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Rotarix

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Rotarix

CLINICAL PHARMACOLOGY

Mechanism Of Action

Prior to rotavirus vaccination programs, rotavirus infected nearly all children by the time they were 5 years of age. Severe, dehydrating rotavirus gastroenteritis occurs primarily among children aged 3 to 35 months.6 Among children up to 3 years of age, approximately 16% of cases before 6 months of age result in hospitalization.7

The exact immunologic mechanism by which ROTARIX protects against rotavirus gastroenteritis is unknown [see Pharmacodynamics]. ROTARIX contains a live, attenuated human rotavirus that replicates in the small intestine and induces immunity.

Pharmacodynamics

Immunogenicity

A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastroenteritis has not been established. Seroconversion was defined as the appearance of anti-rotavirus IgA antibodies (concentration ≥ 20 U/mL) postvaccination in the serum of infants previously negative for rotavirus. In 2 safety and efficacy studies, one to two months after a 2-dose series, 86.5% of 787 recipients of ROTARIX seroconverted compared with 6.7% of 420 placebo recipients and 76.8% of 393 recipients of ROTARIX seroconverted compared with 9.7% of 341 placebo recipients, respectively.

Shedding and Transmission

A prospective, randomized, double-blind, placebo-controlled study was performed in the Dominican Republic in twins within the same household to assess whether transmission of vaccine virus occurs from a vaccinated infant to a nonvaccinated infant. One hundred pairs of healthy twins 6 to 14 weeks of age (gestational age ≥ 32 weeks) were randomized with one twin to receive ROTARIX (N = 100) and the other twin to receive placebo (N = 100). Twenty subjects in each arm were excluded for reasons such as having rotavirus antibody at baseline. Stool samples were collected on the day of or 1 day prior to each dose, as well as 3 times weekly for 6 consecutive weeks after each dose of ROTARIX or placebo. Transmission was defined as presence of the vaccine virus strain in any stool sample from a twin receiving placebo.

Transmitted vaccine virus was identified in 15 of 80 twins receiving placebo (18.8% [95% CI: 10.9, 29.0]). Median duration of the rotavirus shedding was 10 days in twins who received ROTARIX as compared to 4 days in twins who received placebo in whom the vaccine virus was transmitted. In the 15 twins who received placebo, no gastrointestinal symptoms related to transmitted vaccine virus were observed.

Clinical Studies

Efficacy Studies

The data demonstrating the efficacy of ROTARIX in preventing rotavirus gastroenteritis come from 24,163 infants randomized in two placebo-controlled studies conducted in 17 countries in Europe and Latin America. In these studies, oral polio vaccine (OPV) was not coadministered; however, other routine childhood vaccines could be concomitantly administered. Breast-feeding was permitted in both studies.

A randomized, double-blind, placebo-controlled study was conducted in 6 European countries. A total of 3,994 infants were enrolled to receive ROTARIX (n = 2,646) or placebo (n = 1,348). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 14 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was completed by 24 weeks of age. For both vaccination groups, 98.3% of infants were white and 53% were male.

The clinical case definition of rotavirus gastroenteritis was an episode of diarrhea (passage of 3 or more loose or watery stools within a day), with or without vomiting, where rotavirus was identified in a stool sample. Severity of gastroenteritis was determined by a clinical scoring system, the Vesikari scale, assessing the duration and intensity of diarrhea and vomiting, the intensity of fever, use of rehydration therapy or hospitalization for each episode. Scores range from 0 to 20, where higher scores indicate greater severity. An episode of gastroenteritis with a score of 11 or greater was considered severe.8

The primary efficacy endpoint was prevention of any grade of severity of rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 weeks after the second dose through one rotavirus season (according to protocol, ATP). 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% (95% CI: 79.6, 92.1); TVC efficacy was 87.3% (95% CI: 80.3, 92.0). Efficacy against severe rotavirus gastroenteritis through one rotavirus season was 95.8% (95% CI: 89.6, 98.7); TVC efficacy was 96.0% (95% CI: 90.2, 98.8) (Table 4). 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% (95% CI: 8.9, 99.8).

Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one rotavirus season was 100% (95% CI: 81.8, 100); TVC efficacy was 100% (95% CI: 81.7, 100) (Table 4). ROTARIX reduced hospitalizations for all cause gastroenteritis regardless of presumed etiology by 74.7% (95% CI: 45.5, 88.9).

Table 4: Efficacy Evaluation of ROTARIX Through One Rotavirus Season

Infants in Cohort According to Protocola Total Vaccinated Cohortb
ROTARIX
N = 2,572
Placebo
N = 1,302
ROTARIX
N = 2,646
Placebo
N = 1,348
Gastroenteritis cases
Any severity 24 94 26 104
Severec 5 60 5 64
Efficacy estimate against RV GE
  Any severity (95% CI) 87.1%d (79.6, 92.1) 87.3%d (80.3, 92.0)
  Severec (95% CI) 95.8%d (89.6, 98.7) 96.0%d (90.2, 98.8)
Cases of hospitalization due to RV GE 0 12 0 12
Efficacy in reducing hospitalizations due to RV GE (95% CI) 100%d (81.8, 100) 100%d (81.7, 100)
RV GE = rotavirus gastroenteritis; CI = Confidence Interval.
a ATP analysis includes all infants in the efficacy cohort who received two doses of vaccine according to randomization.
b TVC analysis includes all infants in the efficacy cohort who received at least one dose of vaccine or placebo.
c Severe gastroenteritis defined as ≥ 11 on the Vesikari scale.
DStatistically significant vs. placebo (P < 0.001).

A randomized, double-blind, placebo-controlled study was conducted in 11 countries in Latin America and Finland. A total of 63,225 infants received ROTARIX (n = 31,673) or placebo (n = 31,552). An efficacy subset of these infants consisting of 20,169 infants from Latin America received ROTARIX (n = 10,159) or placebo (n = 10,010). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 13 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was completed by the age of 24 weeks of age. For both vaccination groups, the racial distribution of the efficacy subset was as follows: Hispanic 85.8%, white 7.9%, black 1.1%, and other 5.2%; 51% were male.

The clinical case definition of severe rotavirus gastroenteritis was an episode of diarrhea (passage of 3 or more loose or watery stools within a day), with or without vomiting, where rotavirus was identified in a stool sample, requiring hospitalization and/or rehydration therapy equivalent to World Health Organization (WHO) plan B (oral rehydration therapy) or plan C (intravenous rehydration therapy) in a medical facility.

The primary efficacy endpoint was prevention of severe rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 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% (95% CI: 71.7, 92.4); TVC efficacy was 81.1% (95% CI: 68.5, 89.3) (Table 5).

Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one year was 85.0% (95% CI: 69.6, 93.5); TVC efficacy was 80.8% (95% CI: 65.7, 90.0) (Table 5).

Table 5: Efficacy Evaluation of ROTARIX Through One Year

Infants in Cohort According to Protocola Total Vaccinated Cohortb
ROTARIX
N = 9,009
Placebo
N = 8,858
ROTARIX
N = 10,159
Placebo
N = 10,010
Gastroenteritis cases
  Severe 12 77 18 94
Efficacy estimate against RV GE
  Severe (95% CI) 84.7%c (71.7, 92.4) 81.1 %c (68.5, 89.3)
Cases of hospitalization due to RV GE 9 59 14 72
Efficacy in reducing hospitalizations due to RV GE (95% CI) 85.0%c (69.6, 93.5) 80.8%c (65.7, 90.0)
RV GE = rotavirus gastroenteritis; CI = Confidence Interval.
a ATP analysis includes all infants in the efficacy cohort who received two doses of vaccine according to randomization.
bTVC analysis includes all infants in the efficacy cohort who received at least one dose of vaccine or placebo.
c Statistically significant vs. placebo (P < 0.001).

Efficacy Through Two Rotavirus Seasons

The efficacy of ROTARIX persisting through two rotavirus seasons was evaluated in two studies.

