Rubella Virus Vaccine Live (Monograph)

Drug class: Vaccines
ATC class: J07BJ01
VA class: IM100

Medically reviewed by Drugs.com on Dec 22, 2023. Written by ASHP.

Introduction

Rubella virus vaccine live is a preparation of live, attenuated rubella virus that stimulates active immunity to rubella infection. Rubella virus vaccine live is commercially available as a fixed-combination vaccine containing measles, mumps, and rubella antigens (MMR; M-M-R II) and as a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad).

Uses for Rubella Virus Vaccine Live

Rubella virus vaccine live is used to stimulate active immunity to rubella (German measles). Monovalent rubella virus vaccine live (Meruvax II) is no longer commercially available in the US. Rubella virus vaccine live is commercially available in the US as a fixed-combination vaccine containing measles, mumps, and rubella antigens (MMR; M-M-R II) for use in adults, adolescents, and children 12 months of age or older and as a fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad) for use in children 12 months through 12 years of age.

The major objective of rubella immunization is to prevent rubella infection during pregnancy and resultant congenital rubella infection and congenital rubella syndrome (CRS). Congenital rubella infection may cause miscarriage, abortion, stillbirth, fetal anomalies, or asymptomatic infection in the infant. (See Pharmacology: Rubella Virus and Infection.) Because many countries do not have rubella vaccination programs or have only recently implemented such programs, many adults throughout the world remain susceptible. Adults in the US who were born in countries where routine rubella vaccination was not offered are at higher risk for contracting rubella and having infants with CRS compared with adults born in the US.

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP) recommend universal immunization against rubella for all susceptible children, adolescents, and adults, unless rubella virus vaccine live is contraindicated. (See Cautions: Precautions and Contraindications.)

The ACIP, AAP, and AAFP state that the fixed-combination vaccine containing measles, mumps, and rubella vaccine live (MMR) is preferred over monovalent rubella virus vaccine live (no longer commercially available in the US) for both primary immunization and revaccination to assure immunity to all 3 diseases. Alternatively, in children 12 months through 12 years of age when a dose of MMR and a dose of varicella virus vaccine live are indicated for primary immunization, use of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad) can be considered.

Individuals generally can be considered immune to rubella if they have serologic (i.e., laboratory) evidence of rubella immunity, documentation of adequate immunization with at least one dose of live rubella virus-containing vaccine at 12 months of age or older, or were born before 1957 (except women of childbearing potential). Birth before 1957 is not acceptable for evidence of immunity in women who may become pregnant because it provides only presumptive evidence of rubella immunity and does not guarantee that an individual is immune. Rubella infection can occur in some unvaccinated individuals born before 1957 and congenital rubella and CRS can occur among offspring of women infected with rubella during pregnancy. Individuals with an equivocal serologic test should be considered susceptible to rubella unless they have adequate evidence of vaccination or a subsequent serologic test result indicates rubella immunity. Although only one dose of live rubella virus-containing vaccine is required as acceptable evidence of rubella immunity, recommendations for routine childhood immunization include a 2-dose regimen of MMR. The ACIP states that clinical diagnosis of rubella is unreliable and should not be considered in assessing immunity to the disease. Because many rash illnesses may mimic rubella and many rubella infections are unrecognized, the only reliable evidence of previous rubella infection is the presence of serum rubella immunoglobulin G (IgG). Although tests for immunoglobulin (IgM) antibody have been used to diagnose acute and recent rubella infection, IgM tests should not be used to determine rubella immunity since false-positive results can occur. Laboratories that regularly perform antibody testing generally provide the most reliable results because their reagents and procedures are more likely to be strictly standardized. There is no conclusive evidence that individuals who are already immune to rubella when vaccinated are at any increased risk of vaccine-associated adverse effects, and therefore there is no need to test for susceptibility to rubella infection before administering the vaccine. Although routine serologic testing for rubella antibody in women of childbearing potential during clinic visits for routine health care, premarital evaluation, family planning, or diagnosis and treatment of sexually transmitted diseases may identify women who are not immune to rubella before they become pregnant, such testing is not useful unless it is linked to timely follow-up and vaccination of women who are susceptible.

Hemagglutination-inhibiting (HI) antibody testing formerly was the method most frequently used to screen for rubella antibodies. However, this method has been replaced by other assays of equal or greater sensitivity. Enzyme immunoassays (EIAs) are the most commonly used of the newer commercial assays, but latex agglutination, immunofluorescence assay (IFA), passive hemagglutination, hemolysis-in-gel, and virus neutralization tests also are available. Any antibody level above the standard positive cutoff value for the specific assay method can be considered acceptable evidence of immunity. Occasionally, individuals with documented histories of rubella vaccination have serum rubella IgG levels that are not clearly positive by enzyme-linked immunosorbent assay (ELISA); such individuals can be given another dose of MMR and need not be retested for serologic evidence of rubella immunity.

Efforts to vaccinate rubella-susceptible, postpubertal individuals, especially women of childbearing age, should be intensified, particularly among women who emigrated from areas outside the US where routine rubella vaccination may have been unlikely. Therefore, in addition to immunization of children, the following strategies should be followed to hasten the elimination of rubella and CRS in the US: making the general public and health-care providers more aware of the dangers of rubella infection; ensuring that patients are vaccinated as part of routine medical and gynecologic care; ensuring vaccination of all women visiting family planning clinics; ensuring vaccination of unimmunized women immediately after undergoing childbirth, miscarriage, or abortion; vaccinating susceptible women identified during occasions when their children undergo routine examinations or vaccinations; vaccinating susceptible women identified by premarital serology; routinely vaccinating susceptible women before discharge from hospitals, birthing centers, or other medical facilities, unless a specific contraindication exists; requiring proof of immunity (i.e., positive serologic evidence or documented rubella vaccination) for college entry; and requiring proof of immunity for all hospital personnel who might be exposed to patients with rubella or who might be in contact with pregnant patients.

The number of cases of rubella reported in the US has decreased 99% since the licensure of rubella vaccine in 1969 (57,686 cases in 1969 and fewer than 25 cases in 2001); however, the epidemiology of the disease has changed. Since the beginning of the 1990s, most reported cases of rubella in the US have occurred among adults (86% of cases in 1999) and most have involved foreign-born individuals, especially those from Mexico and South America. Although the number of cases of CRS in the US also has declined, CRS now disproportionately affects infants born to foreign-born women (92% of infants with CRS during 1997–1999 had foreign-born mothers). Before the mid-1990s, rubella outbreaks in the US generally occurred among children and adults in religious communities that did not accept vaccination and in unvaccinated individuals in schools, jails, and other closed environments. Rubella outbreaks in several areas of the US (e.g., California, Massachusetts, Connecticut, North Carolina) have occurred principally in Hispanic women, and the risk for both rubella and CRS is increased in this ethnic group, particularly those born outside the US where routine rubella vaccination may not occur. Outbreaks also have been reported in workplaces that employ large numbers of foreign-born workers (e.g., poultry and meat processing plants). An average of 5 CRS cases per year was reported in the US between 1995 and 2000; since 2001, an average of one CRS case per year has been reported. In 2004, a panel of experts stated that rubella is no longer endemic in the US.

Primary Immunization

Infants and Children 12 Months through 12 Years of Age

For routine primary immunization in children, the ACIP, AAP, and AAFP recommend that the first dose of MMR be given at 12 through 15 months of age. Vaccination of younger children solely for rubella protection generally should not be attempted because most infants have maternal antibodies which may prevent a satisfactory immunologic response to the vaccine; however, vaccination with MMR aimed at preventing measles occasionally may be warranted in children as young as 6 months of age in certain situations associated with increased risk of exposure to measles virus (e.g., during measles outbreaks, travel to areas with increased risk of measles). A history of rubella illness or immunization when younger than 12 months of age is not a reliable indicator of immunity and should not be used to exclude children from vaccination. Previously unimmunized children of rubella-susceptible pregnant women should be vaccinated with MMR to minimize the risk of exposing the woman to natural rubella infection.

To improve control of measles, mumps, and rubella, a second dose of MMR is recommended for routine immunization in children. The second dose preferably should be given at 4 through 6 years of age (just prior to entry into kindergarten or first grade), but may be given earlier during any routine visit provided at least 4 weeks (i.e., at least 28 days) have elapsed since the first dose and both the first and second doses are administered beginning at or after 12 months of age. Those who have not previously received the second MMR dose should complete the vaccination schedule by 11–12 years of age (just prior to entry into middle or junior high school). If MMR is administered to infants before their first birthday, they should be considered unimmunized for the purposes of determining the need for further vaccination; they should be revaccinated with a 2-dose regimen of MMR initiated at 12 months of age. Although available data indicate that one dose of rubella virus vaccine live confers long-term, probably life-long, immunity in more than 90% of vaccinees, the potential consequences of rubella vaccine failure are substantial (e.g., congenital rubella) and the additional dose currently recommended provides an added safeguard against such failures.

The ACIP, AAP, and AAFP state that primary immunization against measles, mumps, and rubella can be integrated with primary immunization against diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis B, influenza, pneumococcal disease, poliomyelitis, and varicella. In general, simultaneous administration (on the same day) of the most widely used vaccines, including diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP), Hib conjugate vaccine, MMR, poliovirus vaccine inactivated (IPV), and varicella virus vaccine live, has resulted in seroconversion rates and adverse effects similar to those observed when the vaccines were administered separately. Therefore, the ACIP, AAP, and AAFP recommend simultaneous administration of all vaccines appropriate for the age and previous vaccination status of the recipient, including DTaP, Hib conjugate vaccine, hepatitis B vaccine, influenza vaccine, MMR, IPV, pneumococcal vaccine, and varicella virus vaccine live, especially if an individual is unlikely to return for further vaccination. (See Drug Interactions.)

Internationally Adopted Children and Other Immigrants

Individuals seeking an immigrant visa for permanent US residency must provide proof of age-appropriate vaccination according to the US Recommended Childhood and Adolescent Immunization Schedule or the US Adult Schedule. Although this vaccination requirement applies to all immigrant infants and children entering the US, internationally adopted children younger than 11 years of age are exempt from the overseas vaccination requirements; however, adoptive parents are required to sign a waiver indicating their intention to comply with the vaccination requirements within 30 days after the infant or child arrives in the US. The CDC states that more than 90% of newly arrived internationally adopted children need catch-up vaccinations to meet the US Recommended Immunization Schedules.

The fact that immunization schedules of other countries may differ from US schedules (e.g., different recommended vaccines, recommended ages of administration, and/or number and timing of vaccine doses) also should be considered. Only written vaccination records should be considered as evidence of previous vaccination since such records are more likely to accurately predict protection if the vaccines administered, intervals between doses, and child’s age at the time of vaccination are similar to US recommendations; however, the extent to which an internationally adopted child’s immunization record reflects their protection against disease is unclear and it is possible there may be transcription errors in such records (e.g., single-antigen vaccine may have been administered although a multiple-antigen vaccine was recorded). Although vaccines with inadequate potency have been produced in other countries, most vaccines used worldwide are immunogenic and produced with adequate quality control standards.

When the immune status of an internationally adopted child is uncertain, the ACIP recommends that health-care providers either repeat vaccinations (since this usually is safe and avoids the need to obtain and interpret serologic tests) and/or use selective serologic testing to determine the need for immunizations (helps avoid unnecessary injections). MMR is not used in most countries. Therefore, although serologic testing is available to verify immunization status in children 12 months of age or older, the CDC states that administration of MMR is preferable to serologic testing unless there is documentation that the child has had rubella. The ACIP states that the recommended approach is to revaccinate an internationally adopted child with 1 or 2 doses of MMR (depending on the child’s age) without regard to the child’s prior vaccination record since serious adverse effects after MMR vaccination are rare and there is no evidence that administration of MMR increases the risk for adverse reactions among individuals already immune to measles, mumps, or rubella.

Adolescents and Adults

Most cases of rubella occur in adolescents and young adults, and about 15–20% of adolescent girls and young women (including some who were vaccinated as children) have no detectable rubella antibodies. Therefore, the ACIP and AAP recommend administration of MMR to susceptible prepubertal girls and nonpregnant women of childbearing potential.

Adolescents 11–12 Years of Age

The ACIP, AAP, and AAFP recommend that adolescents who have not previously received a second dose of MMR receive the dose during a routine preadolescent preventive health-care visit at 11–12 years of age. This routine health-care visit provides an opportunity to administer “catch-up” vaccines that were missed at an earlier age, administer vaccines routinely recommended at 11–12 years of age, administer vaccines recommended for certain high-risk adolescents, schedule future appointments that may be necessary to complete recommended immunization schedules, and provide adolescents with other recommended preventive health services such as guidance on health behaviors and screening for biomedical, behavioral, and emotional conditions. During the health-care visit at 11–12 years of age, the vaccination history of the adolescent should be assessed. If the adolescent does not have information regarding their vaccination history, the healthcare provider should attempt to obtain such information through documentation from the parent, previous providers, or school records. When documentation of an adolescent’s vaccination status is not available at the time of the preventive health-care visit, an assumption can be made that the adolescent has received those vaccines required by state laws and regulations that have been in effect for some time (e.g., those required on entry to kindergarten) and these vaccines can be withheld while awaiting documentation. However, vaccine doses currently recommended for adolescents that were not included in previous laws and recommendations should be administered.

Ideally, all vaccines routinely indicated at 11–12 years of age should be administered during the initial adolescent visit (MMR, hepatitis B vaccine, tetanus toxoid and reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap), varicella virus vaccine live). However, since multiple doses of some vaccines are required to complete primary immunization and because simultaneous administration of a large number of vaccines may be indicated in some adolescents, providers may need to be flexible in determining which vaccines to administer during the initial visit and which to schedule for return visits. While specific studies evaluating the safety and efficacy of simultaneous administration of vaccines in adolescents are not available, there is extensive evidence from clinical studies and experience in infants and children that simultaneous administration of the most widely used vaccines does not decrease the antibody response or increase adverse reactions to these vaccines. In circumstances where multiple vaccines (i.e., 4 or more) are indicated in adolescents 11–12 years of age, the provider may choose to defer some vaccines for administration during one or more future visits; however, the vaccines should be prioritized based on which require multiple doses, which diseases pose an immediate threat to the adolescent, and whether the adolescent is likely to return for scheduled visits. During any subsequent visits, the adolescent’s vaccination status should be rechecked and any deficiencies corrected.

Adults

Vaccinating rubella-susceptible, postpubertal, nonpregnant women of childbearing potential confers individual protection against rubella-induced fetal injury. Ideally, rubella antibody levels should be determined in all adolescent girls and women of childbearing potential and those without evidence of immunity should receive MMR if they are not pregnant and understand they should not become pregnant for a specified length of time. (See Cautions: Pregnancy and Lactation.) Lack of serologic tests should not be a deterrent to immunization. Asking these women if they are pregnant, excluding those who are, and informing the others of the theoretical risks are reasonable precautions in a rubella immunization program.

The ACIP recommends that educational and training institutions (e.g., colleges, military bases) seek proof of rubella immunity (positive serologic test results or documentation of rubella vaccination) from all women students and employees of childbearing age and that nonpregnant women who lack proof of immunity be vaccinated unless the vaccine is contraindicated. Premarital serologic tests also are useful to identify rubella-susceptible women prior to their first pregnancy. Pregnant women should be tested for rubella susceptibility and susceptible women should receive the vaccine postpartum before they leave the hospital; seroconversion should be confirmed 6–8 weeks after vaccination in women who received blood products or Rh_o(D) immune globulin. (See Drug Interactions.) There is no evidence that administration of a rubella virus-containing vaccine to a pregnant woman presents any fetal risk, although such a risk cannot be excluded on theoretical grounds. (See Cautions: Pregnancy and Lactation.) Unless contraindicated, vaccination of susceptible women of childbearing age should be part of routine general medical and gynecologic outpatient care; take place in all family-planning settings; and be provided routinely prior to discharge from a hospital, birthing center, or other medical facilities.

Immunization of adult males also may help reduce the spread of rubella. Immunization of adolescent or adult males working in medical facilities that provide care for women of childbearing age and those in settings where young adult males and females congregate has been recommended by the ACIP and CDC. All rubella-susceptible military recruits are required to receive MMR.

Adults in the US who were born in countries where routine rubella vaccination was not offered are at high risk for contracting rubella and having infants with CRS. Vaccinating foreign-born susceptible adults can be challenging since they might have little or no contact with the US health-care system. Health-care providers who treat foreign-born adults should document their rubella immunity with a written record of a rubella virus-containing vaccine or by serologic testing.

