Page 19: Canadian Immunization Guide: Part 4 - Active Vaccines
Last complete chapter revision: April 2016
- Key Information
- Immunizing Agents Available for Use in Canada
- Efficacy, Effectiveness and Immunogenicity
- Recommendations for Use
- Vaccination of Specific Populations
- Serologic Testing
- Administration Practices
- Storage and Handling of Immunizing Agents
- Safety and Adverse Events
- Selected References
Key Information (refer to text for details)
- Rotavirus (RV) is a common cause of gastroenteritis in children; approximately 36% of children with RV gastroenteritis see a physician, 15% visit an emergency department, and 7% require hospitalization.
- Most unimmunized children are infected by 5 years of age.
- First infection usually does not lead to permanent immunity.
- RV vaccine efficacy against diarrhea of any severity in developed world settings is 74% to 87%; efficacy against severe diarrhea is 85% to 98%.
- RV vaccines are well tolerated, but there is a small increased risk of intussusception of between 1 and 7 cases per 100,000 doses in the 7 days following both the first and second doses.
- Recommended for infants starting at 6 weeks of age.
- Should not be given to infants who are known or suspected to be immunocompromised without consultation with a medical expert.
- As a precaution, infants with a history of intussusception should not be given RV vaccine.
- First dose of RV vaccine should be administered starting at 6 weeks of age and before 15 weeks of age. To optimize protection, RV vaccine should be initiated as soon after 6 weeks of age as feasible.
- Rot-1 vaccine (Rotarix®) requires 2 doses (at least 4 weeks apart) and Rot-5 vaccine (RotaTeq®) requires 3 doses (4 to 10 weeks apart).
- Rotavirus vaccines can be given with other routine vaccines at 2 and 4 months of age, or 2, 4 and 6 months of age.
- Parents should be informed of the benefit of RV vaccination in preventing or mitigating severe diarrheal disease in infants.
- Parents should be informed of the low risk of intussusception following RV vaccine, particularly during the 7 days following the first dose. Parent education should include the signs and symptoms of intussusception and the importance of seeking medical care, should symptoms develop.
- RV vaccine reduces physician and emergency room visits for diarrhea and hospital admissions for RV diarrhea
Rotavirus (RV) is a non-enveloped virus belonging to the Reoviridae family. Serotype is defined by two structural proteins: the G protein and P protein. There are multiple variants of both G and P proteins, and, since these two proteins can segregate independently, there are numerous RV serotypes. Although the prevalence of RV serotypes varies, G1P is often the predominant strain in developed regions (for example, North America, Europe and Australia). For additional information about human rotavirus, refer to the Pathogen Safety Data Sheet.
RV is transmitted through the fecal-oral route and there is some evidence that RV can also be transmitted through the respiratory route. The virus is stable in the environment; therefore, it can be transmitted through fomites and environmental surfaces. Household transmission of RV gastroenteritis is common, with at least one other family member experiencing gastroenteritis in 47% of RV cases.
Rotavirus is highly infectious due to the small infective dose, high viral concentrations in stool, and prolonged viral shedding. Viral shedding can begin a few days prior to the onset of symptoms, and can continue until 21 days after the onset of illness. Asymptomatic shedding has been described. RV has an incubation period of 18 hours to 3 days.
Immunocompromised children are at an increased risk of severe, prolonged and even fatal gastroenteritis. Among adults, 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. Outbreaks of RV gastroenteritis, associated with considerable morbidity, have been reported in long-term care facilities.
The impact of breastfeeding on the incidence and severity of RV is unclear. Several studies have shown breastfeeding as protective against symptomatic RV infection in the first 6 to 12 months of life; however, there was no protection when assessed over the first 2 years of life, suggesting that breastfeeding may postpone infection to a later age. In a Canadian study, 25% of children admitted to hospital for RV gastroenteritis were receiving breast milk, suggesting that breastfeeding does not provide complete protection.
Seasonal and temporal patterns
In Canada and other temperate regions, the majority of RV cases occur in late winter and early spring. The seasonality is lost once good RV vaccine coverage occurs in a population.
