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Review Article *Corresponding author Crawford SA, Department of Biology, Southern Connecticut State University, New Haven, CT 06515, Autism vs Vaccines: The Case USA, Tel: 203-321-6972; Email:

Submitted: 09 July 2018 Reopened Accepted: 27 July 2018 Crawford SA* Published: 30 July 2018 Department of Biology, Southern Connecticut State University, USA Copyright © 2018 Crawford

Abstract OPEN ACCESS Regressive autism is the rapid-onset loss of previously acquired milestones in Keywords central nervous system development often associated with seizures that occurs within the first 1-3 years of life. The dramatic CNS changes associated with regressive • Regressive autism autism sometimes rapidly follow the administration of vaccines, highly suggestive of • Vaccines a causal connection that has been the subject of clinical studies worldwide; however, • Immune system clinical research studies to date have failed to validate an association between • Spileptic seizures vaccines and autism. Despite this, recent genetic studies have demonstrated extensive • Neurodevelopment overlap of immune system components shown to be dysregulated in autism and those essential to the establishment of vaccine based immunity. Moreover, the genetic links between autism and the immune system extend to physiological differences in immune system functions that may directly affect central nervous system maturation during critical developmental windows. In this model, vaccine-associated regressive autism (VARA) is the result of the combined effects of predisposing genetic (and/or other) epidemiological factors on immune system functions that predispose at-risk individuals to central nervous system impairment following the administration of routine childhood vaccines.

ABBREVIATIONS to mutations in genes encoding postsynaptic density; in contrast, VARA: Vaccine Associated Regressive Autism; CNS: Central autism-associatedCNS morphology, regressivemutations autismin embryonic has been genes specifically were less linked likely Nervous System; ASD: Disorder; IS: Immune to be associated with the regressive form of this disorder [3]. System; PRR: Pattern Recognition Receptor; DC: Dendritic Cell; TLR: Toll-Like-Receptor; NFkB: Nuclear Factor kappa B; The term itself, “regressive autism”, is loaded; increasingly, NK: Natural Killer Cell; HLA: Human Leukocyte Antigen; IL: researchers and clinicians alike have attempted to describe the Interleukin; CDC: Centers for Disease Control onset of autism as an accumulation of CNS impairments that may ultimately present as developmental losses rather than INTRODUCTION Conceptual definition of vaccine associated regressive prevalence of autism spectrum disorder (ASD) among the 11 (Autismas deficits Disorder of gain if and early Disability signs are Monitoring) missed. In 2014, ADDM the sites overall was autism (VARA) distinguish between purely developmental and regressive forms previously acquired milestones in central nervous system (CNS) 16.8 per 1,000 (one in 59) children aged 8 years and did not Regressive autism may be defined as a rapid-onset loss of occurs only in a small subset of patients with autism; however, of life [1]. The behavioral characteristics of regression often theof the level disorder of disability, [4]. Evidence including suggests intellectual that true disability, clinical on regression average, includedevelopment loss of that language occurs and usually social within skills; theepileptic first severalseizures years may is greater in this group [1]. The timing of onset of regressive brain enlargement as a distinctive feature of regressive autism. Thisalso be research involved showed [1]. Nordahl that et total al. [2], brain have volume identified in 3-year-oldabnormal aautism dramatic, ranges sudden between clinical ranges onset between [5,6]. This 15 and is an 30 important months, boys with regressive autism was approximately 6% larger than distinction,24-81 months, because with it a suggests mean of that 20 a months, critical trigger and demonstrates mechanism non-autistic age-matched boys. Moreover, 22% of boys with responsible for CNS impairment may occur in the same temporal regressive autism showed megalencephaly as compared to timeframe as the onset of . To this end, 5% boys who did not have this disorder. The increase in brain early childhood vaccines have been implicated in the etiology of sudden onset regressive autism by parents and primary health onset of autism symptoms, and was associated only with the care providers who have witnessed sudden changes in behavioral regressivevolume was form first of detectable the disorder. at 4-6 In months addition of to age, abnormalities preceding the in and neurological functions in some young children following

