Article

Updated Aluminum pharmacokinetics following infant exposures through diet and vaccines

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Abstract

Aluminum is a ubiquitous element that is released naturally into the environment via volcanic activity and the breakdown of rocks on the earth's surface. Exposure of the general population to aluminum occurs primarily through the consumption of food, antacids, and buffered analgesics. Exposure to aluminum in the general population can also occur through vaccination, since vaccines often contain aluminum salts (frequently aluminum hydroxide or aluminum phosphate) as adjuvants. Because concerns have been expressed by the public that aluminum in vaccines may pose a risk to infants, we developed an up-to-date analysis of the safety of aluminum adjuvants. Keith et al. [1] previously analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared the resulting body burdens to those based on the minimal risk levels (MRLs) established by the Agency for Toxic Substances and Disease Registry. We updated the analysis of Keith et al. [1] with a current pediatric vaccination schedule [2]; baseline aluminum levels at birth; an aluminum retention function that reflects changing glomerular filtration rates in infants; an adjustment for the kinetics of aluminum efflux at the site of injection; contemporaneous MRLs; and the most recent infant body weight data for children 0-60 months of age [3]. Using these updated parameters we found that the body burden of aluminum from vaccines and diet throughout an infant's first year of life is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory MRL. We conclude that episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.

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... Our study replaces Mitkus et al. [10] an exercise which has been thoroughly excoriated as mere mathematical journey based on the faulty assumption that oral doses of aluminum (of a different form from those found in vaccines) in adult mice could be used to predict the impact of, as if those data can be transformed via math into relevant data for injected forms in human adults and children [11]. In short, the Mitkus paper [10] based an assessment of the safety of water-insoluble forms of injected of aluminum in human adults on a single study of dietary water-soluble forms of aluminum in adult mice (Golub et al., 1989) [12]. ...
... Our study replaces Mitkus et al. [10] an exercise which has been thoroughly excoriated as mere mathematical journey based on the faulty assumption that oral doses of aluminum (of a different form from those found in vaccines) in adult mice could be used to predict the impact of, as if those data can be transformed via math into relevant data for injected forms in human adults and children [11]. In short, the Mitkus paper [10] based an assessment of the safety of water-insoluble forms of injected of aluminum in human adults on a single study of dietary water-soluble forms of aluminum in adult mice (Golub et al., 1989) [12]. This study, cherry-picked from among many by ATSDR, was used to claim that the doses of aluminum used on humans are safe. ...
... This study, cherry-picked from among many by ATSDR, was used to claim that the doses of aluminum used on humans are safe. Mitkus et al. (2011) [10] finding no evidence of adverse effects from dietary aluminum has led the medical and scientific community away from what would have been valuable empirical studies of injected aluminum adjuvants such as dose-escalation studies in infant mice. Studies that use oral citrate solution administration of aluminum, such as (Golub 1989) [12] are of no relevance for study of the toxicity of aluminum types from vaccines, as no vaccine contains citrate or is administered with citrate. ...
Article
Response to anonymous critic who contacted the journal and requested that our study be retracted because people might stop using the MMR vaccine if they learn about the toxicity of aluminum in pediatric vaccines (even though the MMR does not contain any aluminum).
... A majority of vaccines use aluminum salts as an adjuvant [16]. The cumulative dose of aluminum (up to 15 months of postnatal life) is, depending on the manufacturer, several milligrams per child which by far overcomes the amount of aluminum absorbed during breastfeeding [17][18][19]. So, each of the mentioned sources (vaccines and adopted formula) should not be neglected. ...
... Accumulation of aluminum in the femur is much higher than in the brain or the liver [29]. Mitkus et al. [19] proclaimed skeleton A. Cirovic and A. Cirovic as rigid i.e. non-"sensitive" tissue and a good target organ for aluminum to deposit. The skeleton must not be considered as a rigid structure and is not resistant to aluminum toxicity, since it intensively develops after birth. ...
... Vaccination must never be questioned. Mitkus et al. [19] and Keith et al. [17] explored all sources of aluminum in infants (vaccines, breastfeeding and infant formula) and showed that cumulative dose of aluminum was below the minimal risk level. However, potential factors such as iron deficiency, which may promote aluminum toxicity, were not included. ...
Article
Aluminum has adverse effects on human health. Aluminum is poorly transported from the gastrointestinal tract, but if the load is high, a significant level of aluminum may be absorbed. There are two main sources of aluminum in infants - adapted formulas (when an infant is predominantly fed with it), and vaccines. After aluminum enters the circulation, it binds to transferrin and remains mainly in the skeleton for a longer period of time. Transferrin receptor 1 (TfR1) is highly expressed on osteoblast-like cells whereas the number of TfR1 may additionally rise in case of iron deficiency. Since iron deficiency can induce the expression of TfR1, a larger quantities of aluminum may be uptaken by osteoblasts and consequently aluminum may decrease the number of osteoblasts and lead peak bone mass (PBM) closer to the osteoporotic threshold. Iron deficiency may potentiate aluminum-induced toxicity to bones. Aluminum burden in infants has always been considered as harmless whereas a potential increased toxicity of aluminum in high-sensitive infants caused by iron deficiency has not been evaluated.
... Several known methods exist for pediatric dosing by weight. In Clark's Rule [28][29][30][31][32][33][34][35][36][37][38][39] of pediatric dose calculations, for example, the adult body weight reference is usually (as published) considered to be 150 bs. (68 kg) with the calculated dose being converted to mg/kg. ...
... Mitkus et al. [32]'s calculations were based on the day/week propagated error. Mitkus et al. [32] published their study in 2011 when the PTWI was still at 1 mg/kg, further propagating the day/week error. ...
... Mitkus et al. [32]'s calculations were based on the day/week propagated error. Mitkus et al. [32] published their study in 2011 when the PTWI was still at 1 mg/kg, further propagating the day/week error. Thus, current assessments of aluminum accumulation from vaccination and dietary exposures are not correct. ...
Article
Full-text available
FDA regulations require safety testing of constituent ingredients in drugs (21 CFR 610.15). With the exception of extraneous proteins, no component safety testing is required for vaccines or vaccine schedules. The dosing of aluminum in vaccines is based on the production of antibody titers, not safety science. Here we estimate a Pediatric Dose Limit that considers body weight. We identify several serious historical missteps in past analyses of provisional safe levels of aluminum in vaccines, and provide updates relevant to infant aluminum exposure in the pediatric schedule considering pediatric body weight. When aluminum doses are estimated from Federal Regulatory Code given body weight, exposure from the current vaccine schedule are found to exceed our estimate of a weight-corrected Pediatric Dose Limit. Our calculations show that the levels of aluminum suggested by the currently used limits place infants at risk of acute, repeated, and possibly chronic exposures of toxic levels of aluminum in modern vaccine schedules. Individual adult exposures are on par with Provisional Tolerable Weekly Intake “limits”, but some individuals may be aluminum intolerant due to genetics or previous exposures. Vaccination in neonates and low birth-weight infants must be re-assessed; other implications for the use of aluminum-containing vaccines, and additional limitations in our understanding of neurotoxicity and safety levelsof aluminum in biologics are discussed. Project page: http://ipaknowledge.org/Pediatric-Dosing-of-Aluminum.php
... In this paper, we will show that Al is harmful to the CNS, acting in a number of deleterious ways and across multiple levels, to induce biosemiotic entropy [17]. A countervailing view exists [18][19][20], but the assertions of safety are invariably based on weak epidemiological designs, ones that overwhelm significant negative signals with irrelevant noise factors. Such studies that fail to detect significant negative outcomes neither stand up to rigorous scrutiny nor outweigh better designed research, in a vast and growing literature, showing significant negative impacts sustaining the central hypothesis of this paper. ...
... Al is used extensively in food processing, for example, in Al-mordanted dye lakes for food coloring, in coatings for pharmaceutical tablets and vitamin capsules, for emulsifying, as a rising agent, to thicken gravies, and in meat-binders, stabilizing agents and texturizers [18]. Even drinking water is a source of Al exposure, although the amount contained in drinking water is typically far below concentrations in common antacids [21]. ...
... Among the CNS problems in humans attributed to Al are dialysis associated encephalopathy (DAE) [32,62], autism spectrum disorders [9,63,64], Alzheimer's disease, Parkinson's disease, and related dementias [28,36] including those typical in Down syndrome [18]. Experimental and clinical data show the CNS as the most sensitive organ system negatively impacted by Al. ...
Article
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed. (PDF) Aluminum-induced entropy in biological systems: Implications for neurological disease. Journal of Toxicology, 2014, Article ID 491316, 27 pages, 2014. doi:10.1155/2014/491316.. Available from: https://www.researchgate.net/publication/333582751_Aluminum-induced_entropy_in_biological_systems_Implications_for_neurological_disease_Journal_of_Toxicology_2014_Article_ID_491316_27_pages_2014_doi1011552014491316 [accessed Jun 03 2019].
... Le stesse agenzie sarebbero state ben consigliate di ordinare studi tossico-cinetici complementari al fine di evitare la propagazione di informazioni azzardate sulla rapida eliminazione degli adiuvanti a base di allumino [54], specialmente dopo che essi sono diventati consapevoli di studi successivi che mostrano la fagocitosi, la persistenza intracellulare, la migrazione a distanza e la neurotossicità degli adiuvanti a base di alluminio [21,50,69,70]. [73,74] Due studi hanno messo a confronto l'impatto teorico negli infanti dell'alluminio assunto con la dieta e dell'alluminio di derivazioni vaccinica [73,74]. Il principio dei due studi è simile: questi sono calcoli teorici basati sull'assunzione e l'escrezione dell'alluminio dalla nascita fino a 12 mesi di età. ...
... Le stesse agenzie sarebbero state ben consigliate di ordinare studi tossico-cinetici complementari al fine di evitare la propagazione di informazioni azzardate sulla rapida eliminazione degli adiuvanti a base di allumino [54], specialmente dopo che essi sono diventati consapevoli di studi successivi che mostrano la fagocitosi, la persistenza intracellulare, la migrazione a distanza e la neurotossicità degli adiuvanti a base di alluminio [21,50,69,70]. [73,74] Due studi hanno messo a confronto l'impatto teorico negli infanti dell'alluminio assunto con la dieta e dell'alluminio di derivazioni vaccinica [73,74]. Il principio dei due studi è simile: questi sono calcoli teorici basati sull'assunzione e l'escrezione dell'alluminio dalla nascita fino a 12 mesi di età. ...
... Le limitazioni e le imperfezioni metodologiche del modello di Keith et al. [74] hanno giustificato il seguente studio di Mitkus et al. [73]. Mitkus • Mancata presa in considerazione dell'immaturità della filtrazione glomerulare nell'infante che potrebbe influire negativamente sulla rimozione dell'alluminio [73]; dovrebbe essere notato che la questione del la barriera emato-encefalica non è stata presa in considerazione anche se lo sviluppo del sistema nervoso è notoriamente sensibile alle esposizioni tossiche [80]. ...
... In sharp contrast to the quick elimination of soluble Al injected intravenously [93], intramuscular injection of isotopic Al hydroxide is associated with much slower elimination of Al in urine, accounting for 6% of the injected dose 28 days after injection in rabbits [94]. Based on data of this unique experimental toxicokinetic study, the duration for complete translocation of solubilized Al ions from the injected site to blood was calculated to be 5.5 months for Al hydroxide [95]. Consistently, experimental MMF invariably shrinks over time [91]. ...
... In addition, theoretical models based on Flarend's pre-conceptions and short-term results are flawed [7]. For example, Mitkus et al. [95] proposed a model to assess the risk of Al vaccines in infants, by reference to an oral minimal risk level (MRL) extrapolated from animal studies. They only considered solubilized Al, with erroneous calculations of absorption duration. ...
Article
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants. Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II. Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery. Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).
... Since equating the aluminum introduced into the body with food and water (essentially extracellular) to the one injected with the vaccines (exclusively intracellular) is not a matter of science (because of the total diversity in kinetics and bio-dynamics), the Mitkus et al. [1] estimates are not consistent with the significant study of Priest [2], and with the others mentioned in this paper. Indeed, Mitkus et al. [1] state that the burden of aluminium accumulated in the body from vaccines and diet, throughout an infant's first year of life, is significantly less than the corresponding safe level of aluminium burden modeled using the regulatory MRL. ...
... Since equating the aluminum introduced into the body with food and water (essentially extracellular) to the one injected with the vaccines (exclusively intracellular) is not a matter of science (because of the total diversity in kinetics and bio-dynamics), the Mitkus et al. [1] estimates are not consistent with the significant study of Priest [2], and with the others mentioned in this paper. Indeed, Mitkus et al. [1] state that the burden of aluminium accumulated in the body from vaccines and diet, throughout an infant's first year of life, is significantly less than the corresponding safe level of aluminium burden modeled using the regulatory MRL. They conclude by stating that: Those episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns". ...
Article
Full-text available
Background: Post-vaccination adverse reactions (AEs) are a reason of strong debate among scientists. Unfortunately, we often make the mistake of discussing just the epidemiology but not the molecular biology. The action mechanism of the vaccines is still not fully known despite the fact that aluminum adjuvants have been used for about 100 years. Hypothesis: We hypothesized a link between vaccinations and neuroinflammation. The peripheral proinflammatory cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of the vaccines can reach the brain and can cause neuroinflammation after microglia activation. Elevated pro-inflammatory cytokines, particularly TNF-α, have been described in studies regarding the cytokines profile in autistic children. IL-1β represents a cytokine that controls the local pro-inflammatory cascade and thereby affects the balance between protective immunity and destructive inflammation. A subgroup of children with ASD (Autism Spectrum Disorder) has developed neuroinflammation. Several postmortem studies have confirmed the activation of microglia and neuroinflammation. A recent study has shown the presence of aluminum in the brain of individuals with autism and this aluminum was also found in microglia cells. Aluminum from vaccines is redistributed to numerous organs, including brain, where it accumulates. Each vaccine adds to this tissue different level of aluminum. Aluminum, like mercury, activates microglia leading to chronic brain inflammation and neurotoxicity. Conclusion: The molecular mechanisms presented here demonstrate how peripheral cytokines, expressed after vaccination, can cause neuroinflammation in some subjects, after microglia activation, depending on the immunogenetic background and the innate immune memory.
... The only processed food that he had on a regular basis were infant formulas (Aptimal brand). Mitkus et al. 11 estimated the body burden of aluminum during the first 400 days of life for infants on formula diets and for a standard vaccination schedule, and the estimates show that the burden of aluminum from vaccinations exceeds that from dietary sources. 11 The child's aluminum containing vaccinations were: Infanrix DTPa-IPV+Hib (4 doses at 500 μg aluminum per dose), Prevenar13 (3 doses at 125 μg aluminum per dose), NeisVac-C Baxter (1 dose at 500 μg aluminum per dose). ...
... Mitkus et al. 11 estimated the body burden of aluminum during the first 400 days of life for infants on formula diets and for a standard vaccination schedule, and the estimates show that the burden of aluminum from vaccinations exceeds that from dietary sources. 11 The child's aluminum containing vaccinations were: Infanrix DTPa-IPV+Hib (4 doses at 500 μg aluminum per dose), Prevenar13 (3 doses at 125 μg aluminum per dose), NeisVac-C Baxter (1 dose at 500 μg aluminum per dose). The child was also vaccinated with Priorix (2 doses) but this vaccine does not contain an aluminum adjuvant. ...
... Continuing or restricting further vaccination is still controversial because there is no large population study investigating additional granuloma risk following further vaccination [2,3]. Due to the benign nature of aluminum granuloma and the benefit of routine vaccination, we decided to recommend that the patient continue taking routine vaccination [3,4]. ...
... Vaccination is a successful and cost-effective public health intervention. Aluminum-containing adjuvants are used worldwide in many vaccines, including vaccinations for diphtheria, tetanus, pertussis, invasive pneumococcus disease, human papillomavirus, and hepatitis B virus [4,5]. Side effects of aluminum-containing adjuvants are usually accompanied by persistent itch, and it may be challenging to diagnose asymptomatic cases. ...
Article
Full-text available
Vaccination is a successful and cost-effective public health intervention. Aluminum-containing adjuvants are used worldwide to improve the immune response of vaccines. Side effects of aluminum-containing adjuvants in skin and subcutis are usually accompanied by persistent itch, and it may be challenging to diagnose asymptomatic cases. Here we present a case of a 1-year-old girl with asymptomatic subcutaneous nodules. Magnetic resonance imaging (MRI) revealed subcutaneous lesions: 16 mm on the upper right and 4 mm on the upper left arms. Histological examination revealed a granulomatous reaction with lymphoid follicle-like structures in the subcutis, accompanied by a considerable number of macrophages with PAS-positive granular cytoplasm. Moreover, the granules stained positive with aluminon staining, which revealed the existence of aluminum. These findings indicate post-vaccination aluminum granuloma. Due to the benign nature of aluminum granuloma and the benefit of routine vaccination, we decided to recommend that the patient continue taking the routine vaccination.
... Aluminum is not safe, as has been previously indicated [16,17]. While standard pharmacokinetics models presume that plasma clearance reflects low toxicity, numerous studies now point to rapid specific tissue localization as problematic, with serum/plasma clearance without clearance from the body as a source of concern. ...
... Aluminum from vaccines localize to the bone, tying up transferrin (Mitkus, 2011), which is essential for localizing dietary iron to bone marrow for red blood cell production. Thus, pediatric vaccination with aluminum adjuvants may be a concern for anemia. ...
Article
Full-text available
Background: The COVID-19 pandemic has placed significant stressors on the medical community and on the general public. Part of this includes patients skipping well-child visits to reduce risk of exposure to SARS-CoV-2 virus. Published estimates of the duration of whole-body aluminum (Al) toxicity from vaccines in infants from birth to six months indicate that CDC's recommended vaccination schedule leads to unacceptably long periods of time in which infants are in aluminum toxicity (as measured by %AlumTox). Methods: We utilize these established clearance and accumulation models to calculate expected per-body-weight whole-body toxicity of aluminum from vaccines considering for children of all ages under CDC's Catch-Up schedule from birth to ten years, assuming social distancing for 6 months. Our updated Pediatric Dose Limit (PDL) model assumes a linear improvement in renal function from birth to two years. Results: Our results indicate that due diligence in considering alternative spacing and use of non-aluminum containing vaccines when possible will reduce whole body toxicity and may reduce risk of morbidity associated with exposure to aluminum. Conclusions: While reduction or elimination of aluminum exposure from all sources is always a good idea, our results indicate that careful consideration of expected aluminum exposures during regular and Catch-Up vaccination is found to be especially important for infants and children below 2 years of age. We urge caution in the mass re-starting of vaccination under CDC's Catch-Up schedule for children under 12 months and offer alternative strategies to minimize per-day/week/month exposure to aluminum hydroxide following the COVID-19 period of isolation.
... 31 The Centers for Disease Control and Prevention cited a study in which researchers calculated the aluminum exposure from vaccines during infancy and found the total to be far below the minimal risk levels established by the Agency for Toxic Substances and Disease Registry. 32 The aluminum-containing adjuvants are reported to have minimal adverse effects but are effective at improving the antibody response. 33 There are reports of a chronic local granulomatous inflammation known as macrophagic myofasciitis in a small number of patients after receiving intramuscular vaccines containing aluminum. ...
Article
Aluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease.
... It is also found in preservative, emulsifying agents, colorants, and baking powders. Such widespread use of Al in consumable and non consumable items will eventually lead to entry and deposition in human body, (Gura, 2010;Mitkus et al., 2011;Riihimaki and Antero, 2012;Kramer and Heath, 2014;Sjogren et al., 2015;Mahor and Ali, 2015;Exley, 2016;Jakkala et al., 2016;Weidenhamer et al., 2017;Gouda et al., 2018;Mahor and Ali et al., 2018;Yan et al., 2019). ...