HIV-infected Individuals

MMR can be used in individuals with human immunodeficiency virus (HIV) infection who do not have evidence of severe immunosuppression.

The ACIP, AAP, US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others state that all asymptomatic HIV-infected children, adolescents, and adults should receive MMR according to the usually recommended immunization schedules. In addition, MMR should be considered for all symptomatic HIV-infected individuals who do not have evidence of severe immunosuppression and who otherwise would be eligible for such vaccination. Asymptomatic individuals do not need to be evaluated and tested for HIV before decisions concerning immunization are made; such individuals in need of MMR but without evidence of severe immunosuppression should receive the vaccine. Because the immunologic response to vaccines may decrease as HIV disease progresses, vaccination early in the course of HIV infection may be more likely to induce an immune response; in addition, approximately 5% of HIV-infected infants born in the US will be severely immunocompromised at 12 months of age. Therefore, the ACIP and other experts recommend that HIV-infected infants without severe immunosuppression should receive MMR as soon as possible upon reaching their first birthday (i.e., at 12 months of age) and consideration should be given to administering the second dose of MMR as soon as 1 month (i.e., at least 28 days) after the first dose.

MMR is contraindicated in HIV-infected individuals with severe immunosuppression (i.e., children younger than 12 months of age with CD4⁺ T-cell count less than 750/mm³; children 1 through 5 years of age with CD4⁺ T-cell count less than 500/mm³; children 6 years of age or older, adolescents, and adults with CD4⁺ T-cell count less than 200/mm³; children younger than 13 years of age with CD4⁺ T-cell percentage less than 15%). (See Individuals with Altered Immunocompetence under Cautions: Precautions and Contraindications.)

The serologic response to vaccines (including MMR) may be reduced in some HIV-infected patients and may be inversely correlated with the severity of the disease. In addition, MMR may be ineffective in HIV-infected patients who have received high-dose IV immune globulin therapy (e.g., for the prevention of serious bacterial infections) within the 3 months preceding administration of the vaccine. (See Drug Interactions: Immune Globulins.)

MMR may be given to any family member residing in the household or any other close contact of an HIV-infected patient since extensive experience has shown that live, attenuated MMR vaccine viruses are not transmitted from vaccinated individuals to others.

Health-care Personnel

Health-care personnel are at increased risk for acquiring rubella and transmitting the disease to susceptible patients, and the ACIP and the Hospital Infection Control Practices Advisory Committee (HICPAC) recommend that all health-care facilities (i.e., inpatient and outpatient, public and private) ensure that all workers (i.e., medical or nonmedical, paid or volunteer, full- or part-time, student or nonstudent, with or without direct patient-care responsibilities) have adequate documentation of rubella vaccination or immunity (i.e., documentation of vaccination with a dose of rubella virus-containing vaccine given on or after 12 months of age, laboratory evidence of immunity, or laboratory confirmation of disease). Facilities that provide care exclusively to geriatric patients who are at minimal risk for rubella and complications of the disease may be possible exceptions to this recommendation. Health-care workers have a responsibility to avoid transmitting rubella to patients and thereby causing them harm.

Although birth before 1957 generally is considered acceptable evidence of rubella immunity, health-care facilities should consider recommending a dose of MMR to unvaccinated workers born before 1957 who do not have laboratory evidence of rubella immunity or laboratory confirmation of disease. Serologic surveys of hospital workers indicate that 5–9% of those born before 1957 do not have detectable measles antibody and about 6% do not have detectable rubella antibody.

To avoid rubella outbreaks in medical facilities, the CDC recommends that health-care facilities providing care for women of childbearing potential ensure that all personnel (both male and female), volunteer workers, and those frequently using the medical facility for training purposes are immune to rubella. Proof of rubella immunity (i.e., documentation of a dose of rubella virus-containing vaccine, laboratory evidence of rubella immunity, or laboratory confirmation of disease) should be a prerequisite to employment in such facilities. Routine prevaccination serologic tests are not necessary but may be desirable in some cases. Susceptible pregnant personnel and personnel in whom use of the vaccine is contraindicated should not be vaccinated; however, susceptible pregnant personnel should be vaccinated immediately postpartum. Susceptible personnel who work with female patients of childbearing age should be educated about the importance of compliance with rubella vaccination; personnel who still refuse immunization should be transferred to another area of the hospital or termination of their employment should be considered.

Travelers

Rubella occurs worldwide and the risk of exposure to the disease outside the US may be high. Individuals who are not immune and travel outside the US may acquire and import the infection into the US. Vaccination against rubella is not a requirement for entry into any country; all travelers (especially women of childbearing potential) should be immune to rubella.

Postexposure Vaccination

In individuals who have been exposed to natural rubella virus, there is no evidence that administration of a rubella virus-containing vaccine would prevent illness; however, a single exposure may not cause infection. Because postexposure vaccination provides future protection to individuals who do not contract the disease and because there is no evidence that administering a rubella virus-containing vaccine to an individual who is incubating rubella would be harmful, vaccination is recommended by the ACIP and AAP, unless otherwise contraindicated.

Outbreak Control

Rubella outbreak control is essential for eliminating indigenous rubella and preventing congenital rubella infection and CRS. Because the incidence of rubella is low in the US, the CDC states that even a single case of rubella should be considered a potential outbreak. Suspected cases of rubella, CRS, or congenital rubella infection should be reported to local health departments within 24 hours, and such reports should not be delayed while waiting for laboratory confirmation. Control measures should be implemented as soon as a case of rubella is identified; maintaining control measures is essential when pregnant women are possible contacts of patients with rubella.

During a rubella outbreak, patients should be isolated for 5–7 days after rash onset and susceptible contacts should be identified and vaccinated (unless the vaccine is contraindicated). Pregnant women who were exposed to rubella and do not have adequate proof of immunity should be tested for serologic evidence of the disease. Susceptible pregnant women should be counseled regarding the risks for intrauterine rubella infection and should be advised to restrict contact with individuals with confirmed, probable, or suspected rubella for at least 6 weeks after rash onset in the last identified patient and also to avoid activities where they might be exposed to rubella for 6 weeks after the onset of symptoms of rubella in the last patient for whom rubella cannot be ruled out.

If a rubella outbreak occurs in a congregate environment (e.g., household, jail, day-care center, military setting, school, place of worship, athletic event, other social gathering), exposed individuals without adequate proof of rubella immunity should be vaccinated. If an outbreak occurs in a health-care setting (e.g., hospital, doctor’s office, clinic, nursing home, other facility where patients receive subacute or extended care), health-care workers without adequate evidence of immunity should be excluded from work and vaccinated (especially in setting where pregnant women could be exposed). Despite subsequent vaccination, exposed health-care workers should be excluded from direct patient care for 23 days after the last exposure to rubella. Because birth before 1957 does not guarantee immunity, health-care facilities should recommend 2 doses of MMR to workers born before 1957 who do not have laboratory evidence of immunity or laboratory evidence of disease. If a community-wide outbreak occurs, any person exposed to a patient with rubella or CRS who cannot demonstrate proof of immunity should be vaccinated or restricted from contact with patients with rubella or CRS.

The CDC’s recommendations for evaluation and management of suspected rubella outbreaks should be consulted for additional information, including information on criteria for rubella case classification (suspected, probable, confirmed, asymptomatic confirmed), criteria for case classification of CRS (suspected, probable, confirmed, infection only), laboratory diagnosis of rubella and CRS, surveillance and control measures, and outreach activities to prevent future rubella outbreaks.

Related/similar drugs

rubella virus vaccine, measles virus vaccine / mumps virus vaccine / rubella virus vaccine, Priorix, M-M-R II, ProQuad

Rubella Virus Vaccine Live Dosage and Administration

Reconstitution and Administration

The fixed-combination vaccine containing measles, mumps, and rubella antigens (MMR; M-M-R II) is administered by subcutaneous injection. The vaccine should not be administered IV.

MMR is reconstituted by adding the entire amount of diluent supplied by the manufacturer to the vial of lyophilized vaccine and agitating the vial. Only the diluent provided by the manufacturer should be used for reconstitution. Discard the preparation if the lyophilized vaccine does not dissolve completely.

Reconstituted MMR should be inspected visually for particulate matter and discoloration prior to administration. The vaccine should be reconstituted and administered using sterile syringes and needles that are free of preservatives, antiseptics, and detergents, since these substances may inactivate live virus vaccines.

To minimize loss of potency and ensure an adequate immunizing dose, MMR should be administered immediately following reconstitution. (See Chemistry and Stability: Stability.)

The preferred site for subcutaneous injection of MMR is the upper-outer triceps area; injections also can be given into the anterolateral thigh. For children 1 year of age and older, adolescents, and adults, the upper-outer triceps area usually is preferred. To ensure appropriate delivery, subcutaneous injections should be made at a 45° angle using a 5/8-inch, 23- to 25-gauge needle. Prior to injection, care should be taken to ensure that the needle is not in a blood vessel.

Since syncope may occur following vaccination, vaccinees should be observed for approximately 15 minutes after the vaccine dose is administered. If syncope occurs, the patient should be observed until symptoms resolve. Syncope after vaccination occurs most frequently in adolescents and young adults.

When multiple vaccines are administered during a single health-care visit, each vaccine should be given with a different syringe and at different injection sites. Separate injection sites by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.

Dosage

The usual dose of MMR is 0.5 mL and is the same for all individuals. When reconstituted as specified, each 0.5-mL dose of MMR contains not less than 1000 TCID₅₀ of measles virus, 12,500 TCID₅₀ of mumps virus, and 1000 TCID₅₀ of rubella virus. The entire volume of reconstituted solution in the single-dose vial should be administered.

Although a single dose of MMR may provide long-term (probably life-long) immunity against rubella, 2 doses of MMR administered at least 1 month (i.e., at least 28 days) apart are recommended.

For information on dosage of the fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad), see Varicella Virus Vaccine Live 80:12.

Infants and Children 12 Months through 12 Years of Age

For primary immunization against rubella in infants and children, a 2-dose regimen of MMR is recommended and the first dose generally is administered at 12 through 15 months of age. For routine childhood immunization, the ACIP, AAP, and AAFP recommend that the first dose of MMR be given at 12 through 15 months of age and the second MMR dose be routinely given at 4 through 6 years of age (just prior to entry into kindergarten or first grade). The second dose may be given earlier during any routine visit, provided at least 4 weeks (i.e., at least 28 days) have elapsed since the first dose and both the first and second doses are administered beginning at or after 12 months of age.

Adolescents 13 through 18 Years of Age

For primary immunization against rubella in previously unvaccinated adolescents 13 through 18 years of age, a 2-dose regimen of MMR is recommended. The second dose should be administered at least 4 weeks (i.e., at least 28 days) after the initial dose.

Adults

For adults 19 years of age and older, primary immunization consists of 1 or 2 doses of MMR. The minimum interval between doses is 4 weeks (i.e., at least 28 days).

Cautions for Rubella Virus Vaccine Live

The incidence of adverse effects of monovalent rubella virus vaccine live (no longer commercially available in the US) appears to increase with the age of the vaccinee, particularly in postpubertal females. Vaccine-induced adverse effects generally have only been reported in rubella-susceptible vaccinees. There is no conclusive evidence that individuals who are already immune when vaccinated are at any increased risk of vaccine-associated adverse effects.

Systemic Effects

Symptoms associated with natural rubella infection, including mild regional lymphadenopathy, rash, urticaria, fever, malaise, sore throat, dizziness, headache, nausea, vomiting, diarrhea, general aches, and polyneuritis (e.g., paresthesia and pain in the arms and legs), occur occasionally in vaccinees. Rubella-like symptoms may occur 11–20 days after vaccination and usually are mild and transient, generally persisting 1–5 days.

Musculoskeletal and Associated Effects

Arthralgia and, rarely, transient arthritis may occur following administration of rubella virus vaccine live. Joint symptoms are infrequent and generally of brief duration in children but occur in up to about 12–26% of susceptible postpubertal women who receive the vaccine; the incidence of these reactions in adolescent girls appears to be greater than that in children but less than that in adult women. About 10% of postpubertal females develop arthritis-like manifestations. The US Public Health Service Advisory Committee in Immunization Practices (ACIP) states that in large-scale field trials up to 40% of vaccinees developed joint pain, usually of the small peripheral joints, but frank arthritis reportedly occurred in less than 2% of vaccinees.

Acute joint reactions associated with rubella vaccination generally are mild and occur 1–3 weeks after vaccination, usually persist 1 day to several weeks, and rarely recur. Infrequently and principally in adult women, these arthralgic symptoms have been reported to be chronic and recurrent, continuing for months or years; occasionally arthralgic symptoms are accompanied by arthritis and/or neurologic symptoms (e.g., paresthesia, blurred vision, carpal tunnel syndrome). Such symptoms usually are evident within 1 month after initial vaccination and may be associated with prolonged rubella viremia. While the frequency of chronic joint symptoms has been reported to be as high as 5–11% in adult females, other experience from the US and other countries using vaccines containing the RA 27/3 rubella strain suggest that such symptoms occur only rarely.

Although the Institute of Medicine reported in 1991 that some data were consistent with a causal relationship between RA 27/3 rubella vaccine and chronic arthritis in adult women, the evidence was limited in scope and confined to reports from a single institution. Results of a large, retrospective cohort study of women 15–59 years of age did not reveal evidence of an increased risk of new onset chronic arthropathies or neurologic conditions within 1 year following receipt of the currently available rubella virus vaccine live. Several other recent studies also found no evidence of increased risk for new onset of chronic arthropathies among women vaccinated with the RA 27/3 rubella vaccine. Chronic arthritis has been associated with natural rubella infection and has been related to persistent virus and/or viral antigen isolated from body tissues. The frequency of chronic joint complaints is substantially higher following natural infection than following vaccination.

Joint symptoms associated with rubella vaccination tend to be more severe in susceptible women than in children, but adults who develop such symptoms usually have tolerated them well and have not had to disrupt normal (e.g., work) activities. Rarely, however, the symptoms are severe enough to disrupt normal activities. Destruction of the joint has been reported rarely.

Although transient peripheral neuritic complaints have occurred rarely, a causal relationship between the RA 27/3 rubella vaccine and peripheral neuropathies has not been established. Such pain and/or paresthesias may not be associated with specific joints, but they generally follow the same time course for onset and duration and the frequency of recurrence of acute joint symptoms. Myalgia has also been reported rarely following administration of rubella virus vaccine live.

The mechanism of joint abnormalities following administration of rubella virus vaccine live is unclear. It has been suggested that persistence of virus in peripheral blood lymphocytes may occur in a substantial number of affected individuals. It also has been suggested that defective immunity resulting from partial antibody may facilitate persistence of the virus. There is no conclusive evidence that immune complexes contribute to disease pathogenesis. While rubella virus has been isolated from both peripheral blood lymphocytes and synovial cells of children with chronic (primary juvenile) arthritis, a causal relationship has not been established.

Sensitivity Reactions

Allergic reactions have been reported rarely in individuals receiving rubella virus vaccine live. Most hypersensitivity reactions have been minor, consisting of a wheal and flare or urticaria at the injection site. However, more serious hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions as well as related phenomena such as angioneurotic edema (including peripheral or facial edema) and bronchial spasm, have been reported rarely following administration of rubella virus vaccine live or measles, mumps, and rubella virus vaccine live (MMR) in individuals with or without an allergic history. Immediate, anaphylactic reactions to rubella virus vaccine live or MMR are extremely rare. Although more than 70 million doses of rubella virus-containing vaccines (MMR) have been distributed in the US since the Vaccine Adverse Events Reporting System (VAERS) was implemented in 1990, only 33 cases of anaphylactic reactions have been reported after MMR vaccination. In addition, only 11 of these cases occurred immediately after vaccination with manifestations consistent with anaphylaxis. .

MMR contains hydrolyzed gelatin as a stabilizer, which rarely may stimulate hypersensitivity reactions in some individuals. An anaphylactic reaction following MMR vaccination has been reported in the US in at least one individual with IgE-mediated anaphylactic sensitivity to gelatin, and similar cases have been reported elsewhere. (See Cautions: Precautions and Contraindications.) Erythema multiforme, Stevens-Johnson syndrome, rash, urticaria, and vasculitis have been reported rarely with rubella virus vaccine live.

Hematologic Effects

Surveillance of adverse effects in the US and elsewhere indicates that rubella virus-containing vaccines (e.g., MMR) rarely can cause clinically evident thrombocytopenia (e.g., purpura) within 2 months after vaccination. In prospective studies, the reported incidence of clinically evident thrombocytopenia after MMR vaccination ranged from 1 per 30,000 to 1 per 40,000 vaccinated children, with a temporal clustering of cases occurring 2–3 weeks after vaccination. With passive surveillance, the reported incidence ranged from 1 per 100,000 to 1 per million distributed doses. Results of one retrospective study confirmed that a causal relation exists between receipt of MMR and idiopathic thrombocytopenic purpura and indicated that the absolute risk within 6 weeks of vaccination was 1 in 22,300 doses with 2 out of 3 cases occurring in the 6-week post-vaccination period being caused by MMR. However, the incidence of thrombocytopenia reported with natural rubella or measles infection is substantially greater than that reported with vaccination, being approximately 1 per 3000 children during one measles epidemic. Evidence from case reports suggests that the risk of vaccine-induced thrombocytopenia may be increased in individuals with a history of idiopathic thrombocytopenic purpura, particularly for those who developed it with a previous dose of the vaccine (see Cautions: Precautions and Contraindications); however, results of one retrospective study indicate that children with a history of idiopathic thrombocytopenic purpura prior to the first dose of MMR are not at increased risk of vaccine-associated idiopathic thrombocytopenic purpura. In most cases, vaccine-associated thrombocytopenic purpura usually has been transient and benign, although hemorrhage occurred rarely.

Regional lymphadenopathy or leukocytosis have been reported in individuals receiving rubella virus vaccine live.

Other Adverse Systemic Effects

Moderate fever (38.3–39.4°C) occurs occasionally following rubella vaccination, and higher fever occurs less frequently. Syncope, headache, dizziness, malaise, irritability, diarrhea, nausea, vomiting, sore throat, cough, and rhinitis also have been reported.

There have been isolated reports of encephalitis, polyneuritis, and polyneuropathy, including Guillain-Barré syndrome, following administration of vaccines containing rubella virus live; however, the National Academy of Sciences Institute of Medicine concluded that current evidence is insufficient to accept or reject a causal relationship. Forms of optic neuritis, including retrobulbar neuritis, papillitis, and retinitis, occur rarely following viral infections, and have been reported to occur 1–3 weeks following administration of some live virus vaccines. Nerve deafness, otitis media, and conjunctivitis have been reported.

Local Effects

Burning and/or stinging of short duration may occur at the injection site because of the slightly acidic pH of rubella virus vaccine live. Induration, erythema, tenderness or pain, and wheal and flare may occur occasionally at the vaccine injection site. Such reactions usually are mild and transient.

Precautions and Contraindications

MMR is contraindicated in individuals with a hypersensitivity to the vaccine or any component in the formulation, including gelatin. (See Gelatin Allergy under Cautions: Sensitivity Reactions, in Precautions and Contraindications.) In addition, MMR is contraindicated in those with a history of anaphylactic or anaphylactoid reaction to neomycin. (See Neomycin Allergy under Cautions: Sensitivity Reactions, in Precautions and Contraindications.)

MMR is contraindicated in certain other individuals, including pregnant women. (See Individuals with Altered Immunocompetence under Cautions: Precautions and Contraindications and Cautions: Pregnancy, Fertility, and Lactation.)

Sensitivity Reactions

Prior to administration, the recipient and/or parent or guardian should be questioned concerning reactions to previous doses of rubella virus-containing vaccine or MMR. Individuals who have a hypersensitivity reaction to the first dose should be tested for immunity to rubella; if results indicate immunity, a second dose is not necessary. Any individual with an anaphylactic reaction to a previous dose should not receive another dose, regardless of results of serologic testing.

Although the rubella virus used in the preparation of MMR is propagated in human diploid cells, the measles and mumps virus components of MMR are propagated in chick embryo tissue culture and the usual precautions for use in individuals with allergy to egg-related antigens apply to the use of MMR.

Epinephrine should be available for immediate treatment of an anaphylactic reaction if such reaction occurs.

Neomycin Allergy

Because MMR contains trace amounts of neomycin, the vaccine is contraindicated in individuals who have had an anaphylactic or anaphylactoid reaction to topically or systemically administered neomycin.

Neomycin allergy usually is characterized by a delayed-type (cell-mediated) hypersensitivity reaction, such as contact dermatitis, rather than an anaphylactic reaction. Following administration of rubella virus vaccine live to individuals who have had a delayed-type hypersensitivity reaction to neomycin, the typical adverse reaction, if any, is a contact dermatitis (e.g., characterized by an erythematous, pruritic nodule or papule) occurring within 48–96 hours.

The ACIP and the American Academy of Pediatrics (AAP) state that vaccines containing trace amounts of neomycin should not be used in individuals with a history of anaphylactic reaction to neomycin, but use of such vaccines may be considered in those with a history of delayed-type hypersensitivity reaction to neomycin if benefits of vaccination outweigh risks.

Gelatin Allergy

The possibility of allergic reactions to hydrolyzed gelatin, which is present in MMR as a stabilizer, should be considered since anaphylactic reactions to the vaccine have been reported rarely in individuals with anaphylactic sensitivity to gelatin. MMR should not be administered to individuals with a history of anaphylactic reactions to gelatin or gelatin-containing products. Although skin testing for gelatin sensitivity before administering the vaccine to such individuals can be considered, there are no specific protocols for this purpose. Because gelatin used in vaccines manufactured in the US usually is derived from porcine sources and food gelatin may be derived solely from bovine sources, a negative food history does not exclude the possibility of a reaction to the gelatin contained in the vaccines.

Individuals with Altered Immunocompetence

MMR generally is contraindicated in individuals with primary immunodeficiencies (e.g., cellular immune deficiency, hypogammaglobulinemia, dysgammaglobulinemia) and in individuals with suppressed immune responses resulting from acquired immunodeficiency syndrome (AIDS) or other clinical manifestations of human immunodeficiency virus (HIV) infection, blood dyscrasias, leukemia, lymphomas of any type, or any other malignant neoplasms affecting the bone marrow or lymphatic systems.

Replication of rubella vaccine virus may be potentiated in individuals with primary immunodeficiencies (e.g., cellular immune deficiency, hypogammaglobulinemia, dysgammaglobulinemia) or with suppressed immune response resulting from leukemia, lymphoma, other malignancies affecting the bone marrow or lymphatic system, or blood dyscrasias. Severe immunosuppression may be caused by many disease conditions (e.g., congenital immunodeficiency, HIV infection, hematologic or generalized malignancy) and by immunosuppressive therapy. For some conditions, all infected individuals are severely immunocompromised, whereas for other conditions, the degree of immune compromise depends on the severity of the condition, which in turn depends on the disease and treatment stage. Although there is no evidence that wild rubella or rubella virus vaccine live causes serious illness in immunocompromised individuals, concern exists about the potential risk of administering any live virus vaccine to such individuals. Therefore, with the exception of individuals with HIV infection, immunocompromised individuals should not receive a rubella virus-containing vaccine, especially those who are severely immunosuppressed. Ultimately, the patient’s clinician must assume responsibility for determining whether the patient is severely immunocompromised based on clinical and laboratory assessment. MMR should not be given to an individual with a family history of congenital or hereditary immunodeficiency until the immunocompetence of the individual has been documented. The greatest risk associated with administering a live rubella virus-containing vaccine in immunosuppressed patients appears to be with vaccines that also include live measles virus as a component.

MMR generally is contraindicated in individuals receiving immunosuppressive therapy (e.g., alkylating agents, antimetabolites, corticotropin, corticosteroids [at immunosuppressive dosages], radiation therapy), although the manufacturer states that the vaccine is not contraindicated in individuals receiving corticosteroids as replacement therapy (e.g., for Addison’s disease). (See Drug Interactions: Immunosuppressive Agents.)

The ACIP states that use of live virus vaccines can be considered in patients with leukemia, lymphoma, or other malignancies if the disease is in remission and chemotherapy was terminated at least 3 months prior to vaccination.

Antibody responses to MMR and efficacy may be decreased in immunocompromised individuals.

HIV-infected Individuals

The ACIP, AAP, US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others state that MMR should be administered to all asymptomatic HIV-infected individuals according to the usually recommended immunization schedules and should be considered for all symptomatic HIV-infected individuals who do not have evidence of severe immunosuppression and who otherwise would be eligible for such vaccination. The presence of immunocompromised or HIV-infected individuals in a household does not preclude administration of MMR to other household members.