Cite this article: Crawford SA (2018) Autism vs Vaccines: The Case Reopened. J Autism Epilepsy 3(1): 1014. Crawford (2018) Email:

Central Bringing Excellence in Open Access the administration of vaccines [7]. Clinically, this abnormal evidence that the common vaccines administered in infancy and response to vaccination is termed “vaccine encephalopathy”, in childhood (Figure 1) are safe and highly effective in preventing which apparently normal infants or children display a sudden, infections that were once associated with high mortality rates permanent developmental regression and/or seizures with rapid onset following vaccine administration. That the dramatic CNS research designed to assess the potential association of vaccines changes associated with regressive autism can so rapidly follow in the years before vaccines were available [9]. Moreover, the administration of vaccines is highly suggestive of a causative association. A retrospective study of all children in Denmark connection that has been the subject of epidemiological studies with autism have failed to produce a statistically significant worldwide [8]. To date, these studies have failed to validate an the measles-mumps-rubella vaccine administered at 15 months association between vaccines and any type of autism, leading born between 1991-1998 examined the association between to a widespread consensus that there is no connection between relative risk for autism in the vaccinated versus unvaccinated vaccines and autism spectrum disorder (ASD) [8]. The premise and the incidence of autism [10]. This study showed that the of this paper is that these epidemiological studies, investigating a Disease Control (CDC) measured both the cumulative and single potential link between vaccines and autism, have failed to do so daygroup exposures was statistically to antigens similar. in vaccines A 2013 administeredstudy by the Centersto a group for because they have not considered the limitations of population of several hundred children and found that the risk of acquiring based studies in identifying rare case occurrences, nor have autism spectrum disorder (ASD) was not correlated with the these studies addressed the physiological basis for causality that suggests a connection between the onset of autism and immune [11]. The consensus of these studies was that there was no link system (IS) responses to vaccines in some individuals. The highly betweenlevel of antigen autism exposure and early from childhood vaccines vaccines. between 0-2 years of life disturbing association between vaccines and CNS dysfunction clearly deserves a second look. A closer inspection of the study data, however, reveals that there are several areas in which these studies failed to present Epidemiological data Broad-based retrospective and prospective epidemiological with autism in some individuals. Much of this research was based studies conducted over the past decade have provided strong ona definitive the false statementcause-and-effect on the premise potential that association the number of vaccinesof types

Figure 1

Recommended Immunization Schedule for Infants/Children/Adolescents (Centers for Disease Control, 2017). JSM Arthritis 3(1): 1014 (2018) 2/7 Crawford (2018) Email:

Central Bringing Excellence in Open Access of antigens is the only immune-stimulating facet of vaccines. In reality, other components such as adjuvants or the amount demonstrating the points at which these two systems converge to of a single type of immune-active antigen are likely as or more it is now possible to define a comprehensive paradigm important than the number of types of antigens. A second factor factorsdefine mechanistically are present. the role of vaccines in the onset of autism not designed to detect rare events or associations; therefore, null in infants/young children in whom significant IS/autism risk of significance is that these large-scale population studies were Available data suggest a link between genetic polymorphisms be concluded to rule out such occurrences [12]. Thirdly, these [13]. The innate immune system plays an important role in studiesfindings were may notlack designed the power to toassess identify the hypothesisthese events that and vaccines cannot programmingin the innate IS early genes life that responses may influence to vaccine vaccine immunization. responses are not a sole cause of autism but, instead, may play a contributory The immediate innate IS response involves pattern recognition role in the development of autism in individuals predisposed to receptors (PRRs) on dendritic cells (DCs), such as the Toll-like- this disorder due to additional risk factors. Moreover, none of receptors (TLRs) that determine the nature of the antigens autism in vaccine recipients which is the subject of this paper. these studies specifically addressed the subgroup of regressive to immune system activation by vaccines. Variations in pattern Immune system responses to vaccines with potential recognitionrecognized by receptor receptors genes on T (PRRs) and B cells; encoding PRRs areToll-like first responders receptors links to autism (TLRs), human leukocyte antigen (HLA) proteins, cytokines and their receptors have been linked to heterogeneous responses to The plethora of physiological responses induced by antigen/ many different types of vaccines, including measles, hepatitis adjuvant presentation by vaccines presents the possibility for type b, tetanus toxoid, pneumococcal polysaccharide vaccine, based on genetic and/or environmentally associated differences varicellaB, bacillus vaccine, Calmette-Guerin and themeasles, (BCG), mumps, Haemophilus and rubella influenzae vaccine ina varied the activities and complex of each profile of these of immune players system in vaccine-associated (IS) responses immunity. To assess critically the relationship between innate immune responses involving toll-like receptors (TLRs), regressive autism and vaccine administration, it is essential monocytes,(MMR) [14,15]. natural For example, killer (NK) bacillus cells, Calmette-Guerin cytokines and interferon activates production immediately after immunization at birth, followed by antigens and adjuvants to determine whether, and under what T cell responses at 13 weeks post-vaccination [15]. conditions,to define early, any or immediate all IS responses physiological to vaccines responses have the to potential vaccine to disrupt normal brain function in early childhood (Figure 2). As Genetic polymorphisms in these innate IS response genes our general understanding of the relationship between the IS and have also been linked to autism. For example, many genes autism has increased, combined with new research illuminating the early stages of IS activation post vaccine administration, linked to autism code for immune and inflammatory response functions. Garbett et al. [16], identified 31 sets of genes

Figure 2

Early innate immune responses to vaccines. JSM Arthritis 3(1): 1014 (2018) 3/7 Crawford (2018) Email:

Central Bringing Excellence in Open Access differentially expressed in patients with autism as compared seizures are a frequent accompaniment of autism [26]. Thus, the onset of epileptic seizures concomitant with vaccine administration is highly relevant in this context. The National to controls. Of these, 19 were associated with IS functions, ofincluding these genes antigen-specific showed increased immune response,structural inflammation, variability in cellthe death, natural killer (NK) cell function and cell migration. Each Institute for Public health and the Environment in the Netherlands by nuclear factor kappa-B (NF-kB) or interferon regulatory reviewed clinical data of 990 children who experienced epileptic factor,autism stimulates cohort. The the expression production of inflammatory of cytokines that genes, trigger signaled the infantsseizures and in response young children to vaccines in the between general 0-2 population years of age increases between maturation of activated DCs to antigen-presenting cells that, in by1997 2.5-fold and 2006 on the [27]. day The of administration data showed that of an the inactivated risk of seizures vaccine. in Moreover, the risk of developing seizures continues from day haplotypesturn, activate have T cell been receptors linked vis-à-vis both to autismspecific andhuman variations leukocyte in study authors concluded that this elevated risk was the result of vaccineantigen (HLA) induced receptor-antigen immune responses complexes. [17]. SpecificIndividuals HLA with allelic a underlying5 to 14 after genetic administration or structural of disorders live attenuated of the brain vaccines. [27]. The family history or other risk factors for autoimmune disorders Abnormal IS a response to vaccines: links to brain are more likely to experience vaccine-related sequelae than function non-affected individuals [18]. Likewise, individuals with a family IS activation of microglial excitotoxicity is emerging as a primary physiological cause of impaired neurodevelopment. variantshistory of of autoimmune the HLA gene disorders family that are are significantly associated more with vaccine-likely to In the CNS, differences in microglial activation, physiology and induceddevelop autoimmune autism [18]. activation, Research including studies have HLA identifiedDRB1, HLA genetic DRB2, localization have been observed in autistic brains [28]. There are extraordinarily tight connections between the CNS and IS. grouping different autoimmune conditions that are triggered by The duality of microglia structure/function relationships in CNS externalHLA DR4, stimuli and HLA (e.g., DRQ8 exposure [19]. to Several vaccine) reports as a single have syndromesuggested immune surveillance and neurodevelopment represents a critical called “autoimmune syndrome induced by adjuvants” (ASIA) connection between the immune system and the developing brain