... This study explored the ability of a biomaterial that concentrates antigen-specific T H 2 memory T cells, already formed with previous vaccinations, to promote blood perfusion recovery of ischemic tissue. Virtually all persons born in the United States have received childhood vaccinations recommended by the Centers for Disease Control and Prevention, such as those for DTaP (diphtheria, tetanus, and pertussis) and hepatitis B, that contain aluminum, a potent T H 2 adjuvant (22,23). A biomaterial that provides localized release of antigen specific to these T H 2 memory T cells at later times in these patients may transiently recruit and activate these cells to produce cytokines at sites of ischemia and promote vascularization. ...
Article
Full-text available
Ischemic diseases are a leading cause of mortality and can result in autoamputation of lower limbs. We explored the hypothesis that implantation of an antigen-releasing scaffold, in animals previously vaccinated with the same antigen, can concentrate T H 2 T cells and enhance vascularization of ischemic tissue. This approach may be clinically relevant, as all persons receiving childhood vaccines recommended by the Centers for Disease Control and Prevention have vaccines that contain aluminum, a T H 2 adjuvant. To test the hypothesis, mice with hindlimb ischemia, previously vaccinated with ovalbumin (OVA) and aluminum, received OVA-releasing scaffolds. Vaccinated mice receiving OVA-releasing scaffolds locally concentrated antigen-specific T H 2 T cells in the surrounding ischemic tissue. This resulted in local angiogenesis, increased perfusion in ischemic limbs, and reduced necrosis and enhanced regenerating myofibers in the muscle. These findings support the premise that antigen depots may provide a treatment for ischemic diseases in patients previously vaccinated with aluminum-containing adjuvants.
... The FDA-approved aluminum concentration of 850 μg (0.85 mg) per vaccine was deduced from data showing that this quantity of aluminum per injection was able to improve the vaccine's antigenicity and potency [63,65], though did not take into account safety implications nor adapt the equations for a child's corporal weight. It has been stated that it is ethically incorrect that vaccine adjuvants are not utilized to execute experimental safety investigations before to use on humans [66]. ...
Article
Full-text available
Background: For nearly a century, aluminum hydroxide (alum) has continued to be employed as an adjuvant in vaccinations. It was first applied by immunologist Alexander T. Glenny in 1926 to boost the immune response. Its great efficiency has allowed aluminum to continue to be used to date. Methods: Recognized scientific databases such as Google Scholar, Web of Science, and PubMed were utilized to search for the keywords. The selected works were reviewed and analyzed according to their relevance. Only peer-reviewed articles were included in the analysis. Results: Contemporary research carried out on animals has shown that it has a neurotoxic effect. Furthermore, increased aluminum concentrations in the nervous system tissues of people, who died from an autism condition have been discovered by using advanced imaging techniques. The paradigm shift proposes a reconsideration of the use of the alum-based adjuvants and calls for a careful dissection to avoid incorrect interpretations. This proposal does not constitute an attack on vaccination, as nobody refutes the fact that it has been systematically proven to be effective in saving millions of lives. Unfortunately, scientists, who have investigated the toxicity of aluminum-based adjuvants have been unfairly labeled as "anti-vaxxers". Rather, what they have been questioning is the safety of aluminum as an adjuvant. Conclusions: The present work encourages researchers, health regulatory agencies, and even pharmaceutical companies to allow themselves to think about the possibility that aluminum-based adjuvants could be toxic for susceptible children.
... De manera natural, este elemento se encuentra en algunos vegetales y especias. Igualmente, puede estar presente en desodorantes, pastas dentífricas, cementos dentales y prótesis ortopédicas 5 . ...
... Andere Studienkommenjedochunter Zugrundelegung bestimmter Parameter zu der Schlussfolgerung, dass von der Verimpfung alumadjuvantierter Impfstoffe ein minimales Risiko ausgeht und ein eindeutig positives Nutzen-Risiko-Verhältnis besteht. Diese Parameter sind insbesondere: der basale Al-Spiegel bei der Geburt, Al-Retention, welche die tatsächliche glomeruläre Filtrationsrate bei Kindern widerspiegelt, und ein aktuelles pädiatrisches Impfmuster [47]. Allerdings verhalten sich nicht alle Albasierten Adjuvanzien identisch hinsichtlich ihrer physikochemischen und biologischen Eigenschaften [48]. ...
Article
The immunogenicity and efficacy of vaccines is largely governed by nature and the amount of antigen(s) included. Specific immune-stimulating substances, so-called adjuvants, are added to vaccine formulations to enhance and modulate the induced immune response. Adjuvants are very different in their physicochemical nature and are primarily characterized by their immune-enhancing effects. In this report, adjuvants that are components of vaccines licensed in the EU will be presented and their mode of action will be discussed. Aluminum salts have been used for almost a century as vaccine adjuvants. In recent years numerous novel immune-stimulating substances have been developed and integrated into licensed human vaccines. These novel adjuvants are not only intended to generally increase the vaccine-induced antibody titers, but are also aimed at modulating and triggering a specific immune response. The search for innovative adjuvants was considerably stimulated during development of pandemic influenza vaccines. By using squalene-containing oil-in-water adjuvants (namely AS03 and MF59), pandemic influenza vaccines were developed that were efficacious despite a significant reduction of the antigen content. The development of novel adjuvants is a highly dynamic and essential area in modern vaccine design. Some years ago, vaccines for prevention of HPV-induced cervix carcinoma and hepatitis B were licensed that contained the toll-like receptor 4 agonist 3‑O-desacyl-monophosphoryl lipid A (MPL), a detoxified LPS version, as the adjuvant. Quite recently, a herpes zoster vaccine was licensed in Europe with a combination of MPL and the saponin QS21 as adjuvant. This combination of immune enhancers is also used in the formulations of the same manufacturer’s malaria and hepatitis B vaccine. © 2019, Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.
... Aluminum salts have safely been used to adjuvant vaccines since the 1930s and are currently used in vaccines such as hepatitis A, hepatitis B, diphtheria-tetanus-containing vaccines, Hib, and pneumococcal vaccines, but they are not used in the live, viral vaccines, such as measles, mumps, rubella, varicella, and rotavirus. Studies have shown that children who receive aluminum-containing vaccines have serum levels of aluminum that are well below the toxic range [29]. The strongest evidence of the safety of aluminum in childhood vaccines is provided by a recent study in which children aged 9−13 months were evaluated for blood and hair aluminum levels, vaccination history, and cognitive, language, and motor development scores. ...
Article
Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including (1) measles, mumps, and rubella vaccine and autism; (2) thimerosal, a mercury-based vaccine preservative and the risk of neurodevelopmental disorders; (3) vaccine-induced Guillain-Barré syndrome (GBS); (4) vaccine-induced autoimmune diseases; (5) safety of human papillomavirus vaccine; (6) aluminum adjuvant-induced autoimmune diseases and other disorders; and (7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns.
... Further, an error led to the use of an assumed safe tolerable limit of 1 mg/day (all sources), up from 1 mg/week [5]. Important studies impacting views on the tolerable doses of aluminum were impacted as this error propagated [35]. Flaws in the designs of studies that supported current aluminum amounts in vaccines are cause for grave concerns over widespread use of aluminum in vaccines in the current CDC schedule [36]. ...
Article
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Neurodevelopmental disorders, including Autism Spectrum Disorders, have a complex biological and medical basis involving diverse genetic risk and myriad environmental exposures. Teasing apart the role of specific stressors is made challenging due to the large number of apparently contributing associations, gene X environment interactions and phenomimicry [1]. Historically, these conditions have been rare, making causality assessment at the population level infeasible. Only a few vaccines have been tested for association with autism, and it has been shown that improved diagnosis only explains a percentage of the increase in diagnosis. Now, the rates are so high in some countries that public school programs cannot handle the large numbers of special needs students, and professionals are quitting their jobs due to security concerns. Here, I review evidence of the pathophysiology of autism that reconciles the apparent paradox between the high degree of causal heterogeneity in environmental toxins, the absence of common "autism gene," and the high degree of genetic concordance (heritability) of ASD and ASD-like traits. In brief, the sampling of environmental toxins, and thus the environmental toxin sampling liability for ASD varies among families involving different local exposures following injury to normal cellular endoplasmic detoxification and mitochondrial processes from toxic metals. The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, run-away cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload (ER hyper stress), contributing to neuronal and glial apoptosis via the unfolded-protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal retoxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD; the great diversity of genes that are found to have low, but real contributions to ASD risk and the sensitivity of individuals with ASD to environmental toxins. The hindrance of detoxification and loss of cellular energetics leads to apoptosis, release of cytokines and chronic neuroinflammation and microglial activation, all observed hallmarks of ASD. Interference with the development of normal complex (redundant) synapses leads to a pathological variation in neuronal differentiation, axon and dendrite outgrowth, and synaptic protein expression. The most general outcomes are overall simplification of gross synaptic anatomy and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term connections between distant regions of the brain. Failed resolution of the ER stress response leads to re-distribution of neurotoxic metals, and the impaired neurocellular processes lead to subsequent accumulation of a variety of additional types of toxins with secondary, sometime life-threatening comorbidities such as seizures, with overlapping (not mutually exclusive) causality. Reduction of exposure to toxins known to cause mitopathy (mercury) and endoplasmic reticulum dysfunction (mercury and aluminum) during pregnancy and during the early years of development will reduce the risk of ER overload and ER hyper stress, and of ASD diagnosis. This knowledge has immediate clinical translational relevance: post-vaccination symptoms should be heeded as a sign of susceptibility to toxin; Vitamin D can be increased to drive the healthy early phases of the UPR, and mutations in ASD genes encoding proteins with high intrinsic disorder may contraindicate the use of aluminum and mercury for carriers of risk alleles. Clinicians should be alert to a patient’s Vitamin D receptor (BSM) mutational status prior to recommending increased doses. Approaches to improving overall brain health in autistics must be de-stigmatized and given high priority. Reduction of lifetime exposures of industrial and agricultural toxins will improve brain health for the entire human population. Purely genetic studies of ASD, and studies that do not include vaccination as an environmental exposure with potential liability and interactions with genes, are unethical. To qualify as science, studies must test plausible hypotheses, and the absence of association from poorly designed, unethically executed, and underpowered and unsound whole-population association studies have been harmful distractions in the quest for understanding. Skilled paediatricians and ob/gyns will seek evidence of genetic predisposition to environmental susceptibility in the form of non-synonymous substitutions in brain proteins that require ER-folding, and they will provide informed cautions on exposures (from all sources) to environmental toxins to patients and parents of patients with signs of metal and chemical sensitivity. To aid in this, a list of ASD environmental susceptibility protein-encoded genes is presented. A clinical Exome sequence test, followed by loss of function prediction analysis, would point to individuals most susceptible to vaccine metal-induced ER hyper stress leading to failed cellular detoxification.
