Vaccine-Preventable Diseases

Rubella

Rubella is a mild febrile viral disease, which mainly affects children; approximately one-half of rubella infections are subclinical. By far the most important clinical problem associated with rubella is the occurrence of congenital rubella syndrome (CRS) following infection of pregnant women. CRS can result in miscarriages, stillbirths, and fetal malformations, including congenital heart diseases, cataracts, deafness, and mental retardation. The risk of fetal damage is highest when maternal infection occurs just prior to conception or in the earliest months of pregnancy - 85% of CRS cases occur with infection in the first trimester - and is very rare after the twentieth week of pregnancy. Infected infants may appear normal at birth and fetal malformations may not become apparent for several years. Congenital infection can become chronic, and may result in diabetes and panencephalitis later in life. The costs associated with long-term care for cases of CRS represent a huge economic burden for affected families and for society at large ($514,000 per case on average).

Vaccination against rubella was introduced in Canada in 1969. Since the mid-1970s, rubella incidence in Canada has remained relatively low (Figure 10). An average of approximately 1,000 cases (ranging from 237 to 2,450) were reported annually from 1986 to 1995; this represents a mean rate of 4.0 per 100,000 population. A number of college and university outbreaks have been reported in recent years. About one-third of the rubella cases reported in the last 5 years have been among adolescents 10 to 19 years of age. Overall, 50% to 60% of reported cases in Canada occur in persons between the ages of 10 and 39 years. Thirty-two cases of CRS were reported in Canada from 1986 to 1995; however, CRS is believed to be grossly underreported.

The primary objective of vaccination against rubella is to prevent infection during pregnancy. In addition to routine vaccination of children, vaccination is also recommended for all females of childbearing age unless they have documented prior immunization, or laboratory evidence of detectable antibodies from natural infection or previous immunization. Protection of pregnant women and women of childbearing age can be further ensured by vaccination of males, particularly those likely to come into contact with women at risk (such as males in secondary, post-secondary, and health-care institutions).

1998 Update:  In 1998, rubella incidence fell to the lowest number ever recorded nationally at 0.2/100,000 or 67 cases (Figure 4). The majority of cases were diagnosed in the 15- to 19-year-old age group. The highest age-specific incidence was in the younger than one-year-old age group at 2.2/100,000 (eight cases) followed by the one- to four-year-old age group at 0.8/100,000 (13 cases). The male to female ratio was 1:2.

Figure 4) Crude incidence of rubella reported in Canada, 1924 to 1998. No national reporting between 1959 and 1968

Congenital rubella

Paediatrician-based active surveillance through the CPSP began in January 1996, and, since April 1996, cases reported to IMPACT have been forwarded to the CPSP. Paediatricians participating in CPSP are also asked to report infants with congenital rubella infection (CRI), defined as cases with no clinically compatible manifestations but with laboratory confirmation of infection. Given that the majority of infants infected with rubella in utero have no detectable clinical abnormalities at birth and many will go on to develop late-onset manifestations, it is important that CRI cases be identified.

Table 4 shows the number of CRS cases by year of reporting to surveillance systems in Canada from 1996 to 1998. Five older children previously diagnosed but not reported to NDRS were captured by active surveillance in 1996 and 1997. Of the newly diagnosed cases from 1996 to 1998, three were newborns and one was an adolescent with late-onset manifestations.

TABLE 4: Congenital rubella syndrome (CRS) by year of reporting to Canadian Paediatric Surveillance Program (CPSP)/the Immunization Monitoring Program ACTive (IMPACT) Network and Notifiable Diseases Registry System (NDRS), January 1996 to December 1998   Number of CRS reported to CPSP/IMPACT Total number of CRS reported to NDRS Year of reporting Newly diagnosed Previously diagnosed but not reported Total 1996 1 3 4 2 1997 2 2 4 1 1998 1 0 1 1

Table 5 shows the number of CRS cases by year of birth reported in Canada from 1996 to 1998. Since 1996, with enhanced surveillance through CPSP in place, only one to two reports of children born with CRS per year (0.3 to 0.5/100,000 births) have occurred.

TABLE 5: Congenital rubella syndrome by year of birth reported to Canadian Paediatric Surveillance Program (CPSP)/the Immunization Monitoring Program ACTive (IMPACT) Network and Notifiable Diseases Registry System (NDRS), January 1996 to December 1998   Reported to   Year of birth  NDRS only CPSP/IMPACT only NDRS and CPSP/IMPACT Total 1996 1 0 1 2 1997 0 0 1 1 1998 0 0 1 1

Table 6 shows the CPSP data on the characteristics of the three cases born in Canada from 1996 to 1998. Two cases were infants of foreign-born mothers from countries where rubella immunization was not routine. Two cases were potentially preventable because the mothers were tested to be rubella-susceptible during a previous pregnancy but did not receive vaccination.

