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Updated Aluminum pharmacokinetics following infant exposures through diet and vaccines
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.
... 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. ...
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.
... 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. ...
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).
... L'AH est composé de nanoparticules d'environ 2,2 nm x 4,5 nm x 10 nm qui forment spontanément des agrégats microniques ayant un aspect nano-fibreux en microscopie électronique à transmission (Eidi et al., 2015;Mold, Shardlow & Exley, 2016 questions au sujet de la réelle sécurité des adjuvants Al. Il n'existe en effet qu'une seule étude expérimentale citée comme référence pour garantir la sécurité des adjuvants Al qui analyse réellement le devenir des adjuvants dans l'organisme jusqu'à 28 jours après injection intramusculaire (IM) chez des lapins (Flarend et al., 1997) et deux analyses théoriques comparant l'accumulation d'Al issu de l'alimentation et de la vaccination chez les enfants à un seuil de sécurité extrapolé d'observations faites sur modèle animal (Keith, Jones & Chou, 2002;Mitkus et al., 2011). Notons toutefois que l'analyse de la cinétique in vivo des composés Al (adjuvants et vaccins entiers) a récemment été complétée par une étude menée chez le rat démontrant la longue persistance des adjuvants Al dans l'organisme et la translocation vers d'autres organes, ces deux paramètres étant étudiés jusqu'à 80 jours après injection (Weisser et al., 2019). ...
... Deux études ont estimé les quantités théoriques d'Al auxquelles le nourrisson est exposé, par voie alimentaire et vaccinale (Keith, Jones & Chou, 2002;Mitkus et al., 2011). Le principe des deux études est similaire : il s'agit de calculs théoriques fondés sur l'apport et l'excrétion d'Al de la naissance à 12 mois. ...
La vaccination est une avancée majeure de la médecine moderne ayant permis d’éradiquer certaines maladies et d’endiguer la propagation de nombreuses autres. Malgré une bonne tolérance par la population générale, certains individus présentent des difficultés d’élimination des particules aluminiques utilisées comme adjuvant vaccinaux. Ces patients présentent une lésion histopathologique musculaire caractéristique, biopersistante sur le long terme et composée de cellules immunitaires présentant des inclusions intracellulaires de cristaux aluminiques. Cette lésion, associée à un ensemble d'arthromyalgie, de fatigue chronique et de troubles cognitifs, est appelée myofasciite à macrophages (MFM).Les vaccins à base d’aluminium sont des particules pseudo-infectieuses gérées comme des agents pathogènes par des cellules présentatrices d'antigènes via endocytose et élimination ultérieure par l'intermédiaire de la machinerie xéno/autophagique. Par ailleurs, la littérature scientifique a montré que l’oxy-hydroxyde d'aluminium, l’un des principaux adjuvants, peut perturber la réponse autophagique. Cela conforte l’idée que l’intolérance aux adjuvants aluminiques pourrait être la conséquence d’une interaction de type « gènes x environnement » reposant sur une déficience de l’autophagie dans les cellules de l’immunité comme facteur de susceptibilité individuelle aux particules d’aluminium d’origine vaccinale.Les réponses autophagiques et inflammatoires des cellules immunitaires isolées en réponse aux particules aluminiques n’étant pas totalement caractérisées parmi la population globale. Le travail de thèse présenté dans ce manuscrit a donc eu pour premier objectif d’étudier ces réponses chez des individus sains avant de comparer les résultats avec ceux obtenus chez des individus atteint de MFM. Les données ont démontré que de nombreuses interactions entre les mécanismes d’endocytose, d’autophagie et d’inflammation sont mises en œuvre par les cellules de l’immunité en réponse à la présence de particules d’aluminium. Des expérimentations complémentaires seront nécessaires afin de caractériser finement les différentes intrications entre ces mécanismes. Cependant, certaines observations ont laissé entrevoir de subtiles variations de réponse au sein des cellules immunitaires des patients MFM exposées à des particules aluminiques. Ces cellules ont ainsi présenté un équilibre entre autophagie et endocytose penchant en faveur de l’endocytose et associé à une réponse inflammatoire réduite par rapport aux individus sains. Ces