MMR Vaccine

Mechanism of Action

The MMR vaccine is a live-attenuated combination vaccine formulated with live-attenuated viruses, making it a harmless, less virulent version of the infectious agents from which it provides protection. The MMR vaccine stimulates the immune system to protect against measles, mumps, and rubella. Due to its live attenuated nature, the MMR vaccine demonstrates high efficacy but necessitates multiple doses for complete immunity to be attained.[3] Furthermore, this vaccine is recommended for specific patient populations as post-exposure prophylaxis.

The 3 live attenuated viruses in the new MMR vaccine are genetically similar to the corresponding components of the existing MMR vaccine. Humoral immunity was evaluated based on the clinical data from 13 randomized controlled trials, and serologic response thresholds were achieved for all antigens. The Advisory Committee on Immunization Practices (ACIP) has determined that the newly approved MMR vaccine is immunogenic and safe.[6]

Administration

Available Dosage Forms and Strengths

M-M-R II (measles, mumps, and rubella virus vaccine live):

Each single-dose vial contains live attenuated measles virus (Edmonston strain) ≥1000 50% tissue culture infectious doses (TCID50), live attenuated mumps virus (Jeryl Lynn strain) ≥12,500 TCID50, and live attenuated rubella virus (Wistar RA 27/3 strain) ≥1000 TCID50. The inactive ingredients include human serum albumin, chicken egg protein, gelatin, bovine serum, neomycin, sorbitol, and sucrose. The product is supplied as a lyophilized powder with a separate sterile diluent for reconstitution.

Priorix (measles, mumps, and rubella virus vaccine live):

Each single-dose vial contains live attenuated measles virus (Schwarz strain) ≥3.4 log10 50% cell culture infectious doses (CCID50), live attenuated mumps virus (RIT 4385 strain, derived from Jeryl Lynn) ≥4.2 log10 CCID50, and live attenuated rubella virus (Wistar RA 27/3 strain) ≥3.3 log10 CCID50.  Inactive ingredients include bovine serum albumin, lactose, chicken egg protein, mannitol, neomycin sulfate, ovalbumin, and sorbitol; these ingredients are provided as a lyophilized powder with a separate sterile diluent for reconstitution.

Dosage

Estimates of the effectiveness of the MMR vaccine are 99% in measles prevention after a second vaccination, over 95% in the prevention of mumps, and 90% in the prevention of rubella after a single dose. The ACIP recommends that vaccine doses in a series should be obtained from the same manufacturer; however, vaccination should not be delayed if the vaccine from the same manufacturer is unavailable. Clinical trials have demonstrated that both MMR vaccines are safe and efficacious when administered as a second dose and, therefore, interchangeable.[9][10] The 0.5 mL of vaccine, representing the complete contents of the reconstituted vial, shall be administered via intramuscular or subcutaneous injection to the individual, with a minimum interval of 28 days between doses.

• The first dose should be administered to individuals aged 12 to 15 months, and the second should be administered between the ages of 4 and 6 years. The second dose is preferably administered before kindergarten or school entry. Note that the interval between doses should not be shorter than 28 days.[6]
• The vaccine can be administered in 2 doses to unimmunized individuals aged 12 months to 13 years.
• One dose should be given to unimmunized adults born after 1957 unless they travel outside North America, work in healthcare, attend post-secondary educational settings, or serve as military personnel.
• Adults born before 1957 without evidence of measles immunity should receive 1 dose of the MMR vaccine if they are students in postsecondary settings or traveling internationally, or 2 doses if they are health care personnel, unless otherwise indicated by risk assessment.
• The recommendation is to administer the first and/or second dose of MMR vaccine in advance to children who live in or travel to areas with an outbreak of measles (defined as at least three cases with a temporal and spatial relationship) and to children traveling outside the US borders. As per CDC Child immunization schedule notes during international travel, in the specified situations, the initial dose of MMR should be administered between 6 and 11 months of age before departure, followed by subsequent vaccinations according to the recommended schedule—second dose of vaccine, with an interval of at least 28 days apart, typically administered between 12 and 15 months of age.[3]
• Children aged 12 to 23 months should receive the MMR vaccine and a univalent varicella vaccine at the same visit, rather than the measles-mumps-rubella-varicella (MMRV) vaccine, to reduce the risk of fever and febrile seizures. The risk is estimated to be around one additional febrile seizure per 2300 to 2800 doses of MMRV vaccine in this patient cohort.[3]
• Patients with laboratory confirmation of immunity to measles, mumps, or rubella are considered immune to these diseases; therefore, no immunization is necessary. In practice, however, 2 doses of the MMR vaccine are also administered in this situation, which is dictated by the limited availability of monovalent vaccines against these viruses.[3] Seronegative patients who have proof of adequate immunization do not require further vaccination.