TABLE 6: Characteristics of infants with congenital rubella syndrome born in Canada from 1996 to 1998 Year of birth Laboratory-confirmed Clinical manifestations Mother born in Canada Previous maternal rubella IgG screening test Maternal rubella immunization 1996 Yes Multiple No Positive Unknown 1997 Yes Multiple No Negative No 1998 Yes Multiple Yes Negative No Ig Immunoglobulin

So far, no CRI has been reported to CPSP. The degree of underdiagnosis and under-reporting for CRI, CRS with less severe manifestations and CRS with late-onset manifestations is unknown.

Between July 1, 1996 and June 30, 1998, 145 women aged 15 to 44 years with positive RIgM were reported by five (24%) of 21 laboratories participating in the Rubella-Associated Adverse Pregnancy Outcomes Surveillance System (RAAPO). Twenty-one (14.5%) of the eligible cases were pregnant at the time of RIgM testing, of which 19 were from Manitoba where a large outbreak of rubella occurred. Of 14 pregnant women with known immunization histories, eight (57%) had been immunized against rubella, of whom four had been vaccinated less than nine months before IgM testing. Of the 17 pregnant women who did not receive recent rubella vaccination, 11 (64%) had clinically 'healthy' newborns, and six (36%) had adverse pregnancy outcomes, including four induced abortions, one spontaneous abortion and one fetal death. RAAPO failed to capture three CRS cases identified by the other surveillance systems during the same surveillance period. Further evaluation of RAAPO, especially an assessment of under-reporting, is needed.

In summary, rubella infection in women of childbearing age continues to occur in Canada, but the number of newborns with CRS appears to be on a decline. There have been no reports of children with CRI to the CPSP or RAAPO. Based on the data from RAAPO, 36% of pregnant women with serologically confirmed rubella infection experienced fetal loss.

Rubella Vaccine

The rubella virus vaccine currently licensed in Canada incorporates live attenuated virus strain RA 27/3, prepared in human diploid cell culture. It is available as a monovalent vaccine or in combination with mumps and measles vaccines (MMR) or measles vaccine (MR). The vaccine is lyophilized and should be reconstituted just before administration with the diluent provided.

Efficacy and Immunogenicity

Rubella 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 vaccinees and may account for the continued endemicity of rubella. Asymptomatic re-infection has also been observed in women with naturally acquired immunity and very low antibody titres. Rarely, transient viremia can occur in people immune by either natural disease or prior immunization, but transmission to the fetus in this circumstance is believed to be rare.  

Schedule and Dosage  

Immunization schedules and requirements for MMR vaccine vary by province/territory and can be obtained from the local public health department. The dose of rubella vaccine, given either alone or combined with measles vaccine or measles and mumps vaccines, is 0.5 mL given as subcutaneous injection.  

Infants and children  

One dose of live rubella vaccine is recommended routinely for all children on or as soon as practical after their first birthday in combination with measles and mumps vaccines. Rubella vaccine should not be administered prior to 12 months of age. In all provinces and territories, a second dose of rubella vaccine is given at the time of the second dose of measles vaccine, administered at 18 months of age or at school entry and at least 1 month after the first dose. Although a second dose of rubella vaccine 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 vaccine should be given to all female adolescents and women of childbearing age unless they have proof of immunity, which is either a record of prior immunization or laboratory evidence of detectable antibody. At the first visit, rubella immunization status should be assessed. If there is no documentation of prior immunization, one dose of rubella vaccine should be given, preferably as MMR vaccine, since a high proportion of women susceptible to rubella are likely also susceptible to measles. A clinical history of rubella without laboratory confirmation is not a reliable indicator of immunity.  

Every effort should be made to immunize foreign-born adolescents and women from countries where rubella vaccine is in limited use (see Epidemiology section in the Guide ) as soon as possible after entry to Canada or, for women who are pregnant upon presentation, immediately post-partum.

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 rubella vaccine (preferably given as MR or MMR vaccine) in the immediate postpartum period and as soon as practical after delivery. Every effort should be made to immunize 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, and those without documented immunity should be immunized. In addition, vaccine should be given to susceptible people of either sex who may expose pregnant women to rubella.  

Booster Doses and Re-immunization  

Antibody levels developed in response to earlier rubella vaccines decline over time, but this decline may not have great 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 but are not harmful and may provide a marginal protective benefit in the population.  

Serologic Testing  

Pre-immunization: A documented history of immunization is presumptive evidence of immunity. Serologic screening in a person without documented immunization is neither necessary nor recommended, and may result in a missed opportunity to immunize.  

Post-immunization: Serologic testing after immunization is unnecessary. Women of childbearing age without a prior record of immunization who are tested and found to be non-immune serologically should be offered one dose of rubella-containing vaccine. Those with a prior record of immunization who are serologically non-immune may be offered immunization, but such tests are likely to be falsely negative. It is not necessary to repeat immunization even if subsequent serologic tests are also negative, because such individuals usually have other evidence of rubella immunity. Prenatally: Serologic testing for rubella antibody should be a routine procedure during prenatal care for those without written serologic evidence of immunity or prior immunization. Prenatal testing in Ontario and Quebec indicates rates of serosusceptibility of about 7% and 7% to 11% respectively.

Storage Requirements  

Rubella-containing vaccines should be stored in the refrigerator at a temperature of 2o C to 8o C. Once reconstituted, the vaccine should be administered promptly.  

Simultaneous Administration with Other Vaccines  

Rubella-containing vaccines may be administered at the same time but at a separate injection site as DPT-containing vaccines routinely given at 18 months and school entry, as well as adult tetanus-diphtheria vaccine. When administered at the same time as live virus vaccines other than measles and mumps, rubella-containing vaccine( s) should be given at a separate injection site or, if possible, separated by a 4-week interval.  

Adverse Reactions  

Rash and lymphadenopathy occur occasionally. Acute transient arthritis or arthralgia may occur 1 to 3 weeks after immunization, usually persists for 1 to 3 weeks, and rarely recurs. These reactions are uncommon in children, but the frequency and severity increase with age, and 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 RA 27/3. Recently published studies indicate no evidence of increased risk of new onset chronic arthropathies or neurologic conditions in women receiving RA 27/3 rubella vaccine. Paresthesia or pain in the extremities lasting 1 week to 3 months has been reported rarely. However, both the frequency and severity of adverse reactions are less than those associated with natural disease. Serious adverse reactions are rare. There is a growing body of literature to suggest a genetic predisposition to joint manifestations following rubella immunization. However, these manifestations are more serious after natural infection, and immunization against rubella among such people is indicated.  

Contraindications  

Administration of live rubella vaccine during pregnancy should be avoided because of the theoretical risk of CRS in the fetus.  

Rubella vaccine should not be administered to people known to be hypersensitive to the vaccine components, such as antibiotics, used in its preparation; such reactions include anaphylactic hypersensitivity to neomycin. Convincing evidence supports the safety of routine administration of MMR vaccines to all children who have allergy to eggs. Fewer than 2 per 1,000 immunized egg-allergic children have been found to be at risk of anaphylactic reaction to MMR vaccine (see the chapter on Measles Vaccine in the Guide for further details).

Precautions  

Women of childbearing age should be advised to avoid pregnancy for 1 month after immunization. This recommendation is based on the duration of viremia after natural infection and evidence of vaccine safety.  

Rubella vaccine is occasionally 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 700 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 vaccine in pregnancy, or conception within 1 month after receipt, should not be 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.  

As with other live vaccines, rubella vaccine should not be administered to people whose immune mechanism is impaired as a result of disease or therapy, except under special circumstances (see section on Immunization in Immunocompromised Hosts in the Guide). These vaccines would generally be administered to provide protection against measles. The immune response in such individuals may be impaired. Rubella-containing vaccines may be administered to HIV-infected people who are not severely immunosuppressed and among whom use of the vaccine has not been associated with serious adverse reactions.  

Other Considerations  

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; in only one instance was the contact known to be previously immune by serologic testing. Therefore, it is safe to administer vaccine to those who are in contact with susceptible, pregnant women and with immunocompromised people.  

Anti-Rho(D) immune globulin may interfere with response to rubella vaccine. Rubella-susceptible women who receive anti-Rho(D) immune globulin post-partum should either be given rubella vaccine at the same time and tested 3 months later for rubella immunity, or should be immunized with rubella vaccine 3 months postpartum, with follow-up ensured.  

Vaccine must not be administered less than 2 weeks before an immune globulin injection. When immune globulin has been administered, rubella immunization should be delayed for 3 months; it should be delayed for 5 months if given as MMR vaccine (see Chapter on Passive Immunizing Agents in the Guide.) It has been shown that previous or simultaneous blood transfusion does not generally interfere with the antibody response to rubella immunization. In such cases, however, it is recommended that a serologic test be done 6 to 8 weeks after immunization to test the individual's immune status. If the individual is seronegative, a second dose of vaccine should be administered.  

