Assigment .Apa seven . All instructions attached.

Since January 2020 Elsevier has created a COVID-19 resource centre with

free information in English and Mandarin on the novel coronavirus COVID-

19. The COVID-19 resource centre is hosted on Elsevier Connect, the

company's public news and information website.

Elsevier hereby grants permission to make all its COVID-19-related

research that is available on the COVID-19 resource centre - including this

research content - immediately available in PubMed Central and other

publicly funded repositories, such as the WHO COVID database with rights

for unrestricted research re-use and analyses in any form or by any means

with acknowledgement of the original source. These permissions are

granted for free by Elsevier for as long as the COVID-19 resource centre

remains active.

lable at ScienceDirect

European Journal of Paediatric Neurology 36 (2022) 151e158

Contents lists avai

European Journal of Paediatric Neurology

The myth of vaccination and autism spectrum

Lidia V. Gabis a, b, *, Odelia Leon Attia c, Mia Goldman a, Noy Barak d, Paula Tefera a, Shahar Shefer c, Meirav Shaham e, Tally Lerman-Sagie a, f

a Sackler School of Medicine at Tel Aviv University, Israel b Maccabi Health Services, Israel c Weinberg Developmental Center, at Safra Children's Hospital, Tel Hashomer, Israel d Department of Industrial Engineering at Tel-Aviv University, Israel e Department of Statistics at University of Haifa, Haifa, Israel f Pediatric Neurology Unit at Wolfson Medical Center, Holon, Israel

a r t i c l e i n f o

Article history: Received 14 April 2021 Received in revised form 12 December 2021 Accepted 14 December 2021

Keywords: Autism Immunizations Vaccinations Children Myth

* Corresponding author. At Sackler School of Med Israel.

E-mail addresses: [email protected] (L.V. Ga (O.L. Attia), [email protected] (M. Goldma (N. Barak), [email protected] (P. Tefe (S. Shefer), [email protected] (M. Shah (T. Lerman-Sagie).

https://doi.org/10.1016/j.ejpn.2021.12.011 1090-3798/© 2021 European Paediatric Neurology So

a b s t r a c t

Background: Among all of the studied potential causes of autism, vaccines have received some of the most scrutiny and have been the topic of many evidence-based studies. These efforts have led the great majority of scientists, physicians, and public health researchers to refute causation between vaccines and autism. Rationale: This presumed association and concern has been a major contributor to parents’ refusal to immunize their children and has become a major threat to public health in secluded populations over the last two decades, even prior to the COVID-19 pandemic. With the emergence of COVID-19 immuniza- tions, sentiments towards this topic were addressed as a public health concern that may influence the ability to overcome the Corona virus worldwide. Scientific review of data: Despite the overwhelming data demonstrating that there is no link between vaccines and autism, many parents are hesitant to immunize their children because of the alleged association. Other contributing factors to the myths and conspiracy theories surrounding the association between vaccines and autism include the fact that the diagnosis of autism is typically made after the age of receiving the main childhood immunizations, as well as the occasional occurrence of regression after the age of first year vaccinations. In spite of vast evidence that the main contribution to the increase in incidence is from improvement of the diagnostic process, this rapid and publicized rise in autism di- agnoses feeds parental concerns regarding any medical intervention that may be associated with the health of their children. Recommendations: It is plausible that with more evidence-based studies linking autism to specific eti- ologies the myth will diminish and disappear eventually. In an era where conspiracy theories are prevalent on social media, it is critical that evidence-based studies relating autism to specific etiologies be made public, and that information concerning autism diagnosis and causes be made more readily available through social media and parental organizations.

© 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

icine at Tel Aviv University,

bis), [email protected] n), [email protected] ra), [email protected] am), [email protected]

ciety. Published by Elsevier Ltd. Al

1. Introduction

The topic of vaccinations and autism spectrum has been studied and reviewed extensively over the last few decades and is still a heavily debated topicd especially now in the context of the COVID- 19 pandemic. When crossing the terms “vaccination” and “autism”

on Google Scholar, there are 38,200 results with the leading topic being MMR (measles, mumps, & rubella) and the repeated evidence in many thousands of articles against its association with autism.

l rights reserved.

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

In spite of the strong evidence from multiple studies over the last three decades, the public sentiment of hesitancy poses a sig- nificant health risk and may influence the COVID-19 immunization plan. Global medical officials used social media to try to overcome this fear as a major measure to combat the Coronavirus pandemic by enhancing vaccination acceptance [1e3].

Before the COVID-19 pandemic, the influence of the sentiment against immunizations caused suboptimal vaccination coverage in specific populations and resulted in outbreaks of diseases easily preventable by vaccines, such as measles, resulting in significant morbidity and mortality in vulnerable individuals [4].

The largely publicized concern around the rapidly rising inci- dence of autism [5] continues to feed this sentiment. Other contributing factors to the myths and conspiracy theories sur- rounding the association between vaccines and autism include the fact that the diagnosis of autism is typically made after the age of receiving the main childhood immunizations, as well as the occa- sional occurrence of regression after the age of first year vaccina- tions. Additionally, the medical community's inability to provide conclusive answers in regard to the causes and treatment of autism further contributes to the growing concern.

In order to address this topic, we reviewed the current knowl- edge and the multiple publications studying the link between vaccinations and autism, as well as the public state of mind nour- ished by social media and non-scientific influences. Despite the numerous evidence-based studies showing no relationship be- tween immunizations and autism spectrum, the cultural belief of this association is still reinforcing the widespread concern about vaccines, with the COVID-19 pandemic reviving this topic.

2. History of immunizations and of pandemics and epidemics that could have been prevented by immunizations

Vaccines are the most effective way to prevent infectious dis- eases. The history of childhood immunization has had many breakthroughs throughout the years, including Edward Janner's first smallpox vaccination on the 8-year-old James Phipps in 1796, and Louis Pasteur's first rabies vaccination on the 9-year-old Joseph Meister in 1885. Many of the efforts towards vaccine development in the 20th century targeted childhood infectious diseases, including polio, measles and diphtheria.

Most children worldwide receive immunizations against child- hood diseases, with an estimated 2e3 million deaths prevented every year [6]. Nowadays, the CDC-recommended childhood vacci- nations include: Hepatitis B, Tetanus, Diphtheria, Pertussis, Polio, Haemophilus influenzae B, Pneumococcus, Rota-virus, Measles, Mumps, Rubella, varicella, Hepatitis A, Papilloma-virus and Influenza [7]. The global vaccination coverage (i.e., proportion of children that receive recommended vaccines worldwide) remains unchanged in recent years. Both the lack of access to vaccines and the lack of confidence in vaccines are the two main causes for low rates of children immunization in specific communities [8,9]. These com- munities are mostly comprised of developing countries, however developed countries such as the US and England have also reported decreasing rates of childhood vaccination in the past few years [10].

Vaccination during the early phases of life (i.e., infants and children) is crucial due to the immaturity of the immune system, leaving individuals susceptible to vaccine-preventable diseases and even life-threatening conditions. Moreover, lower immunization rates among children may cause vaccine-preventable disease out- breaks in the general population and endanger elderly or immu- nosuppressed individuals. Immunizations as early as the neonatal phase is hypothesized to have beneficial health effects such as fewer required vaccination for immunogenicity or immunomodu- latory boosting effect [11].