Spectrum of clinical illness
RV infections can vary in presentation, including asymptomatic infection, mild disease, severe dehydration, and death. There is typically an acute onset of fever and vomiting. These symptoms are usually followed by diarrhea, which generally lasts 5 to 7 days. Some children may experience only vomiting. In general, few clinical or epidemiologic features distinguish the child with RV diarrhea from those with diarrhea due to other causes, although the triad of fever, vomiting and diarrhea more commonly occurs with RV than with other gastrointestinal viruses.
In the first 3 months of life, illness is generally mild as a result of passively transferred maternal RV antibodies. In infants and children 3 months to 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. Disease is often most severe in children aged 3 months to 24 months, and the majority of hospitalizations for RV (63%) occur in children less than 2 years of age. Although RV gastroenteritis is typically self-limited, it is associated with considerably more health care resource utilization than gastroenteritis due to other causes.
Children can be re-infected because immunity to RV is incomplete following infection; however, subsequent courses of RV gastroenteritis are typically milder than the initial infection.
Incidence and prevalence
RV infections are extremely common worldwide. By 5 years of age, most children will have experienced at least one RV infection. This occurrence is true in both developed and developing countries, suggesting that improved sanitation does not decrease RV transmission. However, mortality due to RV infection is much higher in developing countries. The World Health Organization (WHO) estimates that 453,000 children aged less than 5 years died in 2008 from vaccine-preventable RV infections; most of these children lived in low income countries. Globally, these 453,000 childhood RV deaths account for approximately 5% of all childhood deaths.
In Canada, RV is a common cause of gastroenteritis in children, accounting for 10% to 40% of all childhood gastroenteritis. Based upon Canadian data, although death is extremely rare, RV infection is associated with considerable health care resource utilization. Approximately 36% of children with RV gastroenteritis see a physician, 15% visit an emergency department, and 7% require hospitalization. RV causes the majority of childhood gastroenteritis requiring hospitalization; between 1 in 62 to 1 in 312 children less than 5 years of age will require hospitalization for RV. Parents of children with RV gastroenteritis are more likely than parents of children with other gastroenteritis to miss work, and out-of-pocket costs are considerable for families of affected children, even for cases of low severity. For additional information about the cost benefit of immunization, refer to Benefits of Immunization in Part 1.
Immunizing Agents Available for Use in Canada
- RotaTeq®: live, oral, pentavalent rotavirus vaccine, Merck Canada Inc. (Rot-5)
- ROTARIX®: live, oral, monovalent, attenuated human rotavirus vaccine, GlaxoSmithKline Inc. (Rot-1)
For complete prescribing information, consult the product leaflet or information contained within the product monographs available through Health Canada's Drug Product Database.
Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of vaccines available for use in Canada and their contents.
Efficacy, Effectiveness and Immunogenicity
Efficacy and effectiveness
RV vaccine efficacy against RV diarrhea of any severity in developed world settings is 74% to 87 %, and efficacy against severe diarrhea due to RV is 85% to 98%. Data on the efficacy of an incomplete vaccine series are limited but do suggest that infants vaccinated during the RV season may derive substantial early protection against severe RV disease, despite not having completed a full series of immunization.
Countries with routine RV immunization programs, such as the United States of America (USA), Australia, Brazil and Mexico have seen reductions in the number of infants and children needing hospitalization or emergency department care for RV disease by about 85%. There have also been decreases in all-cause gastroenteritis and RV-specific gastroenteritis across all age groups including adults, supporting the significant role that RV vaccination has played in providing herd protection to others, including adults.
The burden of illness from RV disease in Canada before RV vaccine availability is documented in studies by the Canadian Immunization Monitoring Program, Active (IMPACT). Between 2011 and 2013, of the 1,592 hospitalizations for RV infection documented at IMPACT sites, admission rates at sites in jurisdictions with publicly funded RV immunization programs significantly decreased, while admission rates at sites in jurisdictions without immunization programs did not. In Ontario, when comparing RV-specific gastroenteritis hospitalization in the post-RV vaccine period (August 2011 to March 2013) to the pre-RV vaccine period (January 2003 to July 2006), there was a 75% decrease in hospitalizations.
Correlation between antibody responses and protection from RV disease has not been established. In clinical trials, seroconversion rates were significantly higher in vaccine recipients than placebo groups. Most infants developed antibodies to the vaccine after completing a vaccine series.
Recommendations for Use
RV vaccines are recommended for infants starting at 6 weeks and before 15 weeks of age. The vaccination series should be completed before 8 months of age.
Vaccination may be provided with either RV vaccine. Rot-5 vaccine requires 3 doses, 4 to 10 weeks apart; Rot-1 vaccine requires 2 doses, at least 4 weeks apart. To optimize protection, RV vaccine should be initiated as soon after 6 weeks of age as feasible. RV vaccines can be given with other routine vaccines at 2 and 4 months of age, or 2, 4 and 6 months of age.
The first dose of RV vaccine should be given starting at 6 weeks of age and before 15 weeks of age. Vaccination should not be initiated in infants aged 15 weeks or older, as the safety of providing the first dose of RV vaccine in older infants is not known. The minimum interval between doses of RV vaccine is 4 weeks. All doses of RV vaccine should be administered before 8 months of age.
If an incomplete dose is administered for any reason (for example, infant spits or regurgitates the vaccine) a replacement dose should NOT be administered.
For infants in whom the first dose of RV vaccine is inadvertently administered at age 15 weeks or older, the rest of the RV vaccine vaccination series should be completed with a minimum of 4 weeks between each dose, and all doses should be administered before 8 months of age. Refer to Timing of Vaccine Administration in Part 1 for information about delayed immunization schedules and accelerated immunization schedules. Refer to additional information contained within the product monograph available through Health Canada's Drug Product Database.
Infants with a history of intussusception
Refer to Previous history of intussusception.
Infants with a history of previous RV infection
Infants who have had RV gastroenteritis before receiving the full course of RV vaccinations should still initiate or complete the vaccine series, because the initial infection frequently provides only partial immunity.
Vaccination of Specific Populations
Pregnancy and breastfeeding
Infants living in households with pregnant women can be vaccinated with RV vaccine. The risk of infection and disease from RV vaccine virus is low because most women of childbearing age have pre-existing immunity to RV through natural exposure, and RV infection during pregnancy is not known to pose a risk to the fetus.
The efficacy of RV vaccines is similar among infants who are breastfed and those who are not; therefore, breastfed infants can receive RV vaccine.
Refer to Immunization in Pregnancy and Breastfeeding in Part 3 for additional information about vaccination of infants living in households with a pregnant woman.
Infants born prematurely
Available data indicate that RV vaccine is safe and effective when administered to healthy preterm infants starting at 6 weeks of chronological age, with the first dose administered before 15 weeks of chronological age. The vaccination series should be completed before 8 months of age. Refer to Immunization of Infants Born Prematurely in Part 3 for additional information about RV vaccination of preterm infants.
Patients in health care institutions
In addition to routine practices, further infection control precautions may be indicated when administering RV vaccine in the hospital setting. Refer to Immunization of Patients in Health Care Institutions in Part 3 for additional information about RV vaccination of infants in health care institutions.
In general, immunocompromised infants should not receive live vaccines because of the risk of disease caused by the vaccine strains. Infants with a known or suspected family history of congenital or hereditary immunodeficiency that is a contraindication to vaccination with live vaccine should not receive RV vaccine unless their immune competence has been established. When considering immunization of an immunocompromised infant with RV vaccine, approval from the infant's attending physician should be obtained before vaccination and referral to a consultant with expertise in immunization or immunodeficiency is advised. Severe cases of RV gastroenteritis have been reported after vaccination of infants with Severe Combined Immunodeficiency Disease (SCID); therefore, RV vaccine is contraindicated in these infants.
Refer to Immunization of Immunocompromised Persons in Part 3 for information about the administration of vaccines to infants following exposure to monoclonal antibodies during pregnancy and breastfeeding.
Infants who are travelling, particularly to developing countries, should receive RV vaccine as appropriate for age. Refer to Immunization of Travellers in Part 3 for additional information about RV vaccination of infants who are travelling.
Serologic testing is not recommended before or after receiving RV vaccine.
Each dose of Rot-5 vaccine is 2.0 mL. Each dose of Rot-1 vaccine is 1.5 mL.
Route of administration
RV vaccines are for oral administration only and must not be injected. All doses should be given in a clinic or office setting under the direction of a health care provider.
Refer to Vaccine Administration Practices in Part 1 for additional information about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique, and infection prevention and control. Refer to Intussusception for information about pre-vaccination counselling of parents regarding intussusception.
Interchangeability of vaccines
There are no data on safety, immunogenicity, or efficacy when Rot-1 vaccine is administered as the first dose and Rot-5 vaccine is used as the second dose or vice versa. Given that the two vaccines differ in composition and schedule, the vaccine series should be completed with the same product whenever possible. However, in the event that the product used for a previous dose(s) is unknown, the series should be completed with the available product. If any dose in the series was Rot-5 vaccine, a total of 3 doses of vaccine should be administered. Refer to Principles of Vaccine Interchangeability in Part 1 for additional information about interchangeability of vaccines.
Simultaneous administration of vaccines
RV vaccine may be given at the same time as, or at any time before or after any other live or inactivated vaccine available in Canada, regardless of the route of administration of the other vaccine. Refer to Timing of Vaccine Administration in Part 1 for additional information about simultaneous administration of vaccines.
Storage and Handling of Immunizing Agents
RV vaccines should be stored and transported at +2°C to +8°C. RV vaccines should not be frozen and should be protected from light. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional information and recommendations.
Safety and Adverse Events
Common and local adverse events
In large clinical trials, RV vaccines did not exhibit many differences in adverse events compared to placebo. In one large study, infants who received Rot-5 vaccine had a small, but statistically significant increased rate of diarrhea in the 7 day period after vaccination (10% to 18% versus 6% to 15%). Vaccinees also had a small, but statistically significant, greater rate of vomiting (12% versus 10%).
Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Serious adverse events were not found to be different between RV vaccine and placebo in clinical trials. Among infants given Rot-5 vaccine or placebo in clinical trials, the incidence of serious adverse events was 2.4% in vaccinees and 2.6% in placebo recipients, which was not significantly different. In a study of Rot-1 vaccine or placebo recipients, at least 1 serious adverse event was reported in 1.7% of vaccinees and 1.9% of placebo recipients.
Intussusception in the first year of life occurs at a background rate of about 34 per 100,000 per year; however, the rate varies with age in the first year of life and peaks between 5 and 10 months of age.
Surveillance for intussusception following the introduction of routine infant RV immunization programs in several countries suggested a small increased risk of intussusception following RV vaccination. Subsequent epidemiologic studies using different methods have estimated the risk as between 1 and 7 excess cases of intussusception per 100,000 doses in the 7 days following the first and second dose of RV vaccine. The Global Advisory Committee on Vaccine Safety (GACVS) of the WHO reviewed the findings from these studies and noted that the findings remain reassuring; the risk of intussusception following current RV vaccines is small.
Parents should be informed of the low risk of intussusception following RV vaccine (1 to 7 cases per 100,000 doses), particularly during the 7 days following the first dose. Parent education should include the signs and symptoms of intussusception and the importance of seeking medical care should symptoms develop. They should also be informed that the risk of intussusception remains small compared to the benefit of RV vaccination in preventing disease and of the potential for severe diarrhea from RV.
Vaccine providers should report intussusception in the first 21 days following any dose of RV vaccine, through local public health officials.
In infants, hematochezia (bloody stools) in conjunction with abdominal pain is associated with intussusception. No significant increase in the frequency of bloody stools has been found following use of either RV vaccine.
During a large clinical trial of more than 30,000 children, there were 5 cases of Kawasaki disease in the vaccinated group. The GACVS reviewed all available data from the USA (where Rot-5 vaccine is used) and the European Union (where Rot-1 vaccine is used), to determine if there was any association between Kawasaki disease and RV vaccines, and concluded there was no evidence for a causal association between RV vaccines and Kawasaki disease.
In a study of 63,225 infants, no difference between vaccine and placebo recipients was noted in convulsion-like events.