observations sont en accord avec la littérature scientifique actuelle et pourraient être principalement la conséquence plus que la cause de l’état de santé des patients MFM.Suite aux observations in vitro, des analyses exploratoires in vivo ont été menées afin de développer un modèle murin avec des perturbations de l’autophagie pour étudier l’importance de ce mécanisme dans la prise en charge et le devenir des particules aluminiques. Une étude longue a été réalisée pour tester l’efficacité d’un traitement pharmacologique (hydroxychloroquine) à perturber l’autophagie sans induire de toxicité. Nos résultats montrent que, bien qu’apparemment non toxique pour les animaux, le traitement utilisé n’a pas été en mesure de perturber l’autophagie sur le long terme. Par conséquent, l’étude de l’importance du mécanisme autophagique dans la translocation des particules d’aluminium a été réalisée en privilégiant un modèle de KO génétique. Les données ont confirmé les précédentes observations faites sans mettre en avant de rôle majeur de l’autophagie dans le déplacement des particules d’aluminium depuis le site d’injection initial, au regard du faible effectif d’animaux disponibles pour cette étude.En conclusion, ce travail a permis de mettre en évidence une prise en charge des particules aluminiques d’origine vaccinale d’une grande complexité, nécessitant une approche pluridisciplinaire pour être finement décrite.
... Aluminum salt adjuvants are the most commonly used adjuvant in human vaccines licensed by the FDA and regulatory agencies worldwide, and have been administered to billions of individuals over the past 90 years [33][34][35] . Moreover, aluminum salt adjuvants are currently used in infant vaccines against hepatitis B, diphtheria-tetanus-pertussis (DTaP), Haemophilus influenzae type b (Hib), and pneumococcus infectious agents 36 , with an excellent safety profile 37,38 . ...
... Finally, we anticipate the potential use of DCFHP-alum as an important primary vaccine in previously unvaccinated and uninfected individuals, especially in pediatric populations, including infants. Aluminum salt adjuvants are commonly used in infant vaccines and as part of routine childhood immunization schedules, and their excellent safety profile has been established over decades [33][34][35][36][37][38] . In infants and other DCFHP-alum vaccine recipients naive to SARS-CoV-2 infection or vaccination, we would anticipate robust, cross-reactive responses similar to the naive NHPs studied here. ...
While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants.
... 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". ...
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.
... 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. ...
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.
... 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. ...
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 the most abundant metal in the Earth's crust and is one of the major sources of contamination due to its high prevalence in the environment [59]. In general, exposure to aluminum occurs mainly through the consumption of food, cookware, use of antiperspirants and vaccines, which contain residues and specific aluminum salts in the composition [60][61][62]. The primary route of entry into cells occurs through cell membranes or epithelial cells via ion channels, endocytosis, or receptor-mediated, and its toxicity is similar for humans and other mammals [63,64]. ...
Heavy metals are elements found into the environment mainly due to anthropogenic activities. Naturally occurring and higher released doses cause disorders in the prostate, which depends on appropriate hormonal regulation, and exposure to heavy metals may impair prostate homeostasis. The current work highlighted the main mechanisms of toxicity of different environmental heavy metal contaminants, such as aluminum, arsenic, cadmium, chromium, lead, mercury, and nickel, and their impacts found in the prostate morphophysiology in murine models. The repercussions triggered by heavy metals on the prostate include hormonal imbalance and oxidative damage, leading to morphological alterations, which can vary according to the chemical properties of each element, exposure time and concentration, and age. The information of altered biological pathways and its impacts on the prostate of exposed murines are related to human outcomes being useful in the real context of human exposure.
