MMR Vaccine

Mechanism of Action

The MMR vaccine stimulates the immune system to protect against measles, mumps, and rubella. This vaccine is live attenuated and thus is a harmless, less virulent version of the infectious agents from which it provides protection. Since the MMR vaccine is live attenuated, it has excellent efficacy but requires more than one dose to achieve this immunity.[3]

Administration

Estimates of the effectiveness of the MMR vaccine are 99% in measles prevention after a second vaccination and over 95% in the prevention of mumps, and 90% in the prevention of rubella after a single dose.

• The administration of the first dose should be between 12 to 15 months of age, and the second dose between 18 months of age and school entry. Note that the interval between doses should not be shorter than 28 days.[1]

• For unimmunized children and adolescents, the vaccine can be given in two separate doses between the ages of 12 months and 13 years.

• For unimmunized adults born after 1970, one dose should be given unless they are traveling outside North America, working in health care, students in post-secondary educational settings, or military personnel.

• For unimmunized adults born before 1970, one dose should be given if they are students in post-secondary educational settings or traveling outside North America; two doses if they are working in health care or are military personnel. In general, as mentioned previously, unimmunized adults born before 1970 can be assumed to have natural immunity.

• The recommendation is to give the first and/or second dose of MMR in advance to children who live or travel in areas where there is an outbreak of measles (defined as at least 3 cases that have a temporal and spatial relationship) and children traveling outside US borders. In the situations mentioned above, the first dose of MMR should be given between 6 and 11 months of age and with continued vaccinations according to the current calendar (2 doses of vaccine with an interval of at least 28 days ranging from 12 to 15 months).[3]

• In the case of measles outbreaks, a vaccine can be given to infants after six months of age and then continue vaccinations according to a generally accepted schedule (two doses in 13 to 14 months and ten years, respectively).

• Children between 12 and 23 months should receive the MMR vaccine and a univalent varicella vaccine at the same visit instead of the 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 measles, mumps, or rubella immunity are considered immune to this disease, so there is no need for immunization vaccination. In practice, however, two doses of the MMR vaccine are also given in this situation, which is dictated by the lack of availability of monovalent vaccines against measles, mumps, or rubella.[3]. Seronegative patients who have proof of adequate immunization do not require further immunization. 

Post-exposure Prophylaxis

Immunoglobulin (400 mg/kg) can be administered six days after exposure. The intent is to prevent or reduce the severity of measles, but it is not given to immunocompetent persons who have received one dose of MMR after 12 months of age. This type of post-exposure prophylaxis is only for patients exposed to measles who have an increased risk of complications and also have a contraindication to MMR vaccination. This group includes patients:

• Severe immunodeficiency, regardless of immune status or immunization
• After a 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
• Treated for acute lymphoblastic leukemia until at least six months after the end of immunosuppressive chemotherapy
• Infected with HIV and a percentage of CD4 cells less than 15 percent (all age groups) or CD4 cell counts below 200 cells / mm^3 (age over five years) and patients. They have not received the MMR vaccine after receiving effective antiretroviral therapy.

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] 

Newborn babies and infants up to 6 months of age 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 six days of exposure.

Infants aged between 6 and 12 months may receive the MMR vaccine within 72 hours of exposure or IGIM at a dose of 0.5 ml/kg (maximum dose of 15 ml) or IVIG 400 mg/kg within six days of exposure.

For children of at least 12 months of age, the MMR vaccination is preferable to IGIM or IVIG.