... Further, an error led to the use of an assumed safe tolerable limit of 1 mg/day (all sources), up from 1 mg/week [5]. Important studies impacting views on the tolerable doses of aluminum were impacted as this error propagated [35]. Flaws in the designs of studies that supported current aluminum amounts in vaccines are cause for grave concerns over widespread use of aluminum in vaccines in the current CDC schedule [36]. ...
... Interestingly, a previous study showed that boiling acidic food such as fruits in aluminum pots could induce chemical corrosion and release of aluminum from the pots into food [27]. Furthermore, Al-containing adjuvants were used in several vaccines routinely injected to infants and young children such as diphtheria-tetanus-acellular pertussis (DTP) vaccine, haemophilus influenza type b vaccine, hepatitis B vaccine, and pneumococcal vaccine [28]. Unfortunately, the toxicity of Al in vaccines is still subject of debate [29]. ...
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Toxic element exposure increases risk of neurodevelopmental disorders. However, hair element profiles of well-nourished urban resident children were largely unknown. We identified prevalence and the contributing factors of high hair aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) levels in 111 Thai children (aged 3–7 years old). Most participants were well-nourished with high socioeconomic status. Since ROC curve of hair element data showed inadequate sensitivity for cutoff set-up, US reference hair levels were used to categorize high and low level groups. Nevertheless, compared to the current reference at 5 μg/dL, blood lead cutoff at 2.15 μg/dL provided more consistent results with that of hair lead levels. High As and Pb levels were the first and second most prevalent element, while Al was the element found in highest amount in hair. High hair Al (12% prevalence) levels were associated with being male regardless of age or nutritional status. High hair As levels were associated with living in Bangkok (OR = 6.57) regardless of school type. High hair Pb levels were associated with being under 5 years old and living in Bangkok (OR = 3.06). However, no associations were found between blood Pb, hair Cd, Hg, and tested factors. These findings suggested that under 5-year-old boys living in capital city like Bangkok may be at risk of exposure to multiple toxic elements. Future studies in these children are warranted to identify their exposure sources and proper risk management strategies.
... As stated in text, dosage was determined following the recommendations of the French drug safety agency AFSSAPS (now called ANSM). Of note, the conversion factor of x12.3 used to approximate human to mouse dosage is far lower than the x30 factor used by the Agency for Toxic Substances and Disease Registry (Keith et al., 2002) and by the US Food and Drug Administration (Mitkus et al., 2011). Furthermore, when Hawkes and Benhamu indicate we say that "Engerix vaccine contains 500 μg of Alhydrogel", Hawkes and Benhamu do not cite us correctly and apparently make no difference between the dose of the whole molecule (Alhydrogel: AlOOH) and the dose of Al. ...
... Extrapolating mouse to human dosage is a challenging issue since a firm scientific basis for allometric conversion is still lacking. To approximate human to mouse dosage for aluminum studies, a conversion factor of ×30 is used by the Agency for Toxic Substances and Disease Registry [21] and by the US Food and Drug Administration [22]. Since ASIA usually occurs after multiple aluminum-containing vaccine administrations (up to 12 injectionsnot restricted to a single vaccine-in our experience [23]) administration Autoimmunity Reviews xxx (2018) xxx-xxx AUTREV-02167; No of Pages 3 of important doses may not be so unrealistic. ...
... The Alum N1.9 regimen tested here mimicked the number and order of immunizations performed in RV144 and our SIV-Alum Alh study, but while the gp120 boosts were maintained at the same dose as used in SIV-Alum Alh and RV144 (200 μg each), a much lower dose of Alum N was used in Study 1 (750 μg/dose). Although the FDA and CDC approve of no more than 850 μg of Alum Alhydrogel per dose in human vaccines [37,38], we used 5,000 μg/dose in SIV-Alum Alh to compensate for the welldocumented pharmacokinetic differences among differently sized species [27]. Counterintuitively, this typically means that a drug must be administered at a higher dose in smaller animals such as macaques to obtain the same effects elicited in larger species. ...
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The ALVAC-HIV clade B/AE and equivalent SIV-based/gp120 + Alum vaccines successfully decreased the risk of virus acquisition in humans and macaques. Here, we tested the efficacy of HIV clade B/C ALVAC/gp120 vaccine candidates + MF59 or different doses of Aluminum hydroxide (Alum) against SHIV-Cs of varying neutralization sensitivity in macaques. Low doses of Alum induced higher mucosal V2-specific IgA that increased the risk of Tier 2 SHIV-C acquisition. High Alum dosage, in contrast, elicited serum IgG to V2 that correlated with a decreased risk of Tier 1 SHIV-C acquisition. MF59 induced negligible mucosal antibodies to V2 and an inflammatory profile with blood C-reactive Protein (CRP) levels correlating with neutralizing antibody titers. MF59 decreased the risk of Tier 1 SHIV-C acquisition. The relationship between vaccine efficacy and the neutralization profile of the challenge virus appear to be linked to the different immunological spaces created by MF59 and Alum via CXCL10 and IL-1β, respectively.
... As a vaccine component, aluminum has been extensively tested for safety as part of pre-licensure clinical trials. We know from studies examining the aluminum exposure of infants that the cumulative amount of aluminum from vaccines in the first 6 months of life is actually far less than that received from dietary sources, including both breast milk and formula (Keith et al., 2002;Mitkus et al., 2011). Both sources represent far less exposure than that represented by a regulatory minimal risk level (MRL), which is established by the Agency for Toxic Substances and Disease Registry. ...
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The World Health Organization has named vaccine hesitancy as one of the top ten threats to global health in 2019. The reasons why people choose not to vaccinate are complex, but lack of confidence in vaccine safety, driven by concerns about adverse events, has been identified as one of the key factors. Healthcare workers, especially those in primary care, remain key influencers on vaccine decisions. It is important, therefore, that they be supported by having easy access to trusted, evidence-based information on vaccines. Although parents and patients have a number of concerns about vaccine safety, among the most common are fears that adjuvants like aluminum, preservatives like mercury, inactivating agents like formaldehyde, manufacturing residuals like human or animal DNA fragments, and simply the sheer number of vaccines might be overwhelming, weakening or perturbing the immune system. As a consequence, some fear that vaccines are causing autism, diabetes, developmental delays, hyperactivity, and attention-deficit disorders, amongst others. In this review we will address several of these topics and highlight the robust body of scientific evidence that refutes common concerns about vaccine safety.
... Aluminium salts are commonly used as adjuvants, i.e., additives that prime and boost the immune system in vaccines. Aluminium based adjuvants have a well-established track record [5,6], however, risk of over-vaccination [7] and adverse and toxic effects have been reported [7,8]. The majority of the reported adverse effects are related to breaking self-tolerance e.g. ...
Article
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Aluminium salts have been used as adjuvants in vaccines for almost a century, but still no clear understanding of the mechanisms behind the immune stimulating properties of aluminium based adjuvants is recognized. Aluminium adjuvants consist of aggregates and upon administration of a vaccine, the aggregates will be recognized and phagocytosed by sentinel cells such as macrophages or dendritic cells. The adjuvant aggregates will persist intracellularly, maintaining a saturated intracellular concentration of aluminium ions over an extended time. Macrophages and dendritic cells are pivotal cells of the innate immune system, linking the innate and adaptive immune systems, and become inflammatory and antigen-presenting upon activation, thus mediating the initiation of the adaptive immune system. Both types of cell are highly adaptable, and this review will discuss and highlight how the occurrence of intracellular aluminium ions over an extended time may induce the polarization of macrophages into inflammatory and antigen presenting M1 macrophages by affecting the: endosomal pH; formation of reactive oxygen species (ROS); stability of the phagosomal membrane; release of damage associated molecular patterns (DAMPs); and metabolism (metabolic re-programming). This review emphasizes that a persistent intracellular presence of aluminium ions over an extended time has the potential to affect the functionality of sentinel cells of the innate immune system, inducing polarization and activation. The immune stimulating properties of aluminium adjuvants is presumably mediated by several discrete events, however, a persistent intracellular presence of aluminium ions appears to be a key factor regarding the immune stimulating properties of aluminium based adjuvants.
... Aluminum hydroxide and aluminum phosphate that have positive and negative surface charges, respectively, are the most common aluminum adjuvants that have been used in vaccine development [41], and their electrostatic interactions with oppositely-charged antigens are responsible for the adsorption of antigens on these adjuvants [18]. The surface adsorption of antigens is important owing to: (1) it maintains antigen at the site of injection, allowing rapid recruitment of APCs followed by cytokine release and the induction of local inflammatory reactions [42][43]; (2) it particulates soluble antigens, enhancing their phagocytosis by APCs [15,[44][45]; and (3) it targets antigen to APCs to enhance antigen presentation and activation of T cells [46][47]. ...
