ARCHIVED - Canada Communicable Disease Report

Statement on the recommended use of pentavalent human-bovine reassortant rotavirus vaccine

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Background

In August 2006 a live, oral, pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq™, Merck Frosst Canada, Inc.) was approved for use in Canada for the prevention of rotavirus (RV) gastroenteritis in infants 6 to 32 weeks of age. It was licensed in the United States (US) in February 2006 by the Food and Drug Administration (FDA) and recommended for routine use in infants by the Advisory Committee on Immunization Practices in August 2006 and by the Committee on Infectious Diseases of the American Academy of Pediatrics in 2007. The European Rotavirus Vaccination Advocacy Committee has recently advocated introduction of rotavirus vaccine into childhood immunization programs, although the members agree that further studies on the burden of rotavirus gastroenteritis in Europe need to be done for a better evaluation of the costs and benefits of rotavirus vaccination programs.

In order to facilitate preparation of the National Advisory Committee on Immunization (NACI) recommendations for use of this vaccine, a systematic review of the literature was undertaken focusing on the epidemiology of RV gastroenteritis in Canada and the safety, immunogenicity and efficacy of the vaccine in clinical trials⁽¹⁾. This statement provides recommendations for use of RotaTeq™ in Canadian infants and summarizes what is known regarding the burden of illness associated with RV in Canada, as well as the current knowledge of vaccine efficacy and safety data. As new information regarding RotaTeq™ and/or the burden of illness becomes available, the recommendations in this statement will be reviewed.

Epidemiology of rotavirus disease in Canada

Rotavirus is a double-stranded RNA virus composed of an inner core, an internal capsid and an outer capsid. Viral serotype is defined by two structural viral proteins (VP) in the outer capsid: VP7, the glycoprotein (G protein), and VP4, the protease-cleaved protein (P protein)^(2,3). These outer capsid proteins elicit neutralizing antibodies believed to be important for protection⁽²⁾. Ten VP7 (G) serotypes and 11 VP4 (P) serotypes are known to cause disease in humans. Because the two gene segments that encode these proteins can segregate independently, there is the potential for many VP7/VP4 combinations, and a typing system consisting of both G and P types has been developed⁽²⁾.

In the US and, according to limited data, in Canada, viruses containing six distinct G and P combinations are the most prevalent: P1A[8] G1, P1B[4] G2, P1A[8] G3, P1A[8] G4, P1A[8] G9 and P2A[6] G9; these strains are generally designated by their G serotype specificity (serotypes G1-4 and G9)(4-7) (Table 1). A number of reports suggest that P1A[8] G9 is emerging and spreading(8-15).

Table 1. Prevalent strains of RV among children aged < 5 years, United States 1996-1999, and in two Canadian studies, 1997-1998 and 2005

 

The prevalence of rotavirus G and P serotypes varies geographically and from year to year. While non-G1 serotypes are generally less common, each of the other G types can predominate and cause > 50% of illness in some years⁽¹⁶⁾. These shifting patterns of G-type prevalence from year to year have been clearly demonstrated in the US over a number of years^(16,17).

RV is a common infectious agent that causes gastroenteritis in children worldwide. Because RV gastroenteritis is not a nationally notifiable disease and there are few published population-based Canadian studies, estimates of the prevalence of RV infection and its associated disease burden in Canada are based on several studies in children seen in family physician offices, pediatric clinics, emergency departments and those admitted to hospital (Table 2).

Rotavirus infection has an incubation period of 18 hours to 3 days⁽²²⁾. The disease is transmitted by the fecal-oral route through both close person-to-person contact and through fomites, such as toys and hard surfaces⁽²³⁾. Seasonal peaks in RV disease typically occur in late winter/early spring. Almost all children are infected by 5 years of age. In the first 3 months of life, illness is generally mild as a result of passively transferred maternal RV antibodies. Between 3 months and 5 years of age, there is a spectrum of disease, from mild gastroenteritis to dehydration with shock, electrolyte imbalance and, very rarely in Canada, death. Over half of RV hospitalizations occur in the 6 to 24 month age group, and > 70% of all hospital admissions for diarrhea in this young age group during the peak season (~2 months) are due to RV. In the greater Toronto region during an 8-month study period, over 75% of all children hospitalized for diarrhea were between 6 and 35 months of age, 7% < 6 months of age and 18% aged 36 months to 18 years⁽¹⁹⁾.

In the US, RVs are responsible for 5%-10% of all gastroenteritis episodes among children < 5 years of age; in Toronto they caused 18% and 20% of gastroenteritis in day care centre attendees and in pediatric practices, respectively(20). In the MIRAGE (Measuring the Impact of Rotavirus Acute Gastroenteritis) study, a more recent Canadian study performed over a 6-month period in 2005 and not yet published, 395 children with diarrhea were enrolled in 59 family physician offices and pediatric clinics across the country(21). In that study, 55.4% of episodes (186/336) for which stool samples were available were due to RV. While the proportion of gastroenteritis seen in outpatient settings varies considerably, the majority of severe gastroenteritis requiring rehydration or hospitalization is caused by RV(18,24,25). In Toronto and Quebec, 37% (0 to 18-year-olds) and 72% (0 to 5-year-olds) of childhood gastroenteritis hospitalizations, respectively, were due to RV(18,19). This compares with 39% of childhood gastroenteritis hospitalizations generally reported elsewhere in the literature(26).

The proportion of gastroenteritis attributable to RV in young hospitalized children varies seasonally from a high of 60% to 78% between April and May among children aged 6 months to 3 years of age to 30% to 50% between December and February^(18,20). A similar early spring increase in the proportion of gastroenteritis caused by RV was observed in emergency departments, pediatric practices and day care centres, where RV accounted for half to two-thirds of diarrhea in children 6 to 35 months of age in April and May⁽²⁰⁾.

In general, few clinical or epidemiologic features distinguish the child with RV diarrhea from those with diarrhea due to other causes⁽²⁷⁾. Vomiting occurs in 89% to 97% of cases and usually precedes the onset of diarrhea^(18,21,25). Fever occurs in 53% to 89% of cases^(18,21,25). The presence of fever, vomiting and diarrhea is reported more commonly with RV than with other gastrointestinal viruses. Children from whom RV is isolated are more likely to experience all three symptoms than RV-negative children with gastroenteritis (61.8% vs. 38.7%)⁽²¹⁾. The duration of RV illness is < 1 week in 80% of patients with a mean of 5.8 to 6.1 days. Of hospitalized children, the mean duration of hospitalization is 2-3 days, and < 1% have persistence of fever, vomiting or diarrhea for > 2 weeks^(18,25). At 1-month follow-up, 88% of children have returned to their usual health status, and the remainder have almost regained any weight lost during the episode⁽²⁵⁾.