In the European study, the efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through two rotavirus seasons was 78.9% (95% 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% (95% CI: 61.2, 79.8). The efficacy of ROTARIX against severe rotavirus gastroenteritis through two rotavirus seasons was 90.4% (95% CI: 85.1, 94.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second season post-vaccination was 85.6% (95% CI: 75.8, 91.9).

The efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through two rotavirus seasons was 96.0% (95% CI: 83.8, 99.5).

In the Latin American study, the efficacy of ROTARIX against severe rotavirus gastroenteritis through two years was 80.5% (95% CI: 71.3, 87.1). Efficacy in preventing severe rotavirus gastroenteritis cases occurring only during the second year post-vaccination was 79.0% (95% CI: 66.4, 87.4). The efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through two years was 83.0% (95% CI: 73.1, 89.7).

The efficacy of ROTARIX beyond the second season post-vaccination was not evaluated.

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 (Table 6).

Table 6: Type-Specific Efficacy of ROTARIX Against Any Grade of Severity and Severe Rotavirus Gastroenteritis (According to Protocol)

Type Identifieda Through One Rotavirus Season Through Two Rotavirus Seasons
Number of Cases % Efficacy (95% CI) Number of Cases % Efficacy (95% CI)
ROTARIX
N = 2,572
Placebo
N = 1,302
ROTARIX
N = 2,572
Placebo
N = 1,302
ANY GRADE OF SEVERITY
G1P[8] 4 46 95.6%b
(87.9, 98.8)
18 89c,d 89.8%b
(82.9, 94.2)
G2P[4] 3 4c NS 14 17c 58.3%b
(10.1, 81.0)
G3P[8] 1 5 89.9%b (9.5, 99.8) 3 10 84.8%b (41.0, 97.3)
G4P[8] 3 13 88.3%b (57.5, 97.9) 6 18 83.1%b
(55.6, 94.5)
G9P[8] 13 27 75.6%b (51.1, 88.5) 38 71d 72.9%b
(59.3, 82.2)
Combined non-G1 (G2, G3, G4, G9, G12) typese 20 49 79.3%b (64.6, 88.4) 62 116 72.9%b
(62.9, 80.5)
SEVERE
G1P[8] 2 28 96.4%b
(85.7, 99.6)
4 57 96.4%b
(90.4, 99.1)
G2P[4] 1 2c NS 2 7c 85.5%b
(24.0, 98.5)
G3P[8] 0 5 100%b
(44.8, 100)
1 8 93.7%b
(52.8, 99.9)
G4P[8] 0 7 100%b
(64.9, 100)
1 11 95.4%b
(68.3, 99.9)
G9P[8] 2 19 94.7%b
(77.9, 99.4)
13 44d 85.0%b
(71.7, 92.6)
Combined non-G1 (G2, G3, G4, G9, G12) typese 3 33 95.4%b
(85.3, 99.1)
17 70 87.7%b
(78.9, 93.2)
CI = Confidence Interval; NS = Not significant.
a Statistical analyses done by G type; if more than one rotavirus type was detected from a rotavirus gastroenteritis episode, the episode was counted in each of the detected rotavirus type categories.
b Statistically significant vs. placebo (P < 0.05).
c The P genotype was not typeable for one episode.
d P[8] genotype was not detected in one episode.
e Two cases of G12P[8] were isolated in the second season (one in each group).

REFERENCES

5. Tate JE, Simonsen L, Viboud C, et al. Trends in intussusception hospitalizations among US infants, 1993-2004: implications for monitoring the safety of the new rotavirus vaccination program. Pediatrics 2008;121:e1125-e1132.

6. Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-12):1-13.

7. Parashar UD, Holman RC, Clarke MJ, et al. Hospitalizations associated with rotavirus diarrhea in the United States, 1993 through 1995: surveillance based on the new ICD-9-CM rotavirus-specific diagnostic code. J Infect Dis 1998;177:13-17.

8. Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for severity of diarrheal episodes. Scand J Infect Dis 1990;22:259-267.

Last reviewed on RxList: 9/26/2014
This monograph has been modified to include the generic and brand name in many instances.

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