Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Rubella Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Other considerations Selected references

Rubella is a viral disease that results in a transient erythematous rash, post-auricular or suboccipital lymphadenopathy, arthralgia and low-grade fever. As symptoms are non-specific, it may be mistaken for infection due to parvovirus, adenoviruses or enteroviruses. Adult infection is frequently accompanied by transient polyarthralgia or polyarthritis. Serious complications are rare, and up to 50% of infections are subclinical.

The main goal of immunization is the prevention of rubella infection in pregnancy, which may give rise to congenital rubella syndrome (CRS). This syndrome can result in miscarriage, stillbirth and fetal malformations, including congenital heart disease, cataracts, deafness and mental retardation. Fetal infection can occur at any stage of pregnancy, but the risk of fetal damage following maternal infection is particularly high in the earliest months after conception (85% in the first trimester) with progressive diminution of risk thereafter, and it is very uncommon after the 20th week of pregnancy. Infected infants who appear normal at birth may later show eye, ear or brain damage. Congenital infection may give rise to such problems as diabetes mellitus and panencephalitis later in life. Congenitally infected infants may shed the virus in the urine and in nasopharyngeal secretions for 1 year or more.

The changes since the previous edition of the Canadian Immunization Guide include 1) discontinuation of the marketing of monovalent rubella (R) and measles and rubella (MR) vaccines in Canada, and 2) the development of newer diagnostic methods (specifically polymerase chain reaction and IgG avidity tests) to detect or confirm rubella infection.

Epidemiology

An MMR immunization program for all infants was introduced in Canada in April 1983. The average number of rubella cases reported decreased from approximately 5,300 (1971-1982) to fewer than 30 cases per year (1998-2004). The average annual incidence decreased from 0.08 per 100,000 in 1998 to 0.03 per 100,000 in 2004 (range: 0.02-0.09 per 100,000 per year).

In the two decades following the introduction of routine infant immunization, epidemics of rubella continued to occur every 3 to 10 years with incidence peaking both in the spring and winter months. Many of these outbreaks, including one involving over 3,900 cases in Manitoba in 1997, differentially affected males aged 15-24 years of age who had not been immunized because of previous (before 1983) selective rubella immunization of pre-pubertal girls in some jurisdictions. Since the late 1990s, outbreaks have largely been restricted to isolated clusters of unimmunized people, including those who decline immunization for religious or philosophical reasons.

From 2000 to 2004, fewer than 30 sporadic cases of rubella and 0 to 3 cases of CRS were reported each year in Canada. However, in 2005, in addition to sporadic cases reported in several provinces and territories, there was a rubella outbreak involving over 300 cases in an unimmunized southwestern Ontario community which was philosophically opposed to immunization. These outbreak-related cases accounted for the vast majority of rubella cases in 2005 and primarily involved unimmunized children < 19 years old (median age 11, range 0.3-34 years). Ten cases involved pregnant women, but no cases of CRS have been reported as of March 14, 2006. As a result of immunization rates in excess of 95% in the general population, the outbreak did not spread to the surrounding community.

In Canada, routine infant immunization programs have resulted in sustained high rates of immunity in the general population. In addition, measles elimination strategies since the mid 90s have indirectly resulted in a reduction in the proportion of the susceptible population with the use of rubella-containing vaccines (MR and MMR) for the two-dose routine program and measles elimination catch-up campaigns.

Canada is making progress towards elimination of indigenous rubella infection in pregnancy through routine immunization programs, together with CRS-specific policies to screen 100% of pregnant women for rubella and to offer immunization to all women who are susceptible post-partum. Yet while the rarity of CRS in Canada is a reflection of the impact of these rubella elimination strategies, the risk of cases resulting from importation and limited transmission still exists, both for immigrants arriving from areas of low rubella coverage as well as for Canadian communities and individuals who decline immunization for religious or philosophical reasons. CRS has also been reported in infants of Canadian women who developed rubella infection in pregnancy during travel abroad. Travel-related risk of exposure to rubella may change as more countries initiate childhood rubella immunization programs. By 2003, the majority of Caribbean and South and Central American countries had included rubella in their childhood immunization schedule to comply with the Pan American Health Organization's rubella elimination goals.