Although RV gastroenteritis is typically self-limited and rarely results in long-term sequelae or death, it is associated with considerably more health care utilization than gastroenteritis due to other causes. Among children < 3 years of age with gastroenteritis recruited from physician offices and pediatric clinics across the country between January and June 2005, the expected epidemic RV period in Canada, 55% (186/336) were RV positive; of these RV positive cases, 12% (22) were hospitalized, 27% (50) had an emergency department visit, and 12% (22) required intravenous (IV) rehydration(21). Children with RV were 3.3 times more likely to be hospitalized (13% vs. 4%, p = 0.008), 1.9 times more likely to visit the emergency department (27% vs. 14%, p = 0.0082) and 4.1 times more likely to receive (IV) rehydration (13% vs. 3%, p = 0.0027) than patients with gastroenteritis due to other causes(21). Similarly, children requiring more health care are more likely to have RV infection than diarrhea due to other viral agents. In the Toronto Study, only 10% of children in child care centres with diarrhea who did not see a physician had RV-associated diarrhea(19,20). In contrast 27% of children making a health care visit and 75% of those hospitalized or who received IV hydration in the emergency department had RV-associated diarrhea(19,20). While 20% of children with gastroenteritis in pediatric practices had RV, of those whose condition required hospitalization or IV hydration in the emergency department the proportion with RV rose to 60%(19,20).

Table 2. Overview of Canadian studies of children with diarrhea and RV-associated diarrhea at hospital admission, emergency departments, pediatric practices and day care centres

 

In a study of child care centre attendees, the majority (> 60%) sought medical care for any episode of diarrhea⁽²⁰⁾. While a visit to a pediatrician was adequate for the majority of children with RV diarrhea, > 75% seeking no further care, 17% went on to an emergency department visit, and 6% were either hospitalized or received IV hydration in the emergency department .The Rotavirus Gastroenteritis Cohort Model, an unpublished mathematical model of disease burden which incorporates data from the mirage study as well as published epidemiologic data from Toronto and Quebec, estimates that the majority (57%) of RV-positive cases sought health care resources, 36% visiting a physician, 15% an emergency department and 7% requiring hospitalization⁽²⁸⁾.

All of these data indicate that RV is a common viral illness in Canada.

The Rotavirus Gastroenteritis Cohort Model, estimated the impact of RV gastroenteritis in Canada by the age of 5 years and determined that one child in seven will have sought health care, one child in 20 will have visited an emergency department or have been hospitalized, and one child in 62 will have been hospitalized (Table 3)^{(18-20,28-30)}. This estimate of one in 62 in Canada by the age of 5 years may be high. In the US, estimates have ranged from 1/73 to 1/80. In Canada, several studies have reported RV-associated hospitalization rates. In Toronto, where IV and oral hydration in the emergency department is widely practised, rates of one in 106 were found⁽²⁰⁾, and in Quebec City a hospitalization rate of 320/100,000, or one in 312, occurred between 1985 and 1998⁽³¹⁾. In a subsequent study performed between 1995 and 1999 in Quebec, the hospitalization rate was 450/100,000 or one in 222 children < 5 years of age⁽¹⁸⁾. Thus, the true rate of hospitalization associated with RV in Canadian children is poorly defined. While the rate is likely to vary by geographic region and year, available data suggest that it lies somewhere between 320/100,000 and 1,600/100,000. Given an annual birth cohort of 340,000, as used in the Rotavirus Gastroenteritis Cohort Model, the total annual number of hospitalizations due to RV can be estimated to be between 1,100 and 5,500.

Table 3. Annual RV-associated health care burden among Canadian children < 5 years estimated by the Rotavirus Gastroenteritis Cohort Model⁽²⁸⁾

 

Mortality due to RV in Canada is now extremely low with only one reported death due to RV in recent years. While the number of deaths due to RV-associated diarrhea may be an underestimate, owing to the lack of routine testing for RV infection, the low mortality rate is comparable to the situation in the US, where deaths are rare: 20 to 60 deaths per year attributable to RV⁽³²⁾. From a global perspective that takes into consideration developing countries, RV mortality is very different, with an estimated 610,000 children dying per year, accounting for 5% of all deaths in children < 5 years of age.

Diarrhea in household contacts

Household transmission of RV gastroenteritis is common. Adults who are in contact with young children are at particularly high risk of RV infection. In one Toronto study, during the 2 weeks before or after RV-associated diarrhea in children < 3 years of age, the rates of diarrhea among contacts < 3 years of age, 3 to 18 years of age and adults were 65% to 74%, 38% to 43% and 29% to 35%, respectively^(19,20) A cross-Canada study in 2005 demonstrated that in 47% of RV cases at least one other family member experienced gastroenteritis between 2 weeks before and 2 weeks after the infection. The mean number of additional cases was one. Among these household contacts experiencing diarrhea, 44% were < 2 years old, 37% were 2 to 5 years, 12% were 6 to 18 years, and 22% were adults⁽²¹⁾.

Specific populations affected and risk factors

One approach to immunization program development is to assess the need for a universal or a targeted approach. Recent studies in the US suggest that while there are factors that may characterize children as priorities for intervention, many of these factors, such as being in child care, being recipients of Medicaid or being without insurance, or the presence of another child in the household < 24 months of age, are shared by large proportions of this population, making a targeted approach to immunization impractical⁽³³⁾. It is important to note that at least two of these factors (i.e. day care attendance and health coverage) are considered to be very different in Canada compared with the US. Further, some factors, such as low birth weight, are clearly risk factors but are relatively uncommon, limiting the impact of a targeted approach. In a Canadian prospective study, socio-economic factors, parental marital status, child care arrangements, including day care centre attendance, and ethnicity did not appear to influence rates of RV hospitalization⁽²⁰⁾.

Geographic: The risk of RV gastroenteritis and its outcomes does not appear to vary by geographic region within the US. There are limited data regarding the regional distribution of RV within Canada; further data are needed.

Socio-economic: Limited data suggest that US children with lower socio-economic status are at greater risk⁽³⁴). US children < 24 months of age covered by Medicaid or without insurance (odds ratio [OR] 2.1, 95% confidence interval [CI]1.4 to 3.2) and children having a mother without a high school education (OR 1.5, 95% CI 1.0 to 2.3) are at higher risk of hospitalization due to RV⁽³³⁾. A large Toronto study failed to demonstrate an association between socio-economic-cultural factors and RV hospitalization⁽¹⁹⁾.