152

Ironically, the success of vaccinations in eliminating vaccine- preventable diseases caused many individuals to become more concerned about the adverse effects of vaccinations than the actual disease, resulting in lower vaccine acceptance rates and greater risks of vaccine-preventable diseases to the general population and especially children, as per parental choice. Accordingly, along with the rational of vaccinating children during the vulnerable first years, there is a key challenge to be addressed-the hesitancy of caregivers to vaccinate their children due to fear of adverse effects that vaccinations may cause [12]. In fact, vaccine literacy and mis- conceptions regarding the safety of childhood vaccination and their involvement in long-term adverse effects is the major cause for vaccination refusal [8].

The main misinformation surrounding vaccine safety involves the belief that vaccine formulations contain harmful substances. (e.g., adjuvants, preservatives etc.). Another misconception is that there is an excessive number of vaccinations. Others are concerned about the negative effect on the immune system of children, as well as the proposed correlation to conditions such as autism, diabetes etc. [13e15].

2.1. Vaccine safety

The safety of childhood vaccination has extensively and repeatedly been evaluated over the years [14,16,17]. The meta- analysis of Taylor et al. proved evidence for non-correlation of vaccination and autism for a compelling number of more than 1,256,407 children [18]. Nevertheless, all vaccination can poten- tially cause mild and short-lasting side effects. Vaccines adverse events (AE) in children that should be noted include local events such as pain and swelling in the injection site, as well as systemic events such as fever, irritability, drowsiness, and rash [7]. Serious adverse events (SAE) may include severe rash, severe infections, encephalitis or even death, however such SAE are rare.

Some children with neurological disorders, either progressive and neurodegenerative such as mitochondrial (Leigh Syndrome), or neurodevelopmental genetic disorders, such as Dravet Syndrome (due to SCN1Amutation), may be susceptible to fever with seizures and regression occurring after a febrile episode. Fever after vacci- nations may be perceived by the parents as the cause of those syndromes.

Multiple meta-analyses have been performed to assess AE following each childhood vaccination. The results included local and systemic AE, as well as SAE in very low frequencies. According to a study that assessed 61 meta-analyses that evaluated vaccine safety, specific safety outcomes such as maternal events (e.g., stillbirth or spontaneous abortion) or cardiovascular events were found to be unaffected or even less likely following vaccination [19]. These results, taken in consideration with the rigorous safety tests that vaccines undergo before being clinically approved, as well as the continuous monitoring for AE by health organizations like the CDC and the WHO, provide reassuring evidence in terms of safety profile of the recommended childhood vaccinations.

3. Autism diagnosis and epidemiology

The American Academy of Pediatrics recommends screening all children for ASD at 18 and 24 months followed by a comprehensive evaluation for children with developmental concerns [20]. How- ever, in recent years it has been recommended that they be eval- uated at a younger age and that the diagnosis be made during the second year of life [21e23]. When it comes to age of diagnosis, there is still a large gap between “state-of-the-art” research on autism and mainstream practice. This gap varies in its magnitude between countries, among communities, and in relation to

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

socioeconomic status. In addition, there may be a delay of a few years between detection of early signs and final diagnosis [24]. Nevertheless, parental concerns and initiation of a diagnosis pro- cess commence mostly during the second year of life and this is the period when most childhood immunizations are provided [25,26].

The prevalence of autism has rapidly been rising over the last two decades. From the last CDC report in 2020, about 1 in 54 children has been identified with autism spectrum disorder (ASD) according to estimates from CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. In earlier years, autism was associated primarily with severely affected individuals and the rate of autism was estimated to be only about 1 in 10,000 people. The rapid increase from 1 in 150 children in 2007 to the current 1 in 54 is causing significant concern among many expecting parents [27,28]. The best evidence that the rise in prevalence is mainly due to changes in diagnostic measures is found in studies performed in adult populations that used the new tools and diagnostic criteria to show approximately the same prevalence as in children, of about 2% [29].

Despite the vast evidence that the main contribution to the in- crease in incidence is from improvement of the diagnostic process, this rapid and publicized rise in autism diagnoses feeds the parental concerns regarding any intervention that may be associ- ated with the health of their children.

The additional myth feeding those theories is that there is no known cause for autism e however, in reality, there are many known etiologies. There is not a single cause, but a realm of causes: genetics (more than 100 gene mutations have been associated with autism), advanced paternal age, prenatal and perinatal brain insult and prematurity are among those known causes [30e32].

4. Immune system in autism

In recent years, there has been extensive research conducted to better understand the relationship between the immune system and autism. Decades of research has revealed the vast and intricate connection between the immune system, the nervous system, and behavior [33]. There is abundant evidence suggesting the presence of a pathophysiological relationship between the immune system and autism [33]. Variation in levels of several cytokines, including Transforming Growth Factor Beta (TGF-b), Macrophage Inhibitory factor (MIF), Leptin, Interferon- g, and many different Interleukins have been observed in individuals with autism compared to in- dividuals without autism [33e35]. Many studies have also described various autoimmune phenomena among individuals with autism and among family members of individuals with autism [35,36]. Epigenetic regulation of the immune system has also been studied in the context of autism. These studies have provided evi- dence that certain genes involved in immunity are expressed at higher rates in autistic individuals, further demonstrating the connection between the immune system and ASD [37].

Maternal immune activation during pregnancy has also been comprehensively researched in order to better understand poten- tial etiologies of autism. Infectious outbreaks, particularly the Rubella outbreak of the 1960s, provided substantial evidence that supported maternal immune activation as a risk factor for autism, proving that the disease caused but Rubella virus (and not the vaccine) is directly causing significant brain damage resulting in intellectual disability, autism and blindness [37,38]. Rubella infec- tion is a hallmark of viral infection causing brain damage in the fetus and subsequent neurodevelopmental impairments including intellectual disability and autism. Other TORCH viruses can damage the fetal brain and cause severe neurodevelopmental impairments including autism [39]. Herpes viruses have to potential of causing severe damage and impaired outcomewhen causing infection even

153

postnatally-such as Herpes virus 1,2 [40]. Direct brain damage is also caused by Zika viral infection [41].

Other viruses are known to cause post-infectious brain damage resulting in declining neurological function years after the infec- tion. Subacute Sclerosing Panencephalitis (SSPE) is a neurodegen- erative disorder in late childhood that may develop 2e10 years after the original viral attack, due to reactivation of the measles virus or an inappropriate late immune response. Successful measles vaccination programs directly and indirectly protected the popu- lation against SSPE and have the potential to eliminate SSPE through the elimination of measles [42].

The Maternal Immune Activation (MIA) model served as an experimental model to study the link between maternal exposure and atypical behavior in offspring [34,38]. This model involves introducing a pathogen to pregnant rodents and observing behavioral abnormalities within the offspring [34]. Data from both human and animal studies indicate that the timing of immunogen exposure during pregnancy affects the phenotypic variations in behavior seen in offspring [37]. Studying the relationship between the immune system and autism is useful in for the search of po- tential biological markers for the identification and treatment of ASD (see below the link between fever and behavior in children with autism).

When developing an understanding of the risk factors for autism, the importance of the immune system and its association with the nervous system cannot be ignored. However, this associ- ation should be studied and reported with caution, since it not only may be misunderstood by the public and perceived as causation, but also because this is a large generalization of the concept of individual differences in autism.

With the increasing understanding of many genetic etiologies causing autism, more syndromes are being revealed as involving the immune system and the brain. One example is Velo-cardio- facial syndrome in which the deletion of 22q11.2 including PRODH and COMT genotypes express a phenotype including im- mune deficiencies, autism and neuropsychiatric disorders such as schizophrenia [43]. Other genetic syndromes linking immune dis- orders and autism are Phelan-Mc Dermid syndrome (SHANK3 gene), Down Syndrome, CHARGE Syndrome and channelopathies [44e46].

In addition, prematurity becomes a major etiology causing autism, as well as immune vulnerability [30].

5. Fever, immune system and autism

Another notable association between autism and immunity is the suggested improvement in behavior in children with ASD during fever [47]. There have been many anecdotal reports that the disturbed behaviors in autism, especially stereotypic behavior and inappropriate speech, are noticeably decreased during febrile epi- sodes, with the degree of improvement being unrelated to the severity of fever or ASD [47]. The up-regulation of heat-shock proteins and other mechanisms involved in cellular processes during fever may explain the improvement in cerebral-cortical connectivity that is diminished in ASD [48]. Singh et al. conduct- ed a study that assessed the behavioral outcomes in patients with ASD who received sulforaphane, a substance that also up-regulates the heat shock response including protection from oxidative stress, inflammation, DNA damage, and radiation [48]. Their study indi- cated that there were statistically significant improvements in behavior during treatment with sulforaphane, further suggesting that the up-regulation of cellular defense mechanisms can ameliorate behavioral issues.

Studying the relationship between the immune system and autism by large double-blinded randomized controlled trials and

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

taking into account the anecdotal reports of improvement in communication during fever, may provide additional insight into potential biological markers for the identification and treatment of ASD, unrelated to the cause of the fever.

6. Mercury poisoning and its link to developmental disabilities and autism

One of the main misconceptions encouraging the myth of vac- cinations and autism is the use of mercury-based adjuvants in some of the vaccinations. There is a robust body of evidence stating that significant amounts of neurotoxic substance uptake in the early stages of life can cause severe developmental disorders, including ASD.

Mercury has been well established as a neurotoxic factor, including its involvement in several malignancies as a result of organic mercury exposure (mostly methylmercury, MeHg) via di- etary consumption (e.g., contaminated seafood, grains etc.), medi- cal treatment (e.g., syphilis treatment or teething powder), occupational settings (e.g., chronic exposure to mercury vapors) or any other form of exposure to mercury pollution in the environ- ment [49,50].

The toxic effects of mercury have been demonstrated many times throughout history. One of the most famous cases is the Minamata Disaster in Japan, where industrial mercury pollution was discarded in the Minamata bay thus creating a bio- magnification of mercury in the consumed seafood in the bay, causing severemercury poisoning to the area's population [51]. The toxic effects of mercury poisoning include numerous neurological alterations, such as ataxia, dysarthria, disequilibrium etc., and even mental disorders. The toxic effects of mercury are not limited to the nervous system and include other organs, such as the pancreas and kidneys, and can even result in mortality. Mercury was also iden- tified as fetotoxic, causing disruption to the cerebral architecture in fetal brain development, leading to various neurological disorders in newborns exposed to mercury during pregnancy [52]. Fetuses are at higher risk of mercury toxicity due to the fact that organic mercury passes through and accumulates in the placenta [53].

Metal poisoning in very large doses, including mercury, can cause ASD as well as other severe neurodevelopmental disorders [54]. This link is hypothesized to be driven by metal-induced oxidative stress in the nervous system. In addition to the possible effects of mercury to cause ASD, several studies found enhanced mercury levels in ASD patients or their mothers [55], as high levels of mercury in subjects’ blood, hair, teeth, and urine were positively associated with ASD [56]. There is a similarity between biological abnormalities in ASD patients and pathologies caused by mercury poisoning, as well as other neurodevelopmental disorders [49]. However, the main emphasis is on poisoning and not on negligible levels. Any substance influencing brain function may, when in excess, cause brain damage, such as lipid soluble vitamins (A, D, K, E) as well as vitamin B12 and folate [57].

6.1. The use of thimerosal in vaccines

Thimerosal is an organic mercury-containing (ethylmercury, EtHg), FDA-approved preservative used in vaccines to prevent bacterial and fungal contaminations. EtHg is involved in many similar toxic mechanisms as MeHg [58], however, it is broken down and eliminated from the body faster, thus presenting a more favorable safety profile in general and is specifically less neurotoxic than MeHg [59].

Due to public safety concerns led by anti-vaccination groups, and the concern of cumulative mercury exposure during the first 6 months of life, the use of thimerosal has been excluded from

154

childhood vaccines in the US since 2001, as well as in the European Union and a few other countries [60,61]. According to the CDC, current thimerosal-containing vaccines include four quadrivalent influenza vaccines (Afluria, Flucelvax, Flulaval and Fluzone) and one tetanus and diphtheria vaccine (TDVAX) [62]. The minimum age of use for these approved thimerosal-containing vaccines is 7 years. Moreover, all of these vaccines have a non-thimerosal containing alternative [62]. The World Health Organization supports the continued use of thimerosal-containing vaccines in developing countries given that they are less expensive, are widely available, and are logistically suitable for these regions, while also being safe and effective [61].

As the link between ASD and organic mercury is-well estab- lished, concerns have arisen regarding the use of thimerosal- containing childhood vaccines and the cumulative EtHg exposure as a result. Numerous peer-reviewed studies and meta-analyses investigated the risk for ASD due to thimerosal exposure and found no increased risk of ASD associated with thimerosal- containing vaccines [13,62]. The link between thimerosal and other developmental disabilities (e.g., speech problems or learning difficulties) has also been evaluated and found to demonstrate no association between exposure to thimerosal in vaccines and these disabilities [13]. In contrast, longitudinal studies have found a correlation between higher thimerosal exposure from vaccines and ASD diagnosis [63,64].

Despite research that found no risk for ASD from thimerosal, the exposure to thimerosal in childhood vaccines has been limited worldwide due to the concerns of these effects. Nevertheless, this concern continues to feed the myth, and common words used in anti-vaccine campaigns still include mercury/thimerosal and ASD [65,66], including the current COVID-19 vaccine which does not contain thimerosal.

7. Measles, mumps, and rubella vaccination and autism

The concerns surrounding the MMR vaccine and its posited link to autism have stemmed from a now-disproven publication that falsely claimed there to be a connection between autism and the MMR vaccine [37]. This study's profound impact on subsequent vaccine hesitancy has warranted widespread research into the matter in order to address the concerns regarding its safety. Over the past few decades, many studies have repeatedly disproven the claims associating MMR vaccination with increased incidence of autism. Nevertheless, this ominous and subsequently rejected publication from 1999 in Lancet journal, continues to weaken the acceptance of all accumulating medical evidence for the last 22 years. For this reason, wewould like to refrain frommentioning the author, but a note-worthy fact is that this publication still appears as the first mention among 38,200 publications on Google Scholar when searching for the combination “vaccination and autism”.

The evidence against this link was examined thoroughly in many studies. The following is a short list of some of the many reputable studies that have declined any risk of MMR vaccination causing autism:

� Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study: A nationwide cohort study in Denmark that analyzed population registries in order to link information on MMR vaccinations, other childhood vaccina- tions, autism risk factors, and autism diagnoses. Their study, which included 5,025,754 person-years of follow-up, supported that MMR vaccination does not increase the risk for autism, nor does it provoke autism in susceptible individuals. It also found that there is no associated clustering of ASD cases after MMR vaccination [67].

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

� A population-based study of measles, mumps, and rubella vaccination and autism: A retrospective cohort study that assessed MMR vaccination status and psychiatric diagnoses among 537,303 children born in Denmark between 1991 and 1998. The study provides evidence against a causal relation betweenMMR vaccination and autism. Their data demonstrated a similar risk of autism in vaccinated versus unvaccinated chil- dren, a lack of temporal clustering of autism cases after immu- nization, and that neither autistic disorder nor ASD were linked to MMR vaccination [68].

� The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with develop- ment of autism spectrum disorder: the first case-control study in Asia: a case-control study that looked at MMR vacci- nation history, including number of vaccine injections, and compared data between patients with and without ASD in a genetically homogenous population. The data showed that neither MMR vaccination nor increasing number of vaccine in- jections is associated with an increased risk of ASD [69].

� Autism and measles, mumps, and rubella vaccine: no epide- miological evidence for a causal association: a population- based study in the UK that looked at the incidence of autism before and after the introduction of MMR vaccination. Their analyses showed no causal association between MMR vaccina- tion and autism and no indication of temporal clustering be- tween MMR vaccination and autism diagnoses (B [70].

� Lack of association between measles virus vaccine and autismwith enteropathy: a case-control study: a case-control study that assessed whether children with GI disturbances and autism were more likely than children with GI disturbances alone to have measles virus RNA and/or bowel inflammation, and if the onset of autism and/or GI episode related temporally to receipt of MMR vaccination. The data provided evidence against an association between autism and persistent measles virus RNA in the GI tract or history of MMR vaccination [71].

� Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder: a case-control study that examined 413 vaccination histories of patients with and without ASD to determinewhetherMMR vaccination and thimerosal dosage are related to ASD. The study found no significant differences in MMR vaccination and thimerosal dosage between cases and controls [72].

In addition to the many individual studies showing no correla- tion between MMR vaccination and ASD, a 2014 meta-analysis further reinforced the lack of connection between the two (L. E [18]. The CDC provides online resources explaining the recom- mendation for the MMR vaccine. In the article titled “Under- standing MMR Vaccine Safety”, the CDC provides answers to several questions regarding the safety and necessity of the MMR vaccine. While there is abundant proof that there is no relationship between the MMR vaccine and autism, vaccine hesitancy among parents is still prevalent and poses a serious public health risk.

8. Vaccine safety

The hesitancy surrounding vaccine safety has highlighted the need for reliable information to bemade available to the public. The CDC has made extensive efforts to provide reputable resources that reassure the public about the safety and efficacy of vaccinations. On their website, they encourage people to participate in reporting any possible adverse events associated with receiving vaccinations. The reporting systems they have in place include the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink

155

(VSD). Additionally, the CDC established the Clinical Immunization Safety Assessment (CISA) Project that connects healthcare pro- viders with vaccine safety experts regarding issues pertaining to individual patients or issues that are not already addressed by the CDC.

9. Conspiracy theories and solutions

“Conspiracy theories” are attempts to explain the ultimate causes of significant social and political events and circumstances with claims of secret plots by two or more powerful actors [73e75]. While often thought of as addressing governments, conspiracy theories could accuse any group perceived as powerful and ma- levolent. Conspiracy theories appear to provide broad, internally consistent explanations that allow people to preserve beliefs in the face of uncertainty and contradiction. Consistent with this analysis, research suggests that belief in conspiracy theories is stronger under conditions of uncertainty [76]. Franks and Colleagues [77] note that conspiracy theories have been communicated as devices to cope with collective trauma. Consistent with this reasoning, studies have demonstrated that conspiracy beliefs are associated with feelings of powerlessness [78e80]. Autism is a disorder perceived as mysterious and unpreventable, parents are feeling powerless and doubt the ability of medical professionals to provide help and healing.

The origin of the conspiracy beliefs about vaccines and autism stems from the 1998 Lancet paper previously mentioned [81]. One of the leaders in disproving the vaccine/autism link states that the main conspiracy theory fueling vaccine hesitancy centers around scientific data being faked and harmful side-effects of vaccines being hidden from the public to ensure that pharmaceutical com- panies and governments are able to profit [82,83]. The conspiracy theory concerning the government hiding information may play the biggest role in antivaccine sentiment. Blaming large pharma- ceutical companies as the culprit is also an easy target since they are often imagined as withholding a cure by individuals who are left feeling powerless when they are diagnosed with serious ill- nesses [84].

Belief in conspiracy theories has been fueling vaccine hesitancy. Even though there has been no published studies that significantly illustrate a relation between vaccines and autism, vaccine hesitancy continues as the conspiracy is rooted in individuals not trusting the scientific information that is being released. By fueling conspiracy theories, the feeling of fear increases, leading to ultimately detri- mental effects on public health. Vulnerable populations with less resources are at risk to contagious diseases as well as those with weakened immune systems [85]. Investing energy in trying to decrease antivaccine sentiment should parallel uncovering the actual etiologies of autism.

Conspiracy theories are reinforced by the very basis of Internet search engines. There are “discussion groups” on any topic and user communities. Searching for information will inevitably lead to any source of information, regardless of its validity. Opponents of vac- cines build sites, discussion groups, etc., so that a “reasonable person” who writes the phrase “vaccines, autism, against” this will inevitably reach sites that deal extensively with the subject, and that may seem scientific and authoritative the general public and may create a false representation of the topic. Communication styles within the media [86e88] revealed that vaccination and antivaccination comments use different kinds of language in their communication of information [89]. In addition, the vaccine- skeptical sites were highly interactive, with spaces for community discussion, and oriented towards the creation of people that believe to be affected by vaccination. In contrast authoritative pro- vaccination sites offer limited interactivity and focus on evidence-

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

based knowledge and perceived as aloof and dictatorial [82,90,91]. Political views [92] or words from celebrities sent on social

media can then lead to the spread of misinformation and propa- gation of beliefs about vaccines causing autism [93].

The perceived unexplained rise in autism incidence and the mystery surrounding the causes of autism continues to feed the myth linking autism to immunizations schedule. A study in Italy that investigated vaccine beliefs in Italian mothers concluded that “When trying to make sense of the unpredictable nature of ASD, parents blamed vaccines and their toxic components to try and rationalize the mysterious cause of autism in their child” [94]. This study shows that belief in the theory that vaccines cause autism can be a way for concerned, confused parents to bring more clarity into their situation, reducing their overall anxiety with the disease.

Rachel Casiday, a medical anthropologist who studied British parents' attitudes toward MMR says that scientists should work on making dry scientific facts more compelling and centered around a story [85] and that vaccine information should also be presented in an emotional context. For example, compelling stories that we are aware of as clinicians, but have not been researched systematically, involve the personal stories of families who refrained to immunize their following children after their first child was diagnosed with ASD. Later on the additional siblings of those families whowere not vaccinated were still diagnosed with ASD, thus refuting the family's belief in vaccinations as a cause for autism and supporting a more genetic etiology. Most families refrain from expressing their change in opinion and decline participating in research.