Preparations approved for use in Canada

This chapter will deal only with products currently marketed in Canada.

• M-M-R^®II (measles, mumps and rubella vaccine, live, attenuated), Merck Frosst Canada Ltd.
• Priorix^® (measles, mumps, rubella vaccine, live, attenuated), GlaxoSmithKline Inc.

The rubella virus vaccine currently marketed in Canada incorporates live attenuated virus strain RA 27/3. The RA 27/3 strain replaced other vaccine strains that were less immunogenic. It was introduced in 1980 and is prepared in human diploid cell culture. Rubella vaccine is only available in combination with measles and mumps vaccines (MMR). Consequently, the term "rubella-containing vaccine" is synonymous with MMR. The vaccine is lyophilized and should be reconstituted just before administration with the diluent provided.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

Rubella-containing vaccine stimulates the formation of antibody to rubella virus in over 97% of susceptible individuals. Titres are generally lower than those observed in response to natural rubella infection. Asymptomatic re-infection, manifest by a rise in antibody, has been observed in some vaccinees. Asymptomatic re-infection has also been observed in women with naturally acquired immunity associated with very low antibody titres. Rarely, transient viremia can occur in people who have had natural disease or prior immunization, but transmission to the fetus in this circumstance is believed to be rare.

Recommended usage

Infants and children

One dose of rubella-containing vaccine (MMR) is recommended routinely for all children on or as soon as practical after their first birthday. The second dose, given for measles protection, should be given after 15 months of age and before school entry. The acceptable minimum interval between the first and second dose is at least 1 month. Although a second dose of the rubella component is not believed to be necessary for achieving elimination of CRS, it is not harmful and may benefit those who do not respond to primary immunization (1% to 3% of people).

Adolescents and adults

Rubella-containing vaccine (MMR) should be given to all adolescents and adults unless they have proof of immunity, which is either a record of prior immunization, a documented history of laboratory-confirmed rubella disease or serologic proof of immunity. A clinical history of rubella without laboratory confirmation is not a reliable indicator of immunity. If there is no documentation of prior immunization, one dose of MMR should be given to ensure that these individuals will be protected against rubella and also protected against measles. Refer to the Measles Vaccine chapter for information on indications for receipt of two doses of MMR vaccine.

A priority is to immunize non-pregnant, foreign-born adolescents and women from countries where rubella vaccine is not in use as soon as possible after entry to Canada (see Epidemiology section). Similarly, the rubella immune status of people planning to travel to rubella-endemic countries should be reviewed. Immunization with a single dose of rubella-containing vaccine is recommended if they do not have proof of immunity.

Since up to one-third of cases of CRS occur in second and subsequent pregnancies, it is essential that all women found to be susceptible during pregnancy receive one dose of rubella-containing vaccine in the immediate post-partum period, before hospital discharge. Canadian, U.S. and U.K. studies show that a large proportion of rubella-susceptible women are not immunized post-partum. Hospital standing order policies have been shown to be effective in increasing post-partum immunization rates.

In educational institutions, such as schools, colleges and universities, particular emphasis should be placed on immunization of susceptible female staff and female students of childbearing age because of their relatively high risk of exposure.

In health care settings, the rubella immune status of female employees of childbearing age should be carefully reviewed. Those without documented immunity should be immunized with MMR vaccine. In addition, it is also important that health care workers of either sex be actively immunized against rubella because they may, through frequent face-to face contact, expose pregnant women to rubella.

Schedule and dosage

One dose of MMR vaccine should be administered for rubella protection, with the second dose given for measles protection. The first dose should be given on or after the first birthday and the second dose given at least 1 month after the first and, in children, before school entry. The standard dosage is 0.5 mL. See the Measles Vaccine chapter for details of indications for a second dose.

For single vials, the entire contents of the vial should be injected promptly after reconstitution (0.5-0.7 mL).

Route of administration

Rubella-containing vaccine (MMR) should be administered subcutaneously.

Booster doses and re-immunization

Antibody levels developed in response to earlier generation rubella vaccines declined over time, but this may not have clinical significance since any detectable antibody generally protects against viremic infection. The duration of protection is not yet known, but studies indicate that the duration of both cellular and humoral immunity exceeds 20 years. Booster doses are not considered necessary. However, if a booster dose is given, it is not harmful and may provide protection to the small proportion of individuals left unprotected by the first dose.