Prematurity: A Washington State study found that premature infants are at increased risk of hospitalization from gastroenteritis, including viral gastroenteritis⁽³⁴⁾. In a Toronto study, a history of prematurity was found in 13% of children admitted with RV in the first year of life, which was higher than the regional rate of prematurity of 7%, suggesting the possibility of more severe disease in this group⁽¹⁹⁾.

Low birth weight: In Washington State, infants with low birth weight (< 2500 g) had an increased risk of hospitalization for up to 24 months of age (OR 2.8, 95% CI 1.6 to 5.0)⁽³⁴⁾. This has also been identified as a risk factor for mortality from diarrhea in the US⁽³⁵⁾. Because parental recall of birth weight vs. prematurity may be problematic there may be some overlap between these two risk factors⁽³³⁾.

Breastfeeding: The impact of breastfeeding on the incidence and severity of RV is not entirely clear. In a recent US study, breastfeeding was protective against RV hospitalization in the first 6 months of life (OR 5.1, 95% CI 1.2 to 13.2), and several studies have shown breastfeeding to be protective against symptomatic RV infection⁽³³⁾. However, in a study performed in Bangladesh, although breastfeeding was protective against severe RV diarrhea during the first year of life, with a more pronounced effect among infants exclusively breastfed, there was no overall protection during the first 2 years of life, suggesting that breastfeeding only postponed infection to an older age⁽³⁶⁾. In one Canadian study, a quarter of all children admitted under 1 year of age were receiving breast milk, suggesting that breastfeeding does not provide complete protection⁽¹⁹⁾. Cohort studies report the highest infection rate between 4 and 6 months of age, coinciding with a number of potential factors, such as weaning, declining maternal antibody or increased opportunity for exposure. The greater protection and likelihood of asymptomatic infection afforded infants whose mothers' breast milk had higher levels of glycoprotein lactadherin supports a role for breast milk itself⁽³⁷⁾.

Day care centre attendance: US children in child care were more likely to be hospitalized for RV than those cared for at home, particularly those ≥ 24 months of age⁽³³⁾. It is important to note that there are marked differences between US and Canadian child care in levels of provider education, age at entry and child:staff ratios. A Canadian prospective study failed to find an association with child care arrangement, including day care centre attendance⁽¹⁹⁾.

Presence of another child in the house < 24 months old: This is a recently identified risk factor for RV hospitalization (OR 1.6, 95% CI 1.1 to 2.3)⁽³³⁾. It has also been identified as a risk factor for development of RV diarrhea⁽³⁸⁾. It is important to note that neither study assessed household crowding.

Maternal age < 25 years: This has been identified as a risk for infant RV hospitalization in the United States (OR 1.4, 95% CI 1.0 to 2.0)^(33,34).

Child's gender: In a US study, male children were identified as having a greater risk of RV diarrhea than female children⁽³⁴⁾. A Canadian study showed that significantly more male (57%) than female children presented with diarrhea, although the proportion who were RV positive was similar⁽²⁰⁾. This is also consistent with findings of both the Immunization Monitoring Program, Active (IMPACT), in which 60% of rotavirus cases presenting to the emergency department or hospital were male (Lisa Landry, IMPACT/ PHAC database: personal communication, 2007), and MIRAGE, in which 59% of the rotavirus positive cases were male⁽²¹⁾.

Immunocompromised persons: Children and adults who are immunocompromised because of congenital immunodeficiency, haematopoetic transplantation or solid organ transplantation sometimes experience severe, prolonged and even fatal RV gastroenteritis^(39-42). The median duration of viral shedding is 17 days (4 to 73 days)⁽⁴³⁾.

Nosocomial RV: Children hospitalized with community-acquired RV infection have the potential to be sources of nosocomial cases of infection. IMPACT identified that 32% to 35% of the cases identified in hospitalized children across Canada were nosocomial (Dr. P. Sockett, IMPACT/ PHAC database: personal communication, 2007). A Canadian study in 1990 noted a nosocomial diarrhea (not exclusively rotavirus) rate of 4.5 infected children per 100 admissions⁽⁴⁴⁾.

First Nations and Inuit: Historically in Canada, First Nations and Inuit populations had high rates of RV disease in the 1970s. A prospective study done in the early 1980s found that Inuit infants in remote, isolated northern communities had significantly higher rates of RV-associated diarrhea in the first 6 months of life (0.73 to 1.07 infections per child per year) than First Nations infants (0.36 infections per child per year)⁽⁴⁵⁾.

Adults: Among adults in the US, RV infection causes gastroenteritis primarily in travellers returning from developing countries, parents and persons caring for children with RV gastroenteritis, immunocompromised persons, and older adults⁽⁴⁶⁾. Outbreaks of RV gastroenteritis have been reported in long-term care facilities and are associated with considerable morbidity in this setting^(46-49).

Summary of rotavirus epidemiology

• Rotavirus is a common cause of gastroenteritis in children; overall, approximately 20% of all childhood gastroenteritis is caused by rotavirus.
• Rotavirus is associated with considerable health care utilization, approximately 35% of children with rotavirus gastroenteritis seeing a physician, 15% visiting an emergency department and 7% requiring hospitalization.
• Rotavirus causes the majority of childhood gastroenteritis requiring hospitalization; overall, between 1/62 to 1/312 children < 5 years of age will require hospitalization for rotavirus.
• Household transmission of rotavirus is common, at least one other family member experiencing gastroenteritis in 47% of cases.

Rotavirus vaccines: Rotashield^®

In 1998, Rotashield^® (Wyeth-Lederle Vaccines), a rhesus-human reassortant RV vaccine, was recommended for routine vaccination of US infants in a schedule of three doses at ages 2, 4 and 6 months^(50,51). However, it was withdrawn from the US market within 1 year of its introduction because of an association with intussusception. In the first 9 months after licensure and immunization of > 600,000 children with one to three doses, intussusception developed in 15 children during the 2-week period immediately following vaccine administration⁽²²⁾. The risk of intussusception was approximately 20-fold within 3 to 14 days following the first dose and approximately five-fold within 3 to 14 days following the second dose^(15,52). Overall, the risk associated with the first dose of Rotashield^® was estimated to be approximately 1 case per 5,000 to 10,000 children immunized⁽⁵²⁾. The risk of intussusception appears to have been age-dependent, in that the risk increased with greater age at vaccination, particularly with receipt of the first dose after 3 months of age. Eighty percent of intussusception cases reported occurred in the 38% of infants who were ≥ 90 days old at the time of administration of the first vaccine dose⁽⁵³⁾. Infants immunized with their first dose of Rotashield^® < 3 months of age had a substantially lower risk of intussusception than those who were older (approximately 1/30,000 vs. < 1/8000)⁽⁵³⁾. No vaccine-associated cases of intussusception were observed among infants who received the first dose of Rotashield^® at < 60 days of age⁽⁵³⁾.

