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Mechanisms of Aluminum Adjuvant Toxicity and Autoimmunity in Pediatric Populations

Mechanisms of Aluminum Adjuvant Toxicity and Autoimmunity in Pediatric Populations

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10/24/2012

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 http://lup.sagepub.com/content/21/2/223Theonline version of this article can be found at:DOI: 10.1177/09612033114302212012 21: 223
Lupus 
L Tomljenovic and CA Shaw
Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations
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at University of British Columbia Library on January 12, 2012lup.sagepub.comDownloaded from 
 
Lupus (2012) 21,
223–230
http://lup.sagepub.com
SPECIAL ARTICLE
Mechanisms of aluminum adjuvant toxicity and autoimmunityin pediatric populations
L Tomljenovic
1
and CA Shaw
2
1
Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC,Canada and
2
Departments of Ophthalmology and Visual Sciences and Experimental Medicine and the Graduate Program in Neuroscience,University of British Columbia, Vancouver, BC, Canada
Immune challenges during early development, including those vaccine-induced, can lead topermanent detrimental alterations of the brain and immune function. Experimental evidencealso shows that simultaneous administration of as little as two to three immune adjuvants canovercome genetic resistance to autoimmunity. In some developed countries, by the time chil-dren are 4 to 6 years old, they will have received a total of 126 antigenic compounds along withhigh amounts of aluminum (Al) adjuvants through routine vaccinations. According to the USFood and Drug Administration, safety assessments for vaccines have often not includedappropriate toxicity studies because vaccines have not been viewed as inherently toxic.Taken together, these observations raise plausible concerns about the overall safety of currentchildhood vaccination programs. When assessing adjuvant toxicity in children, several keypoints ought to be considered: (i) infants and children should not be viewed as ‘‘small adults’’with regard to toxicological risk as their unique physiology makes them much more vulnerableto toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., ‘‘ASIA’’), yet children are regularlyexposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed thatperipheral immune responses do not affect brain function. However, it is now clearly estab-lished that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immu-noregulation as well as brain function. In turn, perturbations of the neuro-immune axis havebeen demonstrated in many autoimmune diseases encompassed in ‘‘ASIA’’ and are thought tobe driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily tar-geted by Al adjuvants. In summary, research evidence shows that increasing concerns aboutcurrent vaccination practices may indeed be warranted. Because children may be most at riskof vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse healthimpacts in the pediatric population is urgently needed.
Lupus
(2012)
21,
223–230.
Key word:
adjuvants; aluminum; autoimmunity; immunotoxicity; inflammation; neurotoxic-ity; vaccine safety
Introduction
Aluminum (Al) is highly neurotoxic and has beenshown to impair both prenatal and postnatal braindevelopment in humans and experimental ani-mals.
1–2
In addition to its neurotoxic properties, Alis a potent stimulator of the immune system, whichis the very reason why it is used as an adjuvant.
3–8
Given this, it is somewhat surprising to find that inspite of over 80 years of use, the safety of Al adju-vants continues to rest on assumptions rather thanscientific evidence. For example, nothing is knownabout the toxicology and pharmacokinetics of Aladjuvants in infants and children.
9
On the otherhand, in adult humans long-term persistence of Alvaccine adjuvants can lead to cognitive dysfunctionand autoimmunity.
6,10
Yet, in spite of these obser-vations children continue regularly to be exposed tomuch higher levels of Al adjuvants than adults, viaroutine childhood vaccination programmes.
3,11
Correspondence to: Lucija Tomljenovic, Post-doctoral fellow, NeuralDynamics Research Group, Department of Ophthalmology and VisualSciences, University of British Columbia, 828 W. 10th Ave,Vancouver, BC, V5Z 1L8, CanadaEmail: lucijat77@gmail.com
!
The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203311430221
 at University of British Columbia Library on January 12, 2012lup.sagepub.comDownloaded from 
 
