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Pharmacology: Pharmacodynamics: 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: (See Table 1.)
Click on icon to see table/diagram/imageVaccine 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 as follows: (See Table 2.)
Click on icon to see table/diagram/imageA 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: -1858.0; 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: (See Table 3.)
Click on icon to see table/diagram/imageSustained 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 Table 4. (See Table 4.)
Click on icon to see table/diagram/imageDuring 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; 100.0).
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. (See Table 5.)
Click on icon to see table/diagram/imageIn 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;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 hospitalisation: (See Table 6.)
Click on icon to see table/diagram/imageImpact 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 youngers, 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.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
