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Human Vaccines & Immunotherapeutics 2015In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum... (Review)
Review
In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum hydroxide, aluminum phosphate and alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant. In spite of its wide spread use, surprisingly, the mechanism of how aluminum hydroxide-based adjuvants exert their beneficial effects is still not fully understood. Current explanations for the mode of action of aluminum hydroxide-based adjuvants include, among others, the repository effect, pro-phagocytic effect, and activation of the pro-inflammatory NLRP3 pathway. These collectively galvanize innate as well as acquired immune responses and activate the complement system. Factors that have a profound influence on responses evoked by aluminum hydroxide-based adjuvant applications include adsorption rate, strength of the adsorption, size and uniformity of aluminum hydroxide particles, dosage of adjuvant, and the nature of antigens. Although vaccines containing aluminum hydroxide-based adjuvants are beneficial, sometimes they cause adverse reactions. Further, these vaccines cannot be stored frozen. Until recently, aluminum hydroxide-based adjuvants were known to preferentially prime Th2-type immune responses. However, results of more recent studies show that depending on the vaccination route, aluminum hydroxide-based adjuvants can enhance both Th1 as well as Th2 cellular responses. Advances in systems biology have opened up new avenues for studying mechanisms of aluminum hydroxide-based adjuvants. These will assist in scaling new frontiers in aluminum hydroxide-based adjuvant research that include improvement of formulations, use of nanoparticles of aluminum hydroxide and development of composite adjuvants.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Aluminum Hydroxide; Biomedical Research; Humans; Immunity, Innate; Vaccines
PubMed: 25692535
DOI: 10.1080/21645515.2014.1004026 -
Neurotoxicology Mar 2021
Topics: Aluminum Compounds; Aluminum Hydroxide; Aluminum Oxide; Alzheimer Disease; Animals; Humans; Risk Assessment; Toxicity Tests; Water Pollutants, Chemical
PubMed: 33278452
DOI: 10.1016/j.neuro.2020.12.001 -
International Journal of Toxicology Nov 2016This is a safety assessment of alumina and aluminum hydroxide as used in cosmetics. Alumina functions as an abrasive, absorbent, anticaking agent, bulking agent, and... (Review)
Review
This is a safety assessment of alumina and aluminum hydroxide as used in cosmetics. Alumina functions as an abrasive, absorbent, anticaking agent, bulking agent, and opacifying agent. Aluminum hydroxide functions as a buffering agent, corrosion inhibitor, and pH adjuster. The Food and Drug Administration (FDA) evaluated the safe use of alumina in several medical devices and aluminum hydroxide in over-the-counter drugs, which included a review of human and animal safety data. The Cosmetic Ingredient Review (CIR) Expert Panel considered the FDA evaluations as part of the basis for determining the safety of these ingredients as used in cosmetics. Alumina used in cosmetics is essentially the same as that used in medical devices. This safety assessment does not include metallic or elemental aluminum as a cosmetic ingredient. The CIR Expert Panel concluded that alumina and aluminum hydroxide are safe in the present practices of use and concentration described in this safety assessment.
Topics: Aluminum Hydroxide; Aluminum Oxide; Animals; Consumer Product Safety; Cosmetics; Equipment and Supplies; Government Regulation; Humans; Molecular Structure; Toxicity Tests; Toxicokinetics; United States; United States Food and Drug Administration
PubMed: 27913785
DOI: 10.1177/1091581816677948 -
Journal of Pharmaceutical Sciences Apr 2022Aluminum hydroxide (Al(OH)) and aluminum phosphate (AlPO) are widely used adjuvants in human vaccines. However, a rationale to choose one or the other is lacking since...
Aluminum hydroxide (Al(OH)) and aluminum phosphate (AlPO) are widely used adjuvants in human vaccines. However, a rationale to choose one or the other is lacking since the differences between molecular mechanisms of action of these adjuvants are unknown. In the current study, we compared the innate immune response induced by both adjuvants in vitro and in vivo. Proteome analysis of human primary monocytes was used to determine the immunological pathways activated by these adjuvants. Subsequently, analysis of immune cells present at the site of injection and proteome analysis of the muscle tissue revealed the differentially regulated processes related to the innate immune response in vivo. Incubation with Al(OH) specifically enhanced the activation of antigen processing and presentation pathways in vitro. In vivo experiments showed that only intramuscular (I.M.) immunization with Al(OH) attracted neutrophils, while I.M. immunization with AlPO attracted monocytes/macrophages to the site of injection. In addition, only I.M. immunization with Al(OH) enhanced the process of hemostasis after 96 hours, possibly related to neutrophilic extracellular trap formation. Both adjuvants differentially regulated various immune system-related processes. The results show that Al(OH) and AlPO act differently on the innate immune system. We speculate that these different regulations affect the interaction with cells, due to the different physicochemical properties of both adjuvants.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Aluminum; Aluminum Compounds; Aluminum Hydroxide; Humans; Immunity, Innate; Phosphates; Proteome
PubMed: 35090866
DOI: 10.1016/j.xphs.2022.01.014 -
Lancet (London, England) Mar 2021
Topics: Aluminum Hydroxide; Clinical Trials as Topic; Drug Compounding; Humans; Journalism, Medical; Papillomavirus Vaccines; Phosphates; Placebos; Safety; Societies, Scientific; Vaccines, Combined
PubMed: 33743866
DOI: 10.1016/S0140-6736(21)00382-2 -
Experimental Lung Research 2020Aluminum is the third most abundant metal in the earth's crust and is widely used in industry. Chronic contact with aluminum results in a reduction in the activity of...