Specific Patient Populations

Hepatic impairment: No dose adjustment is provided in the vaccine labeling. Expert opinion suggests that MMR vaccines should be administered early in the course of chronic liver disease to elicit an effective immune response. The American Society of Transplantation Infectious Diseases Community of Practice suggests that children should be vaccinated before liver transplantation.[11]

Renal impairment: No dose adjustment is provided.

Pregnancy considerations: Pregnant women who have not been vaccinated and have laboratory-confirmed measles disease should receive intravenous immunoglobulin after exposure. Measles in pregnant women may have a more severe course and serious complications.[3]

Breastfeeding considerations: The CDC states that the MMR vaccine administered to mothers during lactation does not affect the safety of either the infants or the mothers. The rubella vaccine virus can be secreted in breast milk. The rubella virus is attenuated and generally does not infect the infant. However, transmission and mild clinical infection are possible. No definitive evidence suggests the presence of live attenuated mumps or measles vaccine virus in breast milk. Additionally, the absence of exclusive breastfeeding until 5 months of age can result in a poor response to measles vaccination.[4]

Pediatric patients: The efficacy and safety of the MMR vaccine in infants 12 months or younger are inconclusive. ACIP recommends 2 doses of MMR vaccine administered 28 or more days apart for catch-up immunization of previously unvaccinated children.[6]

Older patients: Clinical studies of MMR vaccines have not evaluated whether patients aged 65 or older respond differently from younger individuals.

Immunoglobulin (400 mg/kg) can be administered 6 days after exposure. The intent is to prevent or reduce the severity of measles; however, it is not administered to immunocompetent individuals who have received 1 dose of MMR after 12 months of age. This post-exposure prophylaxis is only for patients exposed to measles who have an increased risk of complications and are contraindicated from MMR vaccination. This group includes patients:

• With severe immunodeficiency, regardless of immune status or immunization
• Post bone marrow transplant, up to at least 12 months after the end of immunosuppressive therapy or longer if there is a graft-versus-host reaction
• Those treated for acute lymphoblastic leukemia until at least 6 months after completing immunosuppressive chemotherapy
• Those infected with human immunodeficiency virus with a percentage of CD4 cells less than 15% (all age groups) or CD4 cell counts below 200 cells/mm³ (aged 5 and older) who have not received the MMR vaccine after effective antiretroviral therapy

Newborn babies and infants aged up to 6 months should receive immunoglobulin intramuscularly (IGIM) at a dose of 0.5 mL/kg (maximum dose 15 mL) or intravenous immunoglobulin (IVIG) 400 mg/kg within 6 days of exposure. Infants aged 6 to 12 months may receive the MMR vaccine within 72 hours of exposure or IGIM at 0.5 mL/kg (maximum dose of 15 mL) or IVIG 400 mg/kg within 6 days of exposure. For children aged at least 12 months, the MMR vaccination is preferred to IGIM or IVIG. After exposure, children with contraindications for MMR vaccination should receive IVIG 400 mg/kg instead of IGIM.[1][12] 

Adverse Effects

According to the results from a systematic review, adverse events were commonly reported following MMR or MMRV vaccination in infants. Fever was the most common, typically occurring within the second week after vaccination. Higher fever rates were associated with MMRV vaccines and MMR formulations containing the Edmonston B measles strain, compared to those with the Schwarz or Moraten strains. Other systemic events included rash, lymphadenopathy, febrile seizures, and irritability. Less frequent but recognized adverse effects included arthralgia, parotitis, and transient thrombocytopenia.[13]

M-M-R II vaccine: Adverse events reported with M-M-R II vaccine include fever, headache, irritability, and panniculitis. Cardiovascular events such as vasculitis, and gastrointestinal events including nausea, vomiting, diarrhea, parotitis, and pancreatitis have been noted. Otologic effects include otitis media and sensorineural deafness. Ocular events include conjunctivitis, retinitis, and optic neuritis. Hematologic events include leukocytosis, thrombocytopenia, purpura, and lymphadenopathy. Immunologic reactions include anaphylaxis, anaphylactoid reactions, and angioedema. Musculoskeletal complaints include arthralgia and myalgia. Neurological events include encephalitis, encephalopathy, Guillain-Barré syndrome, subacute sclerosing panencephalitis, acute disseminated encephalomyelitis, transverse myelitis, polyneuropathy, seizures (both febrile and afebrile), ataxia, syncope, ocular palsies, and measles inclusion body encephalitis. Respiratory events include pneumonia, rhinitis, and pharyngitis.

