However, autism is a neurodevelopmental condition that has a strong genetic component with genesis before one year of age, when MMR vaccine is typically administered. Several epidemiologic studies have not found an association between MMR vaccination and autism, including a study that found that MMR vaccine was not associated with an increased risk of autism even among high-risk children whose older siblings had autism. Despite strong evidence of its safety, some parents are still hesitant to accept MMR vaccination of their children.
Decreasing acceptance of MMR vaccination has led to outbreaks or resurgence of measles. Health-care providers have a vital role in maintaining confidence in vaccination and preventing suffering, disability, and death from measles and other vaccine-preventable diseases.
The most damaging vaccine safety controversy of recent years began as an exploration of the possible role of measles and measles vaccines in the pathogenesis of inflammatory bowel disease IBD. That work eventually evolved into a speculative hypothesis that the combined measles, mumps, and rubella MMR vaccine may be a cause of autism.
Although numerous scientific studies have refuted a connection between MMR vaccine and autism, some parents are still hesitant to accept MMR vaccination of their children because they are uncertain about the safety of the vaccine. In this review, we summarize the genesis of the controversy, review the scientific evidence against a causal association, describe the effect of the controversy on MMR vaccine acceptance and resurgence of measles outbreaks, and discuss what can be done to bolster vaccine confidence, including the central role of scientists and health-care providers.
Autism, or autism spectrum disorder ASD as it is currently defined, is a developmental disability that can cause significant social, communication, and behavioral challenges. A diagnosis of ASD now includes several conditions that used to be diagnosed separately: autistic disorder, pervasive developmental disorder PDD not otherwise specified, and Asperger syndrome.
ASD with regression represents a subset of children with ASD who have lost previously acquired developmental skills, usually language. The causes of ASD are not known, although genetics plays a strong role 1.
The prevalence of ASD has increased in recent years and is estimated to affect 1 in 59 children in the United States 3. Measles is a highly contagious, acute viral infectious disease caused by a paramyxovirus of the genus Morbillivirus and spread by the respiratory route 4 , 5. The disease is characterized by a prodrome starting about 10—12 days after exposure consisting of fever often high and malaise followed by cough, coryza, and conjunctivitis. The characteristic measles rash, generally occurring around 14 days after exposure, starts as a maculopapular eruption on the head and spreads to the trunk and extremities over the course of 3—4 days Figure 1a.
The rash usually lasts 5—6 days and resolves in the same order in which it appeared. Individuals are infectious from about 4 days before the rash onset to 4 days after the rash onset. Koplik spots, which are blue-white plaques on the mucous membranes of the mouth, are pathognomonic for measles Figure 1b. Complications of measles include diarrhea, otitis media, pneumonia viral or bacterial , vision loss, acute encephalitis, seizures, and death. Infection with measles and subsequent recovery confers lifelong immunity 4 , 5.
Measles remains a significant cause of death and disability in low-income countries 6. Mumps is an acute viral illness caused by a paramyxovirus of the genus Rubulavirus and spread by the respiratory route 7 , 8.
In young children, mumps tends to be a mild illness with nonspecific symptoms occurring about 12—25 days after exposure.
The characteristic parotitis when it does occur develops around 16—18 days after exposure. Up to a quarter of those infected with mumps virus are asymptomatic. Other complications of mumps, which include aseptic meningitis, encephalitis, pancreatitis, and deafness, are relatively rare but occur more commonly in older children and adults. Infection with mumps virus generally confers lifelong immunity 7 , 8. Rubella, commonly known as German measles, is also an acute viral illness that is spread by the respiratory route 9 , It is caused by a togavirus of the genus Rubivirus.
Signs and symptoms of rubella, which occur about 14 days after exposure, are generally mild and include fever, malaise, upper respiratory symptoms, and a maculopapular rash. Subclinical infection occurs in up to half of all those infected and is especially common in young children.
Complications of rubella are uncommon and occur more often in older children and adults. The main concern with rubella is infection during pregnancy and the subsequent risk of congenital rubella syndrome CRS.