Aluminum is the third most abundant metal in the earth's crust and is widely used in industry. Chronic contact with aluminum results in a reduction in the activity of electron transport chain complexes, leading to excessive production of reactive oxygen species (ROS) and oxidative stress. This study aimed to evaluate the effects of short-term exposure of aluminum hydroxide on oxidative stress and pulmonary inflammatory response. Male BALB/c mice were divided into three groups: control group (CG); phosphate buffered saline group (PBSG) and aluminum hydroxide group (AHG). CG was exposed to ambient air, while PBSG and AHG were exposed to PBS or aluminum hydroxide solutions via nebulization, three times per day for five consecutive days. Twenty-four hours after the last exposure, all animals were euthanized for subsequent analysis. Exposure to aluminum hydroxide in the blood resulted in lower platelet levels, higher neutrophils, and lower monocytes compared to CG and PBSG. Aluminum hydroxide promoted the recruitment of inflammatory cells to the lung. Macrophage, neutrophil and lymphocyte counts were higher in AHG compared to CG and PBSG. Protein oxidation and superoxide dismutase activity were higher, while catalase activity and reduced and oxidizes glutathione ratio in AHG were lower compared to CG and PBSG. Furthermore, there was an increase in the inflammatory markers CCL2 and IFN-γ in AHG compared to CG and PBSG. In conclusion, short-term nebulization with aluminum hydroxide induces the influx of inflammatory cells and oxidative stress in adult BALB/c mice.
Topics: Aluminum Hydroxide; Animals; Inhalation Exposure; Lung; Male; Mice, Inbred BALB C; Nanoparticles; Occupational Exposure; Oxidative Stress; Random Allocation
PubMed: 32067522
DOI: 10.1080/01902148.2020.1728595 -
BioMed Research International 2023The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c...
The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c mice. The mice received via orogastric gavage phosphate buffered or 10 mg/kg aluminum hydroxide 3 times a week for 6 months. Administration of aluminum hydroxide decreased hemoglobin, hematocrit, and erythrocyte. In the blood, kidney and liver function markers were evaluated, and long-term administration of aluminum hydroxide led to an increase in AST levels and a decrease in urea levels. The animals exposed to aluminum showed higher lipid and protein oxidation in all the organs analyzed. In relation to the enzymes involved in antioxidant defense, the lungs showed lower superoxide dismutase (SOD) and catalase activity and a lower reduced and oxidized glutathione (GSH/GSSG) ratio. In the liver, aluminum administration led to a decrease in catalase activity and the GSH/GSSG ratio. Lower catalase activity was observed in the small intestine, as well as in the lungs and liver. In addition to alterations in antioxidant defense, increased levels of the chemokine CCL-2 were observed in the lungs, lower levels of IL-10 in the liver and small intestine, and decreased levels of IL-6 in the intestine of the animals that received aluminum hydroxide for 6 months. Long-term exposure to aluminum promoted steatosis in the liver. In the kidneys, mice treated with aluminum presented a decreased glomerular density than in the naive control group. In the small intestine, exposure caused villi shortening. Our results indicate that long-term oral administration of aluminum hydroxide provokes systemic histological damage, inflammation, and redox imbalance.
Topics: Mice; Male; Animals; Antioxidants; Glutathione Disulfide; Glutathione; Catalase; Aluminum Hydroxide; Mice, Inbred BALB C; Aluminum; Oxidation-Reduction; Superoxide Dismutase; Liver; Inflammation; Oxidative Stress
PubMed: 37854793
DOI: 10.1155/2023/4499407 -
Journal of Proteomics Mar 2018Aluminum-based adjuvants are the most widely used adjuvants in human vaccines. A comprehensive understanding of the mechanism of action of aluminum adjuvants at the...
UNLABELLED
Aluminum-based adjuvants are the most widely used adjuvants in human vaccines. A comprehensive understanding of the mechanism of action of aluminum adjuvants at the molecular level, however, is still elusive. Here, we unravel the effects of aluminum hydroxide Al(OH) by a systems-wide analysis of the Al(OH)-induced monocyte response. Cell response analysis by cytokine release was combined with (targeted) transcriptome and full proteome analysis. Results from this comprehensive study revealed two novel pathways to become activated upon monocyte stimulation with Al(OH): the first pathway was IFNβ signaling possibly induced by DAMP sensing pathways like TLR or NOD1 activation, and second the HLA class I antigen processing and presentation pathway. Furthermore, known mechanisms of the adjuvant activity of Al(OH) were elucidated in more detail such as inflammasome and complement activation, homeostasis and HLA-class II upregulation, possibly related to increased IFNγ gene expression. Altogether, our study revealed which immunological pathways are activated upon stimulation of monocytes with Al(OH), refining our knowledge on the adjuvant effect of Al(OH) in primary monocytes.
SIGNIFICANCE
Aluminum salts are the most used adjuvants in human vaccines but a comprehensive understanding of the working mechanism of alum adjuvants at the molecular level is still elusive. Our Systems Vaccinology approach, combining complementary molecular biological, immunological and mass spectrometry-based techniques gave a detailed insight in the molecular mechanisms and pathways induced by Al(OH) in primary monocytes. Several novel immunological relevant cellular pathways were identified: type I interferon secretion potentially induced by TLR and/or NOD like signaling, the activation of the inflammasome and the HLA Class-I and Class-II antigen presenting pathways induced by IFNγ. This study highlights the mechanisms of the most commonly used adjuvant in human vaccines by combing proteomics, transcriptomics and cytokine analysis revealing new potential mechanisms of action for Al(OH).
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Antigen Presentation; Cytokines; Gene Expression Profiling; Humans; Immunity, Innate; Inflammation; Monocytes; Proteomics
PubMed: 29317357
DOI: 10.1016/j.jprot.2017.12.021 -
Molecular Microbiology May 2022Aluminum salts have been successfully utilized as adjuvants to enhance the immunogenicity of vaccine antigens since the 1930s. However, the cellular mechanisms behind...
Aluminum salts have been successfully utilized as adjuvants to enhance the immunogenicity of vaccine antigens since the 1930s. However, the cellular mechanisms behind the immune adjuvanticity effect of these materials in antigen-presenting cells are poorly understood. In this study, we investigated the uptake and trafficking of aluminum oxy-hydroxide (AlOOH), in RAW 264.7 murine and U-937 human macrophages-like cells. Furthermore, we determined the impact that the adsorption to AlOOH particulates has on the trafficking of a Bordetella pertussis vaccine candidate, the genetically detoxified pertussis toxin (gdPT). Our results indicate that macrophages internalize AlOOH by constitutive macropinocytosis assisted by the filopodial protrusions that capture the adjuvant particles. Moreover, we show that AlOOH has the capacity to nonspecifically adsorb IgG, engaging opsonic phagocytosis, which is a feature that may allow for more effective capture and uptake of adjuvant particles by antigen-presenting cells (APCs) at the site of vaccine administration. We found that AlOOH traffics to endolysosomal compartments that hold degradative properties. Importantly, while we show that gdPT escapes degradative endolysosomes and traffics toward the retrograde pathway, as reported for the wild-type pertussis toxin, the adsorption to AlOOH diverts gdPT to traffic to the adjuvant's lysosome-type compartments, which may be key for MHC-II-driven antigen presentation and activation of CD4 T cell. Thus, our findings establish a direct link between antigen adsorption to AlOOH and the intracellular trafficking of antigens within antigen-presenting cells and bring to light a new potential mechanism for aluminum adjuvancy. Moreover, the in-vitro single-cell approach described herein provides a general framework and tools for understanding critical attributes of other vaccine formulations.
Topics: Adjuvants, Immunologic; Aluminum; Aluminum Hydroxide; Animals; Humans; Lysosomes; Macrophages; Mice; Pertussis Toxin; Pertussis Vaccine
PubMed: 35344242
DOI: 10.1111/mmi.14900 -
Journal of Immunology Research 2019Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most... (Review)
Review
Adjuvants are a diverse family of substances whose main objective is to increase the strength, quality, and duration of the immune response caused by vaccines. The most commonly used adjuvants are aluminum-based, oil-water emulsion, and bacterial-origin adjuvants. In this paper, we will discuss how the election of adjuvants is important for the adjuvant-mediated induction of immunity for different types of vaccines. Aluminum-based adjuvants are the most commonly used, the safest, and have the best efficacy, due to the triggering of a strong humoral response, albeit generating a weak induction of cell-mediated immune response. Freund's adjuvant is the most widely used oil-water emulsion adjuvant in animal trials; it stimulates inflammation and causes aggregation and precipitation of soluble protein antigens that facilitate the uptake by antigen-presenting cells (APCs). Adjuvants of bacterial origin, such as flagellin, membranes, and monophosphoryl lipid A (MLA), are known to potentiate immune responses, but their safety and risks are the main concern of their clinical use. This minireview summarizes the mechanisms that classic and novel adjuvants produce to stimulate immune responses.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antigens, Bacterial; Emulsions; Escherichia coli; Humans; Immunity, Cellular; Lipid A; Oils
PubMed: 31205956
DOI: 10.1155/2019/3974127