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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 -
Critical Reviews in Toxicology Oct 2014Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods,... (Review)
Review
Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.
Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007) . Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of "total Al"assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al(+3) to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)(+2) and Al(H2O)6 (+3)] that after complexation with O2(•-), generate Al superoxides [Al(O2(•))](H2O5)](+2). Semireduced AlO2(•) radicals deplete mitochondrial Fe and promote generation of H2O2, O2 (•-) and OH(•). Thus, it is the Al(+3)-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer's disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances.
Topics: Aluminum; Aluminum Hydroxide; Aluminum Oxide; Animals; Carcinogenesis; Cardiovascular System; Central Nervous System; Disease Models, Animal; Dose-Response Relationship, Drug; Endocrine System; Europe; Gastrointestinal Tract; Guidelines as Topic; Humans; Kidney; Liver; Nanoparticles; Occupational Exposure; Randomized Controlled Trials as Topic; Respiratory System; Risk Assessment; Risk Factors
PubMed: 25233067
DOI: 10.3109/10408444.2014.934439 -
Pharmaceutics Jul 2023Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread... (Review)
Review
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.
PubMed: 37514070
DOI: 10.3390/pharmaceutics15071884 -
Cell Feb 2022Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns...
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies, Neutralizing; Antibody Specificity; Antigens, Viral; B-Lymphocytes; COVID-19; Candida albicans; Chlorocebus aethiops; Epitopes; Immunity, Innate; Immunization; Inflammation; Interferons; Lectins, C-Type; Ligands; Lung; Lymph Nodes; Macrophages; Mannans; Mice, Inbred C57BL; Paranasal Sinuses; Protein Subunits; Sialic Acid Binding Ig-like Lectin 1; Solubility; Spike Glycoprotein, Coronavirus; T-Lymphocytes; Transcription Factor RelB; Vero Cells; beta-Glucans; Mice
PubMed: 35148840
DOI: 10.1016/j.cell.2022.01.009 -
Actas Dermo-sifiliograficas Dec 2015Calcinosis cutis (CC) is defined as the deposition of calcium salts in the skin. The condition is divided into 5 types: calciphylaxis and dystrophic, metastatic,... (Review)
Review
Calcinosis cutis (CC) is defined as the deposition of calcium salts in the skin. The condition is divided into 5 types: calciphylaxis and dystrophic, metastatic, idiopathic, and iatrogenic CC. Dystrophic CC is the most common form and usually occurs in association with autoimmune diseases. CC can be treated surgically or with the use of drugs such as diltiazem, bisphosphonates, warfarin, ceftriaxone, probenecid, minocycline, or aluminum hydroxide. Calciphylaxis is defined as calcification of the media of small- and medium-sized blood vessels in the dermis and subcutaneous tissue. Clinically, calciphylaxis causes livedo racemosa, which progresses to retiform purpura and skin necrosis. First-line treatment is with sodium thiosulfate. We present a review of the calcifying disorders of the skin, focusing on their diagnosis and treatment.
Topics: Autoimmune Diseases; Calcinosis; Calciphylaxis; Calcium; Collagen Diseases; Diagnostic Imaging; Humans; Iatrogenic Disease; Phosphorus; Skin Diseases; Skin Diseases, Parasitic; Thiosulfates
PubMed: 26394755
DOI: 10.1016/j.ad.2015.09.001 -
Vaccines Mar 2016Several modes of vaccine delivery have been developed in the last 25 years, which induce strong immune responses in pre-clinical models and in human clinical trials....
Several modes of vaccine delivery have been developed in the last 25 years, which induce strong immune responses in pre-clinical models and in human clinical trials. Some modes of delivery include, adjuvants (aluminum hydroxide, Ribi formulation, QS21), liposomes, nanoparticles, virus like particles, immunostimulatory complexes (ISCOMs), dendrimers, viral vectors, DNA delivery via gene gun, electroporation or Biojector 2000, cell penetrating peptides, dendritic cell receptor targeting, toll-like receptors, chemokine receptors and bacterial toxins. There is an enormous amount of information and vaccine delivery methods available for guiding vaccine and immunotherapeutics development against diseases.
PubMed: 27043641
DOI: 10.3390/vaccines4020009 -
Frontiers in Bioengineering and... 2022Vaccines represent one of the most successful public health initiatives worldwide. However, despite the vast number of highly effective vaccines, some infectious... (Review)
Review
Vaccines represent one of the most successful public health initiatives worldwide. However, despite the vast number of highly effective vaccines, some infectious diseases still do not have vaccines available. New technologies are needed to fully realize the potential of vaccine development for both emerging infectious diseases and diseases for which there are currently no vaccines available. As can be seen by the success of the COVID-19 mRNA vaccines, nanoscale platforms are promising delivery vectors for effective and safe vaccines. Synthetic nanoscale platforms, including liposomes and inorganic nanoparticles and microparticles, have many advantages in the vaccine market, but often require multiple doses and addition of artificial adjuvants, such as aluminum hydroxide. Biologically derived nanoparticles, on the other hand, contain native pathogen-associated molecular patterns (PAMPs), which can reduce the need for artificial adjuvants. Biological nanoparticles can be engineered to have many additional useful properties, including biodegradability, biocompatibility, and are often able to self-assemble, thereby allowing simple scale-up from benchtop to large-scale manufacturing. This review summarizes the state of the art in biologically derived nanoparticles and their capabilities as novel vaccine platforms.
PubMed: 35402394
DOI: 10.3389/fbioe.2022.867119 -
Human Vaccines & Immunotherapeutics Nov 2022Alum adjuvant has always been the first choice when designing a vaccine. Conventional aluminum adjuvant includes aluminum hydroxide, aluminum phosphate, and amorphous... (Review)
Review
Alum adjuvant has always been the first choice when designing a vaccine. Conventional aluminum adjuvant includes aluminum hydroxide, aluminum phosphate, and amorphous aluminum hydroxyphosphate (AAHS), which could effectively induce the humoral, and to a lesser extent, cellular immune responses. Their safety is widely accepted for a variety of vaccines. However, conventional alum adjuvant is not an ideal choice for a vaccine antigen with poor immunogenicity, especially the subunit vaccine in which cellular response is highly demanded. The outbreak of COVID-19 requires a delicately designed vaccine without the antibody-dependent enhancement (ADE) effect to ensure the safety. A sufficiently powerful adjuvant that can induce both Th and Th immune responses is necessary to reduce the risk of ADE. These circumstances all bring new challenges to the conventional alum adjuvant. However, turning conventional microscale alum adjuvant into nanoscale is a new solution to these problems. Nanoscale alum owns a higher surface volume ratio, can absorb much more antigens, and promote the ability to stimulate the antigen-presenting cells (APCs) via different mechanisms. In this review, the exceptional performance of nano alum adjuvant and their preparation methods will be discussed. The potential safety concern of nano alum is also addressed. Based on the different mechanisms, the potential application of nano alum will also be introduced.
Topics: Adjuvants, Immunologic; Alum Compounds; Aluminum; Animals; COVID-19; Humans; Immunity, Cellular; Mice; Mice, Inbred BALB C; Vaccines, Subunit
PubMed: 35471916
DOI: 10.1080/21645515.2022.2060667 -
Ecotoxicology and Environmental Safety May 2023Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al,...
Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 μg/ml or 25 μg/ml Al(OH) for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH) exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH) exposed cerebral organoid, uncovering a novel mechanism for Al(OH)-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH) exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH) exposure on human brain development.
Topics: Child, Preschool; Humans; Human Embryonic Stem Cells; Aluminum Hydroxide; Neurogenesis; Neural Stem Cells; Organoids
PubMed: 37011512
DOI: 10.1016/j.ecoenv.2023.114863