NACI Statement: Update on rotavirus vaccines

Volume 36 ACS-4, July 2010

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)^†

Updated Statement on the use of Rotavirus Vaccines

Contributors

† Members: Dr. J. Langley (Chair), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Dr. N. Crowcroft (Ontario Agency for Health Protection and Promotion), Ms. A. Hanrahan (Alberta Health Services), Dr. B. Henry (BC Centre for Disease Control), Dr. D Kumar (University of Alberta), Dr. A. McGeer (Mount Sinai Hospital), Dr. S. McNeil (Associate Professor of Medicine, University of Alberta), Dr. C. Quach-Thanh (Montreal Children's Hospital), Dr. B. Seifert (Winnipeg Regional Health Authority), Dr. D. Skowronski (BC Centre for Disease Control), Dr. B. Tan (Associate Professor of Pediatrics, Royal University Hospital), Dr. C. Cooper (Canadian Association for Immunization Research and Evaluation)

Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Paediatric Society), S. Pelletier (Community Hospital Infection Control Association), Dr. N. Sicard (Canadian Public Health Association), Dr. V. Senikas (Society of Obstetricians and Gynaecologists of Canada), Dr. P. Plourde (Committee to Advise on Tropical Medicine and Travel), Dr. P. Van Buynder (Council of Chief Medical Officers of Health), Dr. P. Orr (Association of Medical Microbiology and Infectious Disease Canada)

Ex-Officio Representatives: Ms. M. FarhangMehr (Centre for Immunization and Respiratory Infectious Diseases), Dr. S. Desai (Centre for Immunization and Respiratory Infectious Diseases), Dr. B. Law (Centre for Immunization and Respiratory Infectious Diseases), LCol (Dr.) James Anderson (Department of National Defence), Dr. Ezzat Farzad (First Nations and Inuit Health Branch – Office of Community Medicine), Dr. F. Hindieh (Biologics and Genetic Therapies Directorate), Dr. D. Elliott (Centre for Immunization and Respiratory Infectious Diseases, Dr. P. Varughese (Centre for Immunization and Respiratory Infectious Diseases)

DOI

https://doi.org/10.14745/ccdr.v36i00a04

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.

Introduction

Since the publication of the Statement on the Recommended Use of Pentavalent Human-Bovine Reassortant Rotavirus Vaccine in CCDR in January 2008^{Footnote 1} a new rotavirus vaccine (Rotarix™, GlaxoSmithKline Inc.) has been authorized for use. Additional epidemiologic, safety and effectiveness information relevant to the use of rotavirus vaccines has also become available. While the two authorized vaccines (RotaTeq®, Merck Canada, Inc. and Rotarix™) both protect against rotavirus gastroenteritis, they differ in their composition and scheduled usage. This statement provides an update on the recommendations for use of pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq®) and provides information on the safety, efficacy, and recommended use of live, attenuated monovalent human rotavirus vaccine (Rotarix™).

NACI Recommendations:

1. Healthy infants: Rotavirus vaccines are recommended for infants starting at 6 weeks (6 weeks and 0 days) and up to 15 weeks (14 weeks plus 6 days). The vaccination series should be completed by 8 months (8 months plus 0 days). (Recommendation - Grade A - good evidence to recommend immunization)
2. Preterm infants: Infants who are between 6 weeks (6 weeks and 0 days) and 8 months (8 months plus 0 days) of chronological age who are healthy and not hospitalized, can receive RotaTeq® or Rotarix™. The first dose should be given between 6 weeks (6 weeks and 0 days) and up to 15 weeks (14 weeks plus 6 days). The vaccination series should be completed by 8 months (8 months plus 0 days) (Recommendation - Grade A - good evidence to recommend immunization)
3. Immunocompromised Infants: Based on the theoretical risk of live attenuated viral vaccines in immunocompromised infants, and very minimal data in this population, NACI recommends that infants with suspected or known immunocompromising conditions should not receive RotaTeq® or Rotarix™ without consultation with a physician specialist or expert in these conditions. (Recommendation - Grade E - Good evidence to recommend against immunization)
4. Infants with a history of intussusception: NACI recommends, based on current evidence, that infants with a history of intussusception should not be given rotavirus vaccines.(Recommendation - Grade E - good evidence to recommend against immunization)

Methods

NACI reviewed such considerations as the burden of illness of the disease to be prevented and the target population(s), safety, immunogenicity, efficacy, effectiveness of the vaccine(s), vaccine schedules, and other aspects of the overall immunization strategy. Following critical appraisal of individual studies, summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy (Tables 7 and 8) were prepared, and proposed recommendations for vaccine use developed. The Working Group chair and a PHAC medical specialist presented the evidence and proposed recommendations to NACI. Following thorough review of the evidence and consultation at NACI meetings, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text. See the full knowledge synthesis. PHAC maintains documentation of these processes throughout knowledge synthesis and recommendation development.

A literature review was conducted for the previous rotavirus statement^{Footnote 1} using the Medline database, from 1966 to 2007, with the following MeSH headings: Rotavirus infection, rotavirus disease, rotavirus vaccine. In follow up to this, another literature review was done to review relevant publications from 2007 to 2009. The same MeSH headings were used to collect new publications. A brief description from the previous review is presented below, along with new data.

Summary of Epidemiology and Burden of Disease

Rotavirus is a double-stranded RNA virus composed of an inner core, an internal capsid and an outer capsid. The viral serotype is defined by 2 structural viral proteins (VP) in the outer capsid: VP7, the glycoprotein (G protein) and VP4, the protease-cleaved protein (P protein)^{Footnote 2} . These outer capsid proteins elicit neutralizing antibodies believed to be important for protection. Eleven VP7 (G) serotypes and twelve VP4 (P) serotypes are known to cause disease in humans^{Footnote 3} . 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;3).

In the US and, based upon limited data in Canada, six rotavirus serotypes (P1A[8]G1, P1B[4]G2, P1A[8]G3, P1A[8]G4, P1A[8]G9, and P2A[6]G9) cause the majority of disease. These strains are generally designated by their G serotype specificity (serotypes G1-4 and G9). Approximately 55-65% of all RV gastroenteritis in 2 Canadian studies(4;5) were caused by G1 serotype. However, although non-G1 serotypes are generally less common, prevalence of individual serotypes varies year to year and geographically. Each of the other G serotypes can predominate in a given year^{Footnote 6}.

Rotavirus is a common cause of gastroenteritis in children accounting overall for 10% to 40% of all childhood gastroenteritis(7-10). Canadian epidemiologic data has been reviewed previously^{Footnote 1}. Based upon available Canadian data it is estimated that rotavirus gastroenteritis is associated with considerable healthcare utilization with approximately 36% of children with rotavirus seeing a physician, 15% visiting an emergency department, and 7% requiring hospitalization^{Footnote 11}. Rotavirus causes the majority of childhood gastroenteritis requiring hospitalization; overall, between one in 62^{Footnote 11} and one in 312^{Footnote 12} children < 5 years of age will require hospitalization for rotavirus. Parents of children with rotavirus gastroenteritis are more likely than parents of children with non-rotavirus gastroenteritis to miss work (54% versus 37%)^{Footnote 5}. Household transmission is common, with at least one other family member experiencing diarrhea in 47% of rotavirus cases(5;13).