The relationship between vaccine-associated intussusception risk and increased age at first vaccination was confirmed by Rothman et al. using alternative mathematical modeling techniques⁽⁵⁴⁾. On the basis of these analyses, the authors have suggested that much of the adverse effect that Rotashield^® vaccination had on the occurrence of intussusception could have been averted by confining the administration of the vaccine to very young infants^(53,54). The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety (GACVS), after reviewing all available data, concluded that the risk of Rotashield^®-associated intussusception was greater in infants vaccinated after 60 days of age but that insufficient evidence was available to conclude that the use of the vaccine among infants < 60 days of age was associated with a lower risk⁽⁵⁵⁾. GACVS noted that the possibility of an age-dependent risk of intussusception should be taken into account when assessing future RV vaccines.

In addition to intussusception, post-marketing surveillance has suggested an association between Rotashield^® and a spectrum of other gastrointestinal symptoms, including gastroenteritis and hematochezia (bloody stools)⁽⁵⁶⁾.

Pentavalent human-bovine reassortant rotavirus vaccine: RotaTeq™

Vaccine composition

RotaTeq™ is a live, oral, pentavalent vaccine that contains five live reassortant RVs. The RV parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant RVs express one of the outer capsid proteins (G1, G2, G3 or G4) from the human RV parent strain and the attachment protein (P7) from the bovine RV parent strain. The fifth reassortant virus expresses the attachment protein P1[8] (genotype P[8]) from the human RV parent strain and the outer capsid protein G6 from the bovine RV parent strain. The parent bovine strain RV WC3 - G6, P7[5] used in all reassortants has been passaged in African green monkey cells, and the reassortants are propagated in Vero monkey kidney cell lines using standard tissue culture techniques in the absence of antifungal agents.

Each 2 mL vaccine dose contains a minimum level of the five reassortants as follows:

G1:       2.2 x 10⁶ infectious units
G2:       2.8 x 10⁶ infectious units
G3:       2.2 x 10⁶ infectious units
G4:       2.0 x 10⁶ infectious units
P1[8]:   2.3 x 10⁶ infectious units.

Reassortants are suspended in a buffered stabilizer solution. Each vaccine dose is supplied as a single, pre-filled 2 mL unit dose in a plastic dosing tube with a twist-off cap and contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80 and also cell culture media and trace amounts of fetal bovine serum. There are no preservatives or thimerosal present, and all packaging is latex free. No reconstitution or dilution is required.

Immunogenicity

The immune correlates of protection from RV infection and disease are not fully understood. In clinical trials, seroconversion, defined as a 3-fold or greater rise in antibody titre from baseline, for neutralizing antibodies to G1, G2, G3, G4 and P1[8] were significantly higher in vaccine recipients than placebo groups (21% to 76% versus 0% to 7.4%)⁽⁵⁷⁾. Seroconversion rates for IgA antibody to RV were 95% (95% CI 91.2% to 97.8%) among 189 vaccine recipients versus 14.3% (95% CI 9.3% to 20.7%) among 161 placebo recipients⁽⁵⁸⁾.

Efficacy

RotaTeq™ has been evaluated in three phase III trials, the largest of which was the Rotavirus Efficacy and Safety Trial. A total of 71,942 infants have been studied in these phase III trials (36,165 who received RotaTeq™ and 35,560 who received placebo)^(15,58). In these trials, three doses of RotaTeq™ were administered orally beginning at 6 to 12 weeks of age with a 4 to 10 week interval between doses. Doses were administered up to 32 weeks of age without restriction due to breastfeeding or administration of other licensed childhood vaccines, except oral poliovirus vaccine.

Overall, the efficacy of three doses of RotaTeq™ against severe RV gastroenteritis caused by G serotypes contained in the vaccine (G1, G2, G3, G4) was 98.2% (95% CI 89.6% to 100%) and against RV gastroenteritis of any severity was 73.8% (95% CI 67.2% to 79.3%) during the first full rotavirus season after completion of vaccination. The vaccine was designed to prevent RV gastroenteritis caused by the individual G serotypes contained in the vaccine (G1, G2, G3, G4); P1[8] was included in the vaccine to potentially provide cross-protection against non-vaccine G serotypes that may contain P1[8]. On the basis of limited data, the efficacy of the vaccine against RV gastroenteritis of any severity caused by the non-vaccine serotype G9 was 74% (95% CI < 0% to 99.5%) (Table 4). However, it should be noted that the frequency of infection with non-G1 strains was very low. The confidence intervals around the efficacy estimate for G2, G3, G4 and G9 strains are broad and, in fact, cross 1 for G3, G4 and G9. Therefore, further data are needed to establish the efficacy of RotaTeq™ against non-G1 strains.

In a smaller sample of 4,512 infants (2,207 RotaTeq™, 2,305 placebo), the second season efficacy of the vaccine against G1-G4 RV gastroenteritis of any severity was 62.6% (95% CI 44.3% to 75.4%) and that against severe disease was 88.0% (95% CI 49.4% to 98.7%) (36/813 vaccine recipients vs. 88/756 placebo recipients for whom data were available)⁽⁵⁸⁾.

Table 4. Efficacy of RotaTeq™ rotavirus vaccine against RV gastroenteritis caused by G serotypes contained in the vaccine through the first full RV season after completion of vaccination in phase III trials (adapted from the Product Monograph)

 

In the large Rotavirus Efficacy and Safety Trial (REST), among infants included in the per-protocol analysis (28,646 in the vaccine group and 28,488 in the placebo group), RotaTeq™ reduced G1-G4 RV-associated hospitalization or emergency department visits by 94.5% (95% CI 91.2% to 96.6%) and non-urgent office or clinic visits by 86% (95% CI 73.9% to 92.5%)⁽⁵⁸⁾. Further, there was a reduction of 58.9% (95% CI 51.7% to 65.0%) in all gastroenteritis-related hospitalizations after the first dose (Table 5). Among the parents/guardians of the 68,038 infants studied, there was an 86.6% (95% CI 78.0% to 91.9%) reduction in work days lost (65 lost days for parents/guardians of vaccine recipients versus 487 lost days for parents/guardians of placebo recipients)⁽⁵⁸⁾. Similarly, in the MIRAGE Study, parents of children with RV were more likely to take time off work than parents of children with gastroenteritis of other causes (54% vs. 37%, p = 0.003)⁽²¹⁾. Parents of children with RV who took time off work missed an average of 2.6 days compared with 1.8 days for parents of children with gastroenteritis due to other causes (non-significant difference)⁽²¹⁾.