MMR is contraindicated in HIV-infected individuals with severe immunosuppression. (See HIV-Infected Individuals under Uses: Primary Immunization.)

Fever

Fever has been reported. Following vaccination, patients should be monitored for temperature elevations.

Risk of Transmissible Agents in Preparations Containing Albumin

MMR contains recombinant human albumin.

Monovalent rubella virus vaccine live (no longer commercially available in the US) and the fixed-combination vaccine containing measles, mumps, rubella, and varicella antigens (MMRV; ProQuad) contain albumin human. Since albumin human is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD).

Concomitant Illness

The decision whether to administer or delay administration of MMR in an individual with a current or recent acute illness depends largely on the severity of symptoms and etiology of the illness. The manufacturer states that MMR is contraindicated in patients with any febrile respiratory illness or other active febrile infections. The ACIP and AAP state that minor acute illness, such as upper respiratory infection (with or without fever) or mild diarrhea, does not preclude vaccination. However, vaccination of individuals with moderate or severe acute illness (with or without fever) generally should be deferred until they have recovered from the acute phase of the illness. This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly concluding that a manifestation of the underlying illness resulted from vaccination. However, data generally are not available on the safety and immunogenicity of measles, mumps, and rubella virus-containing vaccines in individuals with moderate or severe febrile illness.

Thrombocytopenia

Individuals with thrombocytopenia may be at increased risk of developing more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia after the first dose of monovalent rubella virus vaccine live or MMR may develop thrombocytopenia with repeat doses. Serologic evidence of immunity may be obtained in lieu of vaccination. The decision to vaccinate such individuals should depend on the benefits of immunity and the risks of recurrence or exacerbation of thrombocytopenia.

Risk of Neurodevelopmental Disorders

Although it has been theorized that there is a link between the antigens contained in MMR and neurodevelopmental disorders in children (autism), evidence has been insufficient to support an association between neurodevelopmental disorders and MMR. In 2004, the Immunization Safety Review Committee of the Institute of Medicine (IOM) examined the hypothesis that MMR is causally associated with autism and concluded that the evidence favors rejection of a causal relationship between MMR and autism.

Tuberculosis

Vaccination is not recommended for individuals with untreated, active tuberculosis. Vaccination in these individuals should be deferred until antituberculosis therapy has been initiated. Administration of live, attenuated vaccines is not contraindicated in individuals with a positive tuberculin skin test who do not have active tuberculosis infection. Tuberculin testing is not a prerequisite for administration of rubella virus vaccine live or MMR.

Transmission of Vaccine Virus

Small amounts of the vaccine virus are excreted from the nose or throat of most susceptible individuals 7–28 days after administration of rubella virus vaccine live. While there is a theoretical possibility that the virus could be transmitted to susceptible, close, personal contacts of the vaccinated individual, there is no evidence to indicate that the vaccine virus can be transmitted to contacts and such transmission is not regarded as a significant risk. The vaccine virus can be transmitted in milk to breastfed infants. (See Lactation in Cautions: Pregnancy and Lactation.)

Limitations of Vaccine Effectiveness

MMR may not protect all individuals from rubella.

Safety and efficacy of MMR have not been established for postexposure prophylaxis following exposure to rubella. (See Uses: Postexposure Vaccination.)

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.

MMR that has been mishandled or has not been stored at the recommended temperature should not be administered. (See Chemistry and Stability: Stability.)

Lyophilized and reconstituted vaccine should be protected from light at all times because exposure to light may inactivate the vaccine virus.

Freezing or exposing the diluent supplied by the manufacturer to freezing temperatures should be avoided; the diluent may be refrigerated or stored at room temperature.

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.

Pediatric Precautions

Safety and efficacy of MMR in children younger than 6 months of age have not been established, and use of the vaccine in this age group is not recommended.

Geriatric Precautions

Clinical studies of MMR did not include sufficient numbers of seronegative individuals 65 years of age or older to determine whether these individuals respond differently than younger individuals. Other reported clinical experience has not identified differences in responses between geriatric and younger individuals.

Mutagenicity and Carcinogenicity

The mutagenic or carcinogenic potential of MMR has not been evaluated.

Pregnancy, Fertility, and Lactation

Pregnancy

Although the manufacturer states that MMR should not be administered to pregnant women and that appropriate steps should be taken to prevent conception for 3 months following vaccination, the ACIP and AAP state that women vaccinated with MMR should avoid becoming pregnant for 4 weeks (i.e., 28 days) after vaccination. (See the discussion that follows for more specific details.) Natural rubella infection during pregnancy, especially during the first trimester, may cause congenital abnormalities. Although the teratogenic potential of rubella virus-containing vaccines appears to be less than that of the wild virus and normal infants have been born to women who received such vaccines during early pregnancy, rubella vaccine virus can cross the placenta and safety for the developing fetus has not been established.

When rubella virus vaccine live containing the RA 27/3 strain replaced other rubella vaccines in 1979, concern was raised that the new vaccine might have a higher affinity for fetal tissue and be associated with greater potential for teratogenic effects than previously available vaccines since the RA 27/3 rubella virus strain was derived from an aborted rubella-infected human fetus and is produced in human embryonic lung cell lines. Available data indicate that there is probably no greater risk of placental or fetal infection from RA 27/3 vaccine than from Cendehill or HPV-77 vaccines. There is no evidence to indicate that rubella vaccines, including the RA 27/3 vaccine, can cause defects associated with congenital rubella syndrome (CRS). Although asymptomatic glandular hypospadias has occurred in 2 infants born to rubella-susceptible women who received RA 27/3 vaccine during pregnancy and hypospadias has been noted in infants with CRS, there are no data to suggest that glandular hypospadias is a CRS-associated defect. Based on experience to date, the theoretical maximum risk (derived from the binomial distribution with 95% confidence limits) for serious malformations in infants born to RA 27/3 vaccinees is reported to range from 0–1.6%; however, the overall maximum risk remains far less than the 20% or greater risk of CRS associated with maternal infection with wild rubella virus during the first trimester of pregnancy.

While no cases of CRS-associated defects have been reported, rubella vaccine viruses, including the RA 27/3 strain, can cross the placenta and infect the fetus. Data collected by CDC over an 18-year period indicate that approximately 1.5% of infants born to rubella-susceptible vaccinees had serologic evidence of subclinical rubella infection, regardless of the vaccine strain administered to the mother. The CDC data also indicate that the rubella virus isolation rate from abortuses of women who received the RA 27/3 vaccine is about 3% compared with about 20% for abortuses of women who received the Cendehill or HPV-77 vaccines; this finding provides additional evidence that the RA 27/3 vaccine poses no greater risks of teratogenicity than did these latter vaccines.

The ACIP and CDC state that use of MMR is contraindicated during pregnancy because of the theoretical, albeit small, risk of CRS or other teratogenic effects in infants born to women who receive the vaccine during pregnancy. Reasonable precautions should be taken to preclude vaccination of pregnant women, including asking women if they are pregnant, excluding those who state that they are, informing the others of the theoretical risks to the fetus, and explaining the importance of not becoming pregnant for a specified period of time after vaccination. The manufacturer recommends that pregnancy be avoided for 3 months after receipt of rubella virus-containing vaccine; however while the ACIP also previously recommended that pregnancy be avoided for 3 months after receipt of rubella virus-containing vaccine or MMR, more recent data and experience prompted ACIP to shorten the length of time for this precaution. Based on data from several sources indicating that no cases of CRS have been identified among infants born to women who were inadvertently vaccinated against rubella within 3 months or early in pregnancy, the ACIP now states that pregnancy should be avoided for 28 days after receipt of MMR. The risk of CRS is considered so small as to be negligible in women who are inadvertently vaccinated during pregnancy or in women who become pregnant within 3 months after vaccination; therefore, the ACIP and CDC state that rubella vaccination in these women should not in itself necessitate interruption of pregnancy. Because birth defects, one-third of which are serious, occur in 3–5% of all births, confusion about the etiology of a birth defect may result when the vaccine is administered during pregnancy.

Lactation

Following postpartum vaccination with rubella virus-containing vaccine, rubella vaccine virus reportedly is distributed into milk and can be transmitted to breastfed infants. At least one breastfed infant whose mother received monovalent rubella virus vaccine live exhibited mild clinical illness typical of acquired rubella; however, in other breastfed infants with serologic evidence of rubella infection, none exhibited severe disease and ACIP states that vaccine virus infections from breastfeeding remain asymptomatic. The manufacturer states that MMR should be administered with caution to nursing women. The ACIP states that breast-feeding generally is not a contraindication to administration of MMR since the vaccine appears to pose no special problems for the mother or her nursing infant.

Drug Interactions

Blood Products

Blood products (e.g., whole blood, packed red blood cells, plasma) may interfere with the immune response to certain live virus vaccines, including measles, mumps, and rubella virus vaccine live (MMR; M-M-R II); therefore, MMR should not be administered simultaneously with or for specified intervals before or after administration of blood products.

Administration of MMR should be deferred for at least 3 months following administration of red blood cells (with adenine-saline added); for at least 6 months following administration of packed red blood cells or whole blood; and for at least 7 months following administration of plasma or platelet products.

After receiving MMR, vaccinees should avoid blood products for 2 weeks; if use of a blood product is considered necessary during this period, a repeat vaccine dose should be given after the recommended interval unless serologic testing is feasible and indicates a response to the vaccine was attained.

Immunosuppressive Agents

Individuals receiving immunosuppressive agents (e.g., corticotropin, corticosteroids [at immunosuppressive dosages], alkylating agents, antimetabolites, radiation therapy) may have a diminished response to rubella virus-containing vaccine, and replication of the virus may be potentiated. Vaccination with MMR should be deferred until the immunosuppressive agent is discontinued; the manufacturer states that individuals receiving corticosteroids as replacement therapy (e.g., those with Addison’s disease) generally may receive the vaccine. The exact interval between discontinuance of immunosuppressive therapy and regaining the ability to respond to live virus vaccines is not known, but live viral vaccines generally should not be administered for at least 3 months after discontinuance of immunosuppressive therapy. Individuals with leukemia in remission who have not received chemotherapy for at least 3 months may receive a live virus vaccine. The precise amount and duration of systemically absorbed corticosteroid therapy needed to suppress the immune system of an otherwise healthy individual are not well defined. Although of recent theoretical concern, there is no evidence of increased severe reactions to live vaccines in individuals receiving corticosteroid aerosol therapy, and such therapy is not in itself a reason to delay vaccination. Most experts, including the US Public Health Service Advisory Committee in Immunization Practices (ACIP) and American Academy of Pediatrics (AAP), agree that short-term (less than 2 weeks), low- to moderate-dose systemic corticosteroid therapy; long-term, alternate-day, systemic corticosteroid therapy using low to moderate doses of short-acting drugs; topical corticosteroid therapy (e.g., nasal, cutaneous, ophthalmic); or aerosol corticosteroid therapy; intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive in usual dosages and do not necessarily contraindicate vaccination with live virus vaccines. Although the immunosuppressive effects of corticosteroid therapy vary, many clinicians consider a dose equivalent to 2 mg/kg or 20 mg total of prednisone daily for 2 weeks or longer as sufficiently immunosuppressive to raise concerns about the safety of vaccination with live virus vaccines.

Immune Globulins

Antibodies contained in immune globulin preparations (e.g., immune globulin IM [IGIM], immune globulin IV [IGIV], hepatitis B immune globulin [HBIG], rabies immune globulin [RIG], tetanus immune globulin [TIG], varicella-zoster immune globulin [VZIG]) may interfere with the immune response to certain live virus vaccines, including MMR.

MMR should be deferred for at least 3 months following administration of TIG, HBIG, IGIM used for prophylaxis of tetanus, hepatitis B virus (HBV), or hepatitis A virus (HAV); for at least 4 months following administration of RIG; for at least 5 months following administration of VZIG for varicella prophylaxis or IGIM used for measles prophylaxis in immunocompetent individuals; for at least 6 months following use of cytomegalovirus immune globulin IV (CMV-IGIV) or IGIM used for measles prophylaxis in immunocompromised individuals; for at least 8 months following administration of IGIV for replacement therapy of immunodeficiencies VZIG or IGIV used for postexposure prophylaxis of severe varicella; for at least 8–10 months following administration of IGIV for the treatment of idiopathic thrombocytopenic purpura (ITP); or for at least 11 months following administration of IGIV for Kawasaki syndrome. If simultaneous administration of a vaccine containing rubella virus vaccine live and one of these immune globulin preparations or administration at less than the recommended interval is deemed necessary (e.g., because of imminent exposure to disease), the fact that vaccine-induced immunity may be compromised should be considered and, unless there is serologic evidence of an adequate antibody response to the live virus vaccine, an additional dose of vaccine should be administered at the specified interval. If administered simultaneously, the live virus vaccine and immune globulin should be administered at separate sites anatomically remote from one another. However, MMR may be given prior to discharge from the hospital to susceptible postpartum women who have received Rh_o(D) immune globulin provided that serologic testing is done 8 weeks or longer after vaccination to determine if seroconversion has occurred.

The fact that revaccination may be necessary in individuals who receive an immune globulin preparation shortly after MMR should be considered. In general, vaccine virus replication and stimulation of immunity occur within 7–14 days after administration of a live virus vaccine. Therefore, if the interval between administration of measles virus vaccine live and subsequent administration of one of these preparations is less than 14 days, an additional dose of vaccine should be given after the appropriate interval previously specified, unless serologic testing indicates that an adequate antibody response to the vaccine occurred. An additional dose of vaccine generally is unnecessary if the interval between vaccination and administration of the immune globulin or blood product is longer than 2 weeks.

Live Vaccines

Measles, Mumps, Rubella, and Varicella Vaccines

Rubella virus vaccine live may be administered concurrently with measles virus vaccine live, mumps virus vaccine live, and varicella virus vaccine live.

Rubella virus vaccine live is commercially available in a fixed-combination vaccine containing measles virus vaccine live and mumps virus vaccine live (MMR) to facilitate concomitant administration of all 3 antigens. Administration of MMR results in immunologic responses similar to those obtained with administration of the 3 antigens at separate sites.

MMR may be administered concurrently with monovalent varicella virus vaccine live (Varivax) at a different site using a separate syringe. Results of studies in healthy children 12–36 months of age indicate that seroconversion rates, antibody responses, and adverse effects reported with simultaneous administration of the vaccines are similar to those reported when the vaccines are administered 6 weeks apart. Because there is a theoretical concern that the immune response to one live viral vaccine may be impaired if administered within 1 month of another, if MMR and varicella virus vaccine live are not administered simultaneously then they should be administered at least 1 month apart. There is some evidence that administration of varicella virus vaccine live less than 30 days after MMR decreases the effectiveness of the varicella vaccine. Results of a retrospective cohort study that used data from the Vaccine Safety Datalink (VSD) project and included children 12 months of age or older who were vaccinated during January 1995 to December 1999 indicate that administration of varicella virus vaccine live less than 30 days after MMR results in a 2.5-fold increase in the incidence of breakthrough varicella infections. However, when the vaccines were administered concurrently, there was no increase in the risk for breakthrough infections.

Rubella virus vaccine live also is commercially available in a fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad). Studies using MMRV (ProQuad) in healthy children 1–6 years of age indicate that the antibody responses against measles, mumps, rubella, and varicella antigens following a single dose of ProQuad are similar to those obtained after a single dose of MMR and a single dose of varicella virus vaccine live (Varivax). However, there is some evidence that the relative risk for febrile seizures in infants may be higher with the fixed-combination vaccine MMRV than that reported when a dose of single-antigen varicella virus vaccine live (Varivax) and a dose of MMR are given concomitantly.

Influenza Vaccine Live Intranasal

Because of theoretical concerns that the immune response to one live virus vaccine might be impaired if given within 30 days of another live virus vaccine, if MMR and influenza virus vaccine live intranasal are not administered on the same day, they should be administered at least 4 weeks apart.

Other Live Vaccines

Some oral live vaccines (e.g., rotavirus vaccine live oral, typhoid vaccine live oral) can be administered concomitantly with or at any interval before or after MMR.

Because of theoretical concerns that the immune response to other live virus vaccines might be impaired if given within 30 days of another live virus vaccine, if MMR and yellow fever vaccine are not administered on the same day, they should be administered at least 4 weeks apart.