Article
The nanostructured complexes can result in enhanced vaccine efficacy by facilitating the distribution and uptake of antigens by antigen-presenting cells (APCs), thereby stimulating immune responses. Here, we hypothesized that either directly coating of nanoadjuvants including aluminum phosphate (AlPO4) and adenovirus (Ad) with a modified HPV16 E7 MHC-I specific epitope, RAHYNIVTF49–57, or mixing the CpG oligodeoxynucleotide (CpG-ODN) with the cationic epitope to form nanocomlexes, and their combinational therapy would enhance their anti-tumor effects in a TC-1 mouse model. The positively-charged HPV16 E7 epitope was attracted to the oppositely-charged adjuvants by electrostatic interaction to generate epitope/adjuvant nanocomplexes. We showed that coating the nanosized adjuvants with the cationic epitope increased the particles' surface charge without significant change in their size. We then tested the cellular immunogenicity and therapeutic efficacy of nanocomplexes by measuring IL-10 and IFN-γ production, the expression of CD107a as a marker of CTL response, and tumor growth inhibition. The nanocomplexes were administered either in homologous or heterologous prime-boost regimens, and heterologous immunizations including Ad/Pep-CpG/Pep, CpG/Pep-Ad/Pep, Ad/Pep-Alum/Pep, and Alum/Pep-Ad/Pep induced significantly higher levels of IL-10, IFN-γ, and CD107a-expressing CD8 T cells compared with homologous administrations. Furthermore, the tumor growth was significantly suppressed in mice receiving nanostructured complexes in the heterologous immunizations. Our study highlights the potential of the heterologous prime-boost administration of the epitope-coated nanostructures as an effective immunization strategy.
... Aluminum adjuvants are present in vaccines against hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP), Haemophilus influenzae type b (Hib), human papillomavirus (HPV) and pneumococcus infectious agents (Center for Disease Control, mg of aluminum present as aluminum phosphate (HogenEsch et al., 2018). It is thought that the amount of aluminum found in these vaccines poses a low risk of harm compared to its benefits (Mitkus et al., 2011). In the present study, we used 10-100 µg/mL concentrations which are in the range used by other investigators to assess the in vitro response to ABAs (Ulanova et al., 2001;Mold et al., et al., 2016;Vrieling et al., 2020). ...
Article
Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant’s effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 µg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy.
... However, these ingredients have been proven to be safe at the levels used in vaccines. Aluminum levels in infants from vaccine adjuvant and food sources are safely below risk levels (Mitkus et al. 2011). The only vaccine ingredient that contains mercury is thimerosal, a preservative used to prevent the growth of bacteria. ...
... 7 Multiple high-quality studies have shown that children who receive vaccines containing aluminium adjuvants do not have aluminium in their blood or hair above the minimum risk levels established by the Agency for Toxic Substances and Disease Registry, and they are not at increased risk of adverse neurodevelopmental outcomes. [8][9][10] The GACVS reviewed the available safety data on adjuvants, including aluminium compounds for the first time in 1999, specifically addressing a type of histopathological lesion of unknown origin called macrocytic myofasciitis 11 12 (table 1). In 2004, the Committee recognised the need for surveillance of vaccine adjuvant safety, particularly in low-income and middle-income countries, and made recommendations for WHO to consider developing a website for adjuvant contents of vaccines. ...
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Global gains in vaccination coverage during the early 21st century have been threatened by the emergence of antivaccination groups that have questioned the effectiveness of vaccines to generate public distrust of vaccines and immunisation programmes. This manuscript summarises six key topics that have been at the centre of global discussions on vaccine safety during the early 21st century: thiomersal in multi-dose non-live vaccines, aluminium adjuvants used with several non-live vaccines, autism and auto-immune conditions as possible consequences of vaccination, a risk of immune overload with increasing numbers of vaccinations, and detrimental non-specific effects (NSEs) of vaccination. For each topic, we describe the hypothesis behind the public concern, the evidence reviewed by the WHO’s Global Advisory Committee for Vaccine Safety (GACVS) during 1999–2019, and any significant new data that has emerged since GACVS conclusions were made. Although the scientific evidence on these issues overwhelmingly supports the safety of vaccines, communication messages to caregivers and providers need to condense and convey scientific information in an appropriate way to address concerns contributing to vaccine distrust. In addition, there is need for further studies specifically designed to address both positive and negative NSE of vaccination. The role of GACVS will be increasingly important in evaluating the evidence and engaging the global community in promoting and assuring the safety of vaccines in the decades to come as we move into an era in which we use new vaccination platforms, antigens and formulations.
... 1 5-10 However, both the US Food and Drug Administration Center for Biologics Evaluation and Research and the US Agency for Toxic Substances and Disease Registry concluded that traditional aluminium adjuvants are safe. 11 12 Aluminium adjuvants have been associated with a number of adverse effects, including injection site pain and tenderness, persistent lumps, granulomas, contact dermatitis and postimmunisation headache, 13 but also more severe adverse events such as macrophagic myofasciitis 14 and the autoimmune/inflammatory syndrome induced by adjuvants. 15 Animal models have demonstrated the toxicity of aluminium adjuvants 16 and their translocation away from the injection site. ...
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The Merck Sharp & Dohme Corp aluminium adjuvant ‘amorphous aluminium hydroxyphosphate sulfate’ (AAHS), primarily used in the Gardasil vaccines against human papilloma virus, has been criticised for lack of evidence for its safety. Documentation from Danish authorities and answers from the European Medicines Agency (EMA) suggest that AAHS may not have been sufficiently evaluated. Documentation from the Danish Medicines Agency shows discrepancies in the trial documents of two prelicensure clinical trials with Gardasil in 2002 and 2003. For both trials, the Agency seems to have authorised potassium aluminium sulfate as the adjuvant and not AAHS. In addition, the participants in the trial launched in 2002 were informed that the comparator was saline, even though the comparator was AAHS in an expedient consisting of L-histidine, polysorbate-80, sodium borate and sodium chloride. According to the EMA, AAHS was first introduced in Europe in 2004 as the adjuvant in Procomvax, a vaccine against the hepatitis B virus and Haemophilus influenza type b. The EMA reports that AAHS was introduced without any prelicensure safety evaluation. The adjuvant is described by the company to be both physically and functionally distinct from all other previously used aluminium adjuvants. There is a need for rigorous evaluation of benefits and harms of the adjuvant AAHS.
... It contains plenty of bioactive compounds such as amino acids, minerals, vitamins and sulphur (Roldán et al., 2008). Literature showed that Al is present in environment ubiquitously and is a growing threat to humanity (Mitkus et al., 2011). Lot of studies have been done on neurotoxicity of Al but its potential biochemical toxicity on basic organs are not avaliable. ...
... It contains plenty of bioactive compounds such as amino acids, minerals, vitamins and sulphur (Roldán et al., 2008). Literature showed that Al is present in environment ubiquitously and is a growing threat to humanity (Mitkus et al., 2011). Lot of studies have been done on neurotoxicity of Al but its potential biochemical toxicity on basic organs are not avaliable. ...
... By the way, on 04/30/2018 the U.S. Food and Drug Administration (FDA) asserted: "Aluminium adjuvant containing vaccines have a demonstrated safety profile of over six decades of use and have only uncommonly been associated with severe local reactions. A study conducted by FDA determined that the risk to infants posed by the total Al exposure received from the entire recommended series of childhood vaccines over the first year of life is extremely low (Mitkus et al., 2011). This study provided additional scientific information confirming that the benefits of Al-containing vaccines administered during the first year of life outweigh any theoretical concerns about the potential effect of Al on infants. ...
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Aluminium is widely used in many consumer products, however the primary source of aluminium exposure to the Canadian general population is through food. Aluminium can cause neurotoxicity and reproductive toxicity at elevated exposure levels. Health-based exposure guidance values have been established for oral exposure to aluminium, including a Minimal Risk Level (MRL) by the Agency for Toxic Substances and Disease Registry (ATSDR), a Provincial Tolerable Weekly Intake (PTWI) by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and a Tolerable Weekly Intake (TWI) by the European Food Safety Authority. Aluminium concentration in blood and urine can be used as a tool for exposure characterization in a population. A pharmacokinetic (PK) model was developed based on human dosing data to derive blood Biomonitoring Equivalents (BEs), whereas a mass balance approach was used to derive urine BEs for the above guidance values. The BEs for blood for daily intake consistent with the MRL, PTWI and TWI were 18, 16 and 8 μg/L, respectively. BEs for urine for the same guidance values were 137, 123 and 57 μg/L, respectively. The derived BEs may be useful in interpreting population-level biomonitoring data in a health risk context and thereby screening and prioritizing substances for human health risk assessment and risk management.
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ABSTRACT Epidemic diseases caused by microorganisms have taken an important place in human history since ancient times. Vaccines play an important role in the prevention of epidemics. The emergence of the smallpox vaccine idea by Dr. Edward Jenner for the first time in 1798 brought along the refusal of the vaccine by the circles offering unscientific reasons. In vaccine rejection or vaccine hesitancy; Many factors such as people's past experience with vaccines, superstitions about vaccines, and lack of knowledge about vaccines play a role. The benefits and possible side effects of vaccines have been discussed in many scientific studies and still continue to be discussed. In our world, which has witnessed many epidemics, the Covid-19 pandemic caused by the globally devastating Coronavirus; It has led to a reconsideration of the importance of vaccines and the epidemics seen in human history. In this review; Epidemics witnessed by human history from past to present, the history of vaccines, the concepts of vaccine refusal and vaccine hesitancy, and the reasons that reveal these concepts are discussed. ÖZET Eski zamanlardan günümüze kadar mikroorganizmaların neden olduğu salgın hastalıklar insanlık tarihinde önemli bir yer edinmiştir. Salgın hastalıkların önlenmesinde aşılar önemli bir yer tutmaktadır. İlk kez 1798 yılında Dr Edward Jenner tarafından Çiçek aşısı fikrinin ortaya çıkması, bilimsel olmayan nedenler sunan çevrelerce aşı reddini de beraberinde getirmiştir. Aşı reddi veya aşı kararsızlığında; kişilerin aşılarla ilgili geçmiş tecrübeleri, aşılar ile ilgili hurafeler, aşılar hakkında yeterince bilgi sahibi olunmaması gibi birçok faktör rol almaktadır. Aşıların yararları ve olası yan etkileri bilimsel çevrelerce birçok çalışmada ele alınmış ve hala da ele alınmaya devam etmektedir. Birçok salgına tanıklık etmiş Dünya’mızda son olarak küresel boyutta yıkıcı olan Coronavirus’ün neden olduğu Covid-19 pandemisi; beraberinde aşıların önemini ve insanlık tarihinin gördüğü salgınları yeniden gözden geçirmeye neden olmuştur. Bu derlemede; geçmişten günümüze insanlık tarihinin tanık olduğu salgınlar, aşıların tarihçesi, aşı reddi ve aşı kararsızlığı kavramları, bu kavramları ortaya çıkaran nedenler ele alınmıştır.