... Aluminum is a widespread element in the environment and is present in food, personal care products, and medications. There is no evidence that injection of aluminum-containing vaccines increases the aluminum levels in blood above baseline or minimum risk levels [56,57] and causes systemic disease or neurologic disorders. The safety of aluminum adjuvants is further supported by epidemiologic studies of patients who receive frequent injections of allergens formulated with AH during the course of subcutaneous immunotherapy (SCIT) for allergic diseases [58]. ...
Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread use of aluminum adjuvants is due to their excellent safety profile, which has been established through the use of hundreds of millions of doses in humans over many years. In addition, they are inexpensive, readily available, and are well known and generally accepted by regulatory agencies. Moreover, they offer a very flexible platform, to which many vaccine components can be adsorbed, enabling the preparation of liquid formulations, which typically have a long shelf life under refrigerated conditions. Nevertheless, despite their extensive use, they are perceived as relatively 'weak' vaccine adjuvants. Hence, there have been many attempts to improve their performance, which typically involves co-delivery of immune potentiators, including Toll-like receptor (TLR) agonists. This approach has allowed for the development of improved aluminum adjuvants for inclusion in licensed vaccines against HPV, HBV, and COVID-19, with others likely to follow. This review summarizes the various aluminum salts that are used in vaccines and highlights how they are prepared. We focus on the analytical challenges that remain to allowing the creation of well-characterized formulations, particularly those involving multiple antigens. In addition, we highlight how aluminum is being used to create the next generation of improved adjuvants through the adsorption and delivery of various TLR agonists.
... In addition, Alzheimer's disease, Parkinson's disease, and multiple sclerosis may all be associated with aluminum accumulation toxicity [96,97]. According to research data evaluation, the concentration of aluminum in the blood produced by vaccines administered to one-year-old infants is still much lower than the toxic substances and the prescribed minimum risk level [98]. ...
Although hundreds of different adjuvants have been tried, aluminum-containing adjuvants are by far the most widely used currently. It is worth mentioning that although aluminum-containing adjuvants have been commonly applied in vaccine production, their acting mechanism remains not completely clear. Thus far, researchers have proposed the following mechanisms: (1) depot effect, (2) phagocytosis, (3) activation of pro-inflammatory signaling pathway NLRP3, (4) host cell DNA release, and other mechanisms of action. Having an overview on recent studies to increase our comprehension on the mechanisms by which aluminum-containing adjuvants adsorb antigens and the effects of adsorption on antigen stability and immune response has become a mainstream research trend. Aluminum-containing adjuvants can enhance immune response through a variety of molecular pathways, but there are still significant challenges in designing effective immune-stimulating vaccine delivery systems with aluminum-containing adjuvants. At present, studies on the acting mechanism of aluminum-containing adjuvants mainly focus on aluminum hydroxide adjuvants. This review will take aluminum phosphate as a representative to discuss the immune stimulation mechanism of aluminum phosphate adjuvants and the differences between aluminum phosphate adjuvants and aluminum hydroxide adjuvants, as well as the research progress on the improvement of aluminum phosphate adjuvants (including the improvement of the adjuvant formula, nano-aluminum phosphate adjuvants and a first-grade composite adjuvant containing aluminum phosphate). Based on such related knowledge, determining optimal formulation to develop effective and safe aluminium-containing adjuvants for different vaccines will become more substantiated.
... However, the association between Al-containing adjuvants and ASD is highly controversial [91], as Al adjuvants are linked with minimal adverse effects [92,93]. In research by Mitkus et al. [94], Al diet and vaccine exposure during the first year of life did not exceed the minimal risk levels specified by ATSDR [95]. Additionally, no link between blood and hair Al and the history of immunization by Karwowski et al. [96] in a group of 85 healthy infants aged 9-13 months. ...