An additional concern to using a neurotoxic sub-stance such as Al as an adjuvant in pediatric vac-cine formulations is the fact that infants and youngchildren should not be considered simply as ‘‘smalladults’’ when it comes to toxicological risk. In spiteof this, a review of the literature to date relating toAl-toxicology indicates that the vast majority of previous research and testing has been dedicatedto Al exposure in adults.
12
If a few vaccines admin-istered to adults can result in adverse outcomesassociated with the ‘‘ASIA’’ syndrome, is it reason-able to assume in the absence of experimental evi-dence that the current pediatric schedules, oftenexceeding 30 vaccinations in the first 4 to 6 postna-tal years,
3,13
are safe for children? The purpose of this review is to address the mechanisms of Al adju-vant toxicity with special reference to the develop-ing neuro-immune system and the ‘‘ASIA’’syndrome in order to shed light on this unresolvedand hotly debated question.
Al adjuvants: a toxicological risk to adeveloping child?
Some 15 years ago, Cohen and Shoenfeld made animportant observation: ‘‘It seems that vaccineshave a predilection to aect the nervoussystem.’’
14
Furthermore, according to Israeli andco-workers, alongside their supportive role in vac-cine-induced immune responses, vaccine adjuvantswere found to inflict, by themselves, illnesses of anautoimmune nature.
5
With regard to these state-ments, as well as the ensuing discussion, five keyobservations ought to be considered. First, thereare critical periods in brain development duringwhich even subtle immune challenges (includingthose induced by vaccinations) can lead to perma-nent detrimental alterations of brain and immunefunction.
15–17
Indeed, a single Al-adjuvanted hepa-titis B vaccine administered to newborn primateswithin 24h of birth is sufficient to cause neurode-velopmental delays in acquisition of neonatalreflexes essential for survival.
17
Second, throughmultiple vaccinations preschool children are regu-larly exposed to significant amounts of Al adju-vants.
3,18
Such high exposures to Al repeated overrelatively short intervals during critical neurodeve-lopmental periods constitute a significant neuro-immunotoxicological challenge to neonates andyoung children.
18
Third, despite the prevalentview that peripheral immune responses do notaffect brain function, overwhelming research evi-dence clearly points to the contrary. Namely, it isnow firmly established that there is a bidirectionalneuro-immune cross-talk which plays crucial rolesin immunoregulation, brain function, and mainte-nance of general homeostasis.
19,20
In turn, pertur-bations of the neuro-immune axis have beendemonstrated in a variety of autoimmune/inflam-matory diseases encompassed in the ‘‘ASIA’’ syn-drome.
21–24
Fourth, the very same components of the neuro-immune regulatory system that demon-strably play key roles in both brain developmentand immune function (e.g., immune cyto-kines),
19–20,25
are heavily targeted by Al adjuvants(Table 1). Fifth, experimental evidence demon-strates that a strong adjuvant effect can overcomegenetic resistance to autoimmunity.
26
Thus, the possibility needs to be considered thatrepeated immune system stimulation with multiplevaccines during critical periods of brain develop-ment could result in adverse neurodevelopmentaloutcomes and or/autoimmunity.
18
Mechanisms of immune stimulation byAl adjuvants: what are the risks?
The success of Al as a vaccine adjuvant is due to itspotent and multifactorial stimulatory effects on theimmune system (Table 1). In fact, with the excep-tion of attenuated viruses, in the absence of Al mostantigenic compounds fail to launch an adequateimmune response,
5,27–28
suggesting that a signifi-cant part of the immunostimulatory effects of vac-cines may be driven by the Al-adjuvant itself. Whilethe potency and toxicity of Al-adjuvants should beadequately balanced so that the necessary immunestimulation is achieved with minimal side effects,such balance is difficult to achieve in practice.This is because the same mechanisms that drivethe immunostimulatory effects of adjuvants havethe capacity to provoke a variety of adverse reac-tions, including those associated with the ‘‘ASIA’’syndrome (Table 1).There are additional problems with using a neu-rotoxic substance such as Al as an immune stimu-lator in pediatric vaccinations. First, duringprenatal and early postnatal development thebrain is extremely vulnerable to neurotoxic insults.Not only are these highly sensitive periods of rapidbrain development but also, the blood–brain bar-rier is incomplete and thus more permeable to toxicsubstances during this time.
11,12,29
Additionally, theimmature renal system of neonates significantlycompromises their ability to eliminate environmen-tal toxicants.
11,12
For all these reasons, children are
Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations
L Tomljenovic and CA Shaw
224
Lupus
 at University of British Columbia Library on January 12, 2012lup.sagepub.comDownloaded from 

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