Dermatologic reactions include Stevens-Johnson syndrome, urticaria, erythema multiforme, Henoch-Schönlein purpura, pruritus, acute hemorrhagic edema of infancy, and injection site reactions (such as pain, redness, swelling, and vesiculation). Urogenital effects include orchitis and epididymitis. Adverse reactions affecting the skin include Stevens-Johnson syndrome, acute hemorrhagic edema of infancy,  pruritus, injection site reactions (such as pain, redness, swelling, and vesiculation), Henoch-Schönlein purpura, erythema multiforme, and urticaria. Adverse reactions affecting the urogenital system include orchitis and epididymitis. 

The most common adverse events have been reported (≥10%) in clinical trials in the drug product label of Priorix vaccine by age group:

Ages 12 to 15 months

• Local: Pain (26%) and redness (25%)
• Systemic: Irritability (63%), loss of appetite (45%), drowsiness (45%), and fever (35%)

Ages 4 to 6 years

• Local: Pain (41%), redness (22%), and swelling (11%)
• Systemic: Loss of appetite (21%), drowsiness (27%), and fever (24%)

Ages 7 years and older

• Local: Pain (12%) and redness (12%)

The adverse events associated with specific vaccines are listed below.

MMR Vaccine

Adverse events tend to occur with the first dose of the medication; one to 3 weeks following vaccination, 5% of immunized children experience malaise and fever, which can present with or without a rash that lasts up to 3 days.[2]

MMRV Vaccine

Ten percent or more of vaccine recipients experience redness and pain at the injection site, or a fever of 39 °C (102.2 °F) or less. Fewer than 1% to 10% of patients experience a measles-like, rubella-like, or varicella-like rash in addition to swelling and a fever greater than 39 °C (102.2 °F).[5][14]

Rubella-Containing Vaccines

Rarely, patients receiving rubella-containing vaccines may experience acute transient arthritis or arthralgia 1 to 3 weeks after immunization that lasts 1 to 3 weeks. These symptoms are more common in post-pubertal females, who develop arthralgia in 25% of cases and arthritis in 10% of patients after immunization. No evidence of an increased risk of new-onset chronic arthropathies exists.[5]

Immune thrombocytopenic purpura: A rare adverse reaction to the MMR or MMRV vaccine is immune thrombocytopenic purpura, which may occur within 6 weeks of immunization. In most children, immune thrombocytopenic purpura resolves within 3 months without complication. In these cases, a serologic evaluation can be performed to determine the need for an additional dose. Clinicians should consider the risks of another adverse event of immune thrombocytopenic purpura before a second dose of the vaccine is required.[15]

Encephalitis: Encephalitis occurs in approximately 1 in 1 million doses, compared to 1 in 1000 with infection by the measles virus. Measles encephalitis is due to disseminated measles vaccine virus infection. The neuropathological examination reveals inclusion-body encephalitis.[16]

Febrile Seizures: Children between 12 and 23 months should receive the MMR vaccine and a univalent varicella vaccine at the same visit instead of an MMRV vaccine to reduce the risk of fever and febrile seizures. The incidence of febrile seizures is highest after the first MMR dose.[17] The risk is estimated to be around 1 additional febrile seizure per 2300 to 2800 doses of MMRV vaccine in this patient cohort.[18][19]

Allergies: The trace amount of egg or chicken protein in the MMR and MMRV vaccines is insufficient to cause an allergic reaction in those who are egg-allergic. The recently approved MMR vaccine does not contain gelatin.[20]

Interactions

• Immunosuppressive therapy: Avoid giving the M-M-R II vaccine to individuals receiving immunosuppressive treatment, including high-dose corticosteroids, as this may lead to widespread infection from the vaccine strain.
• Immuneglobulins and blood products: Administering immuneglobulins or blood products around the same time as the M-M-R II vaccine may reduce the vaccine's effectiveness. Follow expert guidelines regarding spacing between such treatments and live vaccines.
• Tuberculin skin testing: The vaccine may temporarily reduce sensitivity to tuberculin skin tests. If testing is needed, it should be performed before, at the same time, or at least 4 to 6 weeks after vaccination.
• Other live vaccines: The M-M-R II vaccine can be given with other live virus vaccines. If not given on the same day, allow at least 1 month between live vaccines to prevent immune interference.
• Anti-CD20 agents:  Anti-CD20 agents may reduce humoral response, potentially limiting the effectiveness of live vaccines like MMR. As a precaution, live vaccines are generally deferred during and for several months after therapy. Consider administering the MMR vaccine at least four weeks before starting anti-CD20 treatment.[21]

Contraindications

Booster doses with a measles-containing vaccine after appropriate vaccination are not necessary.

Contraindications of Vaccines

• Severe allergic reaction/anaphylaxis after a previous dose of MMR/MMRV or after one of the vaccine's components, such as neomycin and gelatin.[5][22]
• Pregnancy or planning should be discouraged within 28 days of vaccination due to the risk of congenital rubella. However, performing a pre-vaccination pregnancy test is unnecessary if the patient denies pregnancy. 
• Long-term immunosuppressive treatment, when administered high doses of steroids, which is at least 2 mg/kg/d or at least 20 mg/d prednisone equivalents for individuals over 10 kg, for more than 14 consecutive days, should postpone MMR vaccination for at least 1 month. However, lower systemic corticosteroids, supporting physiological doses (also known as replacement therapy), and local corticosteroid injections (eg, into joints or tendons) are not contraindications to MMR vaccination.
• HIV infection and severe immunosuppression are defined as the percentage of CD4+ lymphocytes (CD4) less than 15% at any age, which are contraindications. If the percentage of CD4 cells is not available, the threshold values are as follows: CD4 less than 750/mL for children aged 12 months, CD4 below 500/mL for children aged 1 to 5 years, and CD4 less than 200/mL for children aged 5 years and older. 
• Family history of congenital or hereditary immunodeficiency in parents or siblings, except for persons whose immunological system is confirmed by laboratory tests, is a contraindication.[5]
• Other contraindications include immunodeficiency, hematopoietic proliferative diseases, solid tumors, or chemotherapy, and congenital immunodeficiency disorders.

Relative Contraindications

• Treatment with blood products or immunoglobulins within the last 11 months may contain antibodies or interfere with the host response to a live vaccine. Therefore, the recommended interval for such treatment after MMR vaccination is 3 to 11 months, depending on the type of transfused preparation. 
• Anamnesis with thrombocytopenia may show an increased risk of clinically significant thrombocytopenia after immunization with MMR or MMRV. Therefore, decisions on the first dose of MMR for children with a history of thrombocytopenia must consider the risks and benefits. In general, the benefits outweigh the risks. Factors to be evaluated when making this decision include:
  • Relapse of thrombocytopenia after MMR in patients with a history of thrombocytopenia (related and unrelated to the vaccine)
  • Probability of the child's exposure to measles, mumps, and rubella (eg, planned trips abroad, the epidemiology in the place of residence or stay of the child)
• Clinicians can perform serological tests before the second dose of MMR vaccination to determine its necessity. Children with a protective level of antibodies against measles, mumps, and rubella do not require a second dose. However, for children with a history of thrombocytopenia who do not have a protective level of antibodies against measles, mumps, or rubella, decisions on administering a second dose of MMR are assessed individually based on the risks and benefits.
• Acute moderate or severe disease, with or without fever, to avoid the imposition of any vaccine reaction, symptoms of infection, and the vaccine burden with symptoms due to infection. Vaccinate children with mild infections (eg, upper respiratory tract infection, ear infection, diarrhea). Postponing vaccination in such a situation unnecessarily delays the implementation of the immunization program and increases the susceptibility to infection.[5]

Contraindications Do Not Constitute

• Beastfeeding or the reproductive period
• Pregnancy of the mother of a child who is to receive a vaccine or pregnancy in a person near the child
• A person who is immunocompromised in the family or immediate environment
• Asymptomatic HIV infection or HIV infection with mild symptoms, without immune disorders
• Positive tuberculin test (in those with active tuberculosis before vaccination)

A simultaneous tuberculin test should be performed either on the day of MMR vaccination or 4 to 6 weeks after because the measles virus in the vaccine may weaken the skin reaction to tuberculin. In children with a history of mild allergy to egg protein, the risk of anaphylactic reaction after MMR vaccination is the same as in the general population.[5] In children with severe allergies, anaphylaxis is an immediate reaction after ingestion. Allergy to egg protein is automatically included in the group at higher risk of sudden allergic reactions after vaccines. In the case of MMR, gelatin and neomycin are more allergenic than egg protein.[18][19]

Monitoring

Monitor for seizures and anaphylaxis following administration.[23] If syncope occurs, place the patient supine to ensure adequate cerebral perfusion.[24] Monitor complete blood count for possible thrombocytopenia, and monitor for injection site reactions.[https://www.cdc.gov/vaccines/hcp/current-vis/mmr.html] Adverse events should be reported through the Vaccine Adverse Event Reporting System (VAERS).[25]

Toxicity

Limited data are available regarding the safety of administering an additional dose of the MMR vaccine. The administration of an additional dose of a vaccine may be necessary in cases where there is uncertainty about a person's vaccination history or due to programmatic errors, such as vaccination mistakes or errors in the vaccination process. Among 5067 reported instances of excess vaccine doses administered between 2007 and 2017, three-fourths of the cases did not result in adverse events following immunization. The most commonly reported adverse health events were pyrexia (12.8%), injection site erythema (9.7%), injection site pain (8.9%), and headache (6.6%). The percentage of adverse events among these cases was comparable to all cases submitted to the VAERS during the same study period.[25]

Enhancing Healthcare Team Outcomes

Vaccination with the MMR vaccine requires an interprofessional approach as the proper administration of the vaccine changes according to the patient population and the clinical scenario. The mumps outbreaks have increased in the US since 2006. Due to the resurgence of mumps and the risk associated with rubella and measles, increasing MMR coverage is necessary. The availability of MMR vaccines from different manufacturers ensures the continuous supply of vaccines.[6][26]

Children with neurological diseases should be vaccinated following accepted rules and vaccination schedules. One should remember that the risk of severe infection, the need for hospitalization, and complications in children with chronic disease are significantly higher than in the healthy population. Additionally, each infection disrupts rehabilitation, adversely affecting the child's neurological status. Also, children with chronic diseases are more likely to be in healthcare facilities, increasing infection risk.

Contraindications to MMR vaccination in children with neurological diseases are limited and temporary.[5] They include the following:

• Undetermined neurological diagnosis
• Suspicion of progressive central nervous system disease with epilepsy
• Six months after the last convulsive seizure
• Unstabilized neurological condition

Contraindications to MMR vaccination do not include:

• Epilepsy with an excellent response to treatment (at least 6 months without seizures)
• A neurological disorder before the start of vaccination

In children with epilepsy, the recommendation is to administer antipyretic drugs for 6 to 12 days after administration of MMR, as fever that may occur as an adverse reaction may trigger seizures.[2][3] Another recommendation is to educate patients with a multi-disciplinary team about vaccination's perceived but false risks. For example, the association of MMR with autism spectrum disorder (ASD) has aroused much controversy in recent years. Several antivaccine advocacy groups put the hypothesis linking autism and inflammatory bowel disease with MMR vaccination forward in the last century.[27]

In 1998, The Lancet published an article in which researchers reported a link between the MMR vaccine and intestinal leukemia. The article's basis was the temporal relationship between the increased ASD diagnoses (observed since the 1980s) and recommended childhood vaccines against Haemophilus influenzae type B, hepatitis B, chickenpox, pneumococci, influenza, and the MMR vaccine.[27][28] Smoking weakens both innate and adaptive immunity, potentially reducing vaccine efficacy across various formulations. The MMR vaccine remains vital for preventing measles, mumps, and rubella, but smoking may impair optimal antibody response.[29]

The thesis put forward by Wakefield's team serves as the starting point for numerous epidemiological and prospective studies worldwide, which have ruled out a cause-and-effect relationship between vaccination (including MMR) and the occurrence of ASD or inflammatory bowel disease. Subsequent analysis proved that increased ASD diagnoses resulted from changes in ASD recognition criteria as a neurodevelopmental disorder and increasing awareness of this problem. Prospective studies have shown that ASD symptoms often occur in the first year of life, before the first dose of MMR.

In 2004, a journalist revealed that Wakefield's test was conducted in a manner that did not follow medical ethics and was inaccurate. Most of the study's authors officially withdrew unreliable applications, and The Lancet completely retracted the article in 2010.[30] However, if adverse events occur following immunization, clinicians should report them through the VAERS.[31] Interprofessional coordination and collaboration among clinicians, specialists, pharmacists, nurses, and public health professionals can enhance patient outcomes when helping patients accept the MMR vaccine and prevent associated infections.