A recent retrospective study on the burden of rotavirus infections in British Columbia^{Footnote 14} further addresses the issue of the Canadian burden of rotavirus disease. This study included data from administrative databases between 2000 and 2007 in one region in Canada. It found that the incidence of rotavirus disease among children 0-4 years of age was 50.9 per 100 000 population; the hospitalization rate was 20 per 100 000 population. These data have a few important limitations, including a retrospective study design, a limited geographic area investigated, and the use of administrative data.

Prospective surveillance data from the Canadian Immunization Monitoring Program, Active (IMPACT) has recently become available. Between January 2005 and December 2007, 1,359 children were hospitalized(15;16) with lab-confirmed, community-acquired rotavirus gastroenteritis at the 12 IMPACT hospitals. None of the 1,321 cases in which vaccination status was known had received rotavirus vaccine. 63% of cases occurred in infants ≤ 2 years; mean age of cases was 2.4 years. Underlying co-morbidities were present in 32% of children; gastrointestinal disorders accounted for more than 25% of underlying conditions with Crohn's disease and gastroesophageal reflux disease being most common. Overall, 48.6% of admitted children had dehydration and the mean duration of diarrhea and vomiting prior to admission was 2.3 days and 2.4 days, respectively. Healthcare utilization associated with rotavirus infection was considerable; including the emergency room visit that led to the hospital admission, 68.5% of children had 1 visit, 26.4% had 2 visits, 4% had three visits, and 1% had four visits to the Emergency Department. Children spent an average of 7.9 hours in the Emergency Department prior to admission and were hospitalized for an average of 3.4 days. In total, 48 children (3.5%) required intensive care for a mean duration of 2.4 days; no children with community-acquired infection died. A total of 497 children were hospitalized in IMPACT hospitals with laboratory-confirmed, hospital acquired rotavirus gastroenteritis during the same 3 year surveillance period. Thus, hospital acquired infection represented 27% (497/1856) of all admissions for rotavirus gastroenterits. Children less than 1 year of age were disproportionately affected by hospital-acquired rotavirus (59% vs 31% of community-acquired cases). None of the children with hospital-acquired rotavirus infection had received rotavirus vaccine. Two children less than 1 year of age with underlying health conditions and hospital-acquired infections died but neither of these deaths were directly attributable to rotavirus infection.

In summary, available published data demonstrate a considerable burden of illness due to rotavirus among Canadian children under the age of five years.

Update on RotaTeq®

RotaTeq® is a live, oral pentavalent human-bovine reassortant vaccine that contains 5 live reassortant rotaviruses. RotaTeq® has been authorized for use in Canada for the prevention of rotavirus gastroenteritis in infants 6 to 32 weeks of age since August of 2006. It has been recommended for routine use in infants by the Advisory Committee on Immunization Practices (ACIP) in the United States since August 2006. In January of 2008, NACI recommended that RotaTeq® be offered to infants aged 6 to 32 weeks of age whose parents/guardians wish to reduce the risk of rotavirus gastroenteritis^{Footnote 1}.

Update on the safety of RotaTeq®

In Phase III studies of RotaTeq® involving almost 72,000 healthy infants, no increased risk of intussusception or other serious adverse events was observed^{Footnote 17-Footnote 18} In the United States, postmarketing safety of RotaTeq® is being monitored by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) through evaluation of reports to two systems: the passive surveillance system Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD), an active surveillance system.^{Footnote 19}

Between February 2006 and March 2008, approximately 14 million doses of RotaTeq® were distributed in the United States; the number of doses administered is not known(20-22) Available data do not indicate that RotaTeq® is associated with intussusception.(20-21) Assessment of a potential association between RotaTeq® and intussusception was performed by comparing the number of cases of intussusception reported to VAERS following receipt of RotaTeq® to the number of cases expected to occur by chance alone. 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, prior to the introduction of RotaTeq®.

From February 1, 2006 to March 31, 2008, VAERS received reports of 267 cases of intussusception that met the Brighton Collaboration case definition ^{Footnote 22} 91 of these (34%) occurred within 1-21 days of vaccination, 48/91 (53%) occurred within 1-7 days of vaccination. The number of cases of intussusception reported to VAERS during either the 1-21 day period or the 1-7 day period following any dose of RotaTeq® did not exceed the number of cases expected to occur by chance alone. Although an apparent clustering of intussusception cases during the 7 day period following the first dose of RotaTeq® was observed, it is not possible using VAERS data alone to determine whether this observed increase is due to enhanced reporting of intussusception cases following the first vaccine dose or to a slightly increased risk of intussusception in the 7 day period following the first dose^{Footnote 20-Footnote 22}.

Further evaluation of the post-marketing safety of RotaTeq® is available from the Vaccine Safety Datalink (VSD), an active surveillance network of eight managed care organizations distributed across the US and encompassing 2.9% of the US population. The VSD is able to test hypotheses generated by VAERS or pre-marketing clinical studies. Following administration of over 200,000 doses in the VSD, no increased risk of intussusception has been demonstrated in the 30 day period following any dose of RotaTeq®^{Footnote 23}. With more than 160,000 first doses administered in the VSD and pre-licensure trials, no cases of intussusception were identified in the 7 day period following vaccination^{Footnote 23}.

Post-marketing safety surveillance through VAERS and the VSD have also not demonstrated an increased risk of other serious adverse events following vaccination with RotaTeq® including hematochezia, meningitis, encephalitis, seizures, Kawasaki disease, myocarditis, or Gram-negative sepsis(22;24). The Global Advisory Committee on Vaccine Safety (GACVS) recently reviewed all available data from the US (where RotaTeq® has been introduced) and the European Union (where Rotarix™ was being used), on the potential association between Kawasaki disease and rotavirus vaccines and concluded there was no evidence for a causal association between rotavirus vaccines and Kawasaki disease^{Footnote 25}.

In summary, postmarketing surveillance following distribution of more than 14 million doses of RotaTeq® in the US, do not demonstrate or suggest an increased risk of intussusception or other serious adverse events among infants following RotaTeq® vaccine.

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

On May 7, 2010 Health Canada issued an advisory indicating ongoing review of information regarding the presence of porcine circovirus. We are currently reviewing new information regarding the presence of porcine circovirus (PCV-1 and PCV-2) DNA in rotavirus vaccine. While porcine circovirus is considered a contaminant in these vaccines, it is not known to cause illness in humans. Health Canada stated that there is no evidence that the presence of PCV-1 or PCV2 in rotavirus vaccines poses a safety risk to patients and highlighted the fact that rotavirus vaccines have a strong safety record both in clinical trials and in clinical experience with millions of patients. ^{Footnote 26}

Update on the effectiveness of RotaTeq®

In Phase III trials leading to the licensure of RotaTeq®, overall vaccine efficacy of 3 doses of RotaTeq® against severe rotavirus gastroenteritis caused by G serotypes contained in the vaccine (G1, G2, G3, G4) was 98.2% (95% CI 89.6-100%) and against rotavirus gastroenteritis of any severity was 73.8% (95% CI 67.2-79.3%) during the first full rotavirus season after completion of vaccination. Among 144 infants in Phase III trials who received at least one dose of RotaTeq® >10 weeks after a previous dose, similar efficacy against G1-G4 rotavirus gastroenteritis of any severity was observed when compared to infants who received doses on schedule <10 weeks following a previous dose (74%; 95%CI 67-79% vs. 63%; 95% CI, <0-94%)^{Footnote 27}. In the Finnish Extension Study, 21,000 of the approximately 70,000 infants involved in the pivotal Rotavirus Efficacy and Safety Trial (REST) were followed until 3.5 years of age(18;28). Reduction of overall rotavirus gastroenteritis-associated hospitalizations and emergency department visits up to 3.1 years post- dose 3 was 94% (95% CI 91 - 96%); efficacy against rotavirus gastroenteritis of any severity was 63% (95% CI 44 - 75%)^{Footnote 28}. During the same follow up period, evaluation of the serotype-specific prevention of rotavirus gastroenteritis-associated hospitalizations and emergency department visits among infants who had received 3 doses of vaccine revealed sustained reduction in rates of gastroenteritis caused by G1-G4 and G9 rotavirus of 82-95%^{Footnote 29}.