Passive immunization  

The effectiveness of immune globulin for post-exposure prophylaxis of rubella is unknown and as such is not recommended.  

Management of outbreaks  

During outbreaks, people at risk who have not been immunized or do not have serologic proof of immunity should be given vaccine promptly without prior serologic testing. A history of rubella illness is not a reliable indicator of immunity. Even though rubella immunization has not been shown to be protective when given after exposure, it is not harmful. It will protect the individual in future if the current exposure does not result in infection.  

Surveillance  

All suspected and confirmed cases of rubella and CRS must be reported to the appropriate local or provincial/territorial public health authority. In addition to this passive surveillance, CRS is monitored through the Canadian Paediatric Surveillance Program.  

Laboratory confirmation is carried out by serodiagnostic laboratory methods or culture. The specific diagnosis is particularly important in suspect cases who are contacts of pregnant women and in suspect cases of CRS, as well as during outbreaks. A significant, rising antibody titre from acute and convalescent serum samples is confirmatory, the first sample being taken within the first 7 days after illness and the second 10 days after the first. Rapid confirmation may be obtained by testing for rubella-specific IgM antibody in a serum sample taken between 3 days and 1 month after rash onset. There may be false-negative results if the serum sample is taken too early or too late after the clinical illness, and false positives occur frequently, since the test has low positive predictive value outside the outbreak setting. Congenital infection may be confirmed by isolation of the virus in neonatal urine or nasopharyngeal secretions, detection of IgM antibody to rubella virus in blood, or the persistence of antibody to rubella virus beyond the age of 3 months. Consultation with the regional public health laboratory will indicate the availability and applicability of various diagnostic methods for rubella.

Rubella Vaccine Selected References  

Balfour HH, Groth KE, Edelman CK et al. Rubella viraemia and antibody responses after rubella vaccination and reimmunization. Lancet 1981;1:1078-80.

Bottiger M, Morsgren 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.  

Enders G, Nickerl-Pacher U, Miller E et al. Outcome of periconceptional maternal rubella. Lancet 1988;1:1445-47.

Gyorkos TW, Tannenbaum TN, Abrahamowicz M et al. Evaluation of rubella screening in pregnant women. Can Med Assoc J 1998;159(9):1091-97. 

Kimerlin DW. Rubella immunization. Pediatr Ann 1997;26(6):366-70.  

Libman MD, Behr MA, Martel N et al. Rubella susceptibility predicts measles susceptibility: implications for postpartum immunization. Clin Infect Dis 2000;31(6):1501-3.

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

Mitchell LA, Tingle AJ, GraceMet al. Rubella virus vaccine associated arthropathy in postpartum immunized women: influenza of preimmunization serologic status on development of joint manifestations. J Rheumatol. 2000;27(2):418-23. 

Mitchell LA, Tingle AJ, Decarie D et al. Identification of rubella virus T-cell epitopes recognized in anamnestic response to RA27/3 vaccine; associations with boost in neutralizing antibody titer. Vaccine 1999;17(19):2356-65. 

Mitchell LA, Tingle AJ, MacWilliam L et al. HLA-DR class II associations with rubella vaccineinduced joint manifestations. J Infect Dis 1998;177(1):5-12.   

Parkman PD. Making vaccination policy: the experience with rubella. Clin Infect Dis 1999;28(suppl 2):S140-6.  

Ray P, Black S, Shinefield H et al. Vaccine Safety Datalink Team. Risk of chronic arthropathy among women after rubella vaccination. JAMA 1997;278(7):551-56.

Stevenson J, Murdoch G, Riley A et al. Implementation and evaluation of a measles/rubella vaccination campaign in a campus university in the UK following an outbreak of rubella. Epidemiol Infect 1998;121(1):157-64.  

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

Tookey PA, Peckham CS. Surveillance of congenital rubella in Great Britain, 1971-96. BMJ 1999;318:769-70.  

Tookey PA, Jones G, Miller BH et al. Rubella vaccination in pregnancy. CDR (Lond Engl Rev) 1991;1(8):R86-8.  

Valiquete L, Saintonge F, Carsley J et al. Survey of postpartum rubella vaccination, Montreal, Laval, and Montérégie, Quebec, 1992. CCDR 1996;22(5):38-40.   

Weibel RE, Benor DE. National Vaccine Injury Compensation Program, US Public Health Service, Rockville, Maryland 20857, USA . Arthritis Rheum 1996;29(9):1529-34; published erratum in Arthritis Rheum 1996;29(11):1930.