Components of porcine circovirus-1 (PCV-1) were found to be present in Rot-1 vaccine when an independent USA academic research team applied a new technology for detecting viral genetic material. Subsequently, components of PCV-1 and porcine circovirus-2 (PCV-2) were also found in Rot-5 vaccine. Porcine circovirus does not cause illness in humans. There is no evidence that the presence of PCV-1 or PCV-2 in RV vaccines poses a safety risk to vaccines; the WHO and the USA Food and Drug Administration have recommended that the RV vaccines continue to be used.
Guidance on reporting Adverse Events Following Immunization
Vaccine providers are asked to report the following adverse events following immunization (AEFI) in particular, through local public health officials:
- Intussusception in the first 21 days following any dose of RV vaccine.
- Any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.
Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada and Vaccine Safety in Part 2 for additional information about AEFI reporting.
Contraindications and precautions
RV vaccines are contraindicated in infants with SCID; previous history of intussusception; a history of anaphylaxis after previous administration of the vaccine; or proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of vaccines available for use in Canada and their contents.
RV vaccine is contraindicated in infants with SCID due to a risk of severe gastroenteritis. Infants known or suspected to be immunocompromised should not receive RV vaccine without consultation with a physician with expertise in immunization or immunodeficiency.
Previous history of intussusception
As a precaution, infants with a history of intussusception should not be given RV vaccine. About 4% of infants with intussusception will have another episode in the following year; there is no evidence that children who have a history of intussusception are at an increased risk of another intussusception after receiving RV vaccine.
Other medical conditions
RV vaccines can be administered to infants with minor acute illness, with or without fever.
In infants with moderate-to-severe gastroenteritis, RV vaccine should be deferred until the condition improves unless deferral will result in scheduling of the first dose after 15 weeks of age. Infants with mild gastroenteritis can be vaccinated. The immunogenicity and efficacy of the RV vaccines has not been studied in infants with concurrent gastroenteritis; immunogenicity and effectiveness of the vaccine may theoretically be reduced.
The safety and efficacy of RV vaccines has not been established in children with pre-existing, chronic gastrointestinal conditions. However, infants with chronic gastrointestinal disease who are not considered immunocompromised are likely to benefit from RV vaccine and can be vaccinated.
Infants with uncorrected congenital malformation of the gastrointestinal tract, such as Meckel's diverticulum, that would predispose the child to intussusception should not receive RV vaccine.
Refer to Contraindications, Precautions and Concerns in Part 2 for additional information.
Drug-food or drug-drug interactions
There are no restrictions on the infant's consumption of food or liquid, including breast milk, either before or after vaccination with RV vaccine.
No safety or efficacy data are available for the administration of RV vaccine to infants who have recently received immune globulins or other blood products. In theory, there is minimal or no interaction between blood products or Ig preparations, and RV vaccine. RV vaccine may be given concomitantly with, or at any time before or after, an immune globulin preparation or other blood product has been administered.
- Centers for Disease Control and Prevention. The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases. Updated 13th ed., 2015. Accessed June 2015 at: http://www.cdc.gov/vaccines/pubs/pinkbook/index.html
- GlaxoSmithKline Inc. Product Monograph - ROTARIX™. October 2010.
- Merck Frosst Canada Ltd. Product Monograph - RotaTeq®. August 2010.
- National Advisory Committee on Immunization. Statement on Rotavirus Vaccines and Intussusception. Accessed March 2018 at: https://www.canada.ca/en/public-health/services/publications/healthy-living/statement-rotavirus-vaccines-intussusception.html.
- National Advisory Committee on Immunization. Literature review on Rotavirus: disease and vaccine characteristics. Can Commun Dis Rep 2010:36(ACS-14):1-31.
- National Advisory Committee on Immunization. Updated statement of the use of rotavirus vaccines. Can Commun Dis Rep 2010:36(ACS-4):1-37.
- National Advisory Committee on Immunization. Statement on the recommended use of pentavalent human-bovine reassortant rotavirus vaccine. Can Commun Dis Rep 2008:34(ACS-1):1-33.
- World Health Organization. Update on intussusception following rotavirus vaccine administration. Wkly Epidemiol Rec 2014;7(89):57-58. Accessed June 2015 at: http://www.who.int/wer/2014/wer8907.pdf
- World Health Organization. Rotavirus vaccines. Wkly Epidemiol Rec 2007;32(82):285-96.
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