The REST trial was not designed to evaluate the efficacy of less than 3 doses of RotaTeq®. However, post-hoc analysis of hospitalizations and emergency room visits from this study population demonstrated high rates of protection following the first and second dose of vaccine^{Footnote 30}. Between 14 days after dose one and receipt of dose 2, a rate reduction of 100% (95% CI 72-100%) for rotavirus types G1-G4 and of 82% (95% CI 39-97%) for rotavirus due to any serotype was observed; between 2 weeks after dose two and receipt of dose 3, a rate reduction of 91% (95% CI 63-99%) for rotavirus types G1-G4 and of 84% (95% CI 54-96%) for rotavirus due to any serotype was observed. Boom et al evaluated the effectiveness of complete (3-doses) or partial (1 or 2 doses) immunization with RotaTeq® in an urban emergency room in the US. Vaccine effectiveness against rotavirus hospitalization and emergency room visits was 69% (95% CI: 71-100%) following 1 dose, 81% (95% CI: 13-96%) following 2 doses and 88% (95% CI: 68-96%) following 3 doses using a case control design comparing children with lab-confirmed rotavirus gastroenteritis to a group of controls with either rotavirus-negative gastroenteritis or acute respiratory illness. These^{Footnote 32} data suggest that infants vaccinated during the rotavirus season may derive substantial early protection against severe rotavirus disease despite not having completed a full series of immunization.^{Footnote 31}

The impact of routine immunization of US infants with RotaTeq® was recently evaluated by the CDC using data from the National Respiratory and Enteric Virus Surveillance System (NREVSS) and the New Vaccine Surveillance Network (NVSN) using several outcomes: timing of the onset of the season, number of cases, frequency of tests and proportion of tests positive^{Footnote 32}. When compared to the 6 previous seasons (2000-2006), rotavirus activity during the 2007-2008 season was delayed by 15 weeks. During 2000- 2006, median onset of rotavirus disease occurred in mid-December. In 2008, onset of rotavirus activity occurred in late February reflecting an eight week delay. This analysis also showed a dramatic decrease in the overall number of cases reported. In viewing the 2007-2008 season as a whole, a decrease in magnitude of rotavirus illness greater than 50% was observed. While some year-to-year variability in the number of cases can occur, both the total number of tests performed and the number of tests positive for rotavirus were substantially lower during the 2007-2008 rotavirus season than during any of the seasons from 2000 to 2006. In comparing the total number of rotavirus tests performed in the 2007-2008 season, 11% more tests were performed but there was a 67% decrease in the number of positive specimens detected^{Footnote 33}. The delayed season and atypically low percentage of rotavirus-positive tests was observed in all regions studied. Among children enrolled in the NVSN during January 1 - April 30 in 2006, 2007, and 2008, the overall percentage of stool specimens positive for rotavirus was 50%, 45%, and 6%, respectively^{Footnote 34}. This dramatic reduction in the proportion of stools testing positive for rotavirus was observed in children tested in the inpatient settings.

Since the publication of the CDC surveillance results described above, several other studies done in different clinical settings and geographic regions throughout the US have been reported^{Footnote 35-Footnote 41}. Each of these studies has demonstrated considerable reductions in the number of cases of rotavirus gastroenteritis, hospitalizations due to rotavirus gastroenteritis, and proportion of rotavirus tests positive since the initiation of routine rotavirus immunization (with RotaTeq®) among US infants in 2006.

While these results must be viewed with some caution given that the data from the 2007-2008 rotavirus season represent only one season of data, the consistency of the trends observed between the NREVSS, the NVSN and other studies across geographic regions suggest that there has been a dramatic reduction in the burden of disease caused by rotavirus in the US during the 2007-2008 season. This reduction in rotavirus activity coincides with increased use of RotaTeq® following the recommendation of the Advisory Committee on Immunization Practices for universal immunization of US infants in February 2006^{Footnote 42}. While nationally representative vaccine coverage data is not available, information from population-based sentinel immunization information sites in the US indicates an increase in mean coverage with one dose of RotaTeq® among infants aged 3 months from 49.1% in May 2007 to 56.0% in March 2008^{Footnote 43}; mean 3-dose coverage among children aged 13 months increased from 3.4% in May 2007 to 33.7% in March 2008. Most children over the age of 2 years at the start of the 2007-2008 rotavirus season would not have received rotavirus vaccine because they were above the upper age limit to receive RotaTeq® when it was licensed in 2006. The observed reduction in rotavirus activity during the 2007-2008 rotavirus season is greater than can be attributed to direct protective effects in vaccine recipients, suggesting that immunization of a proportion of the population might offer indirect benefits to unvaccinated persons by reducing transmission of rotavirus in the community (i.e. herd immunity).

Ongoing disease surveillance and epidemiological studies in Canada and the US are needed to confirm the impact of rotavirus vaccine on rotavirus disease in 2007-2008 and in future rotavirus seasons. Prospective surveillance data from the Canadian Immunization Monitoring Program, Active (IMPACT) will soon be available to provide better epidemiologic data regarding rotavirus burden of illness and vaccine effectiveness in Canada.  

Monovalent human rotavirus vaccine: Rotarix™

This section contains information on a second vaccine product available in Canada against rotavirus infections. This vaccine has been recommended for use in the routine infant schedule by the ACIP since June 2008 ^{Footnote 43}.

Vaccine composition(44;45)

Rotarix™ is a live, attenuated monovalent G1[P8] human rotavirus vaccine derived from a naturally circulating G1[P8] rotavirus strain 89-12 that was isolated from the stool of a 15-month old child with mild rotavirus diarrhea in December 1988. The parent virus was then passaged in African Green Monkey kidney cells, cloned, and further passaged in Vero cells. The vaccine is supplied as a liquid suspension in single-dose oral applicators for oral administration.

Each 1.5 ml dose of vaccine contains not less than 106.0 CCID50 (cell culture infectious dose 50%) of the parent strain of human rotavirus. The vaccine also contains sucrose, di-sodium adipate, Dulbecco's Modified Eagle Medium, and sterile water. The current Rotarix™ oral applicator product does contain latex, but non-latex products may also be available in 2010. To inquire about non-latex containing product availability or to check lot numbers on existing or future supplies, please contact the manufacturer GlaxoSmithKline Inc.'s Medical Information Line at 1-800-387-7374.