Aluminium (Al) is the most ubiquitous metal in the Earth’s crust. Even though its toxicity is well-documented, the role of Al in the pathogenesis of several neurological diseases remains debatable. To establish the basic framework for future studies, we review literature reports on Al toxicokinetics and its role in Alzheimer’s disease (AD), autism spectrum disorder (ASD), alcohol use disorder (AUD), multiple sclerosis (MS), Parkinson’s disease (PD), and dialysis encephalopathy (DE) from 1976 to 2022. Despite poor absorption via mucosa, the biggest amount of Al comes with food, drinking water, and inhalation. Vaccines introduce negligible amounts of Al, while the data on skin absorption (which might be linked with carcinogenesis) is limited and requires further investigation. In the above-mentioned diseases, the literature shows excessive Al accumulation in the central nervous system (AD, AUD, MS, PD, DE) and epidemiological links between greater Al exposition and their increased prevalence (AD, PD, DE). Moreover, the literature suggests that Al has the potential as a marker of disease (AD, PD) and beneficial results of Al chelator use (such as cognitive improvement in AD, AUD, MS, and DE cases).
... The immunization-enhancing effect of Alum was first reported in the early 1930s [112,113]. Since its discovery, Alum has been commonly used as an adjuvant in human licensed vaccines such as influenza, tetanus, diphtheria, pertussis, poliomyelitis, and HPV [114][115][116]. Alum can also be found in clinical trials for testing melanoma peptide vaccines. ...
Cancer of the skin is by far the most common of all cancers. Although the incidence of melanoma is relatively low among skin cancers, it can account for a high number of skin cancer deaths. Since the start of deeper insight into the mechanisms of melanoma tumorigenesis and their strong interaction with the immune system, the development of new therapeutical strategies has been continuously rising. The high number of melanoma cell mutations provides a diverse set of antigens that the immune system can recognize and use to distinguish tumor cells from normal cells. Peptide-based synthetic anti-tumor vaccines are based on tumor antigens that elicit an immune response due to antigen-presenting cells (APCs). Although targeting APCs with peptide antigens is the most important assumption for vaccine development, peptide antigens alone are poorly immunogenic. The immunogenicity of peptide antigens can be improved not only by synthetic modifications but also by the assistance of adjuvants and/or delivery systems. The current review summarizes the different chemical approaches for the development of effective peptide-based vaccines for the immunotherapeutic treatment of advanced melanoma.
... 37 However, a recent report concluded that "little to none of ingested aluminum appears to be absorbed" through the gastrointestinal tract, 37 and we are unaware of any studies demonstrating an immunologic response to ingested aluminum in humans. Clearly, more research is needed on the human health effects of aluminum, 37,38 including immunologic effects of injected and ingested aluminum, supplemented when feasible with biomarkers of aluminum exposure. 39 If future research continues to demonstrate that aluminum ingested through a normal infant diet is minimally absorbed and has negligible immunologic effect, the absence of dietary aluminum data in the present study would not appear to invalidate the current findings. ...
Objective
To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months.
Methods
A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization.
Results
The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25).
Conclusion
In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.
... Finally, considering the questions of existing reference studies to determine if Al exposure through vaccines may be unsafe, one may remember that serious conceptual and methodological weaknesses have been previously described. Indeed, it has been shown that these three available toxicokinetic studies, an experimental work (Flarend et al. 1997) and two theoretical calculations (Keith et al. 2002;Mitkus et al. 2011), objectively constitute insufficient bases to guarantee the absolute safety of Al adjuvants (Masson et al. 2018). ...
Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuro-modulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuro-modulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.
... Their 'Makes You Wonder' social media campaign also focussed on aluminium safety, aiming to influence consumer preference for aluminium-free products, including vaccines (Boyle, 2015). This is despite longstanding use of aluminium in vaccines, and research determining its negligible risk (Mitkus et al., 2011). Ironically, given CMSRI's clamour for independent research, research supporting adverse effects of aluminium is chiefly from Exley, Gherardi and Shaw (q.v.). ...
