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RotaTeq

CLINICAL PHARMACOLOGY

Rotavirus is a leading cause of severe acute gastroenteritis in infants and young children, with over 95% of these children infected by the time they are 5 years old.5 The most severe cases occur among infants and young children between 6 months and 24 months of age.6

Mechanism Of Action

The exact immunologic mechanism by which RotaTeq protects against rotavirus gastroenteritis is unknown [see Clinical Studies]. RotaTeq is a live viral vaccine that replicates in the small intestine and induces immunity.

Clinical Studies

Overall, 72,324 infants were randomized in 3 placebo-controlled, phase 3 studies conducted in 11 countries on 3 continents. The data demonstrating the efficacy of RotaTeq in preventing rotavirus gastroenteritis come from 6,983 of these infants from the US (including Navajo and White Mountain Apache Nations) and Finland who were enrolled in 2 of these studies: REST and Study 007. The third trial, Study 009, provided clinical evidence supporting the consistency of manufacture and contributed data to the overall safety evaluation.

The racial distribution of the efficacy subset was as follows: White (RotaTeq 68%, placebo 69%); Hispanic-American (RotaTeq 10%, placebo 9%); Black (2% in both groups); Multiracial (RotaTeq 4%, placebo 5%); Asian ( < 1% in both groups); Native American (RotaTeq 15%, placebo 14%); and Other ( < 1% in both groups). The gender distribution was 52% male and 48% female in both vaccination groups.

The efficacy evaluations in these studies included: 1) Prevention of any grade of severity of rotavirus gastroenteritis; 2) Prevention of severe rotavirus gastroenteritis, as defined by a clinical scoring system; and 3) Reduction in hospitalizations due to rotavirus gastroenteritis.

The vaccine was given as a three-dose series to healthy infants with the first dose administered between 6 and 12 weeks of age and followed by two additional doses administered at 4- to 10-week intervals. The age of infants receiving the third dose was 32 weeks of age or less. Oral polio vaccine administration was not permitted; however, other childhood vaccines could be concomitantly administered. Breast-feeding was permitted in all studies.

The case definition for rotavirus gastroenteritis used to determine vaccine efficacy required that a subject meet both of the following clinical and laboratory criteria: (1) greater than or equal to 3 watery or looser-than-normal stools within a 24-hour period and/or forceful vomiting; and (2) rotavirus antigen detection by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of onset of symptoms. The severity of rotavirus acute gastroenteritis was determined by a clinical scoring system that took into account the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes.

The primary efficacy analyses included cases of rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 that occurred at least 14 days after the third dose through the first rotavirus season post vaccination.

Analyses were also done to evaluate the efficacy of RotaTeq against rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 at any time following the first dose through the first rotavirus season postvaccination among infants who received at least one vaccination (Intent-to-treat, ITT).

Rotavirus Efficacy And Safety Trial

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 74.0% (95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5, 67.1). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 98.0% (95% CI: 88.3, 100.0), and ITT efficacy was 96.4% (95% CI: 86.2, 99.6). See Table 8.

Table 8: Efficacy of RotaTeq against any grade of severity of and severe* G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in REST

  Per Protocol Intent-to-Treat†
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 2,834 2,839 2,834 2,839
  Gastroenteritis cases
Any grade of severity 82 315 150 371
Severe* 1 51 2 55
  Efficacy estimate % and (95% confidence interval)
Any grade of severity 74.0 (66.8, 79.9) 60.0
(51.5, 67.1)
Severe* 98.0 (88.3, 100.0) 96.4
(86.2, 99.6)
* Severe gastroenteritis defined by a clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral changes
† ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.

The efficacy of RotaTeq against severe disease was also demonstrated by a reduction in hospitalizations for rotavirus gastroenteritis among all subjects enrolled in REST. RotaTeq reduced hospitalizations for rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 through the first two years after the third dose by 95.8% (95% CI: 90.5, 98.2). The ITT efficacy in reducing hospitalizations was 94.7% (95% CI: 89.3, 97.3) as shown in Table 9.

Table 9: Efficacy of RotaTeq in reducing G1-4 rotavirus-related hospitalizations in REST

  Per Protocol Intent-to-Treat*
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 34,035 34,003 34,035 34,003
Number of hospitalizations 6 144 10 187
Efficacy estimate % and (95% confidence interval) 95.8 (90.5, 98.2) 94.7 (89.3, 97.3)
* ITT analysis includes all subjects who received at least one dose of vaccine.

Study 007

Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 72.5% (95% CI: 50.6, 85.6) and the ITT efficacy was 58.4% (95% CI: 33.8, 74.5). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 100% (95% CI: 13.0, 100.0) and ITT efficacy against severe rotavirus disease was 100% (95% CI: 30.2, 100.0) as shown in Table 10.