Storage and Handling

Rotarix™ should be kept refrigerated at 2°C to 8°C and protected from light.

Immunogenicity

The immune correlates of protection from rotavirus infection and disease are not fully understood. Correlation between antibody responses and protection from disease has not been established and therefore clinical trials for rotavirus vaccine
approval have been based on efficacy rather than immunologic correlates of efficacy.

Evaluation of the immune response to Rotarix™ has been assessed in clinical trials in 6 European countries^{Footnote 44} and 11 Latin American countries^{Footnote 45} that included 1180 immunized infants. In these trials a 2-dose vaccine course resulted in IgA seroconversion rates, defined as serum anti-rotavirus ELISA IgA ≥ 20 U/ml, which ranged from 77.9% to 94.4% (95% CI 73.8% - 97.3%) one to two months following the second dose of vaccine. One North American randomized controlled trial^{Footnote 46} was done that included 421 immunized infants. Infants received either 105.2 ffu or 106.4 ffu viral concentration of vaccine or placebo. Using the same measure of immunity, IgA ELISA ≥ 20U/ml, 67.4%, 78.5% and 6.3% infants respectively, developed antibodies. Seroconversion after one dose was reported for a small subset of infants. Of those who received 105.2 ffu viral concentration of vaccine, 64% of infants developed serum IgA to rotavirus. Among those who received 106.4 ffu viral concentration, 56% developed serum IgA to rotavirus. Also in this study, 20 immunized infants were seronegative after their first dose of vaccine; these infants seroconverted after their second dose. All of the above randomized controlled trials suggest that the majority of infants develop antibodies to the vaccine after completing a two dose series.

The safety and immunogenicity of 2-doses of Rotarix™ was evaluated in 1009 preterm infants.^{Footnote 47} Among a subset of 147 infants born after at least 27 weeks of gestational age, seroconversion (defined as serum anti-rotavirus ELISA IgA ≥ 20 U/ml) was observed in 85.7% (95%CI: 79.0-90.9) of infants one month after the second vaccine dose.

The safety and immunogenicity of 3-doses of Rotarix™ was evaluated in 50 South African children with HIV^{Footnote 49}. Among 21 children with mean CD4 counts of 2145 /mL (SD 746) in whom data was available, seroconversion was observed in 57.1% (95%CI: 36-61) of infants 2 months following the third dose. Data on seroconversion rates after 2 doses is not available.

Efficacy

The efficacy of the authorized formulation of Rotarix™ has been evaluated in 2 Phase III clinical trials(49;50) conducted in Latin America^{Footnote 49} and in Europe^{Footnote 50} in which a total of 21,741 infants have been studied (11,581 who received Rotarix™ and 10,160 who received placebo.) These are summarized in evidence Tables 1, 2 and 9. Efficacy during the second season following immunization was evaluated in the European trial and in a subset of infants enrolled in Latin America (7,175 who received Rotarix™ and 7,062 who received placebo)^{Footnote 51}. These trials enrolled healthy infants aged 6 to 13 weeks (14 weeks minus 1 day). Two doses of Rotarix™ were given orally beginning at 6 -14 weeks of age with a minimum interval of 4 weeks between doses without RESTriction due to breastfeeding or administration of other licensed childhood vaccines. All doses were administered by 24 weeks of age.

Overall, the efficacy of 2 doses of Rotarix™ against severe rotavirus gastroenteritis in Phase III trials was high in the first rotavirus epidemic season following immunization, ranging from 85%^{Footnote 49} to 96%^{Footnote 50}. Protection persisted during the second epidemic rotavirus season, with vaccine efficacy ranging from 79%^{Footnote 51} to 86%^{Footnote 50} (Table 1).

While formal studies of the efficacy of a single dose of Rotarix™ have not been performed, efficacy data are available for the period between Dose 1 to Dose 2 of Rotarix™ in the European Phase III trial^{Footnote 50}. During the period from Dose 1 to before Dose 2 (mean duration: 61 days in each study group), significantly fewer subjects in Rotarix™ group reported any wild-type rotavirus gastroenteritis compared to the placebo group (P-value = 0.019). Vaccine efficacy against any rotavirus gastroenteritis during this interval was 89.8% (95% CI 8.9- 99.8%).

Rotarix™ is a monovalent vaccine designed to protect against G1P[8] rotavirus infection. However, the genotype P[8] is shared by most other circulating strains. Protection induced by natural infection with RV is not limited to G and P antigens, but is also associated with structural proteins VP2 and VP6 (in addition to VP4 and VP7), and to non-structural proteins. Therefore, cross-protection against infection due to non-G1 serotypes was expected and was evaluated in the Phase III clinical trials (Table 2). Although for some strains only a small number of cases were detected, some degree of cross-protection was demonstrated. The efficacy against non-G1 strains ranged from 41%-92% with pooled efficacy against severe RV diarrhea caused by non-G1 types of 88% through two rotavirus seasons^{Footnote 45}. Vaccine efficacy against non-G1 serotypes was statistically higher than in the placebo group for G3P[8], G4P[8], and G9P[8] serotypes but not for G2P[4] serotype. This result could be expected as G2P[4] serotype does not share the P[8] genotype. However, for the second rotavirus season and for the combined first and second seasons, statistically significant efficacy against severe disease due to G2P[4] was observed (85.5%; 95%CI 24.0-98.5). Observed cross-protection against the other serotypes persisted through the second season.

Vaccine efficacy did not decrease in breastfeeding infants. Vaccine efficacy against any RV GE and severe RV GE in the group who were breastfed up to dose one was 86% and in those infants breast fed up to dose two was 96% as compared to 91% and 96% respectively, in the group who was not breast-fed at any of the doses.

Efficacy in pre-term infants and immunocompromised infants has not been evaluated although limited available immunogenicity data suggest that neither pre-term delivery nor asymptomatic or mildly symptomatic HIV infections are likely to affect the efficacy of Rotarix™(47;48). It should be noted that immunogenicity of Rotarix™ in HIV positive infants has only been assessed following 3 doses of vaccine.

Table 1: Summary of efficacy studies of Rotarix ( 49 ; 51 )

	1st Rotavirus Season		2nd Rotavirus Season
	Efficacy ** (%)	95% CI	Efficacy *** (%)	95% CI
Any rotavirus gastroenteritis - Latin America Footnote 49 - Europe Footnote 50	NA 87.1 *	NA 76.9 - 92.1	NA 71.9 *	NA 61.2 -79.8
Severe Rotavirus gastroenteritis (Vesikari score = 11) - Latin America( 49; 51) - Europe Footnote 50	84.7 * 95.8 *	71.7 - 92.4 89.6 - 98.7	79.0 * 85.6 *	66.6 - 87.4 75.8 - 91.9
Hospitalization due to rotavirus gastroenteritis - Latin America Footnote 49 - Europe Footnote 50	85 * 100 *	69.6 - 93.5 81.8 - 100	83.0 * 92.2 *	73.1 - 89.7 65.6 - 99.1
* statistically significant (p<0.05) NA = not available -Efficacy reported for the according-to-protocol cohort, defined as participants who completed the full 2-dose vaccination course and adhered to the protocol; reported efficacy is against any G serotype ** 1st efficacy period was defined as the period 2 weeks post-dose 1 to the end of the first rotavirus epidemic season *** 2nd efficacy period was defined as the period between the visit at the end of the first rotavirus epidemic period to the end of the second rotavirus epidemic period number of infants included in efficacy analysis = 17,867 (9,009 Rotarix vs 8,858 placebo) number of infants included in efficacy analysis = 3,874 (2,572 Rotarix vs 1,302 placebo)

Table 2: Summary of efficacy of Rotarix™ against G1 and non-G1 serotype rotavirus infection evaluated through two seasons of rotavirus( 45 ; 49 - 51 )

	Through One Rotavirus Season				Through Two Rotavirus Seasons
Type	Rotavirus gastroenteritis of any severity		Severe rotavirus gastroenteritis		Rotavirus gastroenteritis of any severity		Severe rotavirus gastroenteritis
G1[P8] Latin America Europe	91.8 * 95.6 *	74.1 - 98.4 87.9 - 98.8	90.8 * 96.4 *	70.5 - 98.2 85.7-99.6	82.1 * 89.8 *	64.6 - 91.9 82.9 -94.2	82.7 * 96.4 *	64.4-92.5 90.4-99.1
G2[P4] Latin America Europe	41.0 62.0	-79.2 - 82.4 <0 - 94.4	45.4 74.7	-81.5 - 85.6 <0 -99.6	38.6 58.3 *	<0 - 84.2 10.1 -81.0	43.8 85.5 *	<0 - 87.9 24.0-98.5
G3[P8] Latin America Europe	NA 89.9 *	NA 9.5-99.8	87.7 * 100 *	8.3-99.7 44.8-100	NA 84.8 *	NA 41.0-97.3	71.9 93.7 *	-47.7-97.1 52.8-99.9
G4[P8] Latin America Europe	NA 88.3 *	NA 57.5-97.9	50.8 100 *	-844-99.2 64.9-100	NA 83.1 *	NA 55.6-94.5	63.1 * 95.4 *	0.7-88.2 68.3-99.9
G9[P8] Latin America Europe	NA 75.6 *	NA 51.1-88.5	90.6 * 94.7 *	61.7-98.9 77.9-99.4	NA 72.9 *	NA 59.3-82.2	87.7 * 85.0 *	72.9-95.3 71.7-92.6
Strains with [P8] genotype Latin America Europe	87.3 * 88.2 *	64.1 - 96.7 80.8-93.0	86.9 * 96.5 *	62.8 -96.6 90.6-99.1	80.5 * NA	67.9 - 88.8 NA	82.2 * NA	70.0 - 90.1 NA
Pooled non G1, (G2, G3, G4, G9, G12) Latin America Europe	NA NA	NA NA	NA NA	NA NA	77.5 * 72.9 *	64.7 - 86.2 62.9-80.5	79.6 87.7 *	67.1 - 87.9 78.9-93.2
* Statistically significant (p<0.05) NA= not available

Effectiveness

Post-marketing studies examining the impact of introduction of Rotarix™ into routine infant immunization programs have demonstrated considerable reductions in overall burden of illness following implementation of a Rotarix™ immunization program. In Australia, among children under 15 months, the annualized rate of gastroenteritis related emergency room visits was lower in the year following introduction of a publicly funded infant rotavirus immunization program than in any of the previous 7 years^{Footnote 52} (75 per 1000 vs 80.6-131.0 per 1000). In Mexico, deaths due to acute diarrhea among children less than 5 years of age dropped 42% when compared to the pre- vaccination period^{Footnote 53}. In Belgium, the proportion of stools collected from children aged ≤ 5 years suffering from diarrhea that were positive for rotavirus fell by more than half in the year following introduction of funding for childhood vaccination with Rotarix™^{Footnote 54}.

Vaccine safety and adverse events

The safety of Rotarix™ has been evaluated in 12 clinical trials^{Footnote 44} involving 76,918 infants (41,479 received Rotarix™, 35,439 received placebo).

Intussusception

The risk of intussusception following Rotarix™ was evaluated in a large-scale safety and efficacy trial conducted in Latin America and Finland (n= 63,225; 31,673 received Rotarix™ and 31,552 received placebo)^{Footnote 45}. No increased risk of intussusception following receipt of Rotarix™ was observed compared to the placebo group. Thirteen cases of intussusception occurred within 31 days of either dose of vaccine (6 in the Rotarix™ group and 7 in the placebo group; RR: 0.85; 95% CI 0.30-2.42). No clustering of intussusception cases was observed within 7 or 14 days following immunization.

In all 11 other clinical trials with Rotarix™ (n= 12,220), a total of 7 cases of intussusception were reported (5 in the Rotarix™ group and 2 in the placebo group)^{Footnote 45}. Across all clinical trials the reported frequency of intussusception was 0.047% for Rotarix™ recipients and 0.05% for placebo recipients.

Following distribution of approximately 23 million doses of Rotarix™ worldwide, in post-marketing surveillance until Jan. 11, 2008, a total of 190 cases of intussusception (0.81/100,000 doses distributed) have been reported to GlaxoSmithKline^{Footnote 55}.

Hematochezia

Hematochezia, defined as the occurrence of bloody stools, was not prospectively solicited in any of the Rotarix™ studies but would be expected to have been captured as an unsolicited event. Hence, a review of unsolicited reports was done in order to assess the occurrence of hematochezia. Various terms were used for reporting adverse events related to blood in stools across studies. Using the Medical Dictionary for Regulatory Activities (MedDRA) High Level Term (HLT) "gastrointestinal hemorrhages" data is provided below on the occurrence of this adverse event. In the Core Integrated Safety Summary, which is an internal GSK database aggregating all clinical trials of Rotarix™ and includes 36,755 Rotarix™ recipients and 34,454 placebo recipients, at least one adverse event within the MedDRA HLT "gastrointestinal hemorrhages" was reported by 19 (0.05%) vaccine recipients and 9 (0.03%) placebo recipients regardless of time-to-onset from vaccination^{Footnote 45}. No statistically significant difference was noted between the Rotarix™ and the placebo groups for each of the considered MedDRA HLT Preferred Terms included under "gastrointestinal hemorrhages (95% CI for relative risk included 1.0). Hematochezia, specifically, was reported in 15 (0.04%) of Rotarix™ recipients and 7 (0.02%) of placebo recipients (RR 1.13; 0.43-3.28). Of the 28 adverse events coded under the MedDRA HLT "gastrointestinal hemorrhages", 24 cases [17 (0.046%) in vaccine recipients and 7 (0.020%) in placebo recipients] had symptom onset within the 31-day post-vaccination period. The events resolved in all cases. None of these 28 subjects were reported to have intussusception^{Footnote 45}.

Other Serious Adverse Events Following Immunization

Serious adverse events were evaluated in 31,673 Rotarix™ recipients compared to 31,552 placebo recipients in a large Phase III trial conducted in Latin America^{Footnote 49} In this trial, a total of 928 (291/10,000) serious adverse events were reported among Rotarix™ recipients and 1047 (332/10,000) serious adverse events were reported in the placebo group (RR 0.88, 95%CI 0.81- 0.96; p=0.005). The rate of hospitalization was 280/10,000 in the Rotarix™ group versus 318/10,000 in the placebo group (RR 0.88; 95%CI 0.88, 95% CI 0.81-0.96; p=0.005).

