Aluminium Hydroxyphosphate Research Articles

Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

PurposeTrustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine’s risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and...

Aluminium Adjuvants – A Nanomaterial used as Adjuvants in Human Vaccines for Decades

Background:Aluminium salts have been used for decades in vaccines as adjuvants to facilitate the adaptive immune response against co-administered antigens. Two types of aluminium adjuvant are mostly used, aluminium oxyhydroxide and aluminium hydroxyphosphate. Both types of aluminium adjuvant consist of nanoparticles that form loose, micrometre sized aggregates at circumneutral pH.Aluminium adjuvants constitute a well-documented example of administration of nanomaterials to humans with infrequent side effects and a safety record generally regarded as excellent. However, despite its prolonged use in human and veterinary medicine, the mechanisms behind the enhanced response and the immune stimulatory effect are still by and large unknown.Methods:The present paper reviews existing ideas regarding the immunostimulatory effects of aluminium adjuvants, with a focus on the induction of an inflammatory response by cellular stress. Reviewed information was obtained from peer-reviewed scientific papers published in 1988 to date with one exception, a paper published 1931.Results:Cellular stress causes extra cellular signalling of Danger Associated Molecular Patterns (DAMPs) and upon phagocytosis of aluminium adjuvants the cells need to manage the ingested particles.Conclusion:A persistent intracellular accumulation of aluminium adjuvants will be a solid depository of sparingly soluble aluminium salts maintaining a constant concentration of Al3+ions in the cytoplasm and this will affect multiple biochemical processes. The cell will be under constant stress and DAMP signalling will occur and we would like to suggest the maintenance of a constant concentration Al3+ions in the cytoplasm as a general underlying feature of the immune stimulation properties of aluminium adjuvants.

Tracing Aluminium-based Adjuvants: Their Interactions with Immune Competent Cells and their Effect on Mitochondrial Activity

Background: Studies revealing the immune stimulatory properties of aluminium-based adjuvants (ABAs) have been impaired by the absence of simple and reliable methods of tracing the adjuvants and their effect on biochemical processes upon endocytosis. Objective: To verify that labelling of ABAs with lumogallion doesn’t affect the physicochemical properties of the adjuvant; tracing cellular interaction with aluminium adjuvants; explore their effect on metabolic activity upon endocytosis. Methods: Physicochemical characterization by Z-potential and size distribution of ABAs labelled with lumogallion. Cellular interactions with ABAs by flow cytometry and confocal microscopy. Metabolic activity explored by measuring transformation of tetrazolium into formazan. Results: No or minor change of zeta potential and average particle size of lumogallion labelled aluminium oxyhydroxide, AlO(OH) and aluminium hydroxyphosphate, Al(OH)x(PO4)y. Both phagocytosing and non-phagocytosing leukocytes became associated with ABAs at concentrations expected after in vivo administration of a vaccine. The ABAs were relatively toxic, affecting both lymphocytes and monocytes, and Al(OH)x(PO4)y was more toxic than AlO(OH). Endocytosed aluminium adjuvant particles were not secreted from the cells and remained intracellular throughout several cell divisions. The presence of ABAs increased the mitochondrial activity of the monocytic cell line THP-1 and peripheral monocytes, as based on the transformation of tetrazolium into formazan. Conclusion: Lumogallion labelled ABAs is a valuable tool tracing interactions between ABAs and cells. Labelled ABAs can be traced intracellularly and ABAs are likely to remain intracellular for a long period of time. Intracellular ABAs increase the mitochondrial activity and the presence of intracellular Al ions is suggested to cause an increased mitochondrial activity.

Sequestering of damage-associated molecular patterns (DAMPs): a possible mechanism affecting the immune-stimulating properties of aluminium adjuvants

Aluminium-based adjuvants (ABAs) have been used in human and veterinary vaccines for decades, and for a long time, the adjuvant properties were believed to be mediated by an antigen depot at the injection site, prolonging antigen exposure to the immune system. The depot hypothesis is today more or less abandoned, and instead replaced by the assumption that ABAs induce an inflammation at the injection site. Induction of an inflammatory response is consistent with immune activation initiated by recognition of molecular patterns associated with danger or damage (DAMPs), and the latter are derived from endogenous molecules that normally reside intracellularly. When extracellularly expressed, because of damage, stress or cell death, a sterile inflammation is induced. In this paper, we report the induction of DAMP release by viable cells after phagocytosis of aluminium-based adjuvants. Two of the most commonly used ABAs in pharmaceutical vaccine formulations, aluminium oxyhydroxide and aluminium hydroxyphosphate, induced a vigorous extracellular expression of the two DAMP molecules calreticulin and HMGB1. Concomitantly, extracellular adjuvant particles adsorbed the DAMP molecules released by the cells whereas IL-1β, a previously reported inflammatory mediator induced by ABAs, was not absorbed by the adjuvants. Induction of extracellular expression of the two DAMP molecules was more prominent using aluminium hydroxyphosphate compared to aluminium oxyhydroxide, whereas the extracellular adsorption of the DAMP molecules was more pronounced with the latter. Furthermore, it is hypothesised how induction of DAMP expression by ABAs and their concomitant adsorption by extracellular adjuvants may affect the inflammatory properties of ABAs.

Iron(III) and aluminium(III) based mixed nanostructured hydroxyphosphates as potential vaccine adjuvants: Preparation and physicochemical characterization

Adjuvants are substances that, when combined with an antigen in a vaccine formulation, potentiate the immune response against that antigen. Aluminium hydroxyphosphate is among the currently used adjuvants in vaccines, while studies on its iron analogue, ferric hydroxyphosphate, are quite limited. In this article we report on the preparation and physicochemical characterization of novel nanostructured iron and aluminium based mixed hydroxyphosphates as potential vaccine adjuvants, prepared by controlled co-precipitation from mixed solutions of Fe(III) and Al(III) chlorides with sodium phosphate and sterilized by autoclaving. The obtained hydroxyphosphates consisted of a network of platy nanoparticles (20–40nm in size), which aggregated in aqueous medium to form secondary micron-sized particles. The obtained nanostructured hydroxyphosphates were characterized by energy dispersive X-ray spectroscopy for elemental composition, X-ray powder diffraction, infrared spectroscopy, zeta-potential measurements for determination of isoelectric point, protein adsorption, and dissolution rate in sodium citrate solution.

Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations.

Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al3+ in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain.

Quadrivalent Human Papillomavirus (HPV) Types 6, 11, 16, 18 Vaccine

The quadrivalent HPV types 6, 11, 16, 18 vaccine (Gardasil®) is a recombinant vaccine comprising purified virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18. The vaccine was highly immunogenic. Geometric mean titres (GMTs) and seroconversion rates for all four HPV types at month 7 in males aged 10-15 years were noninferior to those in females aged 16-23 years, and those in males aged 9-15 years were noninferior to those in females aged 9-15 years. In addition, GMTs and seroconversion rates in males aged 16-26 years receiving the vaccine were higher than those receiving amorphous aluminium hydroxyphosphate sulfate adjuvant (AAHS) control. The quadrivalent HPV vaccine was significantly more effective than AAHS control at decreasing the incidence of HPV 6-, 11-, 16- or 18-related external genital lesions (primary endpoint) in a randomized, double-blind, placebo-controlled, multicentre study in males aged 16-26 years. The most common clinical endpoint was HPV 6- and 11-related condyloma; efficacy was robust against these lesions. The vaccine is also expected to be protective against genital warts in males aged 9-15 years, as the immune response in males of this age group was noninferior to that in males aged 16-26 years. The quadrivalent HPV vaccine was generally well tolerated in males aged 9-26 years. The most common adverse events reported were injection-site related, and most of these were of mild to moderate severity.

The formation, precipitation and structural characterisation of hydroxyaluminosilicates formed in the presence of fluoride and phosphate

Hydroxyaluminosilicates (HAS) are important secondary mineral phases formed by the reaction of silicic acid (Si(OH) 4) with aluminium. Two discrete forms of HAS have been identified (HAS A and HAS B) and their structures and composition determined. Herein we have investigated the formation of HAS in the presence of equimolar Si(OH) 4 and fluoride (F −) or phosphate ( HPO 4 2 - ) . The latter resulted in the precipitation of aluminium hydroxyphosphate and inhibited the formation of HAS except where the concentration of Al was significantly in excess of HPO 4 2 - where HAS A was co-precipitated. There was no evidence of the formation of HAS which included phosphate in the structure. Fluoride did not prevent the formation of HAS, except, possibly, when it was present at four times the concentration of Al, and the inclusion of F in precipitated HAS was confirmed using electron microprobe and solid state NMR. Both HAS A and HAS B were found to incorporate F though evidence from NMR, in particular, suggested that F substituted for OH on Al but not on Si. In addition F was bound to octahedrally and not tetrahedrally co-ordinated Al and this preference appeared to inhibit or delay the dehydroxylation reaction which is involved in the transition between HAS A and HAS B. This is the first report of F-substituted HAS and further research will be required to determine if they are of environmental significance or, indeed, if these inorganic fluorinated polymers are of any value to materials science.

Aluminium compounds for use in vaccines

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.

Structure cristalline d'un nouvel hydroxyphosphate naturel de strontium, fer et aluminium (lulzacite), Sr2Fe(Fe0,63Mg0,37)2Al4(PO4)4(OH)10

Abstract Crystal structure of a new natural strontium, iron and aluminium hydroxyphosphate (lulzacite): Sr2Fe(Fe0.63Mg0.37)2Al4(PO4)4(OH)10. The crystal structure of a new natural strontium, iron and aluminium hydroxyphosphate (lulzacite) has been solved through an X-ray study of a single crystal: – symmetry: triclinic (P1); – unit cell parameters: a=5.457(1) A, b=9.131(2) A, c=9.769(2) A, α=108.47(3)°, β=91.72(3)° and γ=97.44(3); – structural formula: (Sr0.96Ba0.04)2Fe(Fe0.63Mg0.37)2Al4[(P0.98V0.02)O4]4(OH)10 (Z=1). The structure presents along the b axis the alternation, on one hand of infinite chains of edge sharing octahedra (one Fe2+O6 and an AlO6 pair), and, on the other hand, of trimers with a central AlO6 octahedron framed by two mixed (Fe2+,Mg)O6 octahedra. Trimers and chains are linked by the corners of one AlO6 octahedron and two PO4 tetrahedra. Strontium ions are located in the channels of the structure. This structure is isotypic with that of jamesite, a lead arsenate. Similar octahedral building blocks are present in other mineral species: trimers in ludlamite (iron phosphate), chains in various hydroxysalts. © 2000 Academie des sciences / Editions scientifiques et medicales Elsevier SAS lulzacite / hydroxyphosphate / phosphate / strontium / iron / aluminium

Predicting the adsorption of proteins by aluminium-containing adjuvants

The adsorption of two model proteins, albumin and lysozyme, by boehmite or amorphous aluminium hydroxyphosphate adjuvants was studied. Electrostatic attraction has a major role in adsorption. At physiological pH, boehmite, which has a point of zero charge above 7.35, extensively adsorbed albumin, which has an isoelectric point of 4.8, but was not effective in adsorbing lysozyme (isoelectric point, 11.0). Conversely, amorphous aluminium hydroxyphosphate (point of zero charge, 4.0) was effective in adsorbing lysozyme but adsorbed relatively little albumin. The results suggest that the selection of either boehmite or amorphous aluminium hydroxyphosphate as an adjuvant should be based in part on the isoelectric point of the antigen.

ADVERSE REACTIONS IN CHILDREN VACCINATED WITH DPT AND PERTUSSIS VACCINE

A total of 508 children were vaccinated with DPT vaccine (Lot 76 327). The vaccination policy was that basic DPT vaccination started at the age of three months and three injections were given at one‐month intervals. In another 370 cases pertussis vaccine (Lot 76 012) was given. In these, vaccination started at the age of five weeks and three injections were given at four‐week intervals. In the children basically vaccinated with DPT vaccine some local reactions occurred in 26/508(5.1%) cases and systemic reactions in 48/508(9.4%). In the children basically vaccinated with pertussis vaccine local reactions occurred in 13/370(3.5%) cases and systemic reactions in 33/370(8.9%).Booster vaccination with DPT vaccine (Lot 76 327) was given to 565 children aged one–6 years, while 138 children aged 2–6 years were booster vaccinated with pertussis vaccine (Lot 76 012). The children booster vaccinated with DPT vaccine exhibited some local reactions in 118/565(20.9%) cases and some systemic reactions in 53/565(9.3%). In the children vaccinated with pertussis vaccine local reactions occurