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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 -
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 -
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 Toxicology and Environmental... 2007
Review
Topics: Aluminum; Aluminum Compounds; Aluminum Hydroxide; Aluminum Oxide; Animals; Environmental Exposure; Humans; Occupational Exposure; Risk Assessment; Tissue Distribution; Toxicity Tests
PubMed: 18085482
DOI: 10.1080/10937400701597766 -
Chemical Reviews Jan 2006
Review
Topics: Aluminum Hydroxide; Chemistry, Pharmaceutical; Environmental Pollutants; Kinetics; Minerals; Molecular Structure; Water; Water Purification
PubMed: 16402770
DOI: 10.1021/cr040095d -
Journal of Pharmaceutical Sciences Aug 1985
Topics: Aluminum Hydroxide; Chemical Phenomena; Chemistry; Drug Industry; Hydrogen-Ion Concentration
PubMed: 4032280
DOI: 10.1002/jps.2600740825 -
JCI Insight Dec 2023IL-12 is a potent cytokine that can promote innate and adaptive anticancer immunity, but its clinical development has been limited by toxicity when delivered...
IL-12 is a potent cytokine that can promote innate and adaptive anticancer immunity, but its clinical development has been limited by toxicity when delivered systemically. Intratumoral (i.t.) administration can expand the therapeutic window of IL-12 and other cytokines but is in turn limited by rapid drug clearance from the tumor, which reduces efficacy, necessitates frequent administration, and increases systemic accumulation. To address these limitations, we developed an anchored IL-12 designated ANK-101, composed of an engineered IL-12 variant that forms a stable complex with the FDA-approved vaccine adjuvant aluminum hydroxide (Alhydrogel). Following i.t. administration of murine ANK-101 (mANK-101) in early intervention syngeneic mouse tumors, the complex formed a depot that was locally retained for weeks as measured by IVIS or SPECT/CT imaging, while unanchored protein injected i.t. was cleared within hours. One or 2 i.t. injections of mANK-101 induced single-agent antitumor activity across a diverse range of syngeneic tumors, including models resistant to checkpoint blockade at doses where unanchored IL-12 had no efficacy. Local treatment with mANK-101 further induced regressions of noninjected lesions, especially when combined with systemic checkpoint blockade. Antitumor activity was associated with remodeling of the tumor microenvironment, including prolonged IFN-γ and chemokine expression, recruitment and activation of T and NK cells, M1 myeloid cell skewing, and increased antigen processing and presentation. Subcutaneous administration of ANK-101 in cynomolgus macaques was well tolerated. Together, these data demonstrate that ANK-101 has an enhanced efficacy and safety profile and warrants future clinical development.
Topics: Mice; Animals; Interleukin-12; Aluminum Hydroxide; Tumor Microenvironment; Cytokines; Neoplasms
PubMed: 38063196
DOI: 10.1172/jci.insight.168224 -
Journal of Pharmaceutical Sciences Aug 2006Aluminum hydroxide adjuvant, AlO(OH), is used to potentiate the immune response to vaccines by adsorbing the antigen. The structure of aluminum hydroxide adjuvant is...
Aluminum hydroxide adjuvant, AlO(OH), is used to potentiate the immune response to vaccines by adsorbing the antigen. The structure of aluminum hydroxide adjuvant is unusual as it is crystalline but has a high surface area due to its very small primary particles. The purpose of this study was to investigate the chemical and thermal conditions required to synthesize aluminum hydroxide adjuvant that is stable and exhibits a high protein adsorptive capacity. Aluminum hydroxide adjuvant was precipitated using a procedure in which the concentration of reactants was maintained constant throughout the precipitation. The precipitation variables were: 2.50, 2.75, and 3.00 OH/Al molar ratio; 0.5, 4.0, and 5.0 M NaCl; and 25, 60, and 65 degrees C. High sodium chloride concentration and high temperature facilitated the formation of AlO(OH) rather than crystalline forms of aluminum hydroxide, Al(OH)(3). The AlO(OH) produced was not stable because crystalline forms of aluminum hydroxide formed during aging at room temperature. Aluminum hydroxide adjuvant was stabilized for the study period of 12 weeks at room temperature by either the addition of 3.0 M NaCl after precipitation and washing or hydrothermal treatment at 110 degrees C for 4 h. Stabilization by the addition of sodium chloride required a hypertonic concentration of sodium chloride and was not practical as vaccines for parenteral administration are desired to be isotonic (equivalent to 0.15 M NaCl). Stabilization by hydrothermal treatment produced aluminum hydroxide adjuvant, which exhibited a high protein adsorptive capacity that did not change during the 12-week study period.
Topics: Adjuvants, Pharmaceutic; Aluminum Hydroxide; Chemistry, Pharmaceutical
PubMed: 16795021
DOI: 10.1002/jps.20692 -
ACS Applied Materials & Interfaces Jul 2017Insoluble aluminum salts such as aluminum (oxy)hydroxide are commonly used as vaccine adjuvants. Recently, there is evidence suggesting that the adjuvant activity of...
Insoluble aluminum salts such as aluminum (oxy)hydroxide are commonly used as vaccine adjuvants. Recently, there is evidence suggesting that the adjuvant activity of aluminum salt-based materials is tightly related to their physicochemical properties, including nanometer-scale size, shape with long aspect ratio, and low degree of crystallinity. Herein, for the first time, the bicontinuous reverse microemulsion (RM) technique was utilized to synthesize stick-like monodisperse aluminum (oxy)hydroxide nanoparticles with a long aspect ratio of ∼10, length of ∼80 nm, and low degree of crystallinity (denoted as Al-nanosticks). Moreover, the relationship between the physicochemical properties of Al-nanosticks and the bicontinuous RM was discussed. Compared to the commercial Alhydrogel, which contains micrometer-scale aluminum oxyhydroxide particular aggregates with moderate degree of crystallinity, the Al-nanosticks are more effective in adsorbing and delivering antigens (e.g., ovalbumin, OVA) into antigen-presenting cells, activating inflammasomes, and potentiating OVA-specific antibody responses in a mouse model. It is concluded that the aluminum (oxy)hydroxide nanosticks synthesized in the bicontinuous RM are promising new aluminum salt-based vaccine adjuvants.
Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Humans; Mice; Ovalbumin; Vaccines
PubMed: 28621928
DOI: 10.1021/acsami.7b03965 -
Research in Immunology Jun 1992
Review
Topics: Adjuvants, Immunologic; Aluminum; Aluminum Compounds; Aluminum Hydroxide; Animals; Humans; Phosphates
PubMed: 1439128
DOI: 10.1016/0923-2494(92)80059-t