Detailed analysis of publications analysis

Controversy with vaccines, adverse reactions of the MMR vaccine and the negative publicity surrounding it

SHAPE

Measles, Mumps and Rubella Vaccine:

Absence of Evidence for Link

to Autistic-Spectrum Disorders

Henry K. Nguyen, MD Candidate

Increased incidence of measles, mumps, and rubella is directly due to controversies regarding the measles, mumps, and rubella vaccine despite the absence of data supporting a correlation between this combined vaccine and development of autism.

Correspondence to:

Mentor:

Dr. Anshu Kacker

5650 including Abstracts

Methods and materials: A literature search was performed using key phrases, including the search-requisite abbreviation ‘MMR’ (measles, mumps, rubella), such as: ‘autism mmr vaccine’, ‘colitis mmr vaccine’, ‘controversy mmr’, ‘mmr adverse results’, ‘vaccines autism-spectrum disorders’, ‘vaccine effects mmr’, ‘vaccine measles’, and ‘vaccine rubella’. The results were compiled, following which appropriate publications were chosen for review and critical analysis.

Results: Detailed analysis of publications found in the literature search reveal negative health effects arising from administration of the measles, mumps, and rubella vaccine. These effects include: arthritis, aseptic meningitis, fever, lowered platelet count, rash, seizures, and swelling of glands. However, none of the reported ‘side-effects’ include autism and/or autism-spectrum disorders.

Conclusions: Following highly publicized reports by Wakefield and colleagues in the United Kingdom and by Geier and Geier in the United States that directly implicated the measles, mumps and rubella vaccine to childhood autism, ‘colitis’, and neurological disorders, many parents refused vaccine compliance for their children. Although the reports were later retracted, proven fraudulent, and the physicians/scientists discredited along with their work, the observed incidence of these once nearly eradicated diseases rose, particularly measles and mumps. No causal connection of significance between the vaccine for measles, mumps, and rubella and childhood autism, autism-spectrum disorders, or pervasive developmental disorders was found.

ULTRAMINI ABSTRACT: The now-retracted 1998 publication by Wakefield and colleagues suggested a correlation between childhood autism and the measles, mumps, and rubella vaccine. This false report generated controversy as well as directly decreasing vaccine compliance, raising incidence of these diseases. This study evaluates evidence for any potential vaccine — autism correlation.

Table of Contents

Abstract & #8230;. 2

Introduction 4

Materials and methods & #8230;

Results 10

Discussion & #8230; 17

Conclusion 21

References 22

Appendix 24

Introduction

Historical Overview and Background

The general public today considers measles, mumps, and rubella to be relatively benign childhood diseases that are almost completely eradicated. This obliteration of historical diseases (vide infra) 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).That is, these diseases were considered to be ‘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 a fairly high public furor 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 not studied in detail until approximately the mid-1700’s, 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, and this 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 patients skin (hence potentially confused with smallpox), oral lesions, and potential complications in adulthood such as myocarditis, pneumonia, and even a severe ‘sclerosing panencephalitis’ of the sub-acute form, that can result in motor and mental deterioration that may worsen (Gladwin et al., 2014).

In the case of mumps, skin rashes are also observed for child patients, however other significant symptoms can occur, including orchitis (inflammation of the testes), possibly resulting in sterility for post-pubertal males, and parotitis (swelling of one or both parotid glands). In 1934, Goodpasture and Johnson demonstrated that mumps were infective via transmission of saliva from patients having 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, however 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, the “German Measles,” was initially described in 1740 by Friedrich Hoffman (The College of Physicians of Philadelphia, 2015a, 2015b). In the mid-1800’s, the German measles was re-named ‘rubella’ (little red) following a large outbreak in India. Infectivity was demonstrated by disease transfer from infected to healthy children in 1939 in Japan. The utter seriousness of rubella was unfortunately demonstrated some thirty years later when a rubella outbreak in the United States resulted in thousands of miscarriages, as well as over 3500 children being born both deaf and blind, and another 8000 children being born deaf. The total, nearly 20,000 infants born with ‘congenital rubella syndrome’, brought home the highly serious potential consequences for pregnant women exposed to rubella. These arise because the rubella virus can cross the placenta and significantly perturb fetal development. Unfortunately, these highly deleterious consequences might have been at least partially ameliorated had the warnings of public health officials been heeded (The College of Physicians of Philadelphia, 2015a, 2015b) This disaster resulted in stronger efforts towards vaccine development and led to the work by 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 is from 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 the case for 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, with only a maculopapular rash (World Health Organization, n.d.) that disappears after as short a time as three days. However, the consequences of rubella for an exposed pregnant woman make this disease of significance because it causes very serious congenital effects. Indeed, in terms of potential complications, rubella is by far the most serious of the measles, mumps, and rubella group. Embryonic cells are targeted during the period of differentiation and there can be effects in the infant such as pulmonary stenosis, septal defects, patent ductus, blindness, cataract formation, deafness and effects upon the central nervous system including retardation (Gladwin et al., 2014).

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

Autism and The Wakefield Controversy

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

What perhaps caused the most damage, however, was a press conference in which Wakefield directly implicated the MMR vaccine as being responsible for the autistic enterocolitis. At this time he suggested avoidance of the MMR vaccine or use of the individual vaccines rather than the combined MMR vaccine. 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 ‘hype’ and public attention to the controversy concerning the MMR vaccine has led to a significant decrease in parental willingness in MMR vaccine compliance for their children. It later turned out (Deer, n.d., and links therein) that even the supposed children studied by Wakefield and colleagues weren’t real ‘patients; subsequently most of Wakefield’s colleagues 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 stabilizing factor (thimerosal) in the MMR vaccine, led to a similar non-compliance with the vaccine for parents in the United States. As a result, incidence of measles, mumps, and rubella has risen sharply, and what was once a trio of nearly eradicated diseases have begun to return, first in small outbreaks, and now in larger outbreaks putting an unaware population at risk. Indeed, it can be said that due to the near-eradication of MMR, many of the populace, including pregnant women today, are sadly unaware of the consequences of being exposed to rubella and thus the potentially imminent danger 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 justifies the potential risks of vaccine administration. As shown in Table 1 below, the World Health Organization (n.d.) has documented the relatively low advent 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 rash that is generally mild (Centers for Disease Control and Prevention, 2008). Other moderate health issues include arthritis (particularly in women), an ephemeral thrombocytopenic purpura, and possibly seizures (Centers for Disease Control and Prevention, 2008). However, the more severe reactions are quite rare in the general populace, again supporting the advantages of the MMR vaccine. The consequences of administration of the MMR vaccine have been extensively studied, and are not known to include any form(s) of autism-spectrum disorders or colitis. This paper will probe 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 research review utilized online search engines: PubMed, the New England Journal of Medicine, and MEDLINE. The search phrases used 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 de-limiters included publication date (after 2000), authorship, design of study, age of population, and size of samples. Initial reading of abstracts was used to help select articles for review; following this screening and selection, articles were read from abstract to conclusion, results to discussion, and methods if the articles were to be in final selection pool. Exclusion was generally on the basis of date, but exceptions were made. Articles were subdivided into categories concerning research topic and/or research questions as well as study outcomes. Once final selection was made, the evidence table, Section B, Appendix, was prepared. This Table demonstrates sorting by: first author, publication date, evidence level, study design, population of study, intervention where applicable, and results/outcome.

Evidence level was according to the standards set for by the RLRA course director at Medical University of the Americas: 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 – includes retrospective, case-control studies and cohort studies; Level 4: Observational studies without controls – includes cohort studies without controls, case series without controls, case studies without controls (RLRA Syllabus, Medical University of the Americas, 2014).

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

Results

In this section, articles listed in the Evidence Table, Section B. Of the Appendix, are discussed and evaluated in terms of the hypothesis: Increased incidence of measles, mumps, and rubella is directly due to controversies regarding the measles, mumps, and rubella vaccine despite the absence of data supporting a correlation between this combined vaccine and development of autism. Specifically, the scientific literature was queried to learn the nature of adverse effects associated with the MMR vaccine, if any; and whether the MMR vaccine can be correlated with occurrence of pervasive developmental disorders and/or autistic-spectrum disorders. As well, the literature was also queried with respect to the impact of the controversy arising from the Wakefield et al. (1998) and Geier (2004) publications in the United Kingdom and the United States, respectively, upon parental compliance with MMR vaccination for their children. Finally, the literature was queried as to how a non-compliant parental response to the controversy had impacted the population in terms of disease incidence for measles, mumps, and rubella.

Actual Adverse Effects of the MMR Vaccine and Effects of Negative Publicity

As is only logical given the immense effect upon public health implicated by the use of a public health inoculation program such as the measles, mumps, and rubella vaccine, the potential of side effects of the MMR vaccine has been a topic of considerable scientific investigation. However, given the extreme controversy engendered 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 taken place. 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 confidence interval of 95%) as compared with non-immunized children. Furthermore, for those 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/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 for inoculation: aerosol and subcutaneous injection. In this work, Castro et al. (2005) observed many of the commonly observed side effects, as well as a few that had not previously been noted. These included: allergy, cough, fever, influenza, otitis, post-auricular swelling, and rhinitis, as described in Table 2 (vide infra).

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 (Castro, et al., 2005). For those cases where ‘lethargy’ was reported, three patients, a 4.9-fold increase in the seriological 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 found that the mercury (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 that correlated with mercury concentrations. At the time, even though the Wakefield controversy had 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 (Geier and Geier, 2004). In subsequent years, the credentials of this father-son team have been called into question; the younger Geier was found to have falsified his medical credentials, and to be practicing medicine without a license. As well, both father and son were shown to have serious ‘conflict of interest’, serving as expert witnesses in legal cases involving negative reactions to the measles, mumps, and rubella vaccines. Indeed, reporters investigating both Wakefield and Geiers discovered that these individuals (Wakefield and the Geiers) were being paid lucrative salaries to act as expert witnesses in a concerted attack against MMR as well as other vaccines (Deer, n.d.; Deer, 2011). Since the release of their paper attacking the MMR vaccine (Geier and Geier, 2004), their manuscript has 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 adults of college age who had only received a two-dose vaccination in their youth. These data are reported below in Figure 1, illustrating the large increase in mumps incidence, potentially due to the lack of a 3rd vaccination. Dayan and colleagues suggested that the policy for vaccinations be altered to both eliminate mumps and to avert the potential of future outbreaks. As stated previously (vide supra), 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 to 2004. This research revealed an increase in delayed MMR vaccination for those children born in or after 1999, that is, subsequent to the Wakefield controversy (Friederichs et al., 2006). These scientists also found a significant increase in nursery-aged children after 1998; they predicted an overall rate of immunization in Scotland that was over 90%, but remained less than 95%, so that additional immunizations of the population would be required in order to prevent transmission of measles (Friederichs et al., 2006). More specifically, Friederichs et al. (2006) determined that MMR compliance between 1990 and 1998 was greater than 95% annually, with a 95% interval of confidence. Subsequently however, and in direct correlation with the Wakefield et al. (1998) report, MMR compliance had decreased to 91.7% for the year 2000 in Scotland. For the year 2001 in Scotland, the compliance rate for MMR vaccinations had dropped to 90.4% (Friederichs et al., 2006); these data were reported to have a 95% interval of confidence.

A very interesting study by Parker et al. (2006) probed the ‘index patient’ who caused the largest measles outbreak in the United States within a decade. Apparently, a visiting Romanian young woman (17 years old) who was un-vaccinated and 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 measles. Within six weeks, 34 cases of measles had been confirmed (Parker et al., 2006). Of the 34-confirmed cases, approximately 94% were unvaccinated; as well, two patients had been vaccinated but the vaccine failed (Parker et al., 2006). The data from the work of Parker et al. (2006) are shown in Figure 2.

Figure 2: Indiana Patients with Measles From Rash Onset (Parker et al., 2006)

Correlation Between MMR Vaccine and Pervasive Development Disorders/Autistic-spectrum Disorders

The 2004 case-control work of Smeeth et al. (2004) evaluated 4469 controls vs. 1249 patients with autistic-spectrum disorders, in which it was found that typical MMR vaccination was 82.1% for the controls vs. 78% of the autistic-spectrum cases. This result indicated a 0.86 odds ratio, with a 95% confidence interval, for the potential correlation between MMR compliance and subsequent development of autistic-spectrum disorders. These data clearly do not indicate any significant risk for MMR-vaccinated children developing autistic-spectrum disorders. Nonetheless, it was shown by Andrews et al. (2002) that the onset memory of autistic children’s parents tended to be more strongly associated with MMR-inoculation for those diagnoses taking place after the 1998 Wakefield controversy than for similar children diagnosed before the Wakefield et al. (19982) publication and subsequent media coverage. Indeed, Andrews et al. (2002) were able to demonstrate that parental recall of autism and/or autism-spectrum disorder correlating with MMR inoculation was greater following the Wakefield controversy.

Further work by Smeeth et al. (2004), comparing several studies (Figure 3, vide infra) evaluated the potential correlation of MMR-vaccine associated risk of PPD and/or autism and autism-spectrum disorders, and found no evidence of increased risk. Brown et al. (2011), performed a qualitative analysis of parental decision making in the United Kingdom, focusing on the measles, mumps, and rubella vaccine. In this work, performed some ten years after the Wakefield controversy, Brown et al. (2011) determined that those parents who continue to reject the use of the MMR vaccine tended to have complex and/or extreme views that were overall ‘anti-immunization’; in contrast some parents chose separate/single vaccines and reported hearing ‘second-hand’ about the Wakefield controversy. Furthermore, this study provided insight into the thinking of the parents. The general descriptions by parents concerning the Wakefield MMR vaccine controversy comprised five topics: (1) prevalence and severity of measles; (2) policies and health professionals; (3) personal and social consequences of a decision concerning the MMR vaccine; (4) information concerning the measles, mumps, and rubella vaccine and potential alternatives to MMR inoculation; and (5) measles, mumps, and rubella infections (Brown et al., 2011). These investigators also made recommendations with respect to the MMR vaccine, including an increased awareness and adaptation by both medical practitioners and for governmental policy, recognizing the altered understandings of parents.

Figure 3: Meta-analysis of research comparing autism-risk between unvaccinated and vaccinated individuals (Smeeth et al., 2004)

Demicheli (2012) performed a thorough review of the measles, mumps, and rubella vaccine in terms of its overall effectiveness and safety. This work included: six case series (self-controlled) covering nearly 15 million children, five trials (randomized control), 27 studies of cohorts, 17 case-control studies, one clinical trial that was controlled, five trials that were times-series, one trial that was a case-crossover, and two ecological studies (Demicheli, 2012). From this analysis, it was estimated that a single dose of the measles, mumps, and rubella vaccine had the likelihood to prevent clinical mumps at about the 69-81% confidence level for the Jeryl Lynn strain of mumps; a single dose of the MMR vaccine had between a 70-75% effectiveness for prevention of clinical mumps of the Urabe strain (Demicheli, 2012). This author also reported that a single dose of the measles, mumps, and rubella vaccine was likely to be 95% efficacious at prevention of clinical measles (Demicheli, 2012). The study also probed side effects of the vaccine: most importantly, there was no significant correlation between PPD, autism, or Crohn’s disease and the measles, mumps, and rubella vaccine. With respect to other side effects, the risk of thrombocytopenic purpura was 6.3, at a 1.3-30.1 confidence interval; the risk of aseptic meningitis was 14.28 for the Urabe strain of the vaccine, with 95% confidence between 7.93 and 25.71; febrile convulsions occurred for children under the age of five who received the Jeryl Lynn strain of the vaccine (as well as the RIT 4385 strain, the Wistar RA strain, and the Moraten strain) — 95% confidence interval data for febrile convulsions was 1.05-1.15 with a risk ratio of 1.10. Additional data on aseptic meningitis for children receiving the Leningrad-Zagreb strains of the vaccine included a risk of 15.6 with a 95% confidence ration at 10.3 — 24.2 (Demicheli, 2012). Demicheli (2012) proposed the need for more care in both reporting of safety outcomes in studies of the MMR vaccine, as well as more care in design of the measles, mumps, and rubella vaccines (Demicheli, 2012).

Discussion

Due to the concatenation of the 1998 Wakefield et al. paper in the United Kingdom, and the 2004 manuscript by Geier and Geier in the United States, there has been well over fifteen years of ongoing controversy concerning the measles, mumps, and rubella vaccine. Although both papers were retracted, and both groups of scientists (particularly Wakefield) have been discredited, the public understanding of scientific controversies can be somewhat limited, and it is the controversy concerning the putative correlation between the MMR vaccine and autism that has remained at the forefront rather than the fact that no such correlation has ever been found. Indeed, although it may not be simple to directly determine the number of individuals who have been stricken with measles, mumps, and/or rubella due to these controversies, it is evident that both the prevalence and the incidence of these once nearly banished ‘childhood’ diseases has risen. As short a time ago as 2000, the Centers for Disease Control (CDC) declared that measles had been eradicated, yet by 2006 Parker et al. (2006) documented a serious measles outbreak, after no outbreaks had occurred since 1996 (The College of Physicians of Philadelphia, 2015a, 2015b).

Research by Dayan et al. (2008), Friederichs et al. (2006), and Parker et al. (2006) all indicate what appears to be an increased incidence of these diseases, alarming many physicians and public health experts given the ready availability and prevalence of the MMR vaccine. While it was not possible for these studies to directly prove an association between increased prevalence and incidence of rubella, mumps, and/or measles and the MMR controversies, it is possible to demonstrate that the patterns of incidence since 1998 have been altered. Clearly the work of Friederichs et al. (2006) reveals a higher incidence of both mumps and measles following the 1998 Wakefield controversy; in terms of mumps, the work of Dayan et al. (2008) is slightly limited due to the screening system utilized.

As shown above in Table 1, there is no commonly used vaccine that is wholly without risk. For the MMR vaccine, certain symptoms and side effects have been known since its first use on a widespread basis. The work by Benjamin et al. (1992) confirmed the potential risk of children under five years of age, and particularly girls, developing disorders of joints and limbs following the MMR inoculation the work by Demicheli (2012) and Castro et al., (2005) verified the prevalence of milder post-iinoculation symptoms such as rash and fever. Other, more rare side effects of the MMR vaccine include thrombocytopenic purpura, febrile convulsions, and aseptic meningitis, again, all side effects that had been previously documented for the MMR vaccine and were thus corroborated as consistent, low risk potential outcomes of the vaccination. The extensive work of Demicheli (2012) had limitations only in terms of age for patients and was otherwise thorough and detailed. Based on all of the studies reported herein, it can be stated that the potential side effects and/or adverse effects which can be directly correlated with MMR vaccination include: thromobcytopenic purpura, fever, swelling of glands in cheek and neck, aseptic meningitis, and seizures; in no case was any evidence for PPD, autism, and/or autistic-spectrum disorder demonstrated as a consequence of MMR inoculation.

The work by Geier and Geier, (2004), addressing the correlation between the thimerosol/mercury stabilizer in vaccines and neurological or neurodevelopmental diseases was subsequently found to be fraudulent. This work, however, had a significant impact upon the climate of parental decision-making with respect to MMR compliance, and can readily be stated to have been as important in the United States, if not globally, as was the Wakefield et al. (1998) controversy in the United Kingdom.

Indeed, it is obvious that Wakefield and the Geier duo have certainly been a focal point of what might be called the movement against vaccination compliance. A particular issue in this case, and a side-note, is that there is some media responsibility here, although certainly Deer (n.d.; 2011) did more than his part to reveal the fraudulence in the United Kingdom. With the modern era of individuals looking up medical issues online, it becomes increasingly important to not only provide clear-cut information concerning medical controversies, but also to explain such issues in lay terms where possible to assist the public education and ultimate parental decision making that may impact far more than their own child.

Although the report by Wakefield and colleagues (1998) was subsequently retracted, by Wakefield as well as 10 of his 12 collaborators, this report nonetheless had a significant impact upon public understanding of the MMR vaccine specifically, and all vaccines in general. The immense incidence of misinformation and pseudo-science and the correlation of the MMR vaccine with onset of autism in vaccinated children has impacted parental decisions concerning vaccination to this day. Of particular relevance here, the work of Anderberg (2009) demonstrated that it was precisely the more affluent and educated parents who quickly absorbed the Wakefield misinformation and were quicker to halt immunization of their children, and of course communicate with their social sphere. Although Anderberg (2009) could not directly address the parental ‘thinking’ or rational processes, it was obvious that those who were educated and knew about the Wakefield controversy were more likely to avoid MMR compliance, vs. The lesser educated parents who were unaware of the controversy. As well, this controversy demonstrated a clear-cut example to the epidemiological community of what is called ‘response bias’ (also called ‘recall bias’).

Andrews et al. (2002) reported a study in which the ‘onset recall’ by parents for their children having autism or PPD (pervasive developmental disorder) was probed. Whereas parents who had vaccinated their children prior to the 1998 Wakefield controversy did not make a connection between MMR inoculation and the onset of the children’s condition, the opposite was true in the case of those children diagnosed after the Wakefield controversy. After 1998 and the Wakefield controversy, parents of children with a PPD or autism diagnosis recalled onset as being not long after MMR compliance (Andrews et al. (2002).

On a more positive note, despite the distrust of public health vaccination programs, suspicion regarding vaccine safety, a re-emergence of measles in the U.S. And UK, and a decrease in measles, mumps, and rubella protection due to overall decreased immunizations, there may yet be some cause for optimism. The study by Brown et al. (2011) showed that the number of parents choosing to not vaccinate their kids is decreasing. It can be inferred that the controversy surrounding the Wakefield and Geier studies may have begun to subside and parents are realizing that the study was retracted and disproven.

In terms of the work by Wakefield (1998), the original manuscript has been retracted and proven to be fraudulent (The Lancet, 2010; The BMJ, 2011; The Times, 2004). As well, Wakefield himself has lost his medical license, and been found guilty of scientific, medical, and ethical conduct; conflict of interest was also proven in that Wakefield sought to discredit the MMR because he himself had a vaccine patent in process. Additionally, of the 12 original co-authors of the 1998 Wakefield work, ten have formally retracted their analysis suggesting a correlation between autism and the MMR vaccine. Even the organization Autism Watch (2015) has turned against Wakefield.

Indeed research by Smeeth et al. (2004) and by Demicheli (2012) provided clear evidence that no correlation between the MMR vaccine and autistic-spectrum disorders could be made. The only drawback to these studies was a small detail in the work of Smeeth et al. (2004), wherein there was retroactive recording of MMR vaccination dates for children.

It can be said that the work of Demicheli (2012) and Smeeth et al. (2004) not only disproved Wakefield et al.’s 1998 study, but also provided a link in the chain of evidence that led to the disclosure that the work by Wakefield and colleagues was fraudulent. Furthermore, the work by Smeeth et al. (2004) and Demicheli (2012) clearly demonstrates the absence of any correlations between incidences of colitis and/or autism in patients and their prior vaccination with the MMR vaccine.

After this review, it is possible to make recommendations. One possibility would be to compare and evaluate single vaccines vs. The combined MMR vaccine, preferably using quantitative analysis. Because the United States require, with the exception of Iowa, that all children must be inoculated with MMR prior to entering kindergarten, a joint study sponsored by the National Institutes of Health and the Center for Disease Control could evaluate effects of separate inoculations for each of the three diseases vs. one inoculation with the MMR treatment.

Conclusion

From analysis of the literature studied 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. As well, it is 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 development disorders.

References

Anderberg, D. (2009). Anatomy of a Health Scare: Education, Income and the MMR Controversy in the UK. Wrong source cited — found article ===> Journal of Health Economics 03/2011; 30(3):515-30. DOI: 10.1016/j.jhealeco.2011.01.009

Andrews, N.,Miller, E., Taylor, B., Lingam, R., Simmons, A., Stowe, J., Waight, P. (2002). Recall bias, MMR, and autism. Arch Dis Child, 87, 493-4.

ADDED

Autism Watch (2015) http://www.autism-watch.org/news/lancet.shtml

Benjamin, C.M, Chew, G.C., and Silman, A.J (1992). Joint and limb symptoms in children after immunization with measles, mumps, and rubella vaccine. BMJ, 304 (6834), 1075-8.

Berger, A. (2004) Dispatches. MMR: What They Didn’t Tell You BMJ 2004 doi: http://dx.doi.org/10.1136/bmj.329.7477.1293

Brown, K.F., Long, S.J., Ramsay, M., Hudson, M.J., Green, J., Vincent, C.A., Kroll, J.S., Fraser, G., Sevdalis, N. (2011, December 27). UK parents’ decision-making about measles — mumps — rubella (MMR) vaccine 10 years after the MMR-autism controversy: A qualitative analysis. Vaccine, 30, 1855-64.

Castro, J.F., Bennett, J.V., Rincon, H.G., Alvarez y Munoz, M., Sanchez, L.A., and Santos, J.I. (2005, January). Evaluation of immunogenicity and side effects of triple viral vaccine (MMR) in adults, given by two routes: subcutaneous and respiratory (aerosol). Vaccine, 23(8), 1079 — 1084.

CDC, Centers for Disease Control and Prevention. (2008, August 20). Vaccines and Immunizations Home. Retrieved from Vaccines: VPD-VAC/Measles/FAQ Disease and Vaccine: http://www.cdc.gov/vaccines/vpd-vac/measles/faqs-dis-vac-risks.htm

CDC, Centers for Disease Control and Prevention (2014) Vaccination Coverage Among Children in Kindergarten — United States, 2013 — 14 School Year. Available: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6341a1.htm [Accessed 18 January, 2015].

Dayan, G.H., Quinlisk, M.P., Parker, A.A., Barskey, A.E., Harris, M.L., Schwartz, J.M.H., & #8230; Seward, J.F. (2008). Recent Resurgence of Mumps in the United States. The New England Journal of Medicine, 358, 1580-9. Available: DOI: 10.1056/NEJMoa0706589

Deer, B. (2011). How the case against the MMR vaccine was fixed. BMJ. Retrieved from http://dx.doi.org/10.1136/bmj.c5347

Added

Deer, Brian, n.d. Wakefield allies in U.S. shots onslaught are shattered by parallel investigation. Available: http://briandeer.com/wakefield/geier-retraction.htm

Demicheli, V.R.A. (2012). Vaccines for measles, mumps and rubella in children (Review). Cochrane Database of Systematic Reviews (2).

Friederichs, V., Cameron, J.C., and Roberston, C. (2006, March 1). Impact of adverse publicity on MMR vaccine uptake: a population based analysis of vaccine uptake records for one million children, born 1987 — 2004. Arch Dis Child, 91, 465-8.

Geier, D.A., and Geier, M.R. (2004). A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit, 10(3), 33-9.

Gladwin, M., Trattler, B., Mahan, C.S. (2014). Clinical Microbiology Made Ridiculously Simple. Medmaster.

Greaves, W.L., Orenstein, W.A., Hinman, A.R., Nersesian, W.S. (1983). Clinical efficacy of rubella vaccine. Pediatr Infect Dis, 2(4), pp. 284-6.

Parker, A.A., Staggs, W., Gustavo, H.D., Ortega-Sanchez, I.R., Rota, P.A., Lowe, L., & #8230; LeBaron, C.W. (2006). Implications of a 2005 Measles Outbreak in Indiana for Sustained Elimination of Measles in the United States. The New England Journal of Medicine, 355(5), 447-455.

NOT USED Rao, T.S., and Andrade, C. (2011, April). The MMR vaccine and autism: Sensation, refutation, retraction, and fraud. Indian J. Psychiatry, 53(2), pp. 95-6.

ADDED

RLRA Syllabus, Medical University of the Americas, 2014

Smeeth, L., Cook, C., Fombonne, E., Heavey, L., Rodrigues, L.C., Smith, P.G., Hall, A.J. (2004). MMR vaccination and pervasive developmental disorders: a case-control study. Lancet, 364, 963-9.

ADDED

The BMJ (2011) Wakefield’s article linking MMR vaccine and autism was fraudulent. BMJ 2011;342:c7452 doi: http://dx.doi.org/10.1136/bmj.c7452 (Published 06 January 2011)

ADDED

The Lancet (2010) Retraction — Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Volume 375, No. 9713, p445, 6 February 2010 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960175-4/abstract

ADDED

The Times (2004) http://www.thetimes.co.uk/tto/health/article1879347.ece

The College of Physicians of Philadelphia. (2014, July 31). Mumps – History of Vaccines. Retrieved from The History of Vaccines: http://www.historyofvaccines.org/content/articles/mumps

The College of Physicians of Philadelphia. (2015a). Others – Timelines – History of Vaccines. Retrieved from The History of Vaccines: http://www.historyofvaccines.org/content/timelines/others

The College of Physicians of Philadelphia. (2015b). The History of Vaccines. Retrieved from Measles – Timelines – History of Vaccines: http://www.historyofvaccines.org/content/timelines/measles

Wakefield, A., Murch, SH, Anthony, A., Linnell, J., Casson, D.M., Malik, M., Berelowitz, M., Dhillon, AP, Thomson, MA, Harvey, P., Valentine, A., Davies, SE, Walker-Smith, JA. (1998 February 28). RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet, 351(9103), pp. 637-641.

World Health Organization. (n.d.). MODULE 2: Live Attenuated Viruses. 2015. Retrieved January 2, 2015, from http://vaccine-safety-training.org/live-attenuated-vaccines.html

World Health Organization. (2007). Mumps virus vaccines: WHO position paper. Weekly Epidemiological Record (82), pp. 49-60.

Appendix

SECTION A: Summary of Study Designs Reviewed

Study Design

# of Studies

Randomized Clinical Trial

Cohort Study- Retrospective

Cohort Study — Prospective

Retrospective Case Review

Retrospective Chart Review

SECTION B: Evidence Table

First Author

Publication Date

Evidence Level

Design of Study

Population of Study

Intervention

Results/Outcome

Anderberg, Dan

2009

Retrospective – Cohort study

1997-2005

Adults of parenting age from UK Health Survey

Data analysis + correlation study of parental education/income with child immunization children

Controversial information reached educated parents more rapidly. Rational behavior not proven.

Andrews, N

2002

Self-controlled case series

Parents of autistic children with regressive symptoms

N/A

Parental recall of autism onset correlates w / Wakefield controversy if diagnosis after 1998; greater preponderance of ‘MMR-blame’ for post-Wakefield diagnoses than pre-Wakefield diagnoses in terms of parental recall

Benjamin, CM

1992

Retrospective Case-control

1989-1990: 2658 children immunized vs. 2359 not immunized

N/A

MMR vaccine associated with increased risk of episodic joint/limb symptoms, especially in girls and children under 5.

Brown, Katrina F.

2011

Retrospective Cohort study

Parents of children (11 mos-3.5 yrs) eligible for MMR1 vaccine who have not received MMR or any single vaccines

Parental Interviews to determine current MMA-vaccine opinions

Parental opinions against MMR now in minority; generally extremely complex opinions anti-vaccination. Single vaccine choice usually based on Wakefield controversy.

Dayan, Gustavo H.

2008

Cross-sectional study

United States: 2006, ALL reported mumps cases

N/A

Two-dose vaccine failure resulting in mumps outbreak affecting children of college age

Demicheli, Vittorio

2011

Retrospective and Prospective trial comparison

Controlled Trials from Cochrane Central Register

MMR vaccinations

MMR vaccine: [1] 95% effective for clinical measles prevention; [2] 69-81% effective prevention of clinical mumps/Jeryl Lynn strain; [3] 70-75% effective for Urable strain vaccine; [4] No rubella measurement; [5] No significant correlation between MMR vaccination and Crohn’s disease, autism, and other pervasive developmental disorders.

Castro, Jorge

2005

Prospective Cohort study

Los Altos, Mexico study of Adults 18-50 (two groups)

MMR vaccinations by subcutaneous injection or aerosol

Comparison of subcutaneous/aerosol injection populations did not show significant post-MMR effects; Aerosol MMR more effective when baseline titers controlled using multivariate analysis.

Friederichs, V

2006

Epidemiological study

1987-2004 Scottish Children 2004

N/A

Rising susceptibility to measles in children; decreased compliance with MMR suggested arising from Wakefield controversy

Geier, David A.

RETRACTED

2004

Comparative evaluation

U.S. Dept. Of Educ. And CDC Biological Surveillance datasets and live birth data from CDC

N/A

Reported links between mercury/thimerosal- vaccines and neuro-developmental disorders. Recommendations: (a) improved safety profile for MMR vaccine; removal of thimerosal from vaccines

Parker, Amy A.

2006

Study of Series of Cases

Measles outbreak: index patient to 500 individuals

Survey of MMR vaccinations; viral isolation; interviews

Outbreak in children un-vaccinated due to Wakefield (1998) controversy

Smeeth, Liam

2004

Controlled Case study

Post-1973 births: diagnosis of disorders 1987-2001 by physician

N/A

No association between MMR vaccination and autism-spectrum disorders

Medical University of the Americas, Nevis, West Indies

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