Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Measles 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

Measles (rubeola) is a leading cause of vaccine-preventable deaths in children worldwide. There has been a marked reduction in incidence in countries where vaccine has been widely used, but measles remains a serious and common disease in many parts of the world. Complications such as otitis media and bronchopneumonia occur in about 10% of reported cases, even more commonly in those who are poorly nourished and chronically ill, and in infants < 1 year of age. Measles encephalitis occurs in approximately 1 of every 1,000 reported cases and may result in permanent brain damage. Measles infection causes subacute sclerosing panencephalitis (SSPE), a rare but fatal disease. In developed countries, including Canada, death is estimated to occur once in 3,000 cases. Measles during pregnancy results in a higher risk of premature labour, spontaneous abortion and low birth weight infants. Canada has made great progress in its goal of measles elimination, and endemic transmission of measles has been interrupted.

Since the publication of the 2002 Canadian Immunization Guide there have been some changes in the preparations approved for use in Canada.

Epidemiology

Before the introduction of the vaccine, measles occurred in cycles with an increasing incidence every 2 to 3 years. At that time, an estimated 300,000 to 400,000 cases occurred annually. Since the introduction of vaccine, the incidence has declined markedly in Canada (see Figure 8). Between 1989 and 1995, in spite of very high vaccine coverage, there were many large outbreaks involving mainly children who had received one dose of measles vaccine. It was estimated that 10% to 15% of immunized children remained unprotected after a single dose given at 12 months of age, a proportion large enough to allow circulation of the virus. These primary vaccine failures were mainly caused by the interference of persisting maternal antibody. The currently recommended second dose aims to achieve immunity in children who did not respond to their first dose.

In 1996/97, every province and territory added a second dose to its routine schedule, and most conducted catch-up programs in school-aged children with measles or measles/rubella vaccine. These interventions achieved vaccine coverage for the second dose in excess of 85%, reducing the proportion of vulnerable children to such a negligible level that viral transmission could not be sustained.

Measles elimination within a population should be possible, as an effective vaccine is available and there is no non-human reservoir or source of infection. During the XXIV Pan American Sanitary Conference in September 1994, representatives from Canada and other nations resolved to eliminate measles in the Americas by the year 2000. In Canada, sustained transmission has been eliminated by our current schedule and high vaccine coverage. However, as expected, imported cases continue to occur. Secondary spread from these imported cases is self-limited and involves the few Canadians who are still vulnerable. The largest outbreaks have occurred in isolated groups that are philosophically opposed to immunization. Nevertheless, there is very limited secondary transmission of measles in the general population. Between 2001 and 2005, the number of measles cases reported annually ranged from 6 (2005) to 34 (2001) with a yearly average of 14. All cases were imported or import-related.

Most other countries in North, Central and South America have also succeeded in eliminating sustained transmission. In 2005 fewer than 100 measles cases were reported in all of the Western Hemisphere. The situation in other regions is evolving at a slower pace, though measles deaths in Africa have been reduced by 60%, largely through the efforts of The Measles Initiative, a cooperative group led by the Red Cross, in partnership with UNICEF, the Centers for Disease Control and Prevention, the World Health Organization and the United Nations Foundation.

The greatest challenge for future years will be to continue achieving vaccine coverage rates of 95% or more as measles becomes increasingly unfamiliar to Canadian parents. Immunization against measles will continue to be necessary in Canada until global elimination of the disease has been achieved.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

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

Measles vaccine is a live, attenuated virus vaccine and is available in combination with rubella and mumps vaccine. Measles vaccines are generally prepared in chick fibroblast cell cultures. All preparations may contain traces of antibiotics (e.g., neomycin) and stabilizer such as gelatin.

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

Efficacy and immunogenicity

The efficacy of the measles vaccine increases with age at immunization. The main mechanism explaining poor efficacy in children immunized at an early age is the interference by maternal antibody. These antibodies are transferred from the mother to the fetus in utero, and their levels slowly decrease after birth. Most infants have lost their maternal antibody by 12 months of age, but studies have shown that immunization at 15 months of age gives higher numbers of protected individuals. Maternal antibodies are not the only factor in vaccine failure, as the protection appears to reach a plateau after 15 months of age. The efficacy of a single dose given at 12 or 15 months is esti mated to be 85% to 95%. With a second dose, almost 100% of children are protected.

Recommended usage

Infants and children

For routine immunization of all children, two doses of measles vaccine should be given. Infants should receive a first dose combined with mumps and rubella vaccines (MMR) on or shortly after their first birthday; the second dose should be given after 15 months of age but before school entry. It is convenient to link this dose with other routinely scheduled immunizations. Options include giving it with the scheduled immunization at 15 or 18 months of age, with school entry immunization at 4 to 6 years, or at any intervening age that is practicable (such as entry to day care).

Two doses of vaccine given at least 4 weeks apart are recommended for children who

• Have missed MMR immunization on the routine schedule
• Are without an immunization record
• Are without reliable records of measles immunization (e.g., immigrants)
• Were given live measles vaccine and immune globulin (Ig) separated by an inappropriate interval

The recommended interval between Ig-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.

Vaccine may be recommended for children < 12 months of age during outbreaks or international travel to an area where measles is common. MMR may be given as early as 6 months of age. Under these circumstances, or if vaccine was inappropriately given before the child's first birthday, two doses of MMR should still be given after the first birthday.

Post-exposure use

Susceptible individuals > 12 months of age who are exposed to measles may be protected from disease if measles vaccine is given within 72 hours of the exposure. There are no known adverse effects of vaccine given to people incubating measles. Ig given within 6 days of the exposure can modify or prevent disease and may be used for this purpose in infants < 12 months of age, people for whom vaccine is contraindicated, or those for whom more than 72 hours but less than 1 week have elapsed since exposure. Please refer to the Passive Immunizing Agents chapter for more information. Unless it is contraindicated, individuals who receive Ig should be given measles vaccine after the intervals specified in Table 4, see Recent Administration of Human Immune Globulin Products chapter for more information.

Adults

Adults born prior to 1970 can be assumed to have acquired natural immunity to measles. Adults born in 1970 or later who have not had a measles vaccine or have not had natural measles infection should receive a dose of MMR. A second dose of MMR should be offered only to adults born in 1970 or later who are at greatest risk of exposure. These people include

• Travelers to a measles endemic area
• Health care workers
• Military recruits
• Students at post-secondary institutions

Schedule and dosage

Two doses of MMR vaccine should be administered. 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.

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

Route of administration

The vaccine should be administered subcutaneously.

Booster doses and re-immunization

Re-immunization after the standard two-dose schedule is not thought to be necessary at this time.

Serologic testing

There are no routine indications for pre- or post-immunization serology. Persons can generally be presumed to be immune to measles if they were born before 1970, have documented evidence of vaccination with two doses of measles-containing vaccine after their first birthday, laboratory evidence of immunity, or a history of laboratory-confirmed measles disease.

Storage requirements

Measles-containing vaccine should be stored in the refrigerator at a temperature of +2° C to +8° C. 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

Measles-containing vaccine can be given concurrently with other childhood vaccines. Vaccines should be administered using separate syringes and at separate sites. When administered with other live vaccines, like varicella vaccine, measles-containing vaccine should be given at the same time or separated by a minimum 4-week interval.

Adverse reactions

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

Measles vaccine produces a mild, non-transmissible and usually subclinical infection. The most frequent reaction (approximately 5% of immunized children) is malaise and fever with or without rash lasting up to 3 days and occurring 7 to 12 days after MMR immunization. One in 3,000 children with fever may have associated febrile convulsions. Rarely, transient thrombocytopenia occurs within 2 months after immunization, is usually benign and generally resolves within a month. Joint symptoms are associated with the rubella component of MMR. Adverse reactions are less frequent after the second dose of vaccine and tend to occur only in those not protected by the first dose.

Encephalitis has been reported in association with administration of live attenuated measles vaccine at a frequency of approximately 1 per million doses distributed in North America, which is so rare that it is uncertain whether the vaccine is the cause. Nevertheless, the reported incidence is much lower than that observed with the natural disease (approximately 1 per 1,000 cases). There has been a dramatic decline in the incidence of SSPE since the introduction of widespread measles immunization. No vaccine-strain viruses have been isolated from these patients.

In 1998, a group of researchers from the U.K. reported an association between MMR vaccine and autism and inflammatory bowel disease. There were claims that MMR can cause severe developmental problems and that separate injections of each component would be safer. Rigorous scientific studies have been done in countries all over the world, and there is strong scientific evidence to show that there is no association between measles vaccine and autism or inflammatory bowel disease. In 2004, 10 of the original 13 authors retracted the key interpretation concerning a potential association between MMR vaccine and autism and inflammatory bowel disease. Separate administration of the different components of MMR is strongly discouraged, as it will give no health benefit, will increase the proportion of children who fail to receive all three antigens and/or delay achieving complete protection against all three diseases, and will cause unnecessary pain and distress to children. Separate component vaccines are not currently available in Canada.

Contraindications and precautions

Since MMR vaccine contains trace amounts of neomycin and gelatin, people who have experienced anaphylactic reactions to neomycin or who have a documented gelatin allergy should not receive MMR vaccine. Anyone who has experienced anaphylaxis to a previous dose of MMR should not receive the vaccine again. Please refer to the Anaphylaxis: Initial Management in Non-Hospital Settings chapter for more information.

As with other live vaccines, measles-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. It is desirable to immunize close contacts of immunocompromised individuals in order to minimize the risk of exposure to measles. 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. HIV-infected children should receive Ig after recognized exposures to measles because the response to prior immunization may be inadequate. When other susceptible people with immune deficiencies are exposed to measles, passive immunization with Ig should be given as soon as possible. Please refer to the Passive Immunizing Agents chapter for more information.

Although there is no known risk from measles vaccine administered during pregnancy, it should not be given to pregnant women.

Clinical studies have demonstrated that egg allergy should no longer be considered a contraindication to immunization with MMR. In people who have a history of anaphylactic hypersensitivity to hens' eggs (urticaria, swelling of the mouth and throat, difficulty in breathing or hypotension), measles vaccine can be administered in the routine manner without prior skin testing. No special precautions are necessary for children with minor egg hypersensitivity who are able to ingest small quantities of egg uneventfully. No special measures are necessary for children who have never been fed eggs before MMR immunization. Prior egg ingestion should not be a prerequisite for MMR immunization. Please refer to the Anaphylactic Hypersensitivity to Egg and Egg-Related Antigens chapter.

Tuberculosis may be exacerbated by natural measles infection, but there is no evidence that measles vaccine has such an effect. The measles component in MMR vaccine can temporarily suppress tuberculin reactivity. However, tuberculin skin testing is not a prerequisite to the administration of MMR vaccine. If skin testing for tuberculosis is required, it should be done on the same day as immunization or delayed for 4-6 weeks.

Administration of MMR should be deferred if there is any severe acute illness. However, immunization should not be delayed because of minor acute illness, with or without fever.

Other considerations

Outbreak control

A full discussion of measles outbreak control is beyond the scope of this chapter. With the current childhood two-dose schedule for measles vaccine, large outbreaks of measles are not expected to recur. However, because many countries have lower immunization coverage, measles will continue to be imported into Canada. Imported cases will result in limited transmission of measles, usually among unvaccinated children and young adults who have not received two doses of vaccine.

