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.
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,
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 aﬀect the nervoussystem.’’
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.
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.
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.
Second, throughmultiple vaccinations preschool children are regu-larly exposed to signiﬁcant amounts of Al adju-vants.
Such high exposures to Al repeated overrelatively short intervals during critical neurodeve-lopmental periods constitute a signiﬁcant neuro-immunotoxicological challenge to neonates andyoung children.
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.
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.
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),
are heavily targeted by Al adjuvants(Table 1). Fifth, experimental evidence demon-strates that a strong adjuvant eﬀect can overcomegenetic resistance to autoimmunity.
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.
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,
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.
Additionally, theimmature renal system of neonates signiﬁcantlycompromises their ability to eliminate environmen-tal toxicants.
For all these reasons, children are
Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations
L Tomljenovic and CA Shaw
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