Children who have contraindications for MMR vaccination after exposure should receive IVIG 400 mg/kg instead of IGIM.[1]

Adverse Effects

Measles-Mumps-Rubella Vaccine

Adverse events tend to occur with the first dose. 1 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]

Measles-Mumps-Rubella-Varicella Vaccine

Ten percent or more of vaccine recipients experience redness and pain at the injection site or a fever of 39 degrees C or less. Less 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 degrees C.[5][6]

Rubella-containing Vaccines

Patients receiving rubella-containing vaccines may experience acute transient arthritis or arthralgia 1 to 3 weeks post-immunization. These symptoms last 1 to 3 weeks and rarely recur. These symptoms are more common in post-pubertal females, who develop arthralgia in 25% of cases and arthritis in 10% of cases after immunization. There is not any evidence of an increased risk of new-onset chronic arthropathies.[5]

Immune Thrombocytopenic Purpura

A very rare adverse reaction to the MMR or MMRV vaccine is immune thrombocytopenic purpura (ITP), which may occur within six weeks of immunization. In most children, ITP resolves within three months without complication. In these cases, serologic status can undergo an evaluation to determine the need for an additional dose. Clinicians should consider the risks of another adverse event of ITP before a second dose of the vaccine is required.

Encephalitis

Encephalitis occurs in approximately 1 per million doses, compared to 1 in 1000 with infection with the measles virus.

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 risk is estimated to be around one additional febrile seizure per 2300 to 2800 doses of MMRV vaccine in this patient cohort.[7][8]

Allergies

The trace amount of egg or chicken protein in the MMR and MMRV vaccine is insufficient to cause an allergic reaction in those egg-allergic.

Contraindications

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

Contraindications

• Severe allergic reaction/anaphylaxis after a previous dose of MMR / MMRV or after one of the components of the vaccine (e.g., neomycin, gelatin)[5]
• Pregnancy or planning for it - the pregnancy 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. 
• Immunodeficiency
• Hematopoietic proliferative diseases
• Solid tumors/chemotherapy 
• Congenital immunity disorders
• Long-term immunosuppressive treatment, when administering high doses of steroids, i.e., at least 2 mg/kg per day or at least 20 mg/day prednisone equivalents for persons over 10 kg for more than 14 consecutive days, MMR vaccination should be postponed a month. However, lower doses of systemic corticosteroids, supporting physiological doses (the so-called replacement therapy), and local corticosteroid injections (e.g., into joints or tendons) are not contraindications to MMR vaccination.
• HIV infection with severe immunosuppression, defined as the percentage of CD4 + lymphocytes [CD4] below 15 percent at any age or if the percentage of CD4 is not available: CD4 less than 750 /mL for children = 12 months; CD4 below 500 /mL for children 1 to 5 years of age; CD4 less than 200 /mL for children aged over five years. 
• Family history for congenital or hereditary immunodeficiency in parents or siblings, except for persons whose immunological system has been confirmed by laboratory tests.[5]

Relative Contraindications

• Treatment in the last 11 months with blood products or immunoglobulins - may contain antibodies or inhibit the host response to a live vaccine. Therefore, the recommendation is that the interval from administering such treatment to MMR vaccination is from 3 to 11 months, depending on the type of transfused preparation. 
• Anamnesis with thrombocytopenia or 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 thrombocytopenia history must consider the risks and benefits. In general, the benefits outweigh the risks. Factors to be considered when making this decision include:1) relapse of thrombocytopenia after MMR in patients with a history of thrombocytopenia (both related to the vaccine and not related to the vaccine).2) the probability of the child's exposure to measles, mumps, and rubella (e.g., planned trips abroad, the epidemiological situation in the place of residence/stay of the child)
• Before the second dose of MMR vaccination is given, Clinicians can perform serological tests to determine if it is necessary. Children with a protective level of measles, mumps, and rubella antibodies do not need to receive a second dose. However, for children with a history of thrombocytopenia who do not have a protective level of measles, mumps, or rubella antibodies, decisions on administering a second dose of MMR are taken individually to reassess the risks and benefits.
• Acute moderate or severe disease, with or without fever, to avoid the imposition of any vaccine reaction on the symptoms of infection and the vaccine burden with symptoms due to infection. Vaccinate children with mild infections (e.g., upper respiratory tract infection, ear infection, diarrhea). Postponing vaccination in such a situation unnecessarily delays the implementation of the immunization program and lengthens the susceptibility to infection.[5]