Data on the efficacy of fewer than three doses of RotaTeq™ are limited. In a very small study of < 100 children, estimated efficacy in reducing RV hospitalization after one, two and three doses was 29% (95% CI < 0% to 73.3%), 80% (95% CI 8.5% to 95.8%) and 95% (95% CI 91.5% to 96.5%), respectively⁽⁵⁹⁾. In the REST trial, the comparatively higher one-dose efficacy, of 58.9%, in reducing all-cause diarrhea hospitalizations⁽⁵⁸⁾ may be explained by differences in study time and place. The overall efficacy of RotaTeq™ for the prevention of emergency department visits or hospitalization due to all serotypes of RV was 83%, 81% and 95% 2 weeks following the first, second and third dose, respectively⁽⁶⁰⁾.

Table 5. Number of health care contacts and reduction in rates of RV gastroenteritis caused by G serotypes contained in the RotaTeq™ vaccine*

 

RotaTeq™ or placebo was administered to 2,070 pre-term infants (25 to 36 weeks' gestational age) according to their chronological age in the Phase III trials. Vaccine efficacy was evaluated in a subset of 204 pre-term infants (153 evaluable), who were followed for gastroenteritis. Efficacy (70.3%) (95% CI 15% to 95%) was generally similar to that seen in the overall population. However, the confidence bounds crossed zero because the sample size was small⁽¹⁵⁾. Breastfeeding did not appear to diminish the efficacy of a three-dose series of RotaTeq™. Among 1,566 exclusively breastfed infants, the efficacy of the vaccine against RV gastroenteritis of any severity was 68% (95% CI 54% to 78%), the same as the efficacy observed in 1,632 infants who were never breastfed, of 68% (95% CI 46%-82%)⁽⁵⁸⁾.

Vaccine safety and adverse events

Given the relatively low morbidity and mortality associated with natural RV infection in Canada and the US experience with a previous RV vaccine that has now been withdrawn, it is essential that the safety of RV vaccine be carefully reviewed and that it should be deemed considerably safer than natural infection. Experience with the previous rotavirus vaccine and intussusception has demonstrated the importance of conducting post-marketing surveillance to identify rare or very rare adverse events (i.e.1/1000 to 1/10,000 and < 1/10,000, respectively). Detection of an increased risk of intussusception associated with RotaTeq™ will require data on baseline rates of intussusception in the target population in Canada, which are currently lacking.

Intussusception: The risk of intussusception was evaluated in 71,725 infants enrolled in phase III RotaTeq™ efficacy trials^(15,58). In a large-scale safety and efficacy trial designed specifically to evaluate the risk of intussusception, six cases were observed in the RotaTeq™ group versus five cases in the placebo group (multiplicity adjusted relative risk = 1.6, 95% CI 0.4 to 6.4) within 42 days of any vaccine dose⁽⁵⁸⁾. This provides a ratio of 1:49 vs. 1:60 in vaccine vs. placebo recipients. No evidence of clustering of cases of intussusception was observed within a 7- or 14-day window after vaccination for any dose, the period of greatest risk for intussusception associated with Rotashield^®. For the one year follow-up period after administration of the first dose, 13 cases of intussusception were observed in the RotaTeq™ group versus 15 cases in the placebo group (multiplicity adjusted relative risk: 0.9, 95% CI 0.4 to 1.9)⁽⁵⁸⁾.

In the US, post-marketing safety of RotaTeq™ is being monitored by the Centers for Disease Control and Prevention (CDC) and the FDA through both evaluation of reports to the Vaccine Adverse Events Reporting System (VAERS) and active surveillance using data from the Vaccine Safety Datalink (VSD). Additionally, Merck is conducting a post-marketing observational study in 44,000 infants in the US designed to monitor for occurrence of intussusception within 30 days of receipt of RotaTeq™.

As of 31 January, 2007, 3.6 million doses of RotaTeq™ had been distributed in the United States (Merck, unpublished data); the number of doses administered is not known. An assessment of a potential association between RotaTeq™ and intussusception was recently published(61). Background rates of intussusception in infants 6 to 14 weeks of age, 15 to 23 weeks of age and 24 to 35 weeks of age were determined from hospital discharge diagnoses at the VSD study sites for the period 2000-2004, before the use of RotaTeq™. The number of intussusception reports to VAERS following RotaTeq™ vaccination was then compared with the number of cases expected to occur (i.e. the background number of cases of intussusception).

From 1 February, 2006, to 15 February, 2007, VAERS received reports of 35 cases of intussusception that met the Brighton Collaboration case definition(62); 17 of these (49%) occurred within 1 to 21 days of vaccination, 11 (31%) occurred within 1 to 7 days of vaccination, and the other 18 cases occurred between 22 and 73 days after vaccination, with the exception of one case that occurred on the same day as vaccination. Of the 17 cases reported within 21 days of vaccination, nine (53%) occurred following the first dose, eight (47%) occurred following the second, and none followed the third dose. Ten infants (59%) required surgery (including five who required intestinal resection). In the remaining seven infants, intussusception resolved spontaneously or was successfully reduced by barium enema.

On the basis of VSD data for the period 2000-2004, the background rate of intussusception was 18.1 per 100,000 person years (PY) among infants 6 to 14 weeks of age, 32.5 per 100,00 PY in infants 15 to 23 weeks of age and 42.5 per 100,000 PY among infants 24 to 35 weeks of age. By applying these background intussusception rates to the estimated distributed doses per age group, an expected number of 57 cases of intussusception was calculated for the period from one to 21 days after vaccination. Seventeen of these cases would be expected to occur between one and 7 days after vaccination. In contrast, 17 intussusception cases were reported to VAERS that occurred during the period one to 21 days after vaccination, including 11 cases that occurred between one and 7 days after vaccination. Thus, VAERS reports of intussusception following RotaTeq™ vaccination have not been higher than expected according to age-adjusted background rates between one and 21 days after vaccination (relative risk [RR] 0.32, 95% CI 0.17 to 0.55) or between one and 7 days after vaccination (RR 0.61; 95% CI 0.29 to 1.18).