CRS can affect all organ systems in the developing fetus and is more severe when infection occurs early in pregnancy. Fetal demise, premature delivery, deafness, blindness, other severe birth defects, and intellectual disability are some of the health problems associated with CRS, which can be delayed in onset and progress as affected children age. Infection with rubella virus generally confers lifelong immunity 9 , It is recommended as a two-dose series with the first dose at 12—15 months of age and the second dose at 4—6 years of age.
Combination MMR vaccines are live virus vaccines indicated for prevention of measles rubeola , mumps, and rubella. MMR vaccines contain attenuated strains of these three viruses, and various forms of the vaccine have been available since the s 5.
Waning immunity to the mumps component of MMR vaccine has been observed and likely contributes to mumps outbreaks in some types of highly vaccinated populations, such as college students living in dorm settings, necessitating a third MMR dose to help contain outbreaks The combination trivalent MMR vaccine has been the predominant measles-containing vaccine in the United States and other high-income countries for decades. MMR vaccine has advantages over monovalent vaccines for measles, mumps, and rubella or bivalent measles and rubella vaccines.
MMR vaccine requires fewer injections two shots for two doses of each antigen versus four to six separate shots with bivalent or monovalent vaccines and reduces the chance for delays in protection that can result from spacing out vaccines over time. MMR vaccine is well tolerated. MMR vaccine is associated with febrile seizures, which occur at a rate of about 1 in 3,—4, vaccinated children with the first dose.
Thrombocytopenia, or low platelet count, is a rare adverse reaction that occurs at a rate of about 1 case per 30,—40, doses. Arthralgia following MMR vaccination has been observed but primarily in adult women 4 , Live attenuated measles vaccines became available from the early to mids 5. Their introduction in the United States coincided with a dramatic decline in measles cases by the end of the decade Figure 2. Although there was a resurgence of measles in — in the United States and elsewhere 13 , cases continued to decline, and, in , measles was declared eliminated from the United States 14 Figure 2 , meaning that the disease is no longer continuously transmitted.
When measles cases occur in the United States, it is because they are brought in i. Measles was declared eliminated from the Americas in Global measles vaccination, in the form of MMR vaccine or combination measles-rubella vaccination used mainly in low-income countries , has resulted in substantial reduction of measles cases and measles deaths 16 , a testament to the success of measles vaccination programs worldwide.
Measles cases in the United States, — Mumps cases also have declined substantially since the introduction of MMR vaccine, although mumps outbreaks continue to occur in the United States, mostly in older children and college-age individuals, even in situations with highly vaccinated populations The possibility that MMR vaccine may cause autism was first raised by Andrew Wakefield and colleagues in Wakefield had earlier conducted studies of the possible role of measles in IBD, and it was this work in bowel disease that led to a hypothesis about how MMR vaccine could cause a gut pathology that could predispose children to central nervous system toxicity and possibly autism.
Although the hypothesis rested on an MMR vaccine—induced bowel disorder, a possible link between the vaccine and bowel pathology was never established and ultimately disproved. However, a subsequent study by some of the same authors did not find an association between measles vaccination and IBD Other studies also did not find evidence that measles-containing vaccines are associated with an increased risk of IBD 20 — However, these studies involved a monovalent measles vaccine, and Wakefield would later argue that it is the combination MMR vaccine that is the real culprit in enabling the measles vaccine virus to infect the bowel and cause pathology.
The most comprehensive study of a possible association between measles vaccines, including MMR vaccine, and IBD was a population-based study conducted in four large health-care organizations in the United States The study subjects were born between and , with follow-up as long as 25 years or more. The study identified cases of IBD, and each was matched to up to five controls.
No increased risk was found for Crohn disease, ulcerative colitis, or any IBD following MMR vaccine specifically or any measles-containing vaccine in general.
Laboratory studies also played into the debate about possible gastrointestinal pathology related to the measles virus or vaccines. Again, one of these was a study by Wakefield that reported finding measles virus nucleocapsid protein in 13 of 15 patients with Crohn disease However, he and other investigators were unable to replicate these initial findings 26 — Wakefield first proposed this idea in a report in The Lancet in The article was a descriptive report of the clinical features of 12 children who had a history of pervasive developmental disorder nine had autism and intestinal abnormalities.
Despite the limitations of the article 30 , it generated intense media and public attention resulting in decreased MMR vaccination coverage, particularly in the United Kingdom, with resultant re-emergence of measles disease and deaths. Although the article was retracted by the journal because of improprieties in subject recruitment and financial conflicts of interest 31 — 33 , the doubts it raised have lingered. Wakefield has continued to develop and promote his hypothesis.
He has claimed that the combination of developmental regression and gastrointestinal disorders following MMR vaccination is a new syndrome that he has called autistic enterocolitis Studies that have attempted to evaluate the emergence of a new syndrome consistent with autistic enterocolitis, including developmental regression and gastrointestinal disorders, have not found links with MMR vaccination. An analysis using a large database of general medical practices in the United Kingdom found that children with autism were no more likely than children without autism to have gastrointestinal disorders requiring medical evaluation before their diagnosis of autism One of the original authors of the autistic enterocolitis hypothesis subsequently reported seeing similar intestinal changes in children without developmental regression and in unvaccinated children Two separate studies found that the proportion of autistic children with regression or with bowel symptoms was not different between time periods before and after the introduction of MMR vaccine 37 , A study that detected persistent measles virus infection in the intestines of children with autism and bowel problems 39 also was promoted to support the autistic enterocolitis hypothesis.
The study found that 75 of 91 children with developmental disorders and ileal lymphonodular hyperplasia and enterocolitis had evidence of persistent infection compared with 5 of 70 controls. Limitations of the study included uncertainty about the specific developmental disorders of the study participants e.
Furthermore, the study did not distinguish whether the virus particles were from vaccine or wild-type measles viruses. A replication study that attempted to overcome the limitations of the preceding study provided strong evidence that autism is not associated with persistent measles virus RNA in the gastrointestinal tract or with MMR vaccine exposure The study examined ileal and cecal tissue specimens from 25 children with autism and gastrointestinal disturbances and 13 children with gastrointestinal disturbances alone using real-time reverse transcription-polymerase chain reaction to detect measles virus RNA.
Assays were conducted in three laboratories blinded to diagnosis, including the laboratory that made the original findings of a possible link between measles virus and ASD. All three laboratories found no differences between the two groups in the presence of measles virus RNA in the bowel biopsy samples. Beginning soon after publication of the Wakefield paper in , several epidemiologic studies were conducted to evaluate the suggested association between MMR vaccine and autism.
The studies used different designs and were conducted in different populations; each found no increased risk of autism following MMR vaccination. The first studies to be reported were ecologic studies in which population-level trends in MMR vaccination were compared with trends in autism Table 1.
The first study was conducted in a district of London and published in in The Lancet This study included an analysis of whether the introduction of MMR vaccine in the United Kingdom in influenced the incidence of autism.
The study found no sudden change in the incidence of autism after introduction of MMR vaccine and no association between receipt of the vaccine and development of autism. In addition, at two years of age, the MMR vaccination coverage among the autism cases was nearly identical to coverage in children in the same birth cohorts in the whole district of London.
Other ecological studies comparing trends in measles vaccination coverage with corresponding trends in autism were conducted in the United Kingdom, the United States, Japan, and Canada 42 — None of these studies found a correlation between increasing trends in autism and measles vaccination coverage Table 1.
However, ecological studies are limited by their reliance on population-level data in which trends in a certain condition could be affected by changes in several other factors in addition to the exposure of interest. The association between measles vaccination and autism has been evaluated in other studies that used stronger epidemiologic designs, including case-control and cohort studies, that obtain individual-level data and are able to control for confounding factors that could bias the results.
Case-control studies assessed the association between measles vaccination and autism by comparing the measles vaccination histories of children with autism with the measles vaccination histories of control children who did not have autism. None of these studies found an increased risk of autism following measles vaccination with either MMR vaccine or monovalent measles vaccine Table 1.
The largest of the case-control studies, which included 1, cases of pervasive developmental disorder and 4, controls from the UK General Practice Research Database, found a relative risk of 0. Two cohort studies have been conducted of MMR vaccination and autism. In the cohort studies, populations of children were identified from birth or early childhood and grouped according to whether they had received MMR vaccine.
Computerized record systems were used to determine which children were subsequently diagnosed with autism, and the rates of autism were compared between vaccinated and unvaccinated children. One of the cohort studies was conducted in Denmark.
The relative risk associated with MMR was 0. A more recent study addressed the possibility that MMR vaccination is a risk factor only in certain high-risk children The study included about , younger siblings of children who had been diagnosed with ASD.
A meta-analysis of the published epidemiologic studies concluded that MMR vaccine is not associated with an increased risk of autism The evidence for a possible association between MMR vaccine and autism also has been extensively reviewed by three committees of the National Academy of Medicine 53 — 55 , and all have concluded that MMR vaccine does not cause autism.
In the United Kingdom, the Wakefield article had a profound impact, with subsequent decreases in MMR vaccination coverage and a dramatic increase in measles cases 56 — Public confidence in the safety of MMR vaccine showed substantial declines in the early s, possibly influenced by increasing negative media coverage of the MMR vaccine—autism controversy With the retraction of the Wakefield article in 31 and the accumulating evidence that MMR vaccine does not cause autism, MMR vaccine acceptance and vaccination coverage recovered and stabilized in the United Kingdom Measles case counts have decreased, and, in , measles was declared eliminated from the United Kingdom The United States also experienced increased antivaccine sentiment and vaccine hesitancy following the publication of the Wakefield article on the alleged MMR vaccine—autism association, but the effect on coverage appeared less obvious than in the United Kingdom, at least at the national level.
However, substantial numbers of parents up to one-quarter or more express vaccine hesitancy, with intention to delay or space out vaccinations or not vaccinate at all, or express concerns about the risks and benefits of MMR vaccination and childhood immunizations in general 63 , Parents of young children—those with children in the age range for routine MMR vaccination—express the strongest concerns While national coverage with MMR vaccination remains high, vaccine hesitancy tends to cluster geographically, leaving selected communities vulnerable to introduction and spread of vaccine-preventable diseases 63 , 65 , However, in the second decade to , measles outbreaks appeared to be increasing in frequency, resulting in increased case counts Several large outbreaks pushed up case counts in —, with cases in alone These outbreaks originated from imported cases, and most people who developed measles were unvaccinated or had unknown MMR vaccination status 68 — No single cause of autism has been found, and researchers believe that genes and environmental factors such as viruses or chemicals both may contribute.
The kinds of brain abnormalities found in people with autism suggest that the disorder arises when something disrupts normal brain development. One possibility is that early exposure to a virus prods the body into mounting an immune response that somehow goes awry.
In addition to producing antibodies against the virus, the body makes antibodies against itself, resulting in damage to tissues and organs. This "autoimmune" response is what happens in autoimmune diseases such as lupus, and some researchers think a similar response may account for the brain abnormalities found in people with autism. In their study of 48 autistic children and 34 normal children and adults, the researchers measured levels of antibodies to two virusesmeasles virus and human herpesvirusin the subjects' blood.
These antibodies were chosen because they are often used in research on known autoimmune diseases, says Singh, the principal investigator of the project and an assistant research scientist in the College of Pharmacy. The researchers also measured levels of two brain autoantibodies antibodies to brain tissue. One, anti-MBP, is an antibody to myelin basic protein, a protein found in the protective sheaths around nerve fibers in the brain. The other, anti-NAFP, is an antibody to neuron-axon filament protein, a protein that makes up the nerve fibers themselves.
Virus antibody levels were essentially the same in autistic and non-autistic subjects, as the researchers expected. But the majority of autistic children who had virus antibodies also had brain autoantibodies.
The higher the level of virus antibodies, the more likely an autistic child was to have brain autoantibodies. The Lancet retracted this paper in Wakefield was barred from practicing medicine in the United Kingdom.
Since then, there have been more than 20 studies and articles that refuted the connection between MMR vaccine and the development of Autism. Demicheli V et al. MMR vaccine was unlikely to be associated with autism. Another large study examined the trends in autism and MMR immunization coverage in California looking at children born in enrolled in California Kindergartens survey sample of children each year. Dales L et al. JAMA ; 9 : Then there was the suggestion that mercury could be contributing to the increased prevalence of Autism and particularly Thimerosal; this is a mercury-containing organic compound and has been used as a preservative in several vaccines used in the s.
Thimoresal was never present in MMR. It has been removed from all routines vaccines used in childhood except certain vaccines against the flu, in It is important to know that thimerosal breaks down in the body into Ethylmercury and NOT methylmercury.
0コメント