Control interventions in schools or other facilities had little impact when Canada was using a single-dose program. With the two-dose strategy and high vaccine coverage, the benefits of control interventions are likely to be negligible except in settings where vaccine coverage is known to be low. Thus, before any intervention is started, suspected measles cases should be promptly confirmed by culture or serology. If cases are confirmed, contacts should be informed that measles is circulating and advised to update their immunization status if necessary. For practical purposes, all students attending the same school or facility should be considered contacts. Immunization within 72 hours of exposure will usually prevent measles. Should an individual already be immune or infected by measles virus, there is no increased risk of adverse reactions from immu nization with live measles-containing vaccine.

Selected references

Advisory Committee on Epidemiology. Guidelines for control of measles outbreaks in Canada. Canada Communicable Disease Report 1995;21(21):189-95.

Bell A, King A, Pielak K et al. Epidemiology of measles outbreak in British Columbia - February 1997. Canada Communicable Disease Report 1997;23(7):49-51.

Bellini WJ, Rota JS, Lowe LE et al. Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized. Journal of Infectious Diseases 2005;192(10):1686-93.

De Serres G, Boulianne N, Meyer F et al. Measles vaccine efficacy during an outbreak in a highly vaccinated population: incremental increase in protection with age at vaccination up to 18 months. Epidemiology and Infection 1995;115(2):315-23.

De Serres G, Gay NJ, Farrington CP. Epidemiology of transmissible diseases after elimination. American Journal of Epidemiology 2000;151(11):1039-48.

De Serres G, Sciberras J, Naus M et al. Protection after two doses of measles vaccine is independent of interval between doses. Journal of Infectious Diseases 1999;180(1):187-90.

Gay NJ, De Serres G, Farrington CP et al. Assessment of the status of measles elimination from reported outbreaks: United States, 1997-1999. Journal of Infectious Diseases 2004;189(Suppl 1):S36-42.

Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000. Pediatrics 2001;107(5):E84.

Institute of Medicine, Immunization Safety Review Committee (Stratton K, Gable A, Shetty P et al, eds.). Measles-mumps-rubella vaccine and autism. Washington DC: National Academy Press, 2001.

Jadavji T, Scheifele D, Halperin S. Thrombocytopenia after immunization of Canadian children, 1992 to 2001. Pediatric Infectious Disease Journal 2003;22(2):119-22.

King A, Varughese P, De Serres G et al. Measles elimination in Canada. Journal of Infectious Diseases 2004;189(Suppl 1):S236-42.

Madsen KM, Hviid A, Vestergaard M et al. A population-based study of measles, mumps, and rubella vaccination and autism. New England Journal of Medicine 2002;347(19):1477-82.

Markowitz L, Albrecht P, Orenstein WA et al. Persistence of measles antibody after revaccination. Journal of Infectious Diseases 1992;166(1):205-8.

Measles Initiative. Together we can save a life. URL: <http://www.measlesinitiative.org/index3.asp>.

Miller E, Andrews N, Grant A et al. No evidence of an association between MMR vaccine and gait disturbance. Archives of Disease in Childhood 2005;90(3):292-96.

Murch SH, Anthony A, Casson DH et al. Retraction of an interpretation. Lancet 2004;363(9411):750.

Ratnam S, Chandra R, Gadag V. Maternal measles and rubella antibody levels and serologic response in infants immunized with MMRII vaccine at 12 months of age. Journal of Infectious Diseases 1993;168(6):1596-98.

Ratnam S, West R, Gadag V et al. Immunity against measles in school-aged children: implications for measles revaccination strategies. Canadian Journal of Public Health 1996;87(6):407-10.

Strauss B, Bigham M. Does measles-mumps-rubella (MMR) vaccination cause inflammatory bowel disease and autism? Canada Communicable Disease Report 2001;27(8):65-72.

Taylor B, Miller E, Lingam R et al. Measles, mumps and rubella vaccination and bowel problems or developmental regression in children with autism: population study. British Medical Journal 2002;324(7334):393-96.

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