Between 1 February, 2006, and 15 February, 2007, a total of 28,377 doses of RotaTeq™ were distributed in VSD-monitored health maintenance organizations. No intussusception cases occurring within 30 days of RotaTeq™ vaccination have been reported, whereas eight intussusception cases were reported among approximately 240,110 infants who received vaccines other than RotaTeq™.

In summary, post-marketing surveillance following distribution of 3.6 million doses of RotaTeq™ in the US does not demonstrate or suggest an increased risk of intussusception among infants following RotaTeq™ vaccination. This is very reassuring, as the association between intussusception and Rotashield^® was observed following immunization of only approximately 600,000 infants. Because VAERS is a passive reporting system, it is possible that intussusception is underreported. However, given the awareness of both providers and the public regarding the association of the previous rotavirus vaccine (i.e. Rotashield^®) and intussusception, it is unlikely that significant underreporting is occurring.

The CDC and FDA will continue to monitor adverse events reported in the US following vaccination with RotaTeq™.

Hematochezia: The most comprehensive, complete and final dataset on hematochezia comes from the Safety Update Report, which is the complete safety follow-up data integrated across the three Phase III protocols^(15,58) (Merck Frosst Canada, Inc.: personal communication, 2007). Among the 11,690 subjects in the detailed safety cohort of the Phase III trials, the overall incidence of hematochezia within 42 days of the first vaccine dose was 0.6% in each group (39/6,130 in the vaccine group and 34/5560 in the placebo group).

Although not significantly different, an increased rate of hematochezia was observed among negatively adjudicated intussusception cases (i.e. cases that did not meet the study case definition for intussusception) in the Phase III trials. In total, 17 cases of hematochezia were seen in the vaccine group vs. nine in the placebo group (12 cases vs. seven cases within 42 days of any dose and seven cases vs. four cases in the 42 days following dose one). The rate of hematochezia in vaccinees was 0.5% compared with 0.3% among placebo recipients following dose one. Although this difference was not statistically significant, similar differences were not observed after the second or third doses, raising the possibility of an increased risk of hematochezia after the first dose.

A total of 19 cases of hematochezia have been reported to VAERS during post-marketing surveillance in the US, representing 10% of all reports; 68% of reported episodes occurred within 3 days of vaccination, and 68% occurred in infants 2 months of age. The frequency of 19 cases of hematochezia/1.7 million doses of RotaTeq™ distributed is compared with 60 cases/1.5 million doses of Rotashield®.

Other adverse events following immunization: Serious adverse events and deaths were evaluated in 71,725 infants enrolled in phase III trials⁽⁵⁸⁾. Among RotaTeq™ and placebo recipients, the incidence of serious adverse events (2.4% vs. 2.6%, respectively), including deaths (< 0.1% [n = 25] vs. < 0.1% [I = 27], respectively), was similar. The most frequently reported serious adverse events were bronchiolitis (0.6% RotaTeq™ vs. 0.7% placebo), gastroenteritis (0.2% vs. 0.3 %), pneumonia (0.2% vs. 0.2 %), fever (0.1% vs. 0.1 %) and urinary tract infection (0.1% vs. 0.1 %).

No deaths were attributed to vaccination by blinded investigators. Of 52 reported deaths, the most common cause was Sudden Infant Death Syndrome (SIDS) (17/52). Deaths from SIDS were equally distributed between RotaTeq™ and placebo recipients (eight and nine, respectively).

Seizures reported as serious adverse experiences occurred in < 0.1% (27/36,150) of vaccine and < 0.1% (18/35,536) of placebo recipients. Although not statistically significantly different, the number of seizures reported among vaccine recipients was consistently higher than that reported among placebo recipients in each time interval after immunization (Table 6). As the number of febrile seizures reported was the same in both groups (five), the apparent increase in seizure frequency among vaccinees appears to be attributable to non-febrile seizures. Post-marketing surveillance will be necessary to determine whether RotaTeq™ is associated with an increased risk of seizure.

Table 6. Seizures reported by day after vaccination in relation to any dose in Phase III trials of RotaTeq™

 

Kawasaki disease occurred in 5/36,150 infants who received RotaTeq™ and 1/35,536 infants who received placebo during the Phase III clinical trials. This difference was not statistically significant. Additionally, three cases of Kawasaki disease have been reported to VAERS since vaccine licensure in the US in February 2006, following distribution of approximately 6 million doses. One case of Kawasaki disease occurring within 30 days of RotaTeq™ vaccination (65,000 doses administered to children < 1 year) has been observed in the VSD Project. The reported cases of Kawasaki disease following immunization with RotaTeq™ do not represent an increased risk over what would be expected to occur among children < 1 year of age who did not receive the vaccine. There is not a known cause-and-effect relationship between receiving RotaTeq™, or any other vaccine, and the occurrence of Kawasaki disease. The FDA and CDC will continue to monitor cases of Kawasaki disease reported following vaccination with RotaTeq™.

A subset of 11,722 infants were studied in detail to assess other potential adverse experiences. Overall, 47.0% of infants given RotaTeq™ experienced an adverse event following vaccination compared with 45.8% of infants given placebo⁽¹⁵⁾. The most commonly reported adverse experiences that occurred more frequently with RotaTeq™ than with placebo were pyrexia (20.9%), diarrhea (17.6%) and vomiting (10.1%). In the 7-day period after vaccination, vaccinees had a small, but statistically significant, increased rate of diarrhea after every dose (10% vs. 9% following dose one, 9% vs. 6% following dose two, 18% vs. 15% following dose three)⁽¹⁵⁾. Vaccinees also had a small, but statistically significant, greater rate of vomiting (12% vs. 10% following any dose). In the 42-day period after vaccination, vaccinees had a small but significantly greater rate of vomiting (15% vs. 14%), diarrhea (24% vs. 21%), nasopharyngitis (7% vs. 6%), otitis media (15% vs. 13%) and bronchospasm (1.1% vs. 0.7%). Among RotaTeq™ and placebo recipients, the incidence of reported episodes of fever (43% vs. 43%) was the same. The incidence of fever and irritability during the 7-day period after any vaccine dose was similar among RotaTeq™ and placebo recipients.

Safety in pre-term infants: RotaTeq™ or placebo was administered to 2,070 pre-term infants (25 to 36 weeks' gestational age, median 34 weeks) according to their chronological age in the Phase III trials. All pre-term infants were followed for serious adverse experiences, and a subset of 308 infants was monitored for all adverse experiences. There were four deaths throughout the study, two in vaccine recipients (one SIDS and one motor vehicle accident) and two in placebo recipients (one SIDS and one unknown cause). No intussusception cases were reported. Serious adverse experiences occurred in 5.5% of vaccine and 5.8% of placebo recipients. The most common serious adverse experience was bronchiolitis, which occurred in 1.4% of vaccine and 2.0% of placebo recipients. The frequencies of vomiting, diarrhea and irritability were not higher among pre-term infants than term infants within 7 days after administration of RotaTeq™.