Contraindications Do Not Constitute

• A positive tuberculin test in people with active TB infection should receive treatment with anti-tuberculosis before vaccination. A simultaneous tuberculin test should be performed either on the day of MMR vaccination or 4 to 6 weeks after it because the measles virus contained in the vaccine may weaken the skin reaction to tuberculin. 
• Breastfeeding period
• Pregnancy of the mother of a child who is to receive a vaccine or pregnancy in a person in the immediate vicinity of the child
• Reproductive period
• A person who is immunocompromised in the family or immediate environment
• Asymptomatic HIV infection or HIV infection with mild symptoms, without immune disorders
• Allergy to egg protein - in children with a history of mild allergy to a hen egg, the risk of anaphylactic reaction after MMR vaccination is the same as in the general population.[5] 
• In children with severe allergies - anaphylaxis or an immediate reaction after ingestion, the eggs are automatically included in the group of higher risk of sudden allergic reactions, also after vaccines. In the case of MMR, gelatin and neomycin are more allergenic to egg protein.[7][8]

Monitoring

Monitor for seizures and anaphylaxis following administration.[9]

Toxicity

There is little data on the safety of an extra dose of MMR vaccine. The administration of an additional dose of a vaccine may occur as sometimes there is a need to provide immunization to a person with uncertain vaccination history or due to a programmatic error (e.g., vaccination error). Out of 5067 reported excess doses of vaccine administered between 2007 and 2017,  three-fourths of cases did not experience an AEFI (Adverse Events Following Immunization). The most commonly reported adverse health events (AHEs) were pyrexia (12.8%), injection site erythema (9.7%), injection site pain (8.9%), and headache (6.6%). The percentage of AHEs among these cases was comparable to all cases submitted to VAERS during the same study period.[10]

Enhancing Healthcare Team Outcomes

Vaccination with the MMR vaccine requires a multi-disciplinary approach as the proper administration of the vaccine changes according to the patient population and the clinical scenario. 

Vaccination of children with neurological diseases should follow 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. Also, each infection causes a break in rehabilitation, adversely affecting the child's neurological status. Also, children with chronic diseases are more likely to be in health care facilities, making them more vulnerable to infection.

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

• Undetermined neurological diagnosis
• Suspicion of progressive CNS disease with epilepsy
• Six months after the last convulsion seizure
• Unstabilized neurological condition

Contraindications to MMR vaccination do not constitute:

• Epilepsy with a good response to treatment (at least six months without seizures)
• A neurological disorder occurred before the start of vaccination.

In children who have epilepsy, the recommendation is to administer antipyretic drugs for 6 to 12 days after administration of MMR - 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 perceived but false risks of vaccination. For example, the association of MMR with autism spectrum disorder (ASD) is a subject that 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 '90s of the last century.[11] In 1998, Lancet published an article in which researchers reported a link between the MMR vaccine and intestinal leukemia. Its basis was the temporal relationship between the increase in ASD diagnoses (observed since the 1980s) with the rise in recommended childhood vaccines - against Haemophilus influenzae type b, hepatitis B, chickenpox, pneumococci, influenza, and measles mumps and rubella vaccine.[11][12] The thesis put forward by Wakefield's team has become the starting point for many epidemiological and prospective studies worldwide that 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 the increase in ASD diagnoses resulted from changes in ASD recognition criteria as a neurodevelopmental disorder and increasing awareness of this problem. Besides, prospective studies have shown that ASD symptoms often occur in the first year of life, that is, before the first dose of MMR. In 2004, the journalist revealed that Wakefield's test was conducted in a manner not in accordance with medical ethics and was not accurate. Most of the study's authors officially withdrew their unreliable applications, and the Lancet completely retracted the article in 2010.[13] However, if there are any adverse events following immunization (AEFI), clinicians should report them through Vaccine Adverse Event Reporting System (VAERS).[14]