Table 10: Efficacy of RotaTeq against any grade of severity of and severe* G1-4 rotavirus gastroenteritis through the first rotavirus season postvaccination in Study 007

  Per Protocol Intent-to-Treat†
RotaTeq Placebo RotaTeq Placebo
Subjects vaccinated 650 660 650 660
Gastroenteritis cases        
Any grade of severity 15 54 27 64
Severe* 0 6 0 7
Efficacy estimate % and (95% confidence interval)
Any grade of severity 72.5 (50.6, 85.6) 58.4 (33.8, 74.5)
Severe* 100.0 (13.0, 100.0) 100.0 (30.2, 100.0)
* Severe gastroenteritis defined by a clinical scoring system based on the intensity and duration of symptoms of fever, vomiting, diarrhea, and behavioral change
† ITT analysis includes all subjects in the efficacy cohort who received at least one dose of vaccine.

Multiple Rotavirus Seasons

The efficacy of RotaTeq through a second rotavirus season was evaluated in a single study (REST). Efficacy against any grade of severity of rotavirus gastroenteritis caused by rotavirus serotypes G1, G2, G3, and G4 through the two rotavirus seasons after vaccination was 71.3% (95% CI: 64.7, 76.9). The efficacy of RotaTeq in preventing cases occurring only during the second rotavirus season postvaccination was 62.6% (95% CI: 44.3, 75.4). The efficacy of RotaTeq beyond the second season postvaccination was not evaluated.

Rotavirus Gastroenteritis Regardless Of Serotype

The rotavirus serotypes identified in the efficacy subset of REST and Study 007 were G1P1A[8]; G2P1[4]; G3P1A[8]; G4P1A[8]; and G9P1A[8].

In REST, the efficacy of RotaTeq against any grade of severity of naturally occurring rotavirus gastroenteritis regardless of serotype was 71.8% (95% CI: 64.5, 77.8) and efficacy against severe rotavirus disease was 98.0% (95% CI: 88.3, 99.9). The ITT efficacy starting at dose 1 was 50.9% (95% CI: 41.6, 58.9) for any grade of severity of rotavirus disease and was 96.4% (95% CI: 86.3, 99.6) for severe rotavirus disease.

In Study 007, the primary efficacy of RotaTeq against any grade of severity of rotavirus gastroenteritis regardless of serotype was 72.7% (95% CI: 51.9, 85.4) and efficacy against severe rotavirus disease was 100% (95% CI: 12.7, 100). The ITT efficacy starting at dose 1 was 48.0% (95% CI: 21.6, 66.1) for any grade of severity of rotavirus disease and was 100% (95% CI: 30.4, 100.0) for severe rotavirus disease.

Rotavirus Gastroenteritis By Serotype

The efficacy against any grade of severity of rotavirus gastroenteritis by serotype in the REST efficacy cohort is shown in Table 11.

Table 11: Serotype-specific efficacy of RotaTeq against any grade of severity of rotavirus gastroenteritis among infants in the REST efficacy cohort through the first rotavirus season postvaccination (Per Protocol)

Serotype identified by PCR Number of cases % Efficacy (95% Confidence Interval)
RotaTeq
(N=2,834)
Placebo
(N=2,839)
Serotypes present in RotaTeq
  G1P1A[8] 72 286 74.9 (67.3, 80.9)
  G2P1[4] 6 17 63.4 (2.6, 88.2)
  G3P1A[8] 1 6 NS
  G4P1A[8] 3 6 NS
Serotypes not present in RotaTeq
  G9P1A[8] 1 3 NS
  Unidentified* 11 15 NS
* Includes rotavirus antigen-positive samples in which the specific serotype could not be identified by PCR

In a separate post hoc analysis of health care utilization data from 68,038 infants (RotaTeq 34,035 and placebo 34,003) in REST, using a case definition that included culture confirmation, hospitalization and emergency departments visits due to G9P1A[8] rotavirus gastroenteritis were reduced (RotaTeq 0 cases: placebo 14 cases) by 100% (95% CI: 69.6%, 100.0%).

Immunogenicity

A relationship between antibody responses to RotaTeq and protection against rotavirus gastroenteritis has not been established. In phase 3 studies, 92.9% to 100% of 439 recipients of RotaTeq achieved a 3-fold or more rise in serum anti-rotavirus IgA after a three-dose regimen when compared to 12.3%-20.0% of 397 placebo recipients.

REFERENCES

5. Parashar UD et al. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003;9(5):565-572.

6. Parashar UD, Holman RC, Clarke MJ, Bresee JS, Glass RI. 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;177:13-7.

Last reviewed on RxList: 9/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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