Shedding and transmission of vaccine virus: Fecal shedding of vaccine virus was evaluated in a sub-study of 134 infants within REST by viral culture with use of a plaque assay and RNA electropherotyping; a single stool sample was obtained during days 4 to 6 following each vaccination(58). Fecal shedding occurred in 12.7% after the first dose; no shedding was documented after the second or third dose. In a smaller, end-of-shelf-life study(17), all stool samples found to be RV positive by enzyme immunoassay were tested by reverse transcriptase PCR (polymerase chain reaction), and shedding of viable vaccine reassortants was evaluated by plaque assay and RNA electropherotyping. Only one was identified as positive after the first dose. Overall, during Phase III studies, vaccine virus was shed in 8.9% (95% CI 6.2% to 12.3%) of infants after the first dose, none (95% CI 0% to 1.5%) after the second dose and 0.3% (95% CI < 0.1% to 1.4%) after the third dose(17). Shedding occurred from 1 to 15 days after a dose. The potential for horizontal transmission of vaccine virus has not been evaluated.

Dosage and schedule

RotaTeq™ is given as three separate 2 mL oral doses. Correct timing of administration is critical given the apparent age-associated risk of intussusception observed with Rotashield^® and the lack of safety data in infants outside the recommended age range. As detailed earlier (see "Rotavirus vaccines") the risk of intussusception associated with Rotashield^® appears to have been age-dependent, the risk increasing with increased age at vaccination, particularly with receipt of the first dose after 3 months of age. Eighty percent of intussusception cases reported occurred in infants who were ≥ 90 days at the time of administration of the first vaccine dose⁽⁵³⁾. Because of concerns arising from the experience with Rotashield^®, clinical trials with RotaTeq™ have strictly adhered to schedules providing the first dose of vaccine at 6 to 12 weeks of age and completing the vaccination series by 32 weeks of age. Thus, data on the safety of administering the vaccine to infants outside of this age range are lacking.

The first dose of RotaTeq™ vaccine should be administered between 6 and 12 weeks (13 weeks minus a day) of age. The first dose should not be given after 12 weeks of age. Following the initial dose, subsequent doses should be administered at an interval of 4 to 10 weeks between each dose. All doses should be administered by 32 weeks of age.

In the absence of safety data regarding administration of RotaTeq™ in the home setting and given concerns about maintenance of the cold chain, the Committee recommends that all doses be given in a clinic/office setting under the direction of a health care provider.

Interrupted vaccine schedules

If, for any reason, an incomplete dose is administered (e.g., the infant spits or regurgitates the vaccine), a replacement dose is not recommended.

For infants in whom the first dose of RotaTeq™ vaccine is inadvertently administered off label at age ≥ 13 weeks, the rest of the RotaTeq™ vaccination series should be completed with a minimum of 4 weeks between each dose. All doses should be administered by 32 weeks of age.

Previous RV infection

Infants who have had RV gastroenteritis before receiving the full course of RV vaccinations should still initiate or complete the three-dose schedule, because the initial infection frequently provides only partial immunity⁽⁶⁰⁾.

Breastfeeding

Infants who are being breastfed can receive RV vaccine. The efficacy of RV vaccine is similar among breastfed and non-breastfed infants⁽⁶⁰⁾.

Intercurrent illness

Like other vaccines, RV vaccine can be administered to infants with transient mild illnesses and to those with or without fever⁽⁶⁰⁾. See "Precautions" below for guidance on vaccine administration to infants with acute gastroenteritis.

Premature infants (< 37 weeks gestation)

Currently available evidence demonstrates that RotaTeq™ is safe and effective in premature infants, although a relatively small number of pre-term infants have been evaluated. Because premature infants have lower levels of maternal antibodies against RV, they may theoretically be at increased risk of both severe, naturally occurring RV gastroenteritis and of adverse reactions to the rotavirus vaccine. Premature infants who are between 6 and 32 weeks of chronological age can receive RotaTeq™. The first dose of RotaTeq™ vaccine should be administered between 6 and 12 weeks (13 weeks minus 1 day). All doses should be administered by 32 weeks of age.

Exposure of immunocompromised persons or pregnant women to vaccinated infants

Vaccine virus may be shed by up to 13% of recipients of RotaTeq™ between 1 and 15 days after immunization, and this is most likely to occur following the first dose. The potential for horizontal transmission of vaccine virus has not been evaluated. However, the benefit of protecting immunocompromised household contacts from naturally occurring RV by immunizing infants is believed, by most experts, to outweigh the theoretical risk of transmitting vaccine virus. Thus, infants living in households with persons who have or are suspected to have immunosuppressive conditions or who are receiving immunosuppressive medications can be vaccinated. To minimize the risk of transmission of vaccine virus, careful handwashing should be used after contact with the feces of the vaccinated infant (i.e., after changing a diaper).

Infants living in households with pregnant women can be vaccinated. Because most women of childbearing age have pre-existing immunity to RV through natural exposure, the risk of infection and disease from vaccine virus is low. Additionally, rotavirus infection during pregnancy is not known to pose a risk to the fetus.

Storage and handling

RotaTeq™ should be protected from light, stored and transported refrigerated at 2° C to 8° C and should not be frozen. The vaccine should be used before the expiration date and has a shelf life of 2 years when stored under the appropriate conditions. Vaccine should be administered as soon as possible after removal from refrigeration, but administration may be delayed for up to 4 hours if the vaccine has been maintained at temperatures at ≤ 25° C.

Simultaneous administration with other vaccines

When RotaTeq™ was administered concomitantly with other routine infant vaccines in clinical trials it was well tolerated. When administered simultaneously, a three-dose series of RotaTeq™ does not diminish the immune response to Haemophilus influenzae type b conjugate (Hib) vaccine, inactivated poliovirus vaccine (IPV), hepatitis B vaccine, pneumococcal conjugate vaccine, or the diphtheria and tetanus antigens in diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) (Merck, unpublished data, 2005). A reduction in response to pertussis pertactin was observed in the REST clinical trial (Rotavirus Efficacy and Safety Trial)⁽⁵⁸⁾. However, subsequent analysis of antibody responses to pertussis antigens in a larger sample of subjects receiving concomitant RotaTeq™ and DPT-IPV-Hib confirmed a reduction in geometric mean titres to pertactin in the original sample studied from the REST trial, but failed to demonstrate a difference in geometric mean titre to pertactin in the additional subjects studied or in the total sample⁽⁶³⁾. No data have been provided to indicate that RotaTeq™ can be administered with conjugated meningococcal C vaccine. Nonetheless, it is felt that RotaTeq™ may be administered concomitantly with all routinely recommended infant vaccines.