9.1. Solutions to conspiracy theory misinformation

- Presenting anti-conspiracy arguments before the conspiracy theory-presenting anti vaccine arguments rooted in facts can help thosewho do notwant to vaccinate shift their beliefs, but in order to shift population behavior the scientific arguments should be presented before the individuals have been exposed to the conspiracy theory [95]. In regard to those who have been already exposed to conspiracy theories, stronger measures can be taken such as excluding non-vaccinated children from the educational system. Another option which has recently passed in the U.S. state of Oregon requires parents or guardians to watch an education video before they are allowed a vaccination exemption [95].

- In the realm of mass information we are in today, it is crucial that information hygiene is embraced as a society, where in- dividuals deem all information as pathogenic before they accept or propagate it [96]. Social media has shown a clear impact on the public's understanding of science and medicine, as well as the spread of conspiracy theories so it is important to address the misinformation that is surfacing. In order to best appeal to the inflexible minds of victims to conspiracy theorists, communicating messages in an emotional context that is both warm and inclusive of all opinions may serve as the best option for instilling true change in their misguided beliefs. Social me- dia's role in the propagation of misinformation has been sig- nificant, so it is important to find ways to influence the media to portray a more accurate picture about the nature of vaccines.

10. Summary

In spite of vast evidence of vaccine safety and its lack of connection to autism, this myth is still influencing parents to children with autism and general public and increases vaccination refusal rates. A lot of the distrust in vaccinations is rooted in the forceful nature it is put on individuals, without an explanation that is fully understandable to the general public in regards to the

156

reasons of autism. With more evidence of genetic and epigenetic etiologies along with earlier diagnosis of autism the mystery sur- rounding autism symptomatology should be unveiled.

Medical information about vaccine safety should be provided in an effective manner, with special attention paid not only to the content of the information but also to how it is presented, with a focus on providing a welcoming environment for open discussion about the benefits and risks.

This psychological response to diagnosis should guide us into a cautious and empathetic approach when explaining the genetics of autism. This explanation may pose additional burden on the par- ents, although most mutations related to ASD are de-novo and not inherited [31]. It may be easier for the parents to blame an envi- ronmental external factor such as vaccinations, thus this sentiment poses significant health concerns to vulnerable populations. The COVID-19 pandemic, however, clearly exemplified that the diseases that immunizations prevent are far more severe than the vaccina- tions themselves. It is plausible that with more evidence-based studies linking autism to specific etiologies the myth will diminish and disappear eventually.

Declaration of competing interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

[1] Doctorsonly, הנורוקהינוסיחלעזוינ-קייפרתאיםיאפורתווצ:םינוסיחידגנתמבקבאמ . Doctorsonly. https://publichealth.doctorsonly.co.il/2020/12/215090/, 2021.

[2] GOV.UK, Government Targets False Vaccine Information on Social Media - GOV.UK, GOV.UK, 2021. https://www.gov.uk/government/news/government- targets-false-vaccine-information-on-social-media.

[3] Maariv, בירעמ|”העטמעדימוםירקשלומימוימויקבאמםילהנמונחנא“:הנורוקלןוסיח . Maariv. https://www.maariv.co.il/corona/corona-israel/Article-822342, 2021.

[4] J.R. Zucker, J.B. Rosen, M. Iwamoto, R.J. Arciuolo, M. Langdon-Embry, N.M. Vora, J.L. Rakeman, B.M. Isaac, A. Jean, M. Asfaw, S.C. Hawkins, T.G. Merrill, M.O. Kennelly, B. Maldin Morgenthau, D.C. Daskalakis, O. Barbot, Consequences of undervaccination d measles outbreak, New York city, 2018e2019, N. Engl. J. Med. 382 (11) (2020) 1009e1017, https://doi.org/ 10.1056/NEJMoa1912514.

[5] CDC, CDC Data & Statistics on Autism Spectrum Disorder, 2020. [6] World Health Organization, Immunization Coverage, 2020. [7] Centers for Disease Control and Prevention, Possible Side-Effects from Vac-

cines, 2020. [8] L.E. Smith, R. Amlôt, J. Weinman, J. Yiend, G.J. Rubin, A systematic review of

factors affecting vaccine uptake in young children, Vaccine 35 (45) (2017) 6059e6069, https://doi.org/10.1016/j.vaccine.2017.09.046.

[9] R.C. Vanderpool, A. Gaysynsky, W.Y.S. Chou, Using a global pandemic as a teachable moment to promote vaccine literacy and build resilience to misinformation, Am. J. Publ. Health 110 (2020) S284eS285, https://doi.org/ 10.2105/AJPH.2020.305906.

[10] C. de Cock, M. van Velthoven, M. Milne-Ives, M. Mooney, E. Meinert, Use of apps to promote childhood vaccination: systematic review, JMIR MHealth and UHealth 8 (5) (2020), e17371, https://doi.org/10.2196/17371.

[11] A. Saso, B. Kampmann, Vaccine responses in newborns, Semin. Immunopa- thol. 39 (6) (2017) 627e642, https://doi.org/10.1007/s00281-017-0654-9.

[12] O.A. Olusanya, R.A. Bednarczyk, R.L. Davis, A. Shaban-Nejad, Addressing parental vaccine hesitancy and other barriers to childhood/adolescent vacci- nation uptake during the Coronavirus (COVID-19) pandemic, Front. Immunol. 12 (2021) 663074, https://doi.org/10.3389/fimmu.2021.663074.

[13] F. DeStefano, H.M. Bodenstab, P.A. Offit, Principal controversies in vaccine safety in the United States, Clin. Infect. Dis. : Off. Publ. Infect. Dis. Soc. Am. 69 (4) (2019) 726e731, https://doi.org/10.1093/cid/ciz135.

[14] S. Geoghegan, K.P. O'Callaghan, P.A. Offit, Vaccine safety: myths and misin- formation, Front. Microbiol. 11 (2020) 372, https://doi.org/10.3389/ fmicb.2020.00372.

[15] P.H. Streefland, Public doubts about vaccination safety and resistance against vaccination, Health Pol. 55 (3) (2001) 159e172, https://doi.org/10.1016/ s0168-8510(00)00132-9.

[16] M.A. Maglione, L. Das, L. Raaen, A. Smith, R. Chari, S. Newberry, R. Shanman, T. Perry, M.B. Goetz, C. Gidengil, Safety of vaccines used for routine immu- nization of U.S. children: a systematic review, Pediatrics 134 (2) (2014) 325e337, https://doi.org/10.1542/peds.2014-1079.

[17] K. Stratton, A. Ford, E. Rusch, E.W. Clayton (Eds.), Adverse Effects of Vaccines: Evidence and Causality, 2011, https://doi.org/10.17226/13164.

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

[18] L.E. Taylor, A.L. Swerdfeger, G.D. Eslick, Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies, Vaccine 32 (29) (2014) 3623e3629, https://doi.org/10.1016/ j.vaccine.2014.04.085.

[19] R.B. Dimova, C.C. Egelebo, H.S. Izurieta, Systematic review of published meta- analyses of vaccine safety, Stat. Biopharm. Res. 12 (3) (2020) 293e302, https:// doi.org/10.1080/19466315.2020.1763833.