Inactivated Vaccines and Toxoids

MMR may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after inactivated vaccines, recombinant vaccines, polysaccharide vaccines, or toxoids.

The ACIP states that MMR and Haemophilus influenzae type b (Hib) conjugate vaccines may be given concomitantly.

Although specific studies evaluating simultaneous administration of MMR and hepatitis B vaccine, diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP) or tetanus toxoid and reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap) are not available, the ACIP and AAP state that these vaccines may be administered concomitantly.

MMR may be given concomitantly with parenteral inactivated influenza vaccines (using different syringes and different injection sites) or at any interval before or after administration of inactivated influenza vaccines.

The ACIP and AAP state that MMR may be administered concurrently with pneumococcal vaccine, including pneumococcal conjugate vaccine (PCV) or pneumococcal 23-valent polysaccharide vaccine (PPSV23), at a different site using a separate syringe.

Laboratory Test Interferences

Tuberculin

Live attenuated measles, mumps, and rubella virus vaccines have been reported to temporarily suppress tuberculin skin sensitivity; therefore, tuberculin tests (if required) should be done before, simultaneously with, or 4–6 weeks after administration of measles, mumps, and rubella virus vaccine live (MMR; M-M-R II).

Pharmacology

Monovalent rubella virus vaccine live (no longer commercially available in the US) and the fixed-combination vaccine containing measles, mumps, and rubella antigens (measles, mumps, and rubella virus vaccine live [MMR]) stimulate immunity to rubella (German measles) by inducing production of specific antibodies, including rubella hemagglutination-inhibiting (HI) antibodies. Although vaccine-induced antibody titers generally are lower than those stimulated by natural rubella infection, vaccine-induced immunity protects against clinical illness and viremia after natural exposure. Studies using monovalent rubella virus vaccine live indicate that administration of a single dose results in serologic evidence of immunity in 95% of vaccine recipients 12 months of age or older and confers long-term, probably lifelong, protection.

Rubella Virus and Infection

Rubella virus is an RNA virus classified as a Rubivirus in the Togaviridae family. Although 25–50% of rubella infections may be subclinical or asymptomatic, infection in adults and children usually is manifested as a mild, febrile, rash illness that may include lymphadenopathy, malaise, and/or conjunctivitis. Arthralgia and arthritis also can occur and has been reported in up to 70% of adolescent and adult females with the disease. Rare complications of rubella infection include thrombocytopenic purpura, encephalitis, neuritis, and orchitis. The most serious complications of rubella infection occur when women in their first trimester of pregnancy become infected with the virus.

Rubella infection during pregnancy may cause congenital rubella infection and congenital rubella syndrome (CRS). Congenital rubella infection can affect all organs in the developing fetus and result in miscarriage, abortion, stillbirth, fetal anomalies, or asymptomatic infection in the infant. Up to 85–90% of infants born to women who become infected during the first 8–11 weeks of gestation will develop a pattern of birth defects called CRS; 20–25% of infants born to women who become infected during the first 20 weeks of pregnancy develop CRS. CRS may be characterized by one or more fetal anomalies that are auditory (e.g., sensorineural deafness), ophthalmic (e.g., cataracts, microphthalmia, glaucoma, chorioretinitis), cardiac (e.g., patent ductus arteriosus, peripheral pulmonary artery stenosis, atrial or ventricular septal defects), and/or neurologic (e.g., microencephaly, meningoencephalitis, mental retardation). CRS also may result in radiolucent bone defects, hepatosplenomegaly, thrombocytopenia, and purpuric skin lesions and some infants will have both intrauterine and postnatal growth retardation. Infants infected with rubella late in gestation may not exhibit clinical manifestations of CRS; however, any infant infected with rubella in utero can shed the virus for up to 1 year or longer.

Postnatal rubella infection usually is transmitted person-to-person by direct or droplet contact from nasopharyngeal secretion. The incubation period for rubella is 12–23 days. Individuals with rubella are most infectious when rash is erupting, but virus may be shed from 7 days before until 5–7 days after rash onset.

Natural rubella infection appears to result in immunity that is long-lasting and probably life-long. However, reexposure to natural rubella occasionally results in reinfection without clinical illness or detectable viremia. The risk for CRS among infants born to women reinfected with rubella during pregnancy is minimal.

Response to Rubella Virus Vaccine Live

A single subcutaneous dose of monovalent rubella virus vaccine live (no longer commercially available in the US) containing the RA 27/3 strain of live, attenuated rubella virus in susceptible individuals 12 months of age or older induces rubella HI antibodies in at least 97% of vaccinees. Protection against rubella usually is present 21–28 days after vaccination; however, a small percentage (1–5%) of vaccinees may fail to seroconvert after a single dose. Most individuals who do not respond to the first dose of rubella virus vaccine live would be expected to respond to a second dose. Seroconversion in response to rubella vaccination parallels protection from the disease.

Monovalent rubella virus vaccine live containing the RA 27/3 strain of live, attenuated rubella virus induces higher immediate post-vaccination levels of HI, complement-fixing, and neutralizing antibodies than previously available vaccines that contained other strains of rubella virus (Cendehill, HPV-77 DE-5, HPV-77 DK-12) and also induces a broader variety of antibodies, including anti-theta and anti-iota precipitating antibodies, resulting in an immunologic response that more closely resembles that induced by natural rubella infection. The increased levels and broader profile of antibodies induced appear to correlate with greater resistance to subclinical reinfection with the wild-type virus and provide greater confidence for lasting immunity.

The duration of protection from rubella infection following administration of rubella virus-containing vaccine has not been fully determined. Individuals 12 months of age or older who receive a single subcutaneous dose of rubella virus-containing vaccine can be expected to have long-term (for at least 15 years), probably life-long, protection against clinical rubella and asymptomatic viremia. Vaccine-induced rubella HI antibodies have been reported to persist at least 10 years in some individuals. Antibodies measured by neutralization assays or enzyme linked immunosorbent assays (ELISA) are still detectable in most individuals 11–13 years after vaccination. Although data from several studies indicate that levels of vaccine-induced antibodies may decline over time, data from surveillance of rubella and CRS suggest that waning immunity with increased susceptibility to rubella disease does not occur.

Chemistry and Stability

Chemistry

Rubella virus vaccine live is a preparation of live, attenuated rubella virus. Monovalent rubella virus vaccine live (Meruvax II) is no longer commercially available in the US. Rubella virus vaccine live is commercially available in the US in a fixed-combination vaccine with measles virus vaccine live and mumps virus vaccine live (MMR; M-M-R II) and in a fixed-combination vaccine containing MMR and varicella virus vaccine live (MMRV; ProQuad).

Vaccines containing rubella virus vaccine live meet standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. MMR contains the Wistar Institute RA 27/3 strain of rubella virus. The virus is propagated in human diploid (WI-38) cell culture. The potency of MMR is expressed in terms of the amount of virus estimated to infect 50% of a number of standardized tissue culture preparations under specified conditions (Tissue Culture Infective Dose 50% or TCID₅₀). Following reconstitution with the diluent provided by the manufacturer, each 0.5-mL dose of reconstituted MMR contains not less than 1000 TCID₅₀ of measles virus, 12,500 TCID₅₀ of mumps virus, and 1000 TCID₅₀ of rubella virus. Each 0.5-mL dose of the MMR also contains sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), recombinant albumin human (up to 0.3 mg), fetal bovine serum (less than 1 part per million), and approximately 25 mcg of neomycin. The cells, virus pools, fetal bovine serum, and albumin human used in preparation of MMR are screened for the absence of adventitious agents; the albumin human is processed using the Cohn cold alcohol fractionation procedure.

Lyophilized MMR occurs as a light yellow compact crystalline plugs and the reconstituted vaccine occurs as a clear, yellow solutions. MMR do not contain thimerosal or any other preservative.

Stability

In lyophilized form, MMR should be refrigerated at 2–8°C but may be frozen. The vials containing diluent provided by the manufacturer may be refrigerated at 2–8°C or stored at room temperature. During shipping, MMR must be stored at 10°C or less and may be packed in solid carbon dioxide (dry ice). If the vaccine is shipped with dry ice, the diluent must be shipped separately.

Following reconstitution with the diluent provided by the manufacturer, MMR should be refrigerated at 2–8°C and discarded if not used within 8 hours. Both the lyophilized and reconstituted vaccine should be protected from light, which may inactivate the virus.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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