Vaccine hesitancy, the delay or refusal to vaccinate despite availability, is a current global concern, as it threatens to undermine the effectiveness of a pillar of public health. Lying at one extreme of hesitancy are anti-vaccine activists, or anti-vaxxers. Often, they are organised into groups who avidly campaign against vaccines, aiming to persuade others to withhold from vaccination, despite the overwhelming scientific and medical consensus that it is safe and effective. Campaigns of misinformation and doubt-creation against scientific unanimity have been used to protect commercial interests, for instance of the tobacco and fossil fuel industries. This practice has been termed agnotology, or the cultural production of ignorance. Through a case study of a prominent anti-vaccination organisation, this dissertation shows that these organisations employ the same agnotological tactics to cast doubt on the safety and efficacy of vaccines. The motivation of anti-vaccine organisations to agnotology is considered, before examination of its epistemic consequences, specifically its effects on scientific and public inquiry and understanding of vaccines. One case study indicates that manufactured debate by climate sceptics is epistemically detrimental to climate science by impeding inquiry and progress. Anti-vaccine agnotology does not seem to exert this effect on vaccine science, as new vaccines are developed and introduced. This dissertation argues that the dissent of anti-vaxxers is nonetheless epistemically corrupting and ultimately damaging. It creates a manipulative communication environment in which epistemic vices ‒ character traits which impede effective and responsible inquiry ‒ are encouraged and maintained in anti-vaxxers and the general public.
... 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]. ...
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.
... They concluded that episodic exposure to vaccines containing aluminium was significantly less than safe levels of environmental exposure, as recommended by the Agency for Toxic Substances and Disease Registry. 40 Initial treatment of post-vaccination ON involves steroids, typically intravenous methylprednisolone followed by a slow oral steroid taper. 2 In the review by Biotti et al. of 13 GBS-associated ON cases, the authors observed that, although the motor symptoms of GBS dramatically improved, the ON recovery was variable. 16 Only four out of 13 cases reported recovery of visual acuity to 20/25 (6/7.5) or better, although the follow-up intervals varied. ...
A 71-year-old woman presented 2 weeks after vaccination with the first dose of Vaxzevria (AstraZeneca, Oxford) for COVID-19 with a left lower motor neuron facial nerve palsy, which progressed to bilateral involvement. This was accompanied by bilateral proximal leg weakness. She was diagnosed with the ‘facial diplegia with paraesthesia’ variant of Guillain-Barré syndrome. Seven weeks post vaccination she developed painless loss of vision in the right eye. The visual acuity in that eye was light perception only with a right relative afferent pupillary defect and right optic disc swelling. A diagnosis of optic neuritis was made and she received pulsed intravenous methylprednisolone for 3 days, followed by oral prednisolone. The optic neuritis recurred following initial cessation of steroids requiring an extended course of steroids. Despite this, she made a good visual recovery to 6/6 in the affected eye. We present this case and a review of the literature surrounding vaccination and the development of these conditions.
... 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]. ...
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.
... 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. ...
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.
... 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. ...
... 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. ...
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.
... 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. ...
... 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. ...
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.
... 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. ...
... For instance, the Dtap vaccine manufactured by GSK (tradename Kinrix) contains ≤0.6 mg of aluminum present as aluminum hydroxide while Dtap vaccine manufactured by Sanofi-Pasteur (tradename Daptacel) contains 0.33 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). ...
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.
... 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. ...
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.
... 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. ...
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.
... 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. ...
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.
... 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. ...
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.
New vaccine platforms that activate humoral immunity and generate neutralizing antibodies are required to combat emerging pathogens, including influenza virus. A slurry of antigen‐loaded hydrogel microparticles that anneal to form a porous scaffold with high surface area for antigen uptake by infiltrating immune cells as the biomaterial degrades is demonstrated to enhance humoral immunity. Antigen‐loaded‐microgels elicited a robust cellular humoral immune response, with increased CD4⁺ T follicular helper (Tfh) cells and prolonged germinal center (GC) B cells comparable to the commonly used adjuvant, aluminum hydroxide (Alum). Increasing the weight fraction of polymer material led to increased material stiffness and antigen‐specific antibody titers superior to Alum. Vaccinating mice with inactivated influenza virus loaded into this more highly cross‐linked formulation elicited a strong antibody response and provided protection against a high dose viral challenge. By tuning physical and chemical properties, adjuvanticity can be enhanced leading to humoral immunity and protection against a pathogen, leveraging two different types of antigenic material: individual protein antigen and inactivated virus. The flexibility of the platform may enable design of new vaccines to enhance innate and adaptive immune cell programming to generate and tune high affinity antibodies, a promising approach to generate long‐lasting immunity.
