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The MMR vaccine (also known as the MPR vaccine after the Latin names of the diseases) is an immunization vaccine against measles, mumps, and rubella (German measles). It is a mixture of live attenuated viruses of the three diseases, administered via injection. It was first developed by Maurice Hilleman while at Merck.
A licensed vaccine to prevent measles first became available in 1963, and an improved one in 1968. Vaccines for mumps and rubella became available in 1967 and 1969, respectively. The three vaccines (for mumps, measles, and rubella) were combined in 1971 to become the measles-mumps-rubella (MMR) vaccine.
The MMR vaccine is generally administered to children around the age of one year, with a second dose before starting school (i.e. age 4/5). The second dose is a dose to produce immunity in the small number of persons (2–5%) who fail to develop measles immunity after the first dose. In the United States, the vaccine was licensed in 1971 and the second dose was introduced in 1989. It is widely used around the world; since introduction of its earliest versions in the 1970s, over 500 million doses have been used in over 60 countries. The vaccine is sold by Merck as M-M-R II, GlaxoSmithKline Biologicals as Priorix, Serum Institute of India as Tresivac, and Sanofi Pasteur as Trimovax.
Before the widespread use of a vaccine against measles, its incidence was so high that infection with measles was felt to be "as inevitable as death and taxes." Reported cases of measles in the United States fell from hundreds of thousands to tens of thousands per year following introduction of the vaccine in 1963. Increasing uptake of the vaccine following outbreaks in 1971 and 1977 brought this down to thousands of cases per year in the 1980s. An outbreak of almost 30,000 cases in 1990 led to a renewed push for vaccination and the addition of a second vaccine to the recommended schedule. Fewer than 200 cases have been reported each year between 1997 and 2013, and the disease is no longer considered endemic.
The benefit of measles vaccination in preventing illness, disability, and death has been well documented. The first 20 years of licensed measles vaccination in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of intellectual disability, and 5,200 deaths. During 1999–2004, a strategy led by the World Health Organization and UNICEF led to improvements in measles vaccination coverage that averted an estimated 1.4 million measles deaths worldwide. Between 2000 and 2013, measles vaccination resulted in a 75% decrease in deaths from the disease.
Measles is endemic worldwide. Although it was declared eliminated from the U.S. in 2000, high rates of vaccination and good communication with persons who refuse vaccination are needed to prevent outbreaks and sustain the elimination of measles in the U.S. Of the 66 cases of measles reported in the U.S. in 2005, slightly over half were attributable to one unvaccinated individual who acquired measles during a visit to Romania. This individual returned to a community with many unvaccinated children. The resulting outbreak infected 34 people, mostly children and virtually all unvaccinated; 9% were hospitalized, and the cost of containing the outbreak was estimated at $167,685. A major epidemic was averted due to high rates of vaccination in the surrounding communities.
Mumps is another viral disease of childhood that was once very common. If mumps is acquired by a male who is past puberty, a possible complication is bilateral orchitis which can in some cases lead to sterility.
Rubella, otherwise known as German measles, was also very common before the advent of widespread vaccination. The major risk of rubella is in pregnancy. If a pregnant woman is infected, her baby may contract congenital rubella from her, which can cause significant congenital defects.
The combined MMR vaccine was introduced to induce immunity less painfully than three separate injections at the same time, and sooner and more efficiently than three injections given on different dates.
In 2012, the Cochrane Library published a systematic review of scientific studies. Its authors concluded, "Existing evidence on the safety and effectiveness of MMR vaccine supports current policies of mass immunisation aimed at global measles eradication and in order to reduce morbidity and mortality associated with mumps and rubella."
As measles and rubella cause upper respiratory disease that leads to complications of pneumonia and bronchitis which are also caused by varicella, MMR vaccine is beneficial to control exacerbations of chronic obstructive pulmonary disease (COPD) and asthma.
Development, formulation and administration
The component viral strains of MMR vaccine were developed by propagation in animal and human cells. The live viruses require animal or human cells as a host for production of more virus.
For example, in the case of mumps and measles viruses, the virus strains were grown in embryonated hens' eggs and chick embryo cell cultures. This produced strains of virus which were adapted for the hens egg and less well-suited for human cells. These strains are therefore called attenuated strains. They are sometimes referred to as neuroattenuated because these strains are less virulent to human neurons than the wild strains.
The Rubella component, Meruvax, was developed in 1967 through propagation using the human embryonic lung cell line WI-38 (named for the Wistar Institute) that was derived 6 years earlier in 1961.
|Disease Immunized||Component Vaccine||Virus Strain||Propagation Medium||Growth Medium|
|Measles||Attenuvax||Enders' attenuated Edmonston strain||chick embryo cell culture||Medium 199|
|Mumps||Mumpsvax||Jeryl Lynn (B level) strain|
|Rubella||Meruvax II||Wistar RA 27/3 strain of live attenuated rubella virus||WI-38 human diploid lung fibroblasts||MEM (solution containing buffered salts, fetal bovine serum, human serum albumin and neomycin, etc.)|
MMR II is supplied freeze-dried (lyophilized) and contains live viruses. Before injection it is reconstituted with the solvent provided.
The MMR vaccine is administered by a subcutaneous injection.The second dose may be given as early as one month after the first dose. The second dose is a dose to produce immunity in the small number of persons (2–5%) who fail to develop measles immunity after the first dose. In the U.S. it is done before entry to kindergarten because that is a convenient time.
Adverse reactions, rarely serious, may occur from each component of the MMR vaccine. Ten percent of children develop fever, malaise, and a rash 5–21 days after the first vaccination; and 3% develop joint pain lasting 18 days on average. Older women appear to be more at risk of joint pain, acute arthritis, and even (rarely) chronic arthritis. Anaphylaxis is an extremely rare but serious allergic reaction to the vaccine. One cause can be egg allergy. In 2014, the FDA approved two additional possible adverse events on the vaccination label for ADEM (acute disseminated encephalomyelitis), and transverse myelitis, with permission to also add "difficulty walking" to the package inserts.
The number of reports on neurological disorders is very small, other than evidence for an association between a form of the MMR vaccine containing the Urabe mumps strain and rare adverse events of aseptic meningitis, a transient mild form of viral meningitis. The UK National Health Service stopped using the Urabe mumps strain in the early 1990s due to cases of transient mild viral meningitis, and switched to a form using the Jeryl Lynn mumps strain instead. The Urabe strain remains in use in a number of countries; MMR with the Urabe strain is much cheaper to manufacture than with the Jeryl Lynn strain, and a strain with higher efficacy along with a somewhat higher rate of mild side effects may still have the advantage of reduced incidence of overall adverse events.
The Cochrane Library review found that, compared with placebo, MMR vaccine was associated with fewer upper respiratory tract infections, more irritability, and a similar number of other adverse effects.
Naturally acquired measles often occurs with idiopathic thrombocytopenic purpura (ITP, a purpuric rash and an increased tendency to bleed that resolves within two months in children). Between 1 in 25,000 and 1 in 40,000 children are thought to acquire ITP in the six weeks following an MMR vaccination, which is a higher rate than found in unvaccinated populations. ITP below the age of 6 years is generally a mild disease, rarely having long-term consequences.
Claims about autism
In 1998 Andrew Wakefield et al. published a fraudulent paper about twelve children, reportedly with bowel symptoms and autism, or other disorders soon after administration of MMR vaccine, whilst supporting a competing vaccine. In 2010, Wakefield's research was found by the General Medical Council to have been "dishonest", and The Lancet fully retracted the paper. Three months following The Lancet's retraction, Wakefield was struck off the UK medical register, with a statement identifying deliberate falsification in the research published in The Lancet, and was barred from practising medicine in the UK. The research was declared fraudulent in 2011 by the British Medical Journal.
Many peer-reviewed studies have failed to show any association between the vaccine and autism. The Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, the UK National Health Service and the Cochrane Library review have all concluded that there is no evidence of a link.
Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first. Health experts have criticized media reporting of the MMR-autism controversy for triggering a decline in vaccination rates. Before publication of Wakefield's findings, the inoculation rate for MMR in the UK was 92%; after publication, the rate dropped to below 80%. In 1998, there were 56 measles cases in the UK; by 2008, there were 1348 cases, with two confirmed deaths.
In Japan, the MMR vaccination has been discontinued, with single vaccines being used for each disease (or in practice the vaccines are given as two doses. One a combination vaccine for Measles and Rubella MR and the other Mumps vaccine being given as a single dose). Rates of autism diagnosis have continued to increase, showing no correlation with the change.
The MMRV vaccine, a combined measles, mumps, rubella and varicella vaccine, has been proposed as a replacement for the MMR vaccine to simplify administration of the vaccines. Preliminary data indicate a rate of fever fits of 9 per 10,000 vaccinations with MMRV, as opposed to 4 per 10,000 for separate MMR and varicella shots; U.S. health officials therefore do not express a preference for use of MMRV vaccine over separate injections.
In a 2012 study pediatricians and family doctors were sent a survey to gauge their awareness of the increased risk of febrile seizures (fever fits) in the MMRV. 74% of family doctors and 29% of pediatricians were unaware of the increased risk of febrile seizures. After reading an informational statement only 7% of family doctors and 20% of pediatricians would recommend the MMRV for a healthy 12- to 15-month-old child. The factor that was reported as the "most important" deciding factor in recommending the MMRV over the MMR+V was ACIP/AAFP/AAP recommendations (pediatricians, 77%; family physicians, 73%).
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