In the Core Integrated Safety Summary 36,755 Rotarix™ recipients and 34,454 placebo recipients, at least 1 serious adverse event was reported in 1.7% of Rotarix™ recipients and 1.9% of placebo recipients (RR 0.9; 95% CI 0.81-1.01). The relative risks of serious adverse events due to diarrhea, gastroenteritis, and dehydration were lower among Rotarix™ recipients than placebo recipients (Table 3). Overall mortality did not differ significantly between Rotarix™ recipients and placebo recipients. During the course of the studies regardless of time-to-onset, there were 68 (0.19%) deaths following administration of Rotarix™ and 50 (0.15%) deaths following placebo administration with a relative risk of 1.31 [95% CI: 0.89; 1.93]. All reported deaths were assessed by the investigators as not related to vaccination. No statistically significant difference was noted for deaths reported to occur within the 31-day post-vaccination period and for deaths reported to occur during the entire course of studies regardless of time-to-onset.

In order to assess seizures as an adverse unsolicited event, three time periods were assessed: from dose 1 to visit 3, within 31 days after any dose, and 43 days after any dose. Using the Latin American trial, statistically significantly more events coded with the preferred term "convulsions" were reported among Rotarix™ recipients than placebo recipients between dose 1 and 30-90 days following dose 2 (16 [0.05%] versus 6 [0.02%]; p=0.03)^{Footnote 45}. However, no statistically significant difference in these events was observed between Rotarix™ recipients and placebo recipients in any time frame following vaccination if preferred terms encompassing all convulsion-like events were combined^{Footnote 45}. In the European trial, no statistically significant difference was observed between convulsion-related serious adverse events in participants who received Rotarix™ compared with the placebo group within 31 or 43 days after any dose^{Footnote 56}.

Selected other neurologic serious adverse events are shown in Table 3.

Table 3: Summary of Serious Adverse Events (SAE) occurring 0-30 days following any dose(44;58)

Adverse Event	Rotarix™ n=36,755 n (%)	Placebo n=34,454 n (%)	Relative Risk (95% CI)
At least 1 SAE	627 (1.7)	659 (1.9)	0.9 (0.81-1.01)
Diarrhea	9 (0.02)	25 (0.07)	0.35 (0.14-0.78)
Gastroenteritis	72 (0.2)	111 (0.32)	0.62 (0.45-0.84)
Dehydration	9 (0.02)	21 (0.06)	0.43 (0.17-0.97)
Death	33 (0.09)	20 (0.06)	1.64 (0.92-3.02)
Intussusception	9 (0.02)	7(0.02)	1.23 (0.41-3.9)
Bronchiolitis	127 (0.35)	137 (0.4)	0.88 (0.68-1.13)
Pneumonia	122 (0.33)	122 (0.35)	0.99 (0.76-1.28)
Nervous System Any Select other: convulsion febrile seizure encephalitis epilepsy	17 (0.05) 11 (0.03) 3 (0.01) 3 (0.01)   1	24 (0.07) 7 (0.02) 6 (0.02) 0   4 (0.01)	0.65 (0.33-1.27) 1.18 (0.41-3.67) 0.3 (0.04-1.55) 2.99 (0.24-156.9)   0.19 (0.0-2.07)

Kawasaki Disease

No increased risk of Kawasaki disease was observed following administration of Rotarix™ in clinical trials^{Footnote 44}. Overall, Kawasaki disease was reported in 17 (0.03%) of Rotarix™ recipients and 9 (0.02%) of placebo recipients (RR 1.7; 95% CI 0.7-4.4). No clustering of cases was observed in the 31 day period following a dose of vaccine and time between vaccine and onset of disease was highly variable (range 3 days to 9 months).

Solicited Adverse Events Following Immunization

The incidence of solicited adverse events of any severity including fever, cough, diarrhea, vomiting, irritability, and loss of appetite within 7 days of immunization was evaluated in the European trial using diary cards completed by parents/guardians^{Footnote 50}. Reported solicited adverse events did not differ between the infants who received Rotarix™ and those who received placebo following the first or second vaccine dose (Table 4a and Table 4b).

Table 4a. Percentage of subjects with solicited general symptoms assessed as causally related to immunization, data from day 0 to day 7 post first dose Rotarix™ or Placebo ^{Footnote 45} .

	Rotarix MC (N = 914)			Placebo (N = 490)
Symptom	N	%	IC to 95 %	N	%	IC to 95 %
Diarrhea	18	2.0	1.3-3.1	7	1.4	0.6-2.9
Vomiting	44	4.8	3.5-6.4	24	4.9	3.2-7.2
Fever	133	14.6	12.3-17.0	67	13.7	10.8-17.0
Loss of appetite	126	13.8	11.6-16.2	71	14.5	11.5-17.9
Irritability. fussiness	299	32.7	29.7-35.9	171	34.9	30.7-39.3
Cough/runny nose	58	6.3	4.9-8.1	29	5.9	4.0-8.4

Table 4b. Percentage of subjects with solicited symptoms assessed as causally related to immunization, data from day 0 to day 7 post second dose Rotarix™ or Placebo ^{Footnote 45}.

	Rotarix MC (N = 914)			Placebo (N = 490)
Symptom	N	%	IC to 95 %	N	%	IC to 95 %
Diarrhea	6	0.7	0.2-1.4	8	1.6	0.7-3.2
Vomiting	18	2.0	1.2-3.1	23	4.7	3.0-7.0
Fever	164	18.1	15.7-20.8	95	19.5	16.1-23.4
Loss of appetite	118	13.0	10.9-15.4	57	11.7	9.0-14.9
Irritability, fussiness	238	26.3	23.5-29.3	123	25.3	21.5-29.4
Cough/runny nose	53	5.9	4.4-7.6	34	7.0	4.9-9.6

Safety in Preterm Infants

The safety of Rotarix™ was evaluated in 1009 preterm infants (198 were 27-30 weeks gestational age and 801 were 31-36 weeks gestational age)^{Footnote 47}. No difference in the rates of serious adverse events was observed between infants who received Rotarix™ and those who received placebo (5.1% vs 6.8%). Rates of solicited and unsolicited symptoms were comparable between the two groups. No cases of intussusception were reported.

Safety in HIV Infected Infants

The safety of Rotarix™ was evaluated in 100 South African infants (50 received Rotarix™ and 50 received placebo)^{Footnote 48}. Incidence of serious adverse events and solicited and unsolicited adverse events did not differ between the groups.

On May 7, 2010 Health Canada issued an advisory indicating ongoing review of information regarding the presence of porcine circovirus. We are currently reviewing new information regarding the presence of porcine circovirus (PCV-1 and PCV-2) DNA in rotavirus vaccine. While porcine circovirus is considered a contaminant in these vaccines, it is not known to cause illness in humans. Health Canada stated that there is no evidence that the presence of PCV-1 or PCV2 in rotavirus vaccines poses a safety risk to patients and highlighted the fact that rotavirus vaccines have a strong safety record both in clinical trials and in clinical experience with millions of patients^{Footnote 26}.

Viral shedding and transmission

Following administration of Rotarix™, viral antigen shedding in the stool was detected by ELISA in 50% - 80% of infants on day 7 following the first vaccine dose, and 4% - 18% of infants on day 7 following the second dose^{Footnote 56}. When ELISA- positive stools were tested for the presence of live vaccine virus, 17% of vaccinees had live rotavirus detectable in stool at day 7 following the first dose. All observed shedding in vaccinees was asymptomatic.

Trials evaluating the potential for transmission of vaccine virus from vaccines to their contacts are currently underway.

Concomitant administration of other childhood vaccines^{Footnote 45}

Rotarix™ may be administered concomitantly with all routinely recommended infant vaccines. The impact of concomitant administration of Rotarix™ with DTPa-HBV-IPV/Hib, DTPa, DTaP-IPV, Hib, DTPw-HBV, HBV, pneumococcal conjugate vaccine, meningococcal serogroup C conjugate vaccine, and IPV have been evaluated and the immune responses and safety profile have been shown to be unaffected by concomitant administration. Concomitant administration of Rotarix™ and OPV may result in reduced immune response to Rotarix™. Thus, OPV should be given at least 2 weeks apart from Rotarix™

Interchangeability

There are no data on safety, immunogenicity, or efficacy when Rotarix™ is administered as the first dose and RotaTeq® vaccine is used as the second dose or vice versa. Whenever possible, the rotavirus vaccine series should be completed with the same product. However, in the event that the product used for a previous dose(s) is not known, the series should be completed with the available product. If any dose in the series was RotaTeq®, a total of 3 doses of vaccine should be administered.

Dosage and Schedule

Rotarix™ is given as 2 separate 1.5 ml oral doses. Rotarix™ should never be injected.

The first dose of Rotarix™ should be given between 6 weeks (6 weeks plus 0 days) and 15 weeks (14 weeks plus 6 days of age). There should be an interval of at least 4 weeks between the first and second dose. All doses should be completed by the age of 32 weeks (8 months plus 0 days).

In the absence of data regarding administration of Rotarix™ 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 healthcare provider.

Interrupted Schedules

If for any reason an incomplete dose is administered (e.g., infant spits or regurgitates the vaccine), no replacement dose should be administered.

For infants in whom the first dose of Rotarix™ vaccine is inadvertently administered off label at age ≥15 weeks, the REST of the Rotarix™ vaccination series should be completed with a minimum of 4 weeks between each dose. All doses should be administered by 8 months plus 0 days of age.

Previous RV infection

Infants who have had rotavirus gastroenteritis before receiving the full course of vaccinations should still initiate or complete the 2-dose schedule because the initial infection frequently provides only partial immunity^{Footnote 59}.

Breastfeeding The efficacy of Rotarix™ is similar among infants who are breastfed and those who are not^{Footnote 50}; therefore, infants who are being breastfed can receive Rotarix™.

Intercurrent illness
Like other vaccines, Rotarix™ can be administered to infants with transient mild illnesses, and to those with or without fever^{Footnote 59}. See "Precautions" below for guidance on vaccine administration to infants with acute gastroenteritis.

Premature infants (< 37 weeks gestation)
Available data in 1009 preterm infants demonstrates that Rotarix™ is safe and induces similar immune response to that achieved in full term infants^{Footnote 47}. Because premature infants have lower levels of maternal antibodies against rotavirus, they may theoretically be at increased risk of both severe naturally occurring rotavirus gastroenteritis and of adverse reactions to the rotavirus vaccine. A Washington State study found that premature infants have an increased risk for hospitalization from gastroenteritis, including viral gastroenteritis^{Footnote 60}. 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^{Footnote 61}.

Based upon available data, and because of the susceptibility of this population, NACI feels the potential benefit of vaccination of premature infants outweighs the potential risk. Infants who are between 6 weeks and 8 months plus 0 days of chronological age, are healthy and are not hospitalized can receive Rotarix™.

Exposure of immunocompromised persons or pregnant women to vaccinated infants

Following administration of Rotarix™, viral antigen shedding in the stool may be detected in up to 80% of vaccinees with peak shedding observed at 7 days post dose 1. Live rotavirus vaccine is detectable in the stool of 17% of vaccines at day 7 following the first dose.

Data on the potential for horizontal transmission of vaccine virus has not been published. A study on 100 twin pairs has been completed, but has yet to be published^{Footnote 62}. However, the benefit of protecting immunocompromised household contacts from naturally occurring RV by immunizing infants is believed, by many experts, to outweigh the theoretical risk of transmitting vaccine virus^{Footnote 42}. 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 vaccinated infant, especially after handling feces (i.e., after changing a diaper), and before food preparation and direct contact with the immunocompromised person.

Infants living in households with pregnant women can be vaccinated. Because most women of childbearing age have pre-existing immunity to rotavirus 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.

Contraindications

Infants who have a history of anaphylactic reaction to any component of the vaccine or its container should not be vaccinated. Should an infant develop an anaphylactic reaction after receiving one dose of vaccine, further doses should not be given and the child should be referred to an allergist. The Rotarix™ oral applicator contains latex rubber therefore infants with anaphylactic allergy to latex should not receive Rotarix™.

History of intussusception: No association between Rotarix™ and intussusception has been demonstrated in large-scale safety trials or in post-marketing surveillance. However, because of the previously documented association of Rotashield™ (Wyeth-Lederle) 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 Rotarix™. This recommendation may change as further safety data becomes available.

Immunocompromised Infants: While available data of 50 South African children with asymptomatic or minimally symptomatic HIV infection who received 3 doses of Rotarix™ suggest that Rotarix™ is safe and immunogenic in this population, data in other immunocompromised populations is not available. Based on the theoretical risk of live attenuated viral vaccines in immunocompromised infants, and very minimal data in this population, infants with suspected or known immunocompromising conditions should not receive RotaTeq® or Rotarix™ without consultation with a physician specialist or expert in these conditions.

Precautions

Acute gastroenteritis: The immunogenicity and efficacy of Rotarix™ has not been studied in infants with concurrent gastroenteritis. However, in these infants, as is the case with oral polio vaccine, immunogenicity and effectiveness of the vaccine may theoretically be reduced^{Footnote 63}. 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 > 14 weeks plus 6 days of age. Infants with mild gastroenteritis can be vaccinated.

Pre-existing chronic gastrointestinal conditions: The safety and efficacy of Rotarix™ 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.

Recommendations for use of rotavirus vaccines

These recommendations replace the recommendations in the November 2008 statement^{Footnote 1} . NACI recommends the use of the rotavirus vaccines RotaTeq® or Rotarix™ for:

1. Healthy infants: Rotavirus vaccines are recommended for infants starting at 6 weeks ( 6 weeks and 0 days) and up to 15 weeks (14 weeks plus 6 days). (Recommendation - Grade A - good evidence to recommend immunization)

Vaccination may be provided with either pentavalent human-bovine reassortant vaccine (RotaTeq®) or with monovalent human rotavirus vaccine (Rotarix™). Vaccination should not be initiated in infants aged 15 weeks and 0 days or older as the safety of providing the first dose of rotavirus vaccine in older infants is not known. The minimum interval between doses of rotavirus vaccine is 4 weeks. All doses of rotavirus vaccine should be administered by age 8 months, 0 days. (Table 5)

Canadian epidemiology suggests that there is a high prevalence of rotavirus gastroenteritis among children less than 5 years of age. Many of these children require visits to their primary care provider and some require hospitalization. Death in Canada due to rotavirus gastroenteritis is fortunately a rare event. Neither currently authorized product has been associated with an increased risk of intussusception, although ongoing monitoring will continue to play an essential role in our immunization programs.

