RotaTeq Mechanism of Action

Therapeutic Class: RotaTeq is a live, oral pentavalent vaccine which protects against rotavirus gastroenteritis.
Pharmacology: Rotavirus is the leading cause of severe acute gastroenteritis in infants and young children in industrialized and developing countries. Rotavirus gastroenteritis is a universal disease affecting over 95% of infants and young children by the time they are 5 years old, regardless of their socioeconomic status or environmental conditions. Worldwide, it is estimated that 138 million children develop rotavirus gastroenteritis each year which results in 25 million clinic visits, 2.1 million hospitalizations and 352,000-592,000 deaths. In the US, it is estimated that 3.5 million children develop rotavirus gastroenteritis each year which results in 500,000 physician office visits, 55,000 hospitalizations and 20 to 102 deaths. One out of every 8 children will seek care from a physician and one out of every 73 children will be hospitalized for rotavirus gastroenteritis in the US by the time they are 5 years old. The greatest proportion of hospitalizations occurs among infants and young children between 6 months and 24 months of age. If left untreated without prompt oral or intravenous administration of fluids, rotavirus gastroenteritis may cause dehydration that is fatal.
Rotavirus gastroenteritis is a seasonal illness in temperate climates with epidemics occurring in the winter months. Rotavirus gastroenteritis is generally endemic in tropical and subtropical climates. Rotavirus is responsible for approximately 28% to 71% of all hospitalizations for diarrhea worldwide, regardless of geographic region and season.
Mechanism of Action: Protection from natural rotavirus infection is largely serotype specific. The human rotavirus serotypes (G1, G2, G3, G4, and P1[8]) have been selected for RotaTeq because these strains caused nearly 90% of rotavirus disease in the United States from 1996-1999 and over 88% of rotavirus disease worldwide between 1973 and 2003. The exact immunologic mechanism by which RotaTeq protects against rotavirus gastroenteritis is unknown. Studies suggest a combination of factors is important in rotavirus immunity including neutralizing antibodies to the outer capsid G proteins, serum and secretory IgA, and other local mucosal responses (see Immunogenicity as follows).
Efficacy: Overall, 71,942 infants were randomized worldwide in 3 placebo-controlled phase III studies. 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: the Rotavirus Efficacy and Safety Trial (REST) and Study 007. The efficacy evaluations in these studies included: 1) Efficacy against any severity of rotavirus gastroenteritis and 2) Efficacy against severe rotavirus gastroenteritis (see Table 1). The effect on health care contacts for rotavirus gastroenteritis, including hospitalizations and emergency department visits, was also evaluated among the 68,038 infants enrolled in REST and in a subset of 20,736 infants in the Extension study among the Finnish cohort of REST. The infants were followed for up to 2 years in REST and those in the Extension study continued to be followed for up to 3 years post-vaccination. No safety data were collected during the Extension study. The reductions in routine visits to a physician and parent/legal guardian work loss days were also evaluated in REST. The first dose was administered between 6 and 12 weeks of age and subsequent doses were to be given at 4- to 10-week intervals. The third dose was administered to infants as old as 32 weeks of age. Breast-feeding and concomitant administration of other licensed childhood vaccines except for oral poliovirus vaccine (OPV) were permitted in these studies.
As Table 1 shows, RotaTeq was efficacious against rotavirus gastroenteritis of any severity and severe rotavirus gastroenteritis. The efficacy analyses include cases that occurred at least 14 days after the third dose. Severe gastroenteritis is defined as a numerical score of >16 points on a 24-point scale. The scoring system evaluates the clinical manifestations of rotavirus gastroenteritis taking into account the duration and intensity of fever, vomiting, diarrhea, and behavioral changes. The scoring system has been validated to correlate with physician-assessment of the intensity of these signs and symptoms.
Efficacy through the first rotavirus season after vaccination against severe rotavirus gastroenteritis caused by naturally occurring rotavirus of the composite of the G serotypes included in the vaccine (G1-G4) was 98.2%, and efficacy against any severity of rotavirus gastroenteritis was 73.8%. The vaccine was specifically designed to prevent rotavirus gastroenteritis caused by the individual G-serotypes included in the vaccine (G1, G2, G3, and G4); P1[8] was included in the vaccine to potentially provide cross-protection against non-vaccine G-serotypes that may contain P1[8]. Based on limited data, the efficacy against any severity of gastroenteritis caused by the non-vaccine G serotype (G9) was 74.1%. Efficacy of RotaTeq against rotavirus gastroenteritis by G-serotype is shown in Table 1. (See Table 1.)

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Infants with Hospitalizations, Emergency Department Visits, and Non-urgent Visits: RotaTeq reduced the rate of hospitalizations, emergency department visits, non-urgent care visits, and parent/legal guardian work loss days. The reduction in hospitalizations and emergency department visits for rotavirus gastroenteritis caused by serotypes G1-G4 was evaluated among 68,038 infants in REST and in a subset of 20,736 infants in the Extension study among the Finnish cohort of REST. The infants were followed for up to 2 years in REST and those in the Extension study continued to be followed for up to 3 years post-vaccination. During year 3 (RotaTeq n=3,112 infants, placebo n=3,126 infants), there were no health care contacts for rotavirus gastroenteritis in the vaccine group and there was 1 (non-typeable) in the placebo group. Non-urgent care visits and parent/legal guardian work loss days were evaluated for up to two years after vaccination in REST. The rate reductions for health care contacts are shown in Table 2. (See Table 2.)