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Although vaccines have already saved and will continue to save millions of lives, they are under attack. Vaccine safety is the main target of criticism. The rapid distribution of false information, or even conspiracy theories on the internet has tremendously favored vaccine hesitancy. The World Health Organization (WHO) named vaccine hesitancy one of the top ten threats to global health in 2019. Parents and patients have several concerns about vaccine safety, of which the ubiquitous anxieties include inactivating agents, adjuvants, preservatives, or new technologies such as genetic vaccines. In general, increasing doubts concerning side effects have been observed, which may lead to an increasing mistrust of scientific results and thus, the scientific method. Hence, this review targets five topics concerning vaccines and reviews current scientific publications in order to summarize the available information refuting conspiracy theories and myths about vaccination. The topics have been selected based on the author's personal perception of the most frequently occurring safety controversies: the inactivation agent formaldehyde, the adjuvant aluminum, the preservative mercury, the mistakenly-drawn correlation between vaccines and autism and genetic vaccines. The scientific literature shows that vaccine safety is constantly studied. Furthermore, the literature does not support the allegations that vaccines may cause a serious threat to general human life. The author suggests that more researchers explaining their research ideas, methods and results publicly could strengthen the general confidence in science. In general, vaccines present one of the safest and most cost-effective medications and none of the targeted topics raised serious health concerns.
Chapter
Some have said that the Internet is an instrument of democracy. Taken literally, this statement is false. We have to add: it is an instrument of potential democracy. The motto of the Internet can be summarized in the words, paradoxical and politically incorrect, pronounced by Jesus: “Whoever has will be given more” (Matthew, XIII, 12). To navigate in the Internet, to distinguish the pearl from the sow’s ear, you already have to have had access to culture—an access which normally (and I speak from personal experience) is associated with social privilege. The Internet, which potentially could be an instrument that could attenuate cultural inequalities, in the immediate, exasperates them. Schools need the Internet, of course, but the Internet, to be used according to its potential (let’s say realistically one-millionth of its capacity), needs state schools that really teach.
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Patients with Systemic Lupus Erythematosus (SLE) pose a unique dilemma pertaining to immunization against common pathogens. SLE patients are usually not immunized with vaccines based on the fear of either precipitating infection in this immunosuppressed patient population (with live vaccines) or aggravating autoimmunity and hence lupus flares (with any vaccines). However, elevated vulnerability to infection makes patients with SLE precisely the population that needs protection from vaccine-preventable diseases. A summary of guidelines from the Centers for Disease Control and Prevention, professional societies, review articles and expert opinions regarding use of individual vaccines applicable to adults with SLE is presented in this review.
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The manuscript reviews the association between aluminum adjuvants (AlAd) in vaccines and autism spectrum disorder (ASD). Aluminum (Al) is neurotoxic. Infants who have received AlAd in vaccines show a higher rate of ASD. The behavior of mice changes with Al injection. Patients suffering from ASD have higher concentrations of Al in their brains. Thus, AlAd is an etiologic factor in ASD. Immune efficacy led to the use of the AlAd in vaccines; however, the safety of those who are vaccinated with such vaccines has not been considered. The mechanisms of action of AlAd and the pharmacodynamics of injected AlAd used in vaccines are not well-characterized. The association between aluminum adjuvants in the vaccines and autism spectrum disorder is suggested by multiple lines of evidence.
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The details of vaccine development, licensing, and monitoring have never been more important and relevant to the health care conversation in the United States. The potential exists for a preventive medicine such as a vaccine to cause harm, and physicians and patients need to understand the real balance of risks and benefits of immunization. Vaccines given in the United States undergo rigorous testing before licensure as well as extensive postlicensure safety monitoring.
Chapter
Certain ingredients that are present in some vaccines (other than disease-specific antigens), such as gelatin or neomycin, can very rarely cause severe hypersensitivity reactions (e.g. anaphylaxis) in vaccinees with those specific allergies. In addition, some adjuvants can cause increased rates of local reactions, and alum containing adjuvants can cause nodules at the injection site. Vaccine ingredients, including the preservative thimerosal, do not cause autism. Ingredients in vaccines currently routinely recommended to the general population in the U.S. have not been shown to cause any other adverse events.
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Résumé Introduction La vaccination constitue une avancée majeure dans la prévention des maladies infectieuses. Le principe des vaccins est d’induire une protection contre un agent pathogène donné en éduquant le système immunitaire humain. Le vaccin permet de réduire le risque de complications et la mortalité en cas d’exposition ultérieure à l’agent infectieux. État des connaissances Dans cette revue, nous rappelons l’histoire de la vaccination ainsi que les principes immunologiques de base qui sous-tendent la composition des vaccins et la réponse vaccinale. Ainsi, les vaccins permettent au système immunitaire de produire une mémoire immunologique reposant sur les lymphocytes T et B mémoires afin de produire une réponse rapide et efficace lors de l’exposition à l’agent pathogène ciblé. Perspectives L’amélioration des vaccins déjà existants et la découverte de nouveaux vaccins passent par la compréhension fine des déterminants immunologiques de la vaccination. Les défis restent grands, notamment en termes d’agents pathogènes-cibles, de futurs candidat-vaccins mais aussi d’acceptation de la vaccination. Conclusion La compréhension des principes de la vaccination permet ainsi de poursuivre le développement des vaccins et la lutte contre les maladies infectieuses.
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: Cutaneous exposure to aluminum may occur via contact with metal items, medications, and personal care products. Despite the widespread use of aluminum, allergic contact dermatitis is relatively rare. Sensitization is often incidentally identified during patch testing with aluminum-based chambers. This article presents several cases along with a literature review summarizing prevalence and clinical manifestations of cutaneous reactions to aluminum, recommendations for patch testing, sources of aluminum, and reproducibility of aluminum allergy over time.
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The present study was designed to evaluate the possible effects of the paediatric vaccination schedule in the United States on the central nervous system in a murine model. We compared the impact of treatment with the whole vaccines versus true placebo control. Seventy-six pups were divided into three groups: two vaccinated groups and unvaccinated control. The two vaccinated groups were treated between 7 and 21 post-natal days either with one or three times of the vaccine doses per body weight as used in children between newborn and eighteen months of age. The post-vaccination development, neuromotor behaviours and neurobehavioural abnormalities (NBAs) were evaluated in all mouse groups during the 67 post-natal weeks of mouse age. Mouse body weight was affected only in the vaccinated females compared to males and control. Some NBAs such as decreased sociability, increased anxiety-like behaviours, and alteration of visual-spatial learning and memory were observed in vaccinated male and female mice compared to controls. The present study also shows a slower acquisition of some neonatal reflexes in vaccinated female mice compared to vaccinated males and controls. The observed neurodevelopmental alterations did not show a linear relationship with vaccine dose, suggesting that the single dose gave a saturated response. The outcomes seemed to be sex-dependent and transient with age.
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Aluminum and mercury are environmentally ubiquitous. Individually they are both neurotoxic elements with shared neuro-pathogenic pathways: oxidative stress, altered neurotransmission, and disruption of the neuroendocrine and immune systems. In the infant, Al and Hg differ in type of exposure, absorption, distribution (brain access), and metabolism. In environmentally associated exposure (breast milk and infant formulas) their co-occurrences fluctuate randomly, but in Thimerosal-containing vaccines (TCVs) they occur combined in a proprietary ratio; in these cases, low-doses of Thimerosal-ethylmercury (EtHg) and adjuvant-Al present the most widespread binary mixture in less developed countries. Although experimental studies at low doses of the binary Hg and Al mixture are rare, when studied individually they have been shown to affect neurological outcomes negatively. In in vitro systems, comparative neurotoxicity between Al and Hg varies in relation to the measured parameters but seems less for Al than for Hg. While neurotoxicity of environmental Hg (mainly fish methyl-Hg, MeHg) is associated with neurobehavioral outcomes in children, environmental Al is not associated, except in certain clinical conditions. Therefore, the issues of their neurotoxic effects (singly or combined) are discussed. In the infant (up to six months) the organic-Hg and Al body burdens from a full TCV schedule are estimated to reach levels higher than that originating from breastfeeding or from high aluminum soy-based formulas. Despite worldwide exposure to both Al and Hg (inorganic Hg, MeHg, and Thimerosal/EtHg), our knowledge on this combined exposure is insufficient to predict their combined neurotoxic effects (and with other co-occurring neurotoxicants).
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Aluminium (Al) is frequently accessible to animal and human populations to the extent that intoxications may occur. Intake of Al is by inhalation of aerosols or particles, ingestion of food, water and medicaments, skin contact, vaccination, dialysis and infusions. Toxic actions of Al induce oxidative stress, immunologic alterations, genotoxicity, pro-inflammatory effect, peptide denaturation or transformation, enzymatic dysfunction, metabolic derangement, amyloidogenesis, membrane perturbation, iron dyshomeostasis, apoptosis, necrosis and dysplasia. The pathological conditions associated with Al toxicosis are desquamative interstitial pneumonia, pulmonary alveolar proteinosis, granulomas, granulomatosis and fibrosis, toxic myocarditis, thrombosis and ischemic stroke, granulomatous enteritis, Crohn’s disease, inflammatory bowel diseases, anemia, Alzheimer’s disease, dementia, sclerosis, autism, macrophagic myofasciitis, osteomalacia, oligospermia and infertility, hepatorenal disease, breast cancer and cyst, pancreatitis, pancreatic necrosis and diabetes mellitus. The review provides a broad overview of Al toxicosis as a background for sustained investigations of the toxicology of Al compounds of public health importance.