Insufficient data about strain distribution of RV in Canada and geographical and seasonal trends in distribution make prediction of the absolute impact of a universal RV vaccine program difficult. Preliminary effectiveness data in the US after the introduction of RotaTeq® suggest that vaccine effectiveness in vaccinated infants is similar to vaccine efficacy reported in clinical trials and that, in addition, a significant indirect protection of unimmunized persons may be observed even with relatively low coverage rates. Prospective surveillance data from IMPACT will soon be available to provide better RV epidemiologic data regarding burden of illness and rotavirus strain distribution in Canada.

The decision to include rotavirus vaccine(s) in universal, publicly-funded Provincial and Territorial programs will depend upon multiple factors such as detailed cost-benefit evaluation and assessment of other elements of the Erikson and DeWals analytic framework for immunization programs in Canada^{Footnote 64}.

Based on World Health Organization review of the evidence, Strategic Advisory Group of Experts on Immunization (SAGE) recommends the inclusion of rotavirus vaccination of infants into all national immunization programs. In countries where diarrheal deaths account for ≥10% of mortality among children aged <5 years, the introduction of the vaccine is strongly recommended^{Footnote 65}.

2. Preterm infants: Infants who are between 6 weeks and 8 months plus 0 days of chronological age who are healthy and not hospitalized, can receive RotaTeq® or Rotarix™. The first dose should be given between 6 weeks and 14 weeks plus 6 days. (Recommendation Grade A - good evidence to recommend immunization)

Available data in 1009 preterm infants demonstrates that Rotarix™ is safe and induces similar immune response to that achieved in full term infants^{Footnote 47}. A study of RotaTeq® indicated that the live attenuated vaccine was safe and effective in children of this gestational age^{Footnote 1} . Based upon available, data, NACI feels the potential benefit of vaccination of premature infants outweighs the potential risk. Infants who are between 6 weeks and 14 weeks plus 6 days of chronological age who are healthy and not hospitalized, can begin a series of either RotaTeq® or Rotarix™ . The minimum interval between doses of rotavirus vaccine is 4 weeks. All doses of rotavirus vaccine should be administered by age 8 months, 0 days based on chronological age (Recommendation Grade A - good evidence to recommend immunization)

3. Immunocompromised Infants: Based on the theoretical risk of live attenuated viral vaccines in immunocompromised infants, and very minimal data in this population, NACI recommends that infants with suspected or known immunocompromising conditions should not receive RotaTeq® or Rotarix™ without consultation with a physician specialist or expert in these conditions. (Recommendation - Grade E - Good evidence to recommend against immunization)

4. Infants with a history of intussusception:NACI recommends based on current evidence that infants with a history of intussusception should not be given rotavirus vaccines (Recommendation Grade E - good evidence to recommend against immunization).

No association between Rotarix™ or RotaTeq® and intussusception has been demonstrated in large-scale safety trials or in post-marketing surveillance. Children with a history of intussussception were excluded from immunogenicity and efficacy trials. This recommendation is based on the previously documented association of Rotashield™ with increased rates of intussusception, incomplete understanding of the pathogenic mechanisms underlying this increased risk, the lack of data in this population, and the possibility that infants with a history of intussusception are at increased risk of subsequent episodes.

Table 5: Summary of vaccine characteristics and recommended uses of the two currently authorized rotavirus vaccines, RotaTeq® and Rotarix™

Characteristic	RotaTeq®	Rotarix™
Parent rotavirus strain	Human - bovine strain WC3	Human strain 89-12 (Type G1P1A[8])
Vaccine composition	Reassortant strains: G1xWC3; G2xWC3; G3xWC3; G4xWC3; P1A[8]xWC3	Human strain 89-12 (Type G1P1A[8])
Formulation	Liquid (no reconstitution required)	Liquid (no reconstitution required)
Applicator	Latex-free dosing tube	Glass oral applicator with latex rubber in plunger and cap
Volume per dose	2 ml	1.5 mlFootnote 45
# doses in series	3	2
Minimum age at dose 1	6 weeks	6 weeks
Maximum age at dose 1	14 weeks + 6 days	14 weeks + 6 days
Minimal intervals between doses	4 weeks	4 weeks
Maximum age for last dose	8 months + 0 days	8 months + 0 days

Table 6. Levels of evidence based on research design

I	Evidence from randomized controlled trial(s)
II-1	Evidence from controlled trial(s) without randomization
II-2	Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy
II-3	Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III	Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

Table 7. Quality (internal validity) rating

Good	A study (including meta-analyses or systematic reviews) that meets all design- specific criteria* well.
Fair	A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".
Poor	A study (including meta-analyses or systematic reviews) that has at least one design-specific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
* General design specific criteria are outlined in Harris et al.Footnote 66.

Table 8. NACI Recommendations for Immunization

A	NACI concludes that there is good evidenceto recommend immunization.
B	NACI concludes that there is fair evidenceto recommend immunization.
C	NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization, however other factors may influence decision-making.
D	NACI concludes that there is fair evidence to recommend against immunization.
E	NACI concludes that there is good evidence to recommend against immunization.
I	NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.

Table 9 Summary of Evidence for the use of Rotarix™:

Study	Study Design	Number of Participants	Outcomes	Level of Evidence	Quality
Evidence for the Safety of Rotarix™
Dennehy et al. 2005 Footnote 46	Double blinded randomized controlled trial	529 enrolled 421 immunized 108 placebo group	-Solicited daily record for 15 days post vaccination -Unsolicited record for within 43 days of vaccine receipt -Serious adverse events (10-12 months) -Gastroenteritis from first dose until 2 months after 2 dose	I	Good North American Population Small sample size
Ruiz-Palacios et al. 2006 Footnote 49	Double blinded randomized controlled trial	63 225 enrolled 31 673 immunized 31552 placebo	Clinical - including: Severe gastroenteritis, hospitalizations using MedRHA	I	Good
Linhares et al. 2008 Footnote 51	Double blinded randomized controlled trial	15 183 enrolled 7669 immunized 7493 placebo	Clinical - including: Severe gastroenteritis, hospitalizations through active, hospital based surveillance	I	Good
Evidence for the Efficacy of Rotarix™
Ruiz-Palacios et al. 2006 Footnote 49	Double blinded randomized controlled trial	20 169 enrolled 10 159 immunized 10 010 placebo	RT- PCR in cases of gastroenteritis	I	Good
Vesikari et al. 2007 Footnote 50	Double blinded randomized controlled trial	3994 enrolled 2646 immunized 1348 placebo	Clinical - any severity gastroenteritis, hospitalization, health care visit	I	Good
Linhares et al. 2008 Footnote 51	Double blinded randomized controlled trial	20160 enrolled 7397 immunized 7218 placebo	Clinical - hospitalized, severe gastroenteritis Vesikari scale used	I	Good
Evidence for the immunogenicity of Rotarix™
Dennehy et al. 2005 Footnote 46	Double blinded randomized controlled trial	529 enrolled 421 immunized 108 placebo group	IgA ELISA = 20 U/ml	I	Good

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