Serologic testing

Pre-immunization

A documented history of immunization is evidence of immunity. For those without documented immunization, serologic screening is neither necessary nor recommended before vaccination. Performing serologic tests may cause undue delay and result in a missed opportunity to immunize.

Post-immunization

Serologic testing after immunization is unnecessary. It is not necessary to repeat immunization even if subsequent serologic tests are also negative.

Prenatally

Serologic testing for rubella antibody is not necessary during prenatal care for those with documented evidence of serologic immunity or prior immunization. Women without a prior record of immunization who are tested and found to be non-immune serologically should be vaccinated with one dose of rubella-containing vaccine (MMR) in the immediate post-partum period and before discharge from hospital. They need not be screened for rubella antibodies either after immunization or in subsequent pregnancies, since they are likely protected against CRS.

Storage requirements

Rubella-containing vaccine (MMR) should be stored in the refrigerator at a temperature of +2º C to +8º C. The vaccine must be protected from light, which may inactivate the vaccine viruses. Once reconstituted, the vaccine should be administered promptly.

Simultaneous administration with other vaccines

Rubella-containing vaccine (MMR) may be administered at the same time but at a separate injection site as hepatitis B, pneumococcal conjugate, meningococcal conjugate C, Haemophilus influenzae type b, DTaP-IPV and the adolescent/adult Tdap vaccines. Other live vaccines such as varicella may be administered at the same time as MMR vaccine but at separate injection sites. If not administered at the same visit, other live vaccines must be separated by at least a 4-week interval.

Adverse reactions

Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.

Rash and lymphadenopathy occur occasionally. Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization, persisting for approximately 1 to 3 weeks and rarely recurring. These reactions are uncommon in children, but the frequency and severity increase with age. They are more common in post-pubertal females, among whom arthralgia develops in 25% and arthritis-like signs and symptoms in 10% after immunization with rubella vaccine. The frequency of adverse reactions in seronegative women is higher in those who have never been vaccinated than in revaccinated seronegative women.

Published studies indicate no evidence of increased risk of new onset, chronic arthropathies or neurologic conditions in women receiving rubella vaccine. There is some evidence to suggest a genetic predisposition to joint manifestations following rubella immunization. Paresthesia or pain in the extremities lasting 1 week to 3 months has been reported rarely. Both the frequency and severity of adverse reactions are less than those associated with natural disease, and serious adverse reactions are rare.

Contraindications and precautions

Rubella-containing vaccine (MMR) should not be administered to people known to have anaphylaxis to the vaccine components, such as neomycin. There is evidence that it is safe to immunize children who have allergy to eggs with MMR, since fewer than 2 per 1,000 immunized egg-allergic children were found to be at risk of anaphylactic reaction to MMR vaccine. Please refer to the Anaphylactic Hypersensitivity to Egg and Egg-Related Antigens chapter for more information.

As with other live vaccines, rubella-containing vaccine should not be administered to people whose immune mechanism is impaired as a result of disease or therapy, except under special circumstances. The immune response in such individuals may be impaired. Please refer to the Immunization of Immunocompromised Persons chapter for more information.

Infants infected with human immunodeficiency virus (HIV) who are asymptomatic should receive routine MMR vaccination. In addition, MMR is recommended for most symptomatic HIV-infected persons, including children who are symptomatic without evidence of severe immunosuppression. Please consult an infectious disease specialist/immunologist for more specific advice on MMR immunization for HIV-infected people.

Administration of live rubella-containing vaccine during pregnancy should be avoided because of the theoretical risk of CRS in the fetus. Women of childbearing age should be advised to avoid pregnancy for 1 month after immunization. This recommendation is based on the expected duration of viremia after natural infection and the record of vaccine safety. Rubella-containing vaccine has occasionally been administered to women who were unknowingly pregnant at the time or who became pregnant shortly after immunization. Reassurance can be given that no fetal damage has been observed in the babies of over 1,000 susceptible women who received vaccine during their pregnancy and carried to term. The theoretical risk of teratogenicity, if any, is very small. Therefore, receipt of rubella-containing vaccine in pregnancy or conception within 1 month after receipt is not a reason to consider termination of pregnancy.

Breast-feeding is not a contraindication to rubella immunization. Although vaccine virus has been detected in breast milk and transmission can occur, no illness has been reported in the infants.

Small quantities of vaccine-strain virus may be detected in the nasopharynx of some vaccinees 7 to 28 days after immunization, but the risk of transmission to contacts seems to be very low. After many years of vaccine use, only a few cases of possible transmission have been documented. Therefore, it is safe to administer vaccine to those (including health care workers) who are in contact with susceptible pregnant women and with immunocompromised people.

Rh immune globulin (RhIg) may theoretically interfere with the response to rubella-containing vaccine. Rubella-susceptible women who receive RhIg post-partum should be vaccinated with rubella-containing vaccine (MMR) at a separate site, tested 2 months later for rubella immunity and revaccinated if the result is negative.

Rubella-containing vaccine (MMR) must be administered at least 2 weeks before an immune globulin injection. The recommended interval between immune globulin-containing products and MMR immunization varies from 3 to 11 months. Please refer to the Recent Administration of Human Immune Globulin Products chapter for more information. It has been shown that simultaneous red blood transfusion does not interfere with the antibody response to MMR immunization. In such cases, however, it is recommended that a serologic test be done 6 to 8 weeks after immunization to assess the individual's immune status. If the individual is seronegative, a second dose of vaccine should be administered.

Other considerations

Passive immunization

Immune globulin given soon after exposure to rubella may modify or suppress symptoms but is not certain to prevent infection, including congenital infection. Therefore, the routine use of immune globulin in susceptible women exposed to rubella early in pregnancy is not recommended.

Management of outbreaks

During rubella outbreaks, people who have not been immunized or do not have serologic proof of immunity should be given rubella-containing vaccine (MMR) promptly without prior serologic testing. As previously stated, a history of rubella illness is not a reliable indicator of immunity. Although immunization is ineffective after exposure to wild-type rubella, it is not harmful and will provide future protection if the current exposure does not result in infection. It will also provide protection against measles and mumps.

Surveillance and diagnosis

All suspected and confirmed cases of rubella and CRS must be reported to the appropriate local or provincial/territorial public health authority. Laboratory confirmation of rubella is carried out by serologic tests, viral culture and/or reverse transcriptase polymerase chain reaction (RT-PCR). Confirming the diagnosis is particularly important in pregnant women (especially during the first trimester), suspected cases who have contact with pregnant women, suspected cases of CRS and during outbreaks.

Rapid confirmation may be obtained by testing for rubella-specific IgM antibody in a serum sample. The sensitivity of commercial rubella IgM enzyme immunoassays has been found to be approximately 50% for samples collected ≤ 5 days after rash onset and > 90% for samples collected 1 week to 4 weeks afterwards. There may be false-negative IgM results if the serum sample is taken too early or too late after the clinical illness.

A limitation of the IgM test is that some people may have prolonged positive results (> 1 year), and the test has a low positive predictive value outside an outbreak setting. Consequently, when rubella is suspected in pregnant women, positive rubella IgM results should be confirmed using IgG avidity testing, available through the National Microbiology Laboratory in Winnipeg. The presence of low IgG avidity implies a recent infection and confirms the IgM result. In contrast, high IgG avidity implies that the IgM result is false positive (prolonged positive result or re-infection) and therefore does not indicate recent rubella infection; there is thus minimal risk of CRS.

Seroconversion, defined as a greater than four-fold rise in rubella IgG antibody titre between samples obtained at the acute and the convalescent stages, is also confirmatory, the first sample being taken within the first 7 days after illness onset and the second 10 days after the first.

Sporadic cases are those with no epidemiologic link to a laboratory-confirmed case or with no travel history to an area with known rubella activity. These cases must be laboratory-confirmed either by rubella virus isolation or seroconversion. A false-positive IgM result may occur in a sporadic case, even with highly specific IgM assays, because of the very low incidence of disease in Canada (in non-outbreak situations). Therefore, IgM serology is not a reliable test to diagnose sporadic cases.