Background:
Enterotoxigenic Escherichia coli (ETEC) strains cause infectious diarrhea and colonize host intestine epithelia via surface-expressed colonization factors. Colonization factor antigen I (CFA/I), a prevalent ETEC colonization factor, is a vaccine target since antibodies directed to this fimbria have been shown to block ETEC adherence and prevent diarrhea.
Materials and methods:
Two recombinant antigens derived from CFA/I were investigated with a vaccine adjuvant system that displays soluble antigens on the surface of immunogenic liposomes. The first antigen, CfaEB, is a chimeric fusion protein comprising the minor (CfaE) and major (CfaB) subunits of CFA/I. The second, CfaEad, is the adhesin domain of CfaE.
Results:
Owing to their His-tag, recombinant CfaEB and CfaEad, spontaneously bound upon admixture with nanoliposomes containing cobalt-porphyrin phospholipid (CoPoP), as well as a synthetic monophosphoryl lipid A (PHAD) adjuvant. Intramuscular immunization of mice with sub-microgram doses CfaEB or CfaEad admixed with CoPoP/PHAD liposomes elicited serum IgG and intestinal IgA antibodies. The smaller CfaEad antigen benefitted more from liposome display. Serum and intestine antibodies from mice immunized with liposome-displayed CfaEB or CfaEad recognized native CFA/I fimbria as evidenced by immunofluorescence and hemagglutination inhibition assays using the CFA/I-expressing H10407 ETEC strain.
Conclusion:
These data show that colonization factor-derived recombinant ETEC antigens exhibit immunogenicity when delivered in immunogenic particle-based formulations.
While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly booster vaccine, and as a primary vaccine for pediatric use including in infants.
COVID-19 named by the World Health Organization
(WHO) was discovered and act as an agent of the
outbreak of the respiratory tract infection that began
at the beginning of December 2019 near in Wuhan
City, Hubei Province, China . COVID-19 (coronavirus
disease 2019) is a disease cause by pathogenic virus
named severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) and it is very contagious and has
quickly spread around the world. COVID-19 most often
causes respiratory symptoms that can feel much like
a cold, a flu, or pneumonia to more severe diseases
like severe acute respiratory syndrome (SARS) and
Middle East respiratory syndrome (MERS). Most
people with COVID-19 have mild symptoms, but some
people become severely ill. Some people including
those with minor or no symptoms may suffer from
post-COVID conditions — or “long COVID”. Older
adults and people who have certain underlying medical
conditions are at increased risk of severe illness
from COVID-19 and millions of people have died from
COVID-19 globally. Vaccines against COVID-19 are
available, safe and effective in reducing the morbidity,
severity and mortality due to the illness.
During the week 20-26 December 2021, the global
number of new COVID-19 cases increased by 11%
as compared to the previous week of that month;
while the number of new deaths remained similar to
numbers reported during the previous week of that
month. This corresponds to just under 5 million new
cases and over 44 000 new deaths being recorded. As
of 26 December, over 278 million cases and just under
5.4 million deaths have been reported globally.
SARS-CoV-2 was first identified in Malaysia on 25
January 2020; three cases were notified, all of which
were imported from Wuhan, China. On 30 January
2020, WHO declared COVID-19 a public health emergency
of international concern. On 6 February, the
first local transmission was reported in Malaysia in a
close contact of a confirmed COVID-19 case who had
returned from Singapore. The first case in Malaysia
with neither a history of contact with a confirmed
case nor travel to an affected area was reported
on 12 March 2020. By 31 December 2021; or end of
epid week 52/2021, Malaysia had reported 2,761,472
confirmed cases and 31,514 fatalities.
This report provides a comprehensive result of the
pandemic Covid-19 situation in Malaysia from 2020
until 2021. Our intension is to give a comprehensive
overview of our approaches, results from intervention
and some discussion on related results. We describe
mostly technical related events, activities, results
and issues which covers epidemiology of the cases
during the pandemic in Malaysia, cluster of cases,
vaccination activities and programmes, vaccine
development in Malaysia, Hospital preparedness
and response, Malaysia International border control
during pandemic, laboratory activities, genomic
sequencing and Covid-19 research related activities
conducted under the Ministry of Health Malaysia
Aluminum (Al) exposure can lead to oxidative stress and liver inflammatory injury in mice. The overproduction of reactive oxygen species (ROS) activates the NLRP3 inflammasome and further induces liver pyroptosis. However, the participation of pyroptosis in inducing Al-mediated liver injury and the underlying regulatory mechanisms remain largely unclear. Herein, a mice model of subchronic Al exposure was established to investigate the role of pyroptosis in Al-induced liver injury. Then, MCC950 and N-acetylcysteine were used to inhibit NLRP3 inflammasome-mediated pyroptosis and ROS production for exploring the role and the underlying mechanisms of pyroptosis in determining Al-induced liver injury. It was confirmed that Al induced hepatocyte pyroptosis in mice, and that NLRP3 inflammasome-mediated pyroptosis plays a damaging role in Al-induced liver injury. ROS promotes pyroptosis in an Al-induced liver injury model by activating the NLRP3 inflammasome. Collectively, it was shown that ROS promotes pyroptosis to aggravate Al-induced liver injury by activating the NLRP3 inflammasome.
Background:
Restoration of immune tolerance to disease-relevant antigens is an appealing approach to prevent or arrest an organ-specific autoimmune disease like type 1 diabetes (T1D). Numerous studies have identified insulin as a key antigen of interest to use in such strategies, but to date, the success of these interventions in humans has been inconsistent. The efficacy of antigen-specific immunotherapy may be enhanced by optimising the dose, timing, and route of administration, and perhaps by the inclusion of adjuvants like alum. The aim of our study was to evaluate the effect of an insulin peptide vaccine formulated with alum to prevent T1D development in female non-obese diabetic (NOD) mice when administered during late-stage pre-diabetes.
Methods:
Starting at 10 weeks of age, female NOD mice received four weekly subcutaneous injections of an insulin B:8-24 (InsB:8-24) peptide with (Ins+alum) or without Imject® alum (Ins) as adjuvant. Diabetes incidence was assessed for up to 30 weeks of age. Insulin autoantibodies and C-peptide concentrations were measured in plasma and flow cytometric analysis was performed on pancreatic-draining lymph nodes (PLN) and pancreas using an InsB:12-20-reactive tetramer.
Results:
InsB:8-24 peptide formulated in alum reduced diabetes incidence (39%), compared to mice receiving the InsB:8-24 peptide without alum (71%, P < 0.05), mice receiving alum alone (76%, P < 0.01), or mice left untreated (70%, P < 0.01). This was accompanied by reduced insulitis severity, and preservation of C-peptide. Ins+alum was associated with reduced frequencies of pathogenic effector memory CD4+ and CD8+ T cells in the pancreas and increased frequencies of insulin-reactive FoxP3+ Tregs in the PLN. Of interest, insulin-reactive Tregs were enriched amongst populations of Tregs expressing markers indicative of stable FoxP3 expression and enhanced suppressive function.
Conclusion:
An InsB:8-24 peptide vaccine prevented the onset of T1D in late-stage pre-diabetic NOD mice, but only when formulated in alum. These findings support the use of alum as adjuvant to optimise the efficacy of antigen-specific immunotherapy in future trials.
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.
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.
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.
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.
: 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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.