MMR Vaccine and Autism: No Evidence for a Link

Introduction and Historical Background

The general public today considers measles, mumps, and rubella to be relatively benign childhood diseases that are almost completely eradicated. This near-obliteration of once-common diseases came about through an effectively combined measles, mumps, and rubella (MMR) vaccine that is routinely required in the United States for children prior to entering public school kindergarten, in all but the State of Iowa (CDC, 2008; 2014). These diseases were considered "nearly eradicated" until fairly recently, when a controversial set of publications by Wakefield and colleagues (1998) in the United Kingdom, and by Geier and Geier (2004) in the United States, raised considerable public alarm with concomitant media attention, leading many parents to fear that MMR vaccine utilization could result in autism and/or autism-spectrum disorders in their children.

Historically, measles were reported in approximately 900 CE by Rhazes, a Persian physician, who noted that smallpox and measles were distinct diseases (The College of Physicians of Philadelphia, 2015a, 2015b). As early as 1657, measles were reported in Boston, but were not studied in detail until approximately the mid-1700s, when Francis Home first explored the infectivity of this disease in Scotland. His procedure was to expose healthy patients to the blood of infected patients, which did result in measles transference (The College of Physicians of Philadelphia, 2015a, 2015b).

Measles is a generally short-term disease that often affects children. It results in spots and/or rashes on the patient's skin (hence potentially confused with smallpox), oral lesions, and potential complications in adulthood such as myocarditis, pneumonia, and even a severe subacute sclerosing panencephalitis, which can result in motor and mental deterioration that may worsen over time (Gladwin et al., 2014).

In the case of mumps, skin rashes are also observed in child patients; however, other significant symptoms can occur, including orchitis (inflammation of the testes), which can result in sterility for post-pubertal males, and parotitis (swelling of one or both parotid glands). In 1934, Goodpasture and Johnson demonstrated that mumps were infectious via transmission of saliva from patients with mumps to Rhesus monkeys (The College of Physicians of Philadelphia, 2014). By 1948, the first vaccine was made from isolated and inactivated mumps virus; this vaccine was not long-lasting in the immunity it produced, and by 1970 it had been discontinued. In 1967, the Jeryl Lynn strain of mumps was prepared via tissue culture as an attenuated live version; this licensed version is still in use and decreases the incidence of mumps by up to 95% (World Health Organization, 2007).

A third mild but common childhood disease, "German Measles," was initially described in 1740 by Friedrich Hoffman (The College of Physicians of Philadelphia, 2015a, 2015b). In the mid-1800s, German measles was renamed "rubella" (meaning "little red") following a large outbreak in India. Infectivity was demonstrated by disease transfer from infected to healthy children in 1939 in Japan. The serious consequences of rubella were unfortunately demonstrated some thirty years later when a rubella outbreak in the United States resulted in thousands of miscarriages, as well as over 3,500 children born both deaf and blind, and another 8,000 children born deaf. The total — nearly 20,000 infants born with congenital rubella syndrome — made clear the highly serious potential consequences for pregnant women exposed to rubella. These arise because the rubella virus can cross the placenta and significantly disrupt fetal development. Unfortunately, these highly deleterious consequences might have been at least partially prevented had the warnings of public health officials been heeded (The College of Physicians of Philadelphia, 2015a, 2015b). This disaster resulted in stronger efforts toward vaccine development and led to the work of the American physician Stanley A. Plotkin, who developed a rubella vaccine. According to Greaves and colleagues (1983), the rubella vaccine has an efficacy of up to 90%.

While measles and mumps are related as part of the non-segmented, negative RNA-stranded viral family Paramyxoviridae (Gladwin et al., 2014), rubella belongs to the Togavirus family of viruses (World Health Organization, n.d.). The paramyxoviruses can induce host cells to fuse and form giant multinucleated cells — as is also the case with retroviruses and the herpes virus — due to their fusion protein (Gladwin et al., 2014). In children, both measles and mumps are far more severe than rubella, which is generally mild and produces only a maculopapular rash (World Health Organization, n.d.) that may disappear in as few as three days. However, the consequences of rubella for an exposed pregnant woman make this disease significant, because it causes very serious congenital effects. Embryonic cells are targeted during the period of differentiation, and effects in the infant can include pulmonary stenosis, septal defects, patent ductus arteriosus, blindness, cataract formation, deafness, and effects upon the central nervous system including developmental retardation (Gladwin et al., 2014).

It can thus be seen that measles, mumps, and rubella are generally relatively mild childhood diseases that can have potentially serious long-term detrimental effects on newborns, adults, and children. Because these diseases have an extremely high rate of contagion, the scientific community invested considerable effort in the development of successful vaccines. By 1963, the first vaccine for measles reached the public, after considerable testing in rhesus monkeys, efficacy research, and safety trials. The initial measles vaccine, developed by John Enders and colleagues, was used for nearly 12 years, during which time nearly 20 million individuals were vaccinated. Subsequently, in 1969, Merck improved the measles vaccine with a more highly attenuated version that became part of the combined MMR vaccine in present use (The College of Physicians of Philadelphia, 2015a, 2015b). The combination of the separate vaccines into a single, highly effective MMR vaccine led to a nearly 99% reduction in measles incidence in the United States. It is now possible to prevent the occurrence of measles, mumps, and rubella at a level that is well over 90% and may approach nearly 100%.

The Wakefield Controversy and Its Public Impact

In 1998, Wakefield and colleagues published a manuscript in The Lancet, a leading global medical journal. In this report, the group claimed that use of the MMR vaccine could be correlated with colitis and autism in children, based on a case series of twelve children with autistic-spectrum disorders; eight of these were said to have had onset following their MMR vaccination. The paper further described a series of additional symptoms common to these children and defined by Wakefield et al. (1998) as "autistic enterocolitis"; the authors further suggested a potential link between the MMR vaccine and colitis.

What perhaps caused the most damage, however, was a press conference at which Wakefield directly implicated the MMR vaccine as being responsible for the autistic enterocolitis. At this time he suggested avoidance of the combined MMR vaccine or use of the individual vaccines separately. Although the publication by Wakefield and colleagues (1998) was subsequently retracted and Wakefield was found to have conflicts of interest due to his own vaccine patents (Berger, 2004; Deer, n.d.), the media attention surrounding the MMR vaccine controversy led to a significant decrease in parental willingness to comply with MMR vaccination for their children. It later emerged (Deer, n.d., and links therein) that the children described by Wakefield and colleagues were not genuine patients representative of those described; subsequently, most of Wakefield's co-authors on the 1998 publication retracted their support for the work.

The Geier and Geier (2004) work in the United States — particularly focused on a mercury-containing stabilizing agent (thimerosal) in vaccines — led to similar non-compliance with the MMR vaccine among parents in the United States. As a result, the incidence of measles, mumps, and rubella rose sharply. What was once a trio of nearly eradicated diseases began to return, first in small outbreaks and then in larger ones, putting an unprepared population at risk. Indeed, due to the near-eradication of these diseases, many members of the public — including pregnant women today — are sadly unaware of the consequences of rubella exposure and the potentially serious danger it poses for themselves and their unborn offspring.

It should be stated that the MMR vaccine is not without risks, and these have been documented; however, the relatively mild nature of these effects and their low frequency justify the potential risks of vaccine administration. As shown in Table 1, the World Health Organization (n.d.) has documented the relatively low incidence of side effects from the measles vaccine. Most commonly used vaccines — such as those for yellow fever, tuberculosis, rotavirus, polio, and measles — have very low incidence of side effects and/or adverse reactions.

Table 1: Vaccines recommended by WHO (World Health Organization, n.d.)

General side effects from the MMR vaccine are relatively minor, including swelling of neck and cheek glands, fever, and a generally mild rash (Centers for Disease Control and Prevention, 2008). Other moderate health issues include arthritis (particularly in women), ephemeral thrombocytopenic purpura, and possibly seizures (Centers for Disease Control and Prevention, 2008). The more severe reactions are quite rare in the general population, again supporting the overall advantages of the MMR vaccine. The consequences of MMR vaccine administration have been extensively studied and are not known to include any form of autism-spectrum disorders or colitis. This paper probes more fully into correlations between autism-spectrum disorders and the MMR vaccine, as well as examining adverse effects of the combined vaccine.

Materials and Methods

The literature review utilized the online search engines PubMed, the New England Journal of Medicine, and MEDLINE. Search phrases included: "adverse effects MMR," "adverse effects vaccines," "autism-spectrum disorders vaccines," "measles vaccine," "MMR controversy," "MMR vaccine autism," "MMR vaccine colitis," "MMR vaccine effects," "MMR vaccine issues," and "rubella vaccine." Additional delimiters included publication date (after 2000), authorship, study design, age of population, and sample size. Initial reading of abstracts was used to help select articles for review; following this screening and selection, articles were read from abstract to conclusion, then results to discussion, with methods reviewed for those articles in the final selection pool. Exclusion was generally on the basis of date, with exceptions made where warranted. Articles were subdivided into categories according to research topic, research question, and study outcomes. Once final selection was made, the evidence table in the Appendix was prepared. This table demonstrates sorting by: first author, publication date, evidence level, study design, study population, intervention where applicable, and results/outcome.

Evidence levels were classified according to the following standards: Level 1 — Controlled randomized trials; Level 2 — Non-randomized controlled trial, prospective (pre-planned) study with predetermined eligibility criteria and outcome measures; Level 3 — Observational studies with controls, including retrospective, case-control, and cohort studies; Level 4 — Observational studies without controls, including cohort studies without controls, case series without controls, and case studies without controls.

Appropriate graphs, figures, tables, and charts within this manuscript, with the exception of material in the Appendix, are from the cited literature. They are used where necessary to enhance this manuscript, and each item is labeled and properly cited.

Adverse Effects of the MMR Vaccine and Effects of Negative Publicity

Given the immense effect on public health implicated by a vaccination program such as the MMR vaccine, the potential side effects of that vaccine have been a topic of considerable scientific investigation. Following the extreme controversy generated by the reports of Wakefield and colleagues (1998) in the United Kingdom and by Geier and Geier (2004) in the United States, many previous studies have been re-analyzed and new investigations have been conducted.

For example, Benjamin et al. (1992) reported that immunized children had a 1.6-fold higher risk of side effects such as limb symptoms and/or arthritis (with a 95% confidence interval) compared with non-immunized children. Furthermore, for children immunized under age five and for female children, the relative risk of these side effects was 1.6-fold higher, while that of older children was 0.7-fold higher. While these side effects were temporary, they did require hospitalization for three of the children. Limitations of the work of Benjamin et al. (1992) include memory, reporting, and recall bias, as well as selection bias.

In another investigation, Castro and colleagues (2005) studied the effects of the MMR vaccine on adult populations in Mexico, using two methods of inoculation: aerosol and subcutaneous injection. They observed many of the commonly reported side effects, as well as a few that had not previously been noted, including allergy, cough, fever, influenza, otitis, post-auricular swelling, and rhinitis, as described in Table 2.

Table 2: Post-vaccination side effects, patient-reported (Castro et al., 2005)

The work by Castro and colleagues (2005) revealed no significant differences in the nature of reported side effects that could be correlated with method of vaccine delivery. Surprising side effects included lethargy and post-auricular swelling (behind the ear); the latter was uniformly painless and unilateral. For those cases where lethargy was reported — three patients — a 4.9-fold increase in the serological response to mumps was observed, relative to only a 4.5-fold increase in antibodies for those patients who did not report lethargy.