In addition to serum collection for serologic confirmation, all suspected rubella cases should have a nasopharyngeal sample collected for viral culture and genotyping. Genotyping or molecular epidemiology is necessary to track transmission pathways, link cases in outbreaks and document the elimination of a rubella virus strain from a geographic region. Rubella virus genotyping is done at the National Microbiology Laboratory in Winnipeg.

Consultation with an obstetrician is advised when attempting to diagnose fetal rubella infection. Amniotic fluid may be collected for the RT-PCR test.

Congenital infection may be confirmed in infants by isolation of the virus in neonatal urine or nasopharyngeal secretions, detection of IgM antibody to rubella virus in blood or the persistence of IgG antibody to rubella virus beyond the age of 6 months, at which time maternally acquired antibodies usually wane.

Contact the nearest regional virology laboratory for the availability and applicability of the various diagnostic methods for rubella.

Selected references

Best JM, Banatvala JE. Rubella. In: Zuckerman AJ (editor). Principles and practice of clinical virology, 5^th edition. John Wiley and Sons, 2004.

Best JM, O'Shea S, Tipples G et al. Interpretation of rubella serology in pregnancy - pitfalls and problems. British Medical Journal 2002;325(7356):147-48.

Bottiger M, Forsgren M. Twenty years' experience of rubella vaccination in Sweden: 10 years of selective vaccination (of 12-year-old girls and of women postpartum) and 13 years of a general two-dose vaccination. Vaccine 1997;15(14):1538-44.

Centers for Disease Control and Prevention. Control and prevention of rubella: evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital rubella syndrome. Morbidity and Mortality Weekly Report 2001;50(RR-12):1-23.

Charbonneau S, Valiquette L, Bédard L et al. Survey of postpartum rubella vaccination, Montreal, Laval, and Montérégie, Quebec, 1992. Canada Communicable Disease Report 1996;22(5):38-40.

Furesz J, Varughese P, Acres SE et al. Rubella immunization strategies in Canada. Reviews of Infectious Diseases 1985;7(Suppl 1):S191-93.

Gyorkos TW, Tannenbaum TN, Abrahamowicz M et al. Evaluation of rubella screening in pregnant women. Canadian Medical Association Journal 1998;159(9):1091-97.

Health Canada. Proceedings of a meeting of the Expert Advisory Group on Rubella in Canada. Canada Communicable Disease Report 2002;28(Suppl 4):1-24.

Johnson CE, Kumar ML, Whitwell JK et al. Antibody persistence after primary measles-mumps-rubella vaccine and response to a second dose given at four to six vs. eleven to thirteen years. Pediatric Infectious Disease Journal 1996;15(8):687-92.

Macdonald A, Petaski K. Outbreak of rubella originating among high-school students - Selkirk, Manitoba. Canada Communicable Disease Report 1997;23(13):97-101.

Mitchell LA, Tingle AJ, Grace M et al. Rubella virus vaccine associated arthropathy in postpartum immunized women: influence of preimmunization serologic status on development of joint manifestations. Journal of Rheumatology 2000;27(2):418-23.

Pebody RG, Gay NJ, Hesketh LM et al. Immunogenicity of second dose measles-mumps-rubella (MMR) vaccine and implications for serosurveillance. Vaccine 2002;20(7-8): 1134-40.

Plotkin SA. Rubella eradication. Vaccine 2001;19:3311-19.

Reef SE, Frey TK, Theall K et al. The changing epidemiology of rubella in the 1990s: on the verge of elimination and new challenges for control and prevention. Journal of the American Medical Association 2002;287(4):464-72.

Tingle AJ, Mitchell LA, Grace M et al. Randomised double-blind placebo-controlled study on adverse effects of rubella immunization in seronegative women. Lancet 1997;349(9061):1277-81.

Tipples GA, Hamkar R, Mohktari-Azad T et al. Evaluation of rubella IgM enzyme immunoassays. Journal of Clinical Virology 2004;30(3):233-38.

Tookey PA, Peckham CS. Surveillance of congenital rubella in Great Britain, 1971-96. British Medical Journal 1999;318(7186):769-70.

World Health Organization. Standardization of the nomenclature for genetic characteristics of wild-type rubella viruses. Weekly Epidemiology Report 2005;80(14):126-32.

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