[20] S.M. Myers, C.P. Johnson, P.H. Lipkin, J.D. Cartwright, L.W. Desch, J.C. Duby, E.R. Elias, E.B. Levey, G.S. Liptak, N.A. Murphy, A.H. Tilton, D. Lollar, M. Macias, M. McPherson, D.G. Olson, B. Strickland, S.M. Skipper, J. Ackermann, M. Del Monte, M. Yeargin-Allsopp, Management of children with autism spectrum disorders, Pediatrics 120 (Issue 5) (2007) 1162e1182, https://doi.org/10.1542/ peds.2007-2362. American Academy of Pediatrics.

[21] K. Chawarska, F. Shic, S. Macari, D.J. Campbell, J. Brian, R. Landa, T. Hutman, C.A. Nelson, S. Ozonoff, H. Tager-Flusberg, G.S. Young, L. Zwaigenbaum, I.L. Cohen, T. Charman, D.S. Messinger, A. Klin, S. Johnson, S. Bryson, 18-month predictors of later outcomes in Younger siblings of children with autism spectrum disorder: a baby siblings research consortium study, J. Am. Acad. Child Adolesc. Psychiatr. 53 (12) (2014) 1317e1327, https://doi.org/10.1016/ j.jaac.2014.09.015, e1.

[22] D.L. Christensen, J. Baio, K. Van Naarden Braun, D. Bilder, J. Charles, J.N. Constantino, J. Daniels, M.S. Durkin, R.T. Fitzgerald, M. Kurzius-Spencer, L.C. Lee, S. Pettygrove, C. Robinson, E. Schulz, C. Wells, M.S. Wingate, W. Zahorodny, M. Yeargin-Allsopp, Prevalence and characteristics of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2012, MMWR Sur- veillance Summaries 65 (3) (2016) 1e23, https://doi.org/10.15585/ mmwr.ss6503a1.

[23] K. Pierce, V.H. Gazestani, E. Bacon, C.C. Barnes, D. Cha, S. Nalabolu, L. Lopez, A. Moore, S. Pence-Stophaeros, E. Courchesne, Evaluation of the diagnostic stability of the early autism spectrum disorder phenotype in the general population starting at 12 months, JAMA Pediatr. 173 (6) (2019) 578e587, https://doi.org/10.1001/jamapediatrics.2019.0624.

[24] L.V. Gabis, Chapter 4 - autism spectrum disorder: a clinical path to early diagnosis, evaluation, and intervention, in: I. Gozes, J. Levine (Eds.), Neuro- protection in Autism, Schizophrenia and Alzheimer's Disease, Academic Press, 2020, pp. 79e100, https://doi.org/10.1016/B978-0-12-814037-6.00004-5.

[25] CDC, Vaccines for your children by age | CDC. CDC. https://www.cdc.gov/ vaccines/parents/by-age/index.html, 2019.

[26] Israel-Ministry-of-Health, Vaccines for Babies and Children, Ministry of Health, 2020. https://www.health.gov.il/English/Topics/Pregnancy/ Vaccination_of_infants/Pages/default.aspx.

[27] ADDM, Autism and developmental disabilities monitoring. www.cdc.gov/ mmwr, 2012.

[28] ADDM, Facts about CDC's autism and developmental disabilities monitoring (ADDM) network | CDC. https://www.cdc.gov/ncbddd/autism/materials/ addm-factsheet.html, 2020.

[29] P.M. Dietz, C.E. Rose, D. McArthur, M. Maenner, National and state estimates of adults with autism spectrum disorder, J. Autism Dev. Disord. 50 (12) (2020) 4258e4266, https://doi.org/10.1007/s10803-020-04494-4.

[30] L. Allen, O. Leon-attia, M. Shaham, S. Shefer, L.V. Gabis, Autism risk linked to prematurity is more accentuated in girls, PLoS One (2020) 1e12, https:// doi.org/10.1371/journal.pone.0236994.

[31] F.K. Satterstrom, J.A. Kosmicki, J. Wang, M.S. Breen, S. De Rubeis, J.Y. An, M. Peng, R. Collins, J. Grove, L. Klei, C. Stevens, J. Reichert, M.S. Mulhern, M. Artomov, S. Gerges, B. Sheppard, X. Xu, A. Bhaduri, U. Norman, J.D. Buxbaum, Large-scale exome sequencing study implicates both develop- mental and functional changes in the neurobiology of autism, Cell 180 (3) (2020) 568e584, https://doi.org/10.1016/j.cell.2019.12.036, e23.

[32] S.H. Yoon, J. Choi, W.J. Lee, J.T. Do, Genetic and epigenetic etiology underlying autism spectrum disorder, J. Clin. Med. 9 (4) (2020) 966, https://doi.org/ 10.3390/jcm9040966.

[33] P. Goines, J. Van De Water, The immune system's role in the biology of autism, Curr. Opin. Neurol. 23 (Issue 2) (2010) 111e117, https://doi.org/10.1097/ WCO.0b013e3283373514. Curr Opin Neurol.

[34] A. Masi, N. Glozier, R. Dale, A.J. Guastella, The immune system, cytokines, and biomarkers in autism spectrum disorder, Neuroscience Bulletin 33 (2) (2017) 194e204, https://doi.org/10.1007/s12264-017-0103-8.

[35] A. Meltzer, J. Van De Water, The role of the immune system in autism spec- trum disorder, Neuropsychopharmacology 42 (1) (2017) 284e298, https:// doi.org/10.1038/npp.2016.158.

[36] S. Nardone, E. Elliott, The interaction between the immune system and epi- genetics in the etiology of autism spectrum disorders, Front. Neurosci. 10 (JUL) (2016) 1e9, https://doi.org/10.3389/fnins.2016.00329.

[37] H.K. Hughes, E. Mills Ko, D. Rose, P. Ashwood, Immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders, Front. Cell. Neurosci. 12 (November) (2018), https://doi.org/10.3389/ fncel.2018.00405.

[38] D. Ravaccia, T. Ghafourian, Critical role of the maternal immune system in the pathogenesis of autism spectrum disorder, Biomedicines 8 (12) (2020) 1e21, https://doi.org/10.3390/biomedicines8120557.

[39] K. Maeyama, K. Tomioka, H. Nagase, M. Yoshioka, Y. Takagi, T. Kato, M. Mizobuchi, S. Kitayama, S. Takada, M. Nagai, N. Sakakibara, M. Nishiyama, M. Taniguchi-Ikeda, I. Morioka, K. Iijima, N. Nishimura, Congenital cytomeg- alovirus infection in children with autism spectrum disorder: systematic

157

review and meta-analysis, J. Autism Dev. Disord. 48 (5) (2018) 1483e1491, https://doi.org/10.1007/s10803-017-3412-x.

[40] M. Mahic, S. Mjaaland, H.M. Bøvelstad, N. Gunnes, E. Susser, M. Bresnahan, A.- S. Øyen, B. Levin, X. Che, D. Hirtz, T. Reichborn-Kjennerud, S. Schjølberg, C. Roth, P. Magnus, C. Stoltenberg, P. Sur�en, M. Hornig, W.I. Lipkin, Maternal immunoreactivity to Herpes simplex virus 2 and risk of autism spectrum disorder in male offspring, mSphere 2 (1) (2017), https://doi.org/10.1128/ msphere.00016-17.

[41] Q. Shao, S. Herrlinger, S.-L. Yang, F. Lai, J.M. Moore, M.A. Brindley, J.-F. Chen, Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage, Development 143 (22) (2016) 4127e4136, https://doi.org/10.1242/dev.143768. LP.