In a 2004 study, Geier and Geier reported that the mercury from the thimerosal stabilizer in the MMR vaccine could be correlated with development of autism. According to their baseline measurement, Geier and Geier (2004) reported significantly increased odds for autism-spectrum disorders correlating with mercury concentrations. At the time, even though the Wakefield controversy had already been in the news, the Geier father-and-son team did not recommend discontinuance of the MMR vaccine, but did suggest the possible use of separate vaccines for each of measles, mumps, and rubella. In subsequent years, the credentials of this team were called into question; the younger Geier was found to have falsified his medical credentials and to be practicing medicine without a license. Both father and son were also shown to have serious conflicts of interest, having served as expert witnesses in legal cases involving negative reactions to the MMR vaccine. Investigative reporters discovered that both Wakefield and the Geiers were being paid lucrative fees to act as expert witnesses in a concerted attack against the MMR vaccine and other vaccines (Deer, n.d.; Deer, 2011). Their 2004 manuscript has since not only been retracted but has been wholly discredited (Deer, n.d.; Deer, 2011).

The work of Dayan et al. (2008) was a cross-sectional investigation addressing measles and mumps outbreaks in college-aged adults who had received only a two-dose vaccination series in youth. These data illustrate a large increase in mumps incidence, potentially attributable to the absence of a third vaccination dose. Dayan and colleagues suggested that vaccination policy be altered to both eliminate mumps and avert the potential of future outbreaks. As noted previously, mumps in post-pubertal males can potentially lead to sterility (Dayan et al., 2008).

Figure 1: Age-related mumps incidence (Dayan et al., 2008)

The work by Friederichs et al. (2006) was an epidemiological study of all children born in Scotland between 1987 and 2004. This research revealed an increase in delayed MMR vaccination for children born in or after 1999 — that is, subsequent to the Wakefield controversy (Friederichs et al., 2006). These researchers also found a significant increase in susceptibility among nursery-aged children after 1998 and predicted an overall immunization rate in Scotland that, while exceeding 90%, remained below 95%, indicating that additional immunizations of the population would be required to prevent measles transmission. More specifically, Friederichs et al. (2006) determined that MMR compliance between 1990 and 1998 had consistently exceeded 95% annually. Subsequently, however, and in direct temporal correlation with the Wakefield et al. (1998) report, MMR compliance had decreased to 91.7% for the year 2000 in Scotland, and dropped further to 90.4% for 2001 (Friederichs et al., 2006); these data were reported with a 95% confidence interval.

A study by Parker et al. (2006) examined the index patient who caused the largest measles outbreak in the United States within a decade. An unvaccinated 17-year-old Romanian visitor who was in a state of viral incubation attended a gathering of approximately 500 individuals. Fifty of these 500 individuals lacked immunity to measles, and of these, sixteen acquired the disease. Within six weeks, 34 cases of measles had been confirmed (Parker et al., 2006). Of the 34 confirmed cases, approximately 94% were unvaccinated; two patients had been vaccinated but experienced vaccine failure (Parker et al., 2006).

Figure 2: Indiana patients with measles from rash onset (Parker et al., 2006)

Conclusion

From analysis of the literature reviewed herein, side effects of the measles, mumps, and rubella (MMR) vaccine can be shown to include arthritis, aseptic meningitis, fever, joint pain, seizure, and thrombocytopenic purpura. It is also evident that a consequence of the false and retracted report by Wakefield et al. (1998) has been a direct increase in incidence of mumps and measles arising from non-compliance with MMR vaccinations. However, the data clearly do not support any link between use of the MMR vaccine and resultant autism, autistic-spectrum disorders, and/or pervasive developmental disorders. The scientific consensus, supported by multiple large-scale studies and systematic reviews, is unambiguous: the MMR vaccine does not cause autism, and the public health consequences of declining vaccination rates pose a far greater risk than the vaccine's documented and manageable side effects.