[20]. Among the alleles linked to autism are class II DRB1, [29]. Autopsies of individuals with ASD characteristically show particularly in Han Chinese, Egyptian and Saudi populations evidence of neuroinflammation resulting from the production in[21]. children DRB*11 with and ASD DRB*1104 and their allelesmothers occur [21]. more Nazeen frequently et al. [22], in TLRsof cytokines, are expressed interleukins, in microglia, NF-kB astrocytes and other and pro-inflammatory neurons [31]. performedchildren with an integrativeautism. HLA-DR-4 genetic allelesdata analysis occur atthat increased revealed rates that Microgliamolecules has from been activated shown to microglia express high [30]. level In thecell surface CNS, PRRs TLR2 / genes involved in TLR and chemokine signaling pathways are addition, expression of high level TLR3 and low-level expression genetic variants in the innate IS can be used to classify these cases as well as intracellular expression of TLR3 and TLRs1-9 [32]. In significantly associated with ASD and its co-morbidities and that TLR 3 activation in brain microglia induces high level production authors suggested that these dysregulated signaling pathways of TLRs 1, 4, 5 and 9 have been detected in brain astrocytes [32]. notversus only controls represent with a functional a minimum genetic of 70% commonality accuracy. implicating The study the innate IS in the causation of autism, but may also serve as a of IL-12, IL-6, CXCL-10, IL-10, and IFN-b [32]. In astrocytes, TLR- connection to environmental triggers of ASD. As the innate IS is 3 activation resulted in gene expression of IL-6, CXCL-10 and an important determinant of adaptive IS responses to vaccines, IFN-b [33]. Even neurons appear to produce components of the The chemokine receptor, CXCR-1, plays a critical role in dysregulation of this pathway may affect IS pathways activated innate IS, including TLRs 3, 7, 8 and 9 [34]. embryonic brain development; moreover, CXCR-L1 ligand, chemokine signal pathway were shown to be statistically linked by vaccine administration. Dysregulation of the KEGG TLR and resulting from IS dysregulation [35]. Recent research suggests thatfractalkine, CXCR-3 plays is an a critical important role in player the establishment in inflammatory of adaptive disease IS functional studies have shown an association of abnormal TLR/ to autism with 97% or greater probability [23]. Additional levels of CXCR-3 have been observed in patients with autism receptor signal pathway was also shown to be linked to autism in [35].responses Moreover, via regulation two variant of myeloid alleles cell of activation this receptor [34]. have Increased been achemokine comprehensive signal genetic mechanisms data analysis in autism [22]. [24].NOD-like The receptors NOD-like mice have shown that increased levels of CXCR-3 are associated identified in 20-30% of the population [36]. Additional studies in are important in the formation of inflammasomes and in the HCK gene, a Src related tyrosine kinase which plays an important NKproduction cells in autisticof pro-inflammatory children [22]. cytokines. SPP-1 mediated Other genes up regulation linked to rolewith in brain microglial inflammation regulation, [37]. has Dysregulated also been observed expression in autistic of the ofautism IFN-gamma include CCL4, and TBK1the most activation highly unregulated of NF-kB has chemokine also been in children [22] Defects in the leukocyte transendothelial migration pathway have been linked to autism via genetic analysis, which that dysregulation of the innate IS is one of the most reproducible may facilitate their migration across the BBB into brain tissue to geneticdetected associations in children linked with autismto autism. [22]. To These this end, findings differences indicate in innate IS gene expression levels have been documented both in the CNS and peripheral blood of patients with autism [25]. produceSubstantial inflammation research [22]. implicates IS dysfunction in the etiology of epilepsy; for example, altered innate IS signal patterns from timeframe post vaccine administration; moreover, epileptic Epileptic seizures sometimes occur within a relatively short brain tissues causes inflammation that may trigger epileptic JSM Arthritis 3(1): 1014 (2018) 4/7 Crawford (2018) Email:

Central Bringing Excellence in Open Access seizures [38]. Studies of brain tissue pathology in patients to identify rare events and did not assess potential causal physiological connections between IS responses to vaccines and CNS function. This combined study of the IS components activated increasewith epilepsy the permeability have provided of the evidenceblood/brain of barrier neuroinflammation and activate by vaccines and those implicated in the etiology of autism shows associated with the secretion of pro-inflammatory cytokines that that many of the same molecules are involved in both processes (Figure 3). The notion that ASD results from underlying genetic brain microglia [39]. Microglial activation has been linked to and/or physiological conditions that cause impaired CNS epileptic seizuresseizures, is which linked occur to innate in 20-30% and adaptive of patients IS actions with ASDthat development, and that vaccines have no role in the etiology of [40]. Additional research suggests that the onset of recurrent this disorder, is belied by empirical research showing that many Innate IS components implicated in this causation include TNF, of the genes linked to autism are innate IS genes activated by interleukinscan cause brain and damage interferon’s. in ways TLRthat are expression not fully understood in brain tissues [41]. vaccine administration. That the innate IS also plays a critical systems, which may result in disruption of ion channel and point of convergence between vaccines and autism that cannot inhibitoryhas been shown neuron to regulation initiate CNS and inflammation subsequent in epileptogenesis experimental berole ignored. in orchestrating The extensive first-line overlap responses of IS to components vaccines indicates shown toa be dysregulated in autism and, at the same time, essential to the establishment of vaccine based immunity presents a compelling [41]. This conception is supported by physiological studies physiological explanation for the onset of autism in response to indicating increased levels of pro-inflammatory cytokines in vaccines in individuals at the threshold of IS/CNS dysfunction. eitherthe sera endogenous and CSF of or patients exogenous with factors epilepsy that [42]. trigger The innate elevated IS The immunological evidence linking vaccines to IS signalproduction pathways. of pro-inflammatory Innate IS TLR activation cytokines leads may to the be inducedproduction by linked neurodevelopment parameters presented in this of NF-kB, which in turn results in the phosphorylation N-methyl paper establishes a direct physiological connection between neurological impairment and abnormal IS responses to vaccines. To this end, vaccines may induce rapid onset CNS impairment in glutamateD-aspartic reuptakeacid (NMDA) by astrocytes to trigger influxand stimulates of calcium its and production elevated neuronal excitability [43]. In addition, IL-1b both blocks children who show no previous signs of ASD but, nevertheless, inDISCUSSION microglia to further exacerbate neuronal excitability [44]. and CNS damage in response to vaccine administration. This possess IS risk factors predisposing them to brain inflammation the temporal association between the administration of vaccines multifactorial concept is embodied in the Quantitative Threshold The prevailing consensus of the scientific community, that proposes that neurological impairments associated with Autism and the onset of regressive autism is not indicative of a causal SpectrumExposure Disorder (QTE) Model (ASD) of are autism the result (Figure of quantitative 4) [45]. This exposure model connection, is based on population studies that were not designed during critical CNS developmental windows to diverse genetic and

Figure 3 with vaccine associated regressive autism (VARA). (PRRs: pattern recognition receptors; TLRs: Toll-like receptors; NFkB: nuclear factor kappa B.) (Photo credit: Mixed Interplay between abnormal immune system (IS) responses to vaccines, inflammatory activation of neural cells, and functional brain impairments associated

rat brain cultures stained for coronin 1a, found in microglia here in green, and alpha-internexin, in red, found in neuronal processes, Gerry Shaw, 2005, CC-SA 3.0.) (Brain image credit: Henry Vandyke Carter, in Gray’s Anatomy, Lea and Febiger Publisher, 1918-in public domain.) JSM Arthritis 3(1): 1014 (2018) 5/7 Crawford (2018) Email:

Central Bringing Excellence in Open Access environmental factors that, upon attaining a pathophysiological threshold, cause impaired brain development/functions. In this and/or cognitive developmental milestones and/or model, vaccine-associated regressive autism (VARA) is the result • Demonstrable loss of previously acquired behavioral of the combined effects of predisposing genetic (and/or other) administration; epidemiological factors in addition to vaccines that contribute initial onset of seizures within 0-14 days of vaccine cumulatively to IS overload and CNS functional impairment. This function do not subside over time. model explains why most children who receive vaccines do not • Observed changes in cognitive, behavioral and/or neural experience CNS effects, while vaccine administration may trigger It should be noted; however, that vaccines may potentiate CNS pathophysiology in a subset of children with additional risk neural impairment also in children with the developmental factors, both genetic and environmental. form of the disorder as its effects on IS interactions with the CNS may exacerbate pre-existing neurodevelopmental conditions. The consensus of the epidemiological data that failed to Moreover, vaccine associated neural impairments are not only identify any association between vaccines and autism is not pertinent to sudden regression but may be also in play in cases inaccurate; rather, the study designs were not appropriate for where there is latency between the vaccine administration and detecting an indirect, multifactorial cause-and-effect association the manifestation of autism. between vaccines and neurodevelopmental disorders in at-risk individuals. The conclusion reached by the CDC study authors, CONCLUSION that autism risk is not associated with vaccines based on the Taken together, the IS dysfunctions observed in patients observed uniform antigen exposure levels measured in all with autism provide a compelling explanation for the observed vaccine recipients, fails to address the effect of these antigen neurological impairments associated with this disorder. exposure levels on brain development in a group of at-risk Furthermore, the IS /autism connection provides a physiological basis for the effects of vaccines on CNS integrity in individuals or otherwise determined. This reductionist approach represents with risk factors for impaired IS function. The challenge now achildren fundamental who possess misunderstanding significant autism of the riskcomplex, factors, multifactorial genetically confronting clinicians and researchers is to develop protocols to and its physiological association with immune identify infants at risk for adverse reactions to vaccines that may system activities. The premise of this paper is that sudden- precipitate the onset of ASD/seizures. onset, regressive autism may occur in a select group of “at risk” infants and young children in whom the presence of risk factors REFERENCES associated with altered immunological responses to antigenic 1. Barbeau W. Neonatal and regressive forms of autism: Diseases with stimulation may present a direct cause and effect relationship between vaccine administration and autism. 2. similarNordahl symptoms CW, Lange but N, a Lidifferent DD, Barnett etiology. LA, Med Lee Hyp. A, Buonocore 2017; 109: MH,46-52. et al. Brain enlargement is associated with regression in preschool-age termed “vaccine associated regressive autism” (VARA) that This paper specifically addresses a subset of ASD, is characterized by a dramatic and rapid loss of previously boys with autism spectrum disorders. Proc Natl Acad Sci U S A. 2011; demonstrated developmental milestones and/or the onset of 3. 108:Atlad 20195-20200.óttir HÓ, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, vaccine administration in the absence of traumatic injury or Eaton WW, et al. Association of family history of autoimmune diseases seizure disorder in a short (0-14 days) timeframe following other variables during this timeframe that could account for this andBaio autism J, Wiggins spectrum L, Christensen disorders. DL, Pediatrics. Maenner 2009;MJ, Daniels 124: 687-694.J, Warren Z, et CNS event. The proposed clinical criteria for diagnosis of “vaccine al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 4. associated regressive autism” VARA includes: Years - Autism and Developmental Disabilities Monitoring Network, ween 5. vaccine administration and onset of disorder; 11 Sites, United States. MMWR Surveill Summ. 2018; 67: 1-23. • Defined temporal relationship of 0-14 days bet patterns in autism: Variation across informants, methods, and timing. Ozonoff S, Gangi D, Hanzel EP, Hill A, Hill MM, Miller M, et al. Onset

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Cite this article Crawford SA (2018) Autism vs Vaccines: The Case Reopened. J Autism Epilepsy 3(1): 1014.

JSM Arthritis 3(1): 1014 (2018) 7/7