[42] H. Campbell, N. Andrews, K.E. Brown, E. Miller, Review of the effect of measles vaccination on the epidemiology of SSPE, Int. J. Epidemiol. 36 (6) (2007) 1334e1348, https://doi.org/10.1093/ije/dym207.

[43] K.M. Antshel, A. Aneja, L. Strunge, J. Peebles, W.P. Fremont, K. Stallone, N. Abdulsabur, A.M. Higgins, R.J. Shprintzen, W.R. Kates, Autistic spectrum disorders in velo-cardio facial syndrome (22q11.2 deletion), J. Autism Dev. Disord. 37 (9) (2007) 1776e1786, https://doi.org/10.1007/s10803-006-0308- 6.

[44] J. Artigas-Pallar�es, E. Gabau-Vila, M. Guitart-Feliubadal�o, [Syndromic autism: II. Genetic syndromes associated with autism], Rev. Neurol. 40 (Suppl 1) (2005) S151eS162.

[45] C.M. Dias, C.A. Walsh, Recent advances in understanding the genetic archi- tecture of autism, Annu. Rev. Genom. Hum. Genet. 21 (2020) 289e304, https://doi.org/10.1146/annurev-genom-121219-082309.

[46] M.N. Ziats, O.M. Rennert, The evolving diagnostic and genetic landscapes of autism spectrum disorder, Front. Genet. 7 (2016) 65, https://doi.org/10.3389/ fgene.2016.00065.

[47] L.K. Curran, C.J. Newschaffer, L.C. Lee, S.O. Crawford, M.V. Johnston, A.W. Zimmerman, Behaviors associated with fever in children with autism spectrum disorders, Pediatrics 120 (6) (2007), https://doi.org/10.1542/ peds.2007-0360.

[48] K. Singh, S.L. Connors, E.A. Macklin, K.D. Smith, J.W. Fahey, P. Talalay, A.W. Zimmerman, Sulforaphane treatment of autism spectrum disorder (ASD), Proc. Natl. Acad. Sci. U.S.A. 111 (43) (2014) 15550e15555, https:// doi.org/10.1073/pnas.1416940111.

[49] S. Bernard, A. Enayati, L. Redwood, H. Roger, T. Binstock, Autism: a novel form of mercury poisoning, Med. Hypotheses 56 (4) (2001) 462e471, https:// doi.org/10.1054/mehy.2000.1281.

[50] J.P. Novo, B. Martins, R.S. Raposo, F.C. Pereira, R.B. Ori�a, J.O. Malva, C. Fontes- Ribeiro, Cellular and molecular mechanisms mediating methylmercury neurotoxicity and neuroinflammation, Int. J. Mol. Sci. 22 (6) (2021), https:// doi.org/10.3390/ijms22063101.

[51] L. Yang, Y. Zhang, F. Wang, Z. Luo, S. Guo, U. Str€ahle, Toxicity of mercury: molecular evidence, Chemosphere 245 (2020) 125586, https://doi.org/ 10.1016/j.chemosphere.2019.125586.

[52] A.C. Jackson, Chronic neurological disease due to methylmercury poisoning, Canad. J. Neurol. Sci. Le J. Canad. Des Sci. Neurol. 45 (6) (2018) 620e623, https://doi.org/10.1017/cjn.2018.323.

[53] K.M. Rice, E.M. Walker, M. Wu, C. Gillette, E.R. Blough, Environmental mercury and its toxic effects, J. Prevent. Med. Public Health ¼ Yebang Uihakhoe Chi 47 (2) (2014) 74e83, https://doi.org/10.3961/jpmph.2014.47.2.74.

[54] I. Kaur, T. Behl, L. Aleya, M.H. Rahman, A. Kumar, S. Arora, R. Akter, Role of metallic pollutants in neurodegeneration: effects of aluminum, lead, mercury, and arsenic in mediating brain impairment events and autism spectrum disorder, Environ. Sci. Pollut. Res. Int. 28 (8) (2021) 8989e9001, https:// doi.org/10.1007/s11356-020-12255-0.

[55] J.K. Kern, D.A. Geier, L.K. Sykes, B.E. Haley, M.R. Geier, The relationship be- tween mercury and autism: a comprehensive review and discussion, J. Trace Elem. Med. Biol. : Organ of the Society for Minerals and Trace Elements (GMS) 37 (2016) 8e24, https://doi.org/10.1016/j.jtemb.2016.06.002.

[56] R. Sulaiman, M. Wang, X. Ren, Exposure to aluminum, cadmium, and mercury and autism spectrum disorder in children: a systematic review and meta- analysis, Chem. Res. Toxicol. 33 (11) (2020) 2699e2718, https://doi.org/ 10.1021/acs.chemrestox.0c00167.

[57] S.-S. Zhou, Y.-M. Zhou, D. Li, Q. Ma, Early infant exposure to excess multivi- tamin: a risk factor for autism? Autism Res. Treat. (2013) 963697, https:// doi.org/10.1155/2013/963697, 2013.

[58] J.F. Risher, P. Tucker, Alkyl mercury-induced toxicity: multiple mechanisms of action, Rev. Environ. Contam. Toxicol. 240 (2017) 105e149, https://doi.org/ 10.1007/398_2016_1.

[59] J.G. D�orea, M. Farina, J.B.T. Rocha, Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury, J. Appl. Toxicol. : JAT 33 (8) (2013) 700e711, https://doi.org/10.1002/jat.2855.

[60] L.K. Ball, R. Ball, R.D. Pratt, An assessment of thimerosal use in childhood vaccines, Pediatrics 107 (5) (2001) 1147e1154, https://doi.org/10.1542/ peds.107.5.1147.

[61] M. Bigham, R. Copes, Thiomersal in vaccines: balancing the risk of adverse effects with the risk of vaccine-preventable disease, Drug Saf. 28 (2) (2005) 89e101, https://doi.org/10.2165/00002018-200528020-00001.

[62] US Food and Drug Administration, Thimerosal and Vaccines, 2018. [63] D.A. Geier, J.K. Kern, M.R. Geier, Increased risk for an atypical autism diagnosis

following Thimerosal-containing vaccine exposure in the United States: a prospective longitudinal case-control study in the Vaccine Safety Datalink,

L.V. Gabis, O.L. Attia, M. Goldman et al. European Journal of Paediatric Neurology 36 (2022) 151e158

J. Trace Elem. Med. Biol. 42 (2017a) 18e24, https://doi.org/10.1016/ j.jtemb.2017.03.005.

[64] D.A. Geier, J.K. Kern, K.G. Homme, M.R. Geier, Abnormal brain connectivity spectrum disorders following thimerosal administration, Dose-Response 15 (1) (2017b), https://doi.org/10.1177/1559325817690849, 155932581769084.

[65] G.J. Kang, S.R. Ewing-Nelson, L. Mackey, J.T. Schlitt, A. Marathe, K.M. Abbas, S. Swarup, Semantic network analysis of vaccine sentiment in online social media, Vaccine 35 (29) (2017) 3621e3638, https://doi.org/10.1016/ j.vaccine.2017.05.052.