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Among the parents/guardians of the 68,038 infants studied for up to 2 years in REST, there was an 86.6% reduction in work loss days, with 65 work loss days among parents/guardians of recipients of RotaTeq recipients compared with 487 work loss days among parents/guardians of placebo recipients.
The reduction in hospitalizations and emergency department visits for rotavirus gastroenteritis by serotype identified in stool in REST and the Extension is shown in Table 3. (See Table 3.)

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Efficacy between Doses: The protective efficacy of RotaTeq against the incidence of rotavirus gastroenteritis of any severity caused by serotypes G1-G4 in the intervals between doses was not statistically significant. This was evaluated in a post hoc analysis of data from the clinical efficacy cohort of REST (n=5,673 infants).
The protective efficacy of RotaTeq as measured by a reduction in the rate of hospitalizations and emergency department visits for rotavirus gastroenteritis caused by serotypes G1-G4 in the intervals between doses during administration of the 3-dose vaccination series was evaluated in post hoc analyses of data from REST (n=68,038 infants). The results of these analyses are presented in Table 4. (See Table 4.)

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Efficacy through Multiple Rotavirus Seasons: The efficacy of RotaTeq persisted through the second rotavirus season after vaccination. Among a subset of 4,451 infants who were evaluated, efficacy against any severity of rotavirus gastroenteritis caused by the composite of the vaccine G-serotypes through two seasons after vaccination was 71.3%. The efficacy of RotaTeq in preventing cases occurring only during the second rotavirus season postvaccination was 62.6% (see Table 5). The efficacy of RotaTeq beyond the second season postvaccination was not evaluated. (See Table 5.)

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Safety and Efficacy in Pre-term Infants: RotaTeq was generally well tolerated and prevented rotavirus gastroenteritis in infants born prematurely. RotaTeq or placebo was administered to 2,070 pre-term infants (25 to 36 weeks gestational age) according to their chronological age in a placebo-controlled study. In a subset of 204 vaccinated infants (99 in the vaccine group), protective efficacy, as measured by a reduction in the incidence of rotavirus gastroenteritis of any severity caused by vaccine serotypes (G1-G4) that occurred at least 14 days after the third dose of vaccine through the first full rotavirus season after vaccination, was 70.3 % [95 % CI <0, 94.7]. In 2,070 vaccinated infants (1,007 in the vaccine group) in REST, protective efficacy, as measured by a reduction in the rate of hospitalizations and emergency department visits for rotavirus gastroenteritis caused by G1-G4 from 14 days for up to 2 years after the third dose, was 100% [95 % CI 74, 100] (see Table 6). Likewise, the protective efficacy, as measured by a reduction in the rate of hospitalizations and emergency department visits for rotavirus gastroenteritis caused by any serotype from 14 days for up to 2 years after the third dose, was 100% [95% CI 82, 100]. (See Table 6.)

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Effectiveness: The results of the three post-licensure vaccine effectiveness studies presented in Table 7 demonstrated high and consistent reduction in rotavirus-related or all-cause gastroenteritis hospitalizations, emergency department visits and office visits. These vaccine effectiveness data from the US and France also showed that RotaTeq provided strain specific effectiveness against G12P[8] and sustained protection against rotavirus-related hospitalizations and emergency department visits in children up to the 7th year of life. (See Table 7.)

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Safety, Efficacy and Immunogenicity with Concomitant Administration of RotaTeq and Other Vaccines: RotaTeq was well tolerated and efficacious when administered concomitantly with other licensed childhood vaccines. The efficacy of RotaTeq was evaluated among a subset of infants in the US who received Haemophilus influenzae type b and hepatitis B vaccine, diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, inactivated poliovirus vaccine (IPV) and pneumococcal conjugate vaccine. The efficacy of RotaTeq was 89.5% against rotavirus gastroenteritis of any severity caused by the composite of the G-serotypes included in the vaccine for the first rotavirus season after vaccination (see Table 8). The immune responses to the specified vaccines were largely unaffected by RotaTeq. Of the 17 antigens studied, the antibody responses were similar among vaccine and placebo recipients except for a slightly diminished response to one of the three antigens tested for pertussis (pertactin). (See Table 8.)

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Immunogenicity: A relationship between antibody responses to RotaTeq and protection against rotavirus gastroenteritis has not yet been established. However, RotaTeq induces antibodies that neutralize human serotypes G1, G2, G3, G4 and P1[8]. In phase III clinical studies, 92.9% to 100% of recipients of RotaTeq achieved a significant rise in serum anti-rotavirus IgA after a three-dose regimen.