General Information

Rotarix is a live, attenuated rotavirus vaccine derived from the human 89-12 strain, which belongs to G1P[8] type. Rotarix replicates in the small intestine and induces immunity. The exact immunologic mechanism by which Rotarix protects against rotavirus gastroenteritis is unknown.

Rotarix is specifically indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4 and G9) when administered as a two-dose series in infants and children.

Mechanism of Action

Rotarix is a live, attenuated rotavirus vaccine derived from the human 89-12 strain, which belongs to G1P[8] type. The rotavirus strain is propagated on Vero cells. After reconstitution, the final formulation (1 mL) contains at least 106.0 median Cell Culture Infective Dose (CCID50) of live, attenuated rotavirus. The exact immunologic mechanism by which Rotarix protects against rotavirus gastroenteritis is unknown.

Side Effects

Adverse events associated with the use of Rotarix may include, but are not limited to, the following:

• fussiness/irritability
• cough/runny nose/fever
• loss of appetite
• loss of appetite
• diarrhea
• dehydration
• gastroenteritis

Dosing/Administration

Rotarix is supplied as a vial of lyophilized vaccine to be reconstituted with a liquid diluent designed for oral administration. The vaccination series consists of two 1-mL doses administered orally. It is recommended that the first dose be administered to infants beginning at 6 weeks of age. There should be an interval of at least 4 weeks between the first and second dose. The two-dose series should be completed by 24 weeks of age.

Clinical Trial Results

FDA Approval was based on the results of four clinical trials.

Efficacy Evaluation of Rotarix through One Rotavirus Season
This randomized, double-blind, placebo-controlled study enrolled 3,994 infants in Europe. Vaccine or placebo was given to healthy infants as a two-dose series, with the first dose administered orally from 6 through 14 weeks of age followed by one additional dose administered at least four weeks after the first dose. The two-dose series was completed by 24 weeks of age. The primary efficacy endpoint was prevention of any grade of severity rotavirus gastroenteritis caused by naturally occurring rotavirus from two weeks after the second dose through one rotavirus season. Other efficacy evaluations included prevention of severe rotavirus gastroenteritis, as defined by the Vesikari scale, and reductions in hospitalizations due to rotavirus gastroenteritis and all cause gastroenteritis regardless of presumed etiology. Analyses were also done to evaluate the efficacy of Rotarix against rotavirus gastroenteritis among infants who received at least one vaccination (total vaccinated cohort, TVC). Efficacy of Rotarix against any grade of severity of rotavirus gastroenteritis through one rotavirus season was 87.1 percent (95 percent CI: 79.6, 92.1); TVC efficacy was 87.3 percent (95 percent CI: 80.3, 92.0). Efficacy against severe rotavirus gastroenteritis through one rotavirus season was 95.8 percent (95 percent CI: 89.6, 98.7); TVC efficacy was 96.0 percent (95 percent CI: 90.2, 98.8). The protective effect of Rotarix against any grade of severity of rotavirus gastroenteritis observed immediately following dose 1 administration and prior to dose 2 was 89.8 percent (95 percent CI: 8.9, 99.8). Efficacy of Rotarix in reducing hospitalizations for rotavirus gastroenteritis through one rotavirus season was 100 percent (95 percent CI: 81.8, 100); TVC efficacy was 100 percent (95 percent CI: 81.7, 100). Rotarix reduced hospitalizations for all cause gastroenteritis regardless of presumed etiology by 74.7 percent (95 percent CI: 45.5, 88.9).

Efficacy Evaluation of Rotarix through One Year
This randomized, double-blind, placebo-controlled study enrolled 63,225 infants in Latin America and Finland. Vaccine or placebo was given to healthy infants as a two-dose series with the first dose administered orally from 6 through 13 weeks of age followed by one additional dose administered at least four weeks after the first dose. The two-dose series was completed by 24 weeks of age. The primary efficacy endpoint was prevention of severe rotavirus gastroenteritis caused by naturally occurring rotavirus from two weeks after the second dose through one year (ATP). Analyses were done to evaluate the efficacy of Rotarix against severe rotavirus gastroenteritis among infants who received at least one vaccination (TVC). Reduction in hospitalizations due to rotavirus gastroenteritis was also evaluated (ATP). Efficacy of Rotarix against severe rotavirus gastroenteritis through one year was 84.7 percent (95 percent CI: 71.7, 92.4); TVC efficacy was 81.1 percent (95 percent CI: 68.5, 89.3). Efficacy of Rotarix in reducing hospitalizations for rotavirus gastroenteritis through one year was 85.0 percent (95 percent CI: 69.6, 93.5); TVC efficacy was 80.8 percent (95 percent CI: 65.7, 90.0).

Efficacy through Two Rotavirus Seasons
The efficacy of Rotarix persisting through two rotavirus seasons was evaluated in two studies.
European Study
The efficacy of Rotarix against any grade of severity of rotavirus gastroenteritis through two rotavirus seasons was 78.9 percent (95 percent CI: 72.7, 83.8). Efficacy in preventing any grade of severity of rotavirus gastroenteritis cases occurring only during the second season post-vaccination was 71.9 percent (95 percent CI: 61.2, 79.8). The efficacy of Rotarix against severe rotavirus gastroenteritis through two rotavirus seasons was 90.4 percent (95 percent CI: 85.1, 94.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second season post-vaccination was 85.6 percent (95 percent CI: 75.8, 91.9). The efficacy of Rotarix in reducing hospitalizations for rotavirus gastroenteritis through two rotavirus seasons was 96.0 percent (95 percent CI: 83.8, 99.5).
Latin American Study
The efficacy of Rotarix against severe rotavirus gastroenteritis through two years was 80.5 percent (95 percent CI: 71.3, 87.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second-year, post-vaccination was 79.0 percent (95 percent CI: 66.4, 87.4). The efficacy of Rotarix in reducing hospitalizations for rotavirus gastroenteritis through two years was 83.0 percent (95 percent CI: 73.1, 89.7).

Efficacy Against Specific Rotavirus Types
The type-specific efficacy against any grade of severity and severe rotavirus gastroenteritis caused by G1P[8], G3P[8], G4P[8], G9P[8], and combined non-G1 (G2, G3, G4, G9) types was statistically significant through one year. Additionally, type-specific efficacy against any grade of severity and severe rotavirus gastroenteritis caused by G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and combined non-G1 (G2, G3, G4, G9) types was statistically significant through two years.

Ongoing Study Commitments

• GlaxoSmithKline has agreed to a large-scale observational post-licensure safety study in the U.S to assess the potential serious risk of intussusception and other serious adverse effects (specifically Kawasaki disease, hospitalizations due to acute lower respiratory tract infections, and convulsions) in recipients of ROTARIX. The study will include approximately 44,000 vaccinated subjects (adjustments to the sample size will be made based on the background rate of intussusception). The study will be designed to detect an increased relative risk of intussusception due to vaccine with a relative risk of 2.5 or greater and with 80 percent power.
  Protocol Submission: November 2008
  Study Start: June 2009
  Final Report Submission: March 2012