RotaTeq™ cannot be administered with oral polio vaccine, as concomitant administration of the two vaccines has not been studied, but this is irrelevant in Canada, where IPV is used exclusively.

Contraindications

Persons who are hypersensitive to RotaTeq™ or to any of its ingredients or any components of the container should not receive the vaccine, and individuals who experience symptoms suggestive of hypersensitivity after receiving a dose of RotaTeq™ should not receive further doses.

History of intussusception: No association between RotaTeq™ and intussusception has been demonstrated in large-scale safety trials involving over 70,000 infants or through post-marketing surveillance following distribution of 3.6 million doses of vaccine in the US. However, because of the previously documented association of Rotashield^® with increased rates of intussusception, incomplete understanding of the pathogenic mechanisms underlying this increased risk and the possibility that infants with a history of intussusception are at increased risk of subsequent episodes, infants with a history of intussusception should not be given RotaTeq™ until further post-licensure safety data are available.

Immunocompromise: Infants known or suspected to be immunocompromised should not receive RotaTeq™. There are no safety or efficacy data available for its administration to immunocompromised patients, as these patients were excluded from clinical trials.

Precautions

Administration of blood transfusions or blood products, including immunoglobulins, within 42 days before administration of RotaTeq™ may be associated with decreased vaccine efficacy. However, this has not been studied.

Acute gastroenteritis: The immunogenicity and efficacy of RotaTeq™ has not been studied in infants with concurrent gastroenteritis. However, in these infants, as is the case with oral polio vaccine, the immunogenicity and effectiveness of the vaccine may theoretically be reduced⁽⁶⁴⁾. Therefore, in infants with moderate to severe gastroenteritis, rotavirus vaccine should be deferred until the condition improves, unless deferral will result in scheduling of the first dose at ≥ 13 weeks of age. Infants with mild gastroenteritis can be vaccinated.

Pre-existing chronic gastrointestinal conditions: The safety and efficacy of RotaTeq™ has not been established in children with pre-existing chronic gastrointestinal conditions. However, infants with chronic gastrointestinal disease who are not receiving immunosuppressive therapy are likely to benefit from rotavirus vaccination and therefore can be vaccinated.

Recommended usage

Although the limited available Canadian data demonstrate a high prevalence of illness associated with RV gastroenteritis among Canadian children, with an estimated 1/62 to 1/312 children < 5 years of age experiencing an RV-associated hospitalization lasting an average of 2 to 3 days, the disease is typically self-limited and only very rarely associated with long-term sequelae or death. However, it is associated with a noteworthy societal disruption when time off work for caregivers is considered.

Because RV causes only approximately 20% of all diarrheal illness in Canadian children, even a highly effective vaccine will appear ineffective to the general public. Insufficient data about the strain distribution of RV in Canada, and geographic and seasonal trends in distribution make prediction of the absolute impact of a universal RV vaccine program difficult. It must be recognized that vaccine effectiveness may be lower than the vaccine efficacy reported in clinical trials. Using the burden of disease estimated by the Rotavirus Gastroenteritis Cohort Model (Table 3) and the observed vaccine efficacy in clinical trials (Tables 4 and 5), and assuming that approximately 94% of RV disease in Canada is caused by RV strains contained in RotaTeq™, implementation of universal immunization of all Canadian infants could be expected to prevent as many as 56,000 cases of RV gastroenteritis, 33,000 physician visits, 15,000 emergency department visits and 5,000 hospitalizations annually. If the hospitalization rate is actually lower than that estimated by the Rotavirus Gastroenteritis Cohort Model, as suggested by the limited published Canadian data demonstrating hospitalization rates as low as 320/100,000, universal immunization may prevent as few as 1,000 hospitalizations annually. Prospective surveillance data from IMPACT will soon be available to provide better RV epidemiologic data regarding burden of illness and RV strain distribution in Canada.

Canadian epidemiology suggests that individual infants and their families are likely to benefit from immunization with RotaTeq™. The vaccine has been approved for use in infants 6 to 32 weeks of age and should be offered to infants whose parents/guardians wish to reduce the risk of rotavirus. The first dose must be given within 12 weeks of age. Adherence to recommendations regarding the timing of administration of RotaTeq™ should be ensured, as the safety of its administration outside of these age recommendations is not known (see earlier section, Dosage and Schedule).

The decision to include RotaTeq™ in universal, publicly funded provincial and territorial programs will depend upon other factors, such as detailed cost-benefit evaluation and assessment of other elements of the Erikson and DeWals analytic framework for immunization programs in Canada⁽⁶⁵⁾.

Research questions

Some outstanding questions about RotaTeq™ that will influence the overall impact of the vaccine can only be determined in post-licensure studies. These include the following:

1. The efficacy of vaccine for fewer than three doses, especially given the strict age of approval.
2. The impact of the timing of vaccine dosing in relation to onset of the RV season.
3. Duration of protection in the second year and beyond.
4. The role of the vaccine in preventing disease caused by non-G1 serotypes (especially G2 and G3) and non P1[8]-containing G serotypes.
5. Determination of protective efficacy through serotyping of circulating strains and relative importance of heterotypic and homotypic immune responses and protection⁽⁵⁰⁾.
6. Impact of herd immunity.

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^†Members: Dr. J. Langley (Chairperson), Dr. T. Tam (Executive Secretary), Dr. K. Laupland, Dr. S. Dobson, Dr. B. Duval, Ms. A. Hanrahan, Dr. J. Kellner, Dr. A. McGeer, Dr. S. McNeil, Dr. M-N Primeau, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan, Dr. B. Warshawsky.

Liaison Representatives: Dr. P. Hudson (CPHA), Dr. B. Bell (CDC), Dr. D. Money (SOGC), Ms. K. Pielak (CNCI), Dr. B. Larke (CCMOH), Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE), Dr. P. Orr (AMMI Canada).

Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. RM. Ramsignh (FNIHB), Dr. P. Laforce (DND), Dr. B. Law (IRID), Ms. R. Hickey (TMP).

^{† †}This statement was prepared by Dr. Shelly McNeil, and approved by NACI and the Public Health Agency of Canada.