[66] N. Yiannakoulias, C.E. Slavik, M. Chase, Expressions of pro- and anti-vaccine sentiment on YouTube, Vaccine 37 (15) (2019) 2057e2064, https://doi.org/ 10.1016/j.vaccine.2019.03.001.

[67] A. Hviid, J.V. Hansen, M. Frisch, M. Melbye, Measles, mumps, rubella vacci- nation and autism a nationwide cohort study, Ann. Intern. Med. 170 (8) (2019) 513e520, https://doi.org/10.7326/M18-2101.

[68] K.M. Madsen, A. Hviid, M. Vestergaard, D. Schendel, J. Wohlfahrt, P. Thorsen, J. Olsen, M. Melbye, A population-based study of measles, mumps, and rubella vaccination and autism, N. Engl. J. Med. 347 (19) (2002) 1477e1482, https:// doi.org/10.1056/NEJMoa021134.

[69] Y. Uno, T. Uchiyama, M. Kurosawa, B. Aleksic, N. Ozaki, The combined measles, mumps, and rubella vaccines and the total number of vaccines are not asso- ciated with development of autism spectrum disorder: the first case-control study in Asia, Vaccine 30 (28) (2012) 4292e4298, https://doi.org/10.1016/ j.vaccine.2012.01.093.

[70] B. Taylor, E. Miller, C.P. Farrington, M.C. Petropoulos, I. Favot-Mayaud, J. Li, P.A. Waight, Autism and measles, mumps, and rubella vaccine: no epidemi- ological evidence for a causal association, Lancet (London, England) 353 (9169) (1999) 2026e2029, https://doi.org/10.1016/s0140-6736(99)01239-8.

[71] M. Hornig, T. Briese, T. Buie, M.L. Bauman, G. L, Lack of association between measles virus vaccine and autism with enteropathy: a case-control study, PLoS Med. 3 (9) (2008), https://doi.org/10.1371/journal.pone.0003140.

[72] Y. Uno, T. Uchiyama, M. Kurosawa, B. Aleksic, N. Ozaki, Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vac- cines and risk of autism spectrum disorder, Vaccine 33 (21) (2015) 2511e2516, https://doi.org/10.1016/j.vaccine.2014.12.036.

[73] D. Aaronovitch, Voodoo Histories : the Role of the Conspiracy Theory in Shaping Modern History, Riverhead books, New York (N.Y.), 2010. http://lib. ugent.be/catalog/rug01:001362461.

[74] J. Byford, Conspiracy Theories: A Critical Introduction, Springer, 2011. [75] B.L. Keeley, Of conspiracy theories, J. Philos. 96 (3) (1999) 109e126. [76] J.W. van Prooijen, N.B. Jostmann, Belief in conspiracy theories: the influence of

uncertainty and perceived morality, Eur. J. Soc. Psychol. 43 (1) (2013) 109e115, https://doi.org/10.1002/ejsp.1922.

[77] B. Franks, A. Bangerter, M. Bauer, Conspiracy theories as quasi-religious mentality: an integrated account from cognitive science, social representa- tions theory, and frame theory, Front. Psychol. 4 (2013) 424.

[78] M. Abalakina-Paap, W.G. Stephan, T. Craig, W.L. Gregory, Beliefs in conspir- acies, Polit. Psychol. 20 (3) (1999) 637e647, https://doi.org/10.1111/0162- 895X.00160.

[79] R. Pratt, Theorizing conspiracy, Theor. Soc. 32 (2) (2003) 255e271, https://

158

doi.org/10.1023/A:1023996501425. [80] D. Zarefsky, Conspiracy arguments in the lincoln-douglas debates, J. Am.

Forensic Assoc. 21 (2) (1984) 63e75, https://doi.org/10.1080/ 00028533.1984.11951275.

[81] S. Plotkin, J.S. Gerber, P.A. Offit, Vaccines and autism: a tale of shifting hy- potheses, Clin. Infect. Dis. 48 (4) (2009) 456e461, https://doi.org/10.1086/ 596476.

[82] A. Kata, A postmodern Pandora's box: anti-vaccination misinformation on the Internet, Vaccine 28 (7) (2010) 1709e1716, https://doi.org/10.1016/ j.vaccine.2009.12.022.

[83] P.A. Offit, Deadly Choices: How the Anti-vaccine Movement Threatens Us All, Basic Books, 2015 (AZ).

[84] R. Blaskiewicz, The Big Pharma conspiracy theory, Med. Writ. 22 (4) (2013) 259e261, https://doi.org/10.1179/2047480613z.000000000142.

[85] L. Gross, A broken trust: lessons from the vaccine-autism wars, PLoS Biol. 7 (5) (2009), https://doi.org/10.1371/journal.pbio.1000114.

[86] M. Dredze, D.A. Broniatowski, K.M. Hilyard, Zika vaccine misconceptions: a social media analysis, Vaccine 34 (30) (2016) 3441e3442, https://doi.org/ 10.1016/j.vaccine.2016.05.008.

[87] T.G. Safford, L.C. Hamilton, E.H. Whitmore, To Combat the Pandemic, 2017. [88] M. Sharma, K. Yadav, N. Yadav, K.C. Ferdinand, Zika virus pandemic-analysis of

Facebook as a social media health information platform, Am. J. Infect. Control 45 (3) (2017) 301e302, https://doi.org/10.1016/j.ajic.2016.08.022.

[89] L. Grant, B.L. Hausman, M. Cashion, N. Lucchesi, K. Patel, J. Roberts, Vaccination persuasion online: a qualitative study of two provaccine and two vaccine- skeptical websites, J. Med. Internet Res. 17 (5) (2015) e133, https://doi.org/ 10.2196/jmir.4153.

[90] K.M. Douglas, J.E. Uscinski, R.M. Sutton, A. Cichocka, T. Nefes, C.S. Ang, F. Deravi, Understanding conspiracy theories, Polit. Psychol. 40 (S1) (2019) 3e35, https://doi.org/10.1111/pops.12568.

[91] M.B. Moran, M. Lucas, K. Everhart, A. Morgan, E. Prickett, What makes anti- vaccine websites persuasive? A content analysis of techniques used by anti- vaccine websites to engender anti-vaccine sentiment, J. Commun. Healthc. 9 (3) (2016) 151e163, https://doi.org/10.1080/17538068.2016.1235531.

[92] D. Kahan, D. Braman, G. Cohen, J. Gastil, P. Slovic, Who fears the HPV vaccine, who doesn't, and why? An experimental study of the mechanisms of cultural cognition, Law Hum. Behav. 34 (2010) 501e516, https://doi.org/10.1007/ s10979-009-9201-0.

[93] J.R. Zaller, The Nature and Origins of Mass Opinion, Cambridge university press, 1992.

[94] M. Pivetti, G. Melotti, C. Mancini, Vaccines and autism: a preliminary quali- tative study on the beliefs of concerned mothers in Italy, Int. J. Qual. Stud. Health Well-Being 15 (1) (2020) 1754086, https://doi.org/10.1080/ 17482631.2020.1754086.

[95] D. Jolley, K.M. Douglas, Prevention is better than cure: addressing anti-vaccine conspiracy theories, J. Appl. Soc. Psychol. 47 (8) (2017) 459e469, https:// doi.org/10.1111/jasp.12453.

[96] D.R. Grimes, Health disinformation & social media, EMBO Rep. 21 (11) (2020) 2e5, https://doi.org/10.15252/embr.202051819.