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Aluminium hydroxide (AH) and aluminium phosphate (AP) adjuvants, labelled with 26Al, were injected intramuscularly (i.m.) in New Zealand White rabbits. Blood and urine samples were collected for 28 days and analysed for 26Al using accelerator mass spectrometry to determine the absorption and elimination of AH and AP adjuvants. 26Al was present in the first blood sample (1 h) for both adjuvants. The area under the blood level curve for 28 days indicates that three times more aluminium was absorbed from AP adjuvant than AH adjuvant. The distribution profile of aluminium to tissues was the same for both adjuvants (kidney > spleen > liver > heart > lymph node > brain). This study has demonstrated that in vivo mechanisms are available to eliminate aluminium-containing adjuvants after i.m. administration. In addition, the pharmacokinetic profiles of AH and AP adjuvants are different.
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Aluminum (Al) has been etiologically and epidemiologically related to several neurologic conditions, including Alzheimer's disease (AD). The effects of Al long-term exposure were investigated to describe the associated behavioral and brain modifications. Adult rats were intraperitoneally injected three times a week for 6 months with ecological doses of Al gluconate (0.85 mg/kg). The Al overload was confirmed by the significantly increased level of Al in serum. We assessed fear conditioning, spatial memory and emotional reactivity by shuttle-box task, Morris water maze, and open-field, respectively. The performance of the experimental animals at the shuttle-box task was significantly lower (p <.01) compared to that of control. The experimental animals had impaired spatial memory, with lower and more fluctuant performance at Morris water maze. The noxious-driven behavior of the experimental animals was also altered, with significantly lower activity scores (p <.05), and high emotionality scores (p <.01) at the open-field. We recovered and processed the brain for aluminum and amyloid deposits. The brains of experimental animals, studied by optical microscopy, displayed a massive cellular depletion in the hippocampal formation, particularly, the CAl field, and also in the temporal and parietal cortex. We observed numerous ghost-like neurons with cytoplasmic and nuclear vacuolations, and with Al deposits. The hippocampus contained extracellular accumulations of Al and amyloid surrounded by nuclei of degenerating cells, which we interpreted as neuritic plaques. The cerebrovasculature was distorted, with a significant thickening of the wall of capillaries, associated with amyloid deposits. These behavioral and neuropathological modifications associated with long-term exposure to Al are reminiscent of those observed in AD.
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Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.
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Objectives After completing this article, readers should be able to: 1. Recognize age-related changes in pharmacokinetics and pharmacodynamics of drugs. 2. Describe the dynamics of rational drug dosing for neonates and children. 3. Identify areas of challenge where more drug research is needed during development.
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Macrophagic myofasciitis (MMF) is an inflammatory myopathy related to aluminum-containing vaccines. Described in 1998, most cases were reported in adults, with only 22 cases being reported in children. Three children aged between 13 months and 3(1/2) years were investigated in our institution for neuromuscular symptoms. They underwent thorough clinical, familial, and laboratory investigations, electroneuromyography, muscle biopsy with transmission electron microscopy, scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), and, in one case, brain magnetic resonance imaging. They had received regular immunizations. Two patients were hypotonic and one presented with myotonia. Muscle biopsy of all patients presented macrophagic infiltrates with intracytoplasmic aluminum content as revealed by SEM/EDS analysis. Their diverse clinical picture does not support a direct relationship between local morphologic findings and systemic symptoms. The atypical clinical presentation of these children may not result from the superposition of MMF upon a background systemic neuromyopathy, suggesting instead that they are two coincident and independent conditions. Although the finding of macrophage infiltrates in muscle tissue is not new, the identification of aluminum content is recent. The use of tissue sections for aluminum detection and mapping by SEM/EDS is conclusive for, diagnosis; it has not been reported previously in a pathology journal, to the authors' knowledge.
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Note: This article was originally published with an incorrect version of the Acknowledgments, which appeared on p. 218 of the print version. The correct version of the Acknowledgments appeared on pp. 1–2. The corrected article is available below.
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Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg 0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo 'case' studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in 'generic physiologically-based pharmacokinetic' models.
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Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.
Article
Moreno A, Domínguez C, Ballabriga A. Aluminium in the neonate related to parenteral nutrition. Acta Pædiatr 1994;83:25–9. Stockholm. ISSN 0803–5253 Sources of aluminium loading and exposure in preterm and full-term newborns were studied. Parenteral nutrition solutions were the main source of aluminium representing 88.7% of total aluminium intake. Blood and urine aluminium levels were followed over a 28-day period in a group of 26 preterm and 9 term infants while receiving parenteral nutrition (duration 15.6 ± 8.7 days) and later when being formula fed. Urine levels were followed up to 13 weeks in a subgroup of the neonates. Serum aluminium levels (0.86 ± 0.38 μmol/l) and urine aluminium/crcatinine ratio (1.52 ± 0.81 μmol/ mmol) were increased when the infants were receiving parenteral nutrition compared with the control group (p<0.001). The urine aluminium/creatinine ratio remained high up to 10 weeks following withdrawal of parenteral nutrition and suggested tissular loading. This was confirmed after high aluminium levels were found in post-mortem brain and bone samples from two preterm and one full-term infant. We conclude that both preterm and full-term neonates are susceptible to accumulation of aluminium in tissue while receiving parenteral nutrition.
Article
Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy.
Article
The study reported here was done: to evaluate maternal toxicity and fetal toxicity of AlCl3 in mice; to determine the ability of Al, administered to the mother, to accumulate in the fetus; to quantitate and compare maternal-placental-fetal Al content following gestational exposure to AlCl3; and to determine the influence of route of administration (oral vs intraperitoneal) on the above parameters. Total fetal Al content was significantly increased to maternal Al content following both ip and oral routes of maternal exposure to AlCl3. In Utero exposure of mice to AlCl3, at levels which do not cause maternal toxicity, resulted in decreased fetal weight and increased incidence of fetal resorptions. Differences in ip versus oral dosing were observed in placental and fetal weight changes, maximum fetal Al burden, placental Al content, and maternal liver Al content. In every case, changes were greater with ip dosing. In comparison with published studies on rats, mice appear to be more resistant to the toxic effects of AlCl3.
Article
To investigate the possibility that premature infants may be vulnerable to aluminum toxicity acquired through intravenous feeding, we prospectively studied plasma and urinary aluminum concentrations in 18 premature infants receiving intravenous therapy and in 8 term infants receiving no intravenous therapy. We also measured bone aluminum concentrations in autopsy specimens from 23 infants, including 6 who had received at least three weeks of intravenous therapy. Premature infants who received intravenous therapy had high plasma and urinary aluminum concentrations, as compared with normal controls: plasma aluminum, 36.78 +/- 45.30 vs. 5.17 +/- 3.1 micrograms per liter (mean +/- S.D., P less than 0.0001); urinary aluminum:creatinine ratio, 5.4 +/- 4.6 vs. 0.64 +/- 0.75 (P less than 0.01). The bone aluminum concentration was 10 times higher in infants who had received at least three weeks of intravenous therapy than in those who had received limited intravenous therapy: 20.16 +/- 13.4 vs. 1.98 +/- 1.44 mg per kilogram of dry weight (P less than 0.0001). Creatinine clearances corrected for weight did not reach expected adult values until 34 weeks of gestation. Many commonly used intravenous solutions are found to be highly contaminated with aluminum. We conclude that infants receiving intravenous therapy have aluminum loading, which is reflected in increased urinary excretion and elevated concentrations in plasma and bone. Such infants may be at high risk for aluminum intoxication secondary to increased parenteral exposure and poor renal clearance.
Article
To assess aluminum toxicity to the Al-exposed pregnant female and her developing offspring, pregnant rabbits received 20 sc Al lactate injections (0, 25, 100, or 400 mumol Al/kg/inj) between Days 2 and 27 of gestation. Fifty-eight percent perinatal mortality resulted from the highest dose. At 2 days postpartum litters were culled to six offspring. Three of the offspring of Al-treated does were cross-fostered to a non-Al-treated doe in exchange for three of the non-Al-treated doe's offspring. Tissue Al concentrations in 0- to 2-day-old offspring positively correlated with their does' Al exposure, but were lower than Al concentrations in placental tissue or in does 5 weeks postpartum, suggesting that the placenta partially protects the fetus from Al. Offspring of 25 mumol group does gained body weight faster than controls, whereas 400 mumol group does and their offspring gained weight less rapidly than controls. The weight of milk consumed by offspring inversely correlated with their does' Al exposure. Learning a classically conditioned reflex was facilitated by lower and impaired by higher Al exposure in offspring conditioned at 7 and 11 weeks of age. Offspring receiving higher Al exposure also showed impaired memory of the learned reflex. Aluminum appears to distribute into the developing fetus where it accumulates and can produce delayed effects which may be beneficial following lower but detrimental following higher exposure concentrations.
Article
During a 40-day balance study, eight adult males were fed two levels of aluminium: 5 mg/day for 20 days (control diet) and 125 mg/day for 20 days (test diet). Every subject excreted more than 96% and more than 74% of his aluminium intake in his faeces when fed the test and control diets, respectively. Subjects excreted two- to five-fold more aluminium in their urine and had significantly higher levels of aluminium in their sera when fed the test diet rather than the control diet. No retention of aluminum was detected when faecal and urinary losses of aluminium were compared with intakes.
Article
An estimate of glomerular filtration rate has been derived for children from body length (L, in centimeters) and plasma creatinine (Pcr, in milligrams per deciliter): GFR = 0.55 L/Pcr. The near universality of this estimate in children led us to seek a similar formula for estimating GFR in full-term infants during the first year of life. We measured Pcr in 137 healthy infants and performed creatinine clearance (Ccr) studies in 63 of them aged greater than or equal to 5 days. Beyond the first week, Pcr averaged 0.39 +/- 0.01 (0.10 SD) mg/dl. The estimate of GFR from 0.55 L/Pcr overestimated Ccr by 24% (P less than 0.001). Based on the calculation of a new constant from Ccr X Pcr/L, GFR was more accurately estimated from 0.45 L/Pcr (mean difference of Ccr - 0.45 L/Pcr = -0.4 +/- 3.7 (SE) ml/min X 1.73 m2) in full-term infants between 1 and 52 weeks of age. Because the constant 0.45 and Pcr do not change significantly during this period, GFR can be approximated at the bedside from body length of the healthy full-term infant (GFR = 0.45 L/0.39 = 1.1 L).
Article
1 ²⁶ Al and ⁶⁷ Ga were given as citrates to a healthy male volunteer by intravenous injection. The retention of both tracers was studied by body radioactivity measurement. Levels in blood and excreta were determined by y-ray spectrometry and/or accelerator mass spectrometry. 2 More than half of the ²⁶ Al had left the blood after 15 min and the decline continued, leaving <1% in blood after 2 d; the losses occurred both to renal excretion and through uptake by other compartments. Estimated excre tion up to 13 d was 83% (urine) and 1.8% (faeces). Whole-body retention of 15% at 13 d declined to ∼4% at 1178 d, when the daily reduction corresponded to a bio logical half-life of 7 y, suggesting that sustained intake of dietary aluminium may lead to a progressively increas ing internal deposit. 3 The metabolism of ⁶⁷ Ga differed markedly from that of ²⁶ Al in all aspects studied.
Article
Sources of aluminium loading and exposure in preterm and full-term newborns were studied. Parenteral nutrition solutions were the main source of aluminium representing 88.7% of total aluminium intake. Blood and urine aluminium levels were followed over a 28-day period in a group of 26 preterm and 9 term infants while receiving parenteral nutrition (duration 15.6 +/- 8.7 days) and later when being formula fed. Urine levels were followed up to 13 weeks in a subgroup of the neonates. Serum aluminium levels (0.86 +/- 0.38 mumol/l) and urine aluminium/creatinine ratio (1.52 +/- 0.81 mumol/mmol) were increased when the infants were receiving parenteral nutrition compared with the control group (p < 0.001). The urine aluminium/creatinine ratio remained high up to 10 weeks following withdrawal of parenteral nutrition and suggested tissular loading. This was confirmed after high aluminium levels were found in post-mortem brain and bone samples from two preterm and one full-term infant. We conclude that both preterm and full-term neonates are susceptible to accumulation of aluminium in tissue while receiving parenteral nutrition.
Article
There is concern that environmental and dietary aluminum (Al) might cause developmental toxicity. To better understand this concern, we reviewed published studies which administered Al compounds to pregnant animals and measured accumulation of Al in mother, fetus, or born offspring. A total of 7 studies were identified which administered Al during gestation and evaluated fetal accumulation. Another 7 studies administered Al at least until birth and then evaluated accumulation in mothers and/or pups. These 14 studies included 4 different Al compounds (hydroxide, chloride, lactate, and citrate) administered by 4 different routes (gavage, feed, intraperitoneal injection, and subcutaneous injection) with total doses ranging from 13.5 to 8,400 mg/kg. Fetal Al levels were not increased in 6 of 7 studies and pup Al levels were not increased in 4 of 5 studies in which they were measured. Maternal Al levels were increased in some studies, but there was no consistent pattern of organ-specific accumulation and several positive studies were contradicted by subsequent reports from the same laboratory. Placental levels were increased in 6 of 9 studies and were greater than corresponding fetal levels. The weight of evidence in these studies suggests that environmental and dietary Al exposures are unlikely to pose risks of Al accumulation to pregnant animals or their fetuses.
Article
Borak J, Wise JP. 1998. Does aluminum exposure of pregnant animals lead to accumulation in mothers of their offspring? Teratology 57:127–139 In response to the article referenced above, Drs. M. Golub and J. Domingo wrote a Letter to the Editor (Teratology 1998;58:225). Included in that letter was the following statement: “We also urge Drs. Borak and Wise to fulfill their ethical obligation to acknowledge sources of support when submitting manuscripts for publication.” This comment would not have been necessary if the article by Borak and Wise had included an acknowledgment of their outside support in their article. The authors had disclosed this outside support in the cover letter to the editor when the manuscript was supplied initially and later after revisions. They did not include an Acknowledgment section in the manuscript. The editorial office should have suggested that they do that. We apologize for any confusion this caused.
Article
This MiniReview updates and expands the MiniReview of aluminium toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of 26Al, analyzed by accelerator mass spectrometry, now enables determination of Al toxicokinetics under physiological conditions. There is concern about aluminium in drinking water. The common sources of aluminium for man are reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is the primary common source. Al bioavailability from food has not been adequately determined. Industrial and medicinal exposure, and perhaps antiperspirant use, can significantly increase absorbed aluminium. Inhalation bioavailability of airborne soluble Al appears to be about 1.5% in the industrial environment. Al may distribute to the brain from the nasal cavity, but the significance of this exposure route is unknown. Systemic Al bioavailability after single underarm antiperspirant application may be up to 0.012%. All intramuscularly injected Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to all tissues. Distribution and renal excretion appear to be enhanced by citrate. Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes. There appears to be carrier-mediated efflux of Al citrate from the brain. Elimination half-lives of years have been reported in man, probably reflecting release from bone. Al elimination is primarily renal with < or = 2% excreted in bile. The contribution of food to absorbed Al needs to be determined to advance our understanding of the major components of Al toxicokinetics.
Article
We studied rat retinal changes due to aluminum (Al) toxicosis with a transmission electron microscope (TEM) and an energy dispersive X-ray analyzer (EDXA). Normal 4-week-old Wistar Kyoto rats were divided randomly into Al toxicosis and control groups. The Al toxicosis group was injected ip with 0.3 ml of 4% aluminum chloride (AlCl3) per day every day for 16 weeks. The retina was examined with a TEM and EDXA at 8, 12, and 16 weeks after starting injections with AlCl3. There was a statistically significant increase in the serum Al concentration in the Al toxicosis group (p < 0.001). We observed prominent pathologic changes at 16 weeks after the first injections. Thin retinal pigment epithelium (RPE), and disappearance of the photoreceptor outer and inner segments and nuclei were observed. There were high-density irregular granules in the outer and inner plexiform layers and in the inner nuclear layer. We found dense granules in the cells, which remained between the RPE and the inner nuclear layer. EDXA detected Al in the high-density irregular granules in these areas. Al injected ip caused accumulation of Al in the rat retina and the destruction of photoreceptor cells. These findings indicate that Al is toxic to the retina.
Article
Some vaccines contain aluminum adjuvants to enhance the immunological response, and it has been postulated that this aluminum could contribute to adverse health effects, especially in children who receive a vaccination series starting at birth. The pharmacokinetic properties and end-point toxicities of aluminum are presented. In assessing the relevance of dietary and medical aluminum exposure to public health, we estimated infant body burdens during the first year of life for breast milk and formula diets and for a standard vaccination schedule. We then compared those body burdens with that expected for intake at a level considered safe for intermediate-duration exposure. The methodology blends intake values and uptake fractions with an aluminum retention function derived from a human injection study using radioactive 26Al. The calculated body burden of aluminum from vaccinations exceeds that from dietary sources, however, it is below the minimal risk level equivalent curve after the brief period following injection.
Article
Until 1990 biokinetic studies of aluminium metabolism and biokinetics in man and other animals had been substantially inhibited by analytical and practical difficulties. Of these, the most important are the difficulties in differentiating between administered aluminium and endogenous aluminium-especially in body fluids and excreta and the problems associated with the contamination of samples with environmental aluminium. As a consequence of these it was not possible to detect small, residual body burdens of the metal following experimental administrations. Consequently, many believed aluminium to be quantitatively excreted within a short time of uptake in all, but renal-failure patients. Nevertheless, residual aluminium deposits in a number of different organs and tissues had been detected in normal subjects using a variety of techniques, including histochemical staining methods. In order to understand the origins and kinetics of such residual aluminium deposits new approaches were required. One approach taken was to employ the radioisotope (67)Ga as a surrogate, but this approach has been shown to be flawed-a consequence of the different biological behaviours of aluminium and gallium. A second arose from the availability, in about 1990, of both (26)Al-a rare and expensive isotope of aluminium-and accelerator mass spectrometry for the ultra-trace detection of this isotope. Using these techniques the basic features of aluminium biokinetics and bioavailability have been unravelled. It is now clear that some aluminium is retained in the body-most probably within the skeleton, and that some deposits in the brain. However, most aluminium that enters the blood is excreted in urine within a few days or weeks and the gastrointestinal tract provides an effective barrier to aluminium uptake. Aspects of the biokinetics and bioavailability of aluminium are described below.
Article
Aluminium adjuvants are the most widely used adjuvants in both human and veterinary vaccines. These adjuvants have been used in practical vaccination for more than 60 years and are generally recognized as safe and as stimulators of Th2 immunity. The present review gives a short introduction to the pioneering research at the start of the use of aluminium compounds as adjuvants, including references on the chemistry of these compounds. Analytical methods for identifying the most commonly used aluminium compounds, such as boehmite and aluminium hydroxyphosphate, are mentioned. Emphasis is placed on the important factors for antigen adsorption and on the latest work using gene-deficient mice in the research of the mechanism of aluminium adjuvants in terms of cytokine and T-cell subset stimulation. Key references on the ability of aluminium adjuvants to stimulate IgE and also in vivo clearing of aluminium adjuvants are discussed. Furthermore, the review addresses the issue of local reactions in the context of injection route and local tissue disturbance. Possible new applications of aluminium adjuvants in, for example, combined aluminium-adsorbed protein and DNA oligonucleotide vaccines as well as the possible use of aluminium adjuvants in combination with IL-12 to stimulate Th1-type immune responses are mentioned.
Article
Macrophagic myofasciitis is a novel, "inflammatory myopathy" described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff-positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease.