (95% CI: -81.5;86.6), 74.7 (95% CI :- 386.2;99.6). No point estimate was available for the remaining study.

Protective efficacy in Africa

A clinical study performed in Africa (Rotarix: N = 2,974; placebo: N = 1,443) evaluated Rotarix given at approximately 10 and 14 weeks of age (2 doses) or 6, 10 and 14 weeks of age (3 doses). The vaccine efficacy against severe rotavirus gastro-enteritis during the first year of life was 61.2% (95% CI: 44.0;73.2). The protective vaccine efficacy (pooled doses) observed against any and severe rotavirus gastro-enteritis is presented in the following table: 

Genotype                 Any rotavirus gastro-enteritis       Severe rotavirus gastro- Rotarix N=2,974                      enteritis†
Placebo N=1,443                      Rotarix N=2,974
Placebo N=1,443
Efficacy (%)                          Efficacy (%)
95% CI                              95% CI
G1P[8]                  68.3                                  56.6
53.6;78.5                           11.8;78.8
G2P[4]                  49.3                                  83.8
4.6;73.0                            9.6;98.4
G3P[8]                  43.4*                                 51.5*
<0.0;83.7                           <0.0;96.5
G8P[4]                  38.7*                                 63.6
<0.0;67.8                           5.9;86.5
G9P[8]                  41.8*                                 56.9*
<0.0;72.3                           <0.0;85.5
G12P[6]                 48.0                                  55.5*
9.7;70.0                            <0.0; 82.2
Strains with P[4]       39.3                                  70.9 genotype                7.7;59.9                            37.5;87.0 Strains with P[6]       46.6                                  55.2* genotype                9.4;68.4                            <0.0;81.3 Strains with P[8]       61.0                                  59.1 genotype                47.3;71.2                           32.8;75.3 † Severe gastro-enteritis was defined as a score 11 on the Vesikari scale * Not statistically significant (p  0.05). These data should be interpreted with caution 
Sustained efficacy up to 3 years of age in Asia

A clinical study conducted in Asia (Hong Kong, Singapore and Taiwan) (Total vaccinated cohort: Rotarix: N = 5,359; placebo: N = 5,349) evaluated Rotarix given according to different schedules (2, 4 months of age; 3, 4 months of age).

During the first year, significantly fewer subjects in the Rotarix group reported severe rotavirus gastro-enteritis caused by the circulating wild-type RV compared to the placebo group from 2 weeks after Dose 2 up to one year of age (0.0% versus 0.3%), with a vaccine efficacy of 100% (95% CI: 72.2 ; 100).

The protective vaccine efficacy after two doses of Rotarix observed against severe rotavirus gastro-enteritis up to 2 years of age is presented in the following table: 
Efficacy up to 2 years of age
Rotarix N = 5,263
Placebo N = 5,256
Vaccine efficacy (%) against severe rotavirus gastro-enteritis (95% CI) Genotype                       Severe†
G1P[8]                         100 (80.8;100)
G2P[4]                         100* (<0.0;100)
G3P[8]                         94.5 (64.9;99.9)
G9P[8]                         91.7 (43.8;99.8)
Strains with P[8] genotype 95.8 (83.8;99.5)
Circulating rotavirus          96.1 (85.1;99.5) strains
Vaccine efficacy (%) against rotavirus gastro-enteritis requiring hospitalisation and/or rehydration therapy in a medical facility (95% CI) Circulating rotavirus          94.2 (82.2;98.8) strains
† Severe gastro-enteritis was defined as a score >11 on the Vesikari scale * Not statistically significant (p  0.05). These data should be interpreted with caution 
During the third year of life, there were no cases of severe RV gastro-enteritis in the Rotarix group (N = 4,222) versus 13 (0.3%) in the placebo group (N = 4,185). Vaccine efficacy was 100% (95% CI: 67.5 ; 100). The severe RV gastro-enteritis cases were due to RV strains G1P [8], G2P [4], G3P [8] and G9P [8]. The incidence of severe RV gastro-enteritis associated with the individual genotypes was too small to allow calculation of efficacy. The efficacy against severe RV gastro-enteritis requiring hospitalisation was 100% (95% CI: 72.4; 100).

Protective efficacy of the liquid formulation

Since the immune response observed after 2 doses of Rotarix liquid formulation was comparable to the immune response observed after 2 doses of Rotarix lyophilised formulation, the levels of vaccine efficacy observed with the lyophilised formulation can be extrapolated to the liquid formulation.

Immune response

The immunologic mechanism by which Rotarix protects against rotavirus gastro-enteritis is not completely understood. A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastro-enteritis has not been established.

The following table shows the percentage of subjects initially seronegative for rotavirus (IgA antibody titres < 20 U/ml) (by ELISA) with serum anti-rotavirus IgA antibody titers  20 U/ml one to two months after the second dose of vaccine or placebo as observed in different studies with Rotarix lyophilised formulation.

Schedule          Studies             Vaccine                       Placebo conducted in
N       %  20 U/ml           N        %  20 U/ml
95% CI                       95% CI
2, 3 months       France,             239     82.8                  127      8.7
Germany                     77.5;87.4                    4.4;15.0  2, 4 months       Spain               186     85.5                  89       12.4
79.6;90.2                    6.3;21.0
3, 5 months       Finland, Italy      180     94.4                  114      3.5 90.0;97.3                    1.0;8.7
3, 4 months       Czech               182     84.6                  90       2.2 Republic                    78.5;89.5                    0.3;7.8  2, 3 to 4         Latin               393     77.9%                 341      15.1% months            America; 11                 73.8;81.6                    11.7;19.0 countries
10, 14 weeks      South Africa,       221     58.4                  111      22.5 and 6, 10, 14     Malawi                      [51.6;64.9]                    [15.1;31.4] weeks
(Pooled)

In three comparative controlled trials, the immune response elicited by Rotarix liquid formulation was comparable to the one elicited by Rotarix lyophilised formulation.

Immune response in preterm infants

In a clinical study conducted in preterm infants, born after at least 27 weeks of gestational age, the immunogenicity of Rotarix was assessed in a subset of 147 subjects and showed that Rotarix is immunogenic in this population; 85.7% (95% CI: 79.0; 90.9) of subjects achieved serum anti-rotavirus IgA antibody titers  20 U/ml (by ELISA) one month after the second dose of vaccine.


Effectiveness
In observational studies, vaccine effectiveness was demonstrated against severe gastro- enteritis leading to hospitalisation due to rotavirus of common genotypes G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8] as well as the less common rotavirus genotypes G9P[4] and G9P[6]. All of these strains are circulating worldwide.


Effectiveness after 2 doses in preventing RVGE leading to hospitalization 
Countries                Age range                N (1)           Strains   Effectiveness Period                                     (cases/controls)                 % [95% CI] High Income countries
Belgium                    < 4 yrs             160/198              All       90 [81;95] 2008-2010(2)                3-11 m                                            91 [75;97]
< 4 yrs               41/53            G1P[8]      95 [78;99]
< 4 yrs              80/103            G2P[4]      85 [64;94]
3-11 m                                          83 [11;96] (3)
< 4 yrs               12/13            G3P[8]    87* [<0;98](3)
< 4 yrs               16/17            G4P[8]    90 [19;99] (3)
Singapore                  < 5 yrs             136/272             All        84 [32;96] 2008-2010(2)                                     89/89            G1P[8]      91 [30;99]
Taiwan                     < 3 yrs           275/1,623(4)          All        92 [75;98] 2009-2011                                                         G1P[8]     95 [69;100]
US                         < 2 yrs                85/1,062(5)      All        85 [73;92] 2010-2011                                                         G1P[8]      88 [68;95]
G2P[4]      88 [68;95]
8-11 m                                  All        89 [48;98]
US                         < 5 yrs                 74/255(4)      G3P[8]      68 [34;85] 2009-2011
Middle Income Countries
Bolivia                    < 3 yrs           300/974                All     77 [65;84](6) 2010-2011                  6-11 m                                            77 [51;89]
< 3 yrs                                G9P[8]     85 [69;93]
6-11 m                                            90 [65;97]
< 3 yrs                                G3P[8]     93 [70;98]
G2P[4]     69 [14;89]
G9P[6]     87 [19;98]
Brazil                     < 2 yrs                115/1,481        All      72 [44;85](6) 2008-2011                                                         G1P[8]     89 [78;95]
G2P[4]     76 [64;84]
(5)
Brazil                     < 3 yrs               249/249           All       76 [58;86] 2008-2009(2)               3-11 m                                            96 [68;99]

< 3 yrs               222/222 (5)         G2P[4]        75 [57;86]
3-11 m                                                 95 [66;99] (3) El Salvador                < 2 yrs               251/770 (5)           All         76 [64;84](6) 2007-2009                  6-11 m                                                   83 [68;91]
Guatemala                  < 4 yrs                  NA(7)              All          63 [23;82] 2012-2013
Mexico                     < 2 yrs                  9/17(5)          G9P[4]        94 [16;100] 2010
Low Income Countries
Malawi                     < 2 yrs              81/234(5)              All          63 [23;83] 2012-2014 m: months yrs: years
* Not statistically significant (P ≥ 0.05). These data should be interpreted with caution.
(1) The number of fully vaccinated (2 doses) and unvaccinated cases and controls is given.
(2) GSK sponsored studies
(3) Data from a post-hoc analysis
(4) Vaccine effectiveness was calculated using rotavirus-negative hospital control participants (estimates from Taiwan were calculated using combined rotavirus-negative hospital control and non-diarrhoea hospital control participants).
(5) Vaccine effectiveness was calculated using neighborhood controls.
(6) In subjects who did not receive the full course of vaccination, the effectiveness after one dose ranged from 51% (95% CI: 26;67, El Salvador) to 60% (95% CI: 37; 75, Brazil).
(7) NA: Not available. Vaccine effectiveness estimate is based on 41 fully vaccinated cases and 175 fully vaccinated controls.


Impact on mortality§
Impact studies with Rotarix conducted in Panama, Brazil and Mexico showed a decrease in all cause diarrhoea mortality ranging from 17% to 73% in children less than 5 years of age, within 2 to 4 years after vaccine introduction.

Impact on hospitalisation§
In a retrospective database study in Belgium conducted in children 5 years of age and younger, the direct and indirect impact of Rotarix vaccination on rotavirus-related hospitalisation ranged from 64% (95% CI: 49;76) to 80% (95% CI: 77;83) two years after vaccine introduction. Similar studies in Armenia, Australia,Brazil, Canada El Salvador and Zambia showed a reduction of 45 to 93% between 2 and 4 years after vaccine introduction.

In addition, nine impact studies on all cause diarrhoea hospitalisation conducted in Africa and Latin America showed a reduction of 14% to 57% between 2 and 5 years after vaccine introduction.
§
NOTE: Impact studies are meant to establish a temporal relationship but not a causal relationship between the disease and vaccination. Natural fluctuations of the incidence of the disease may also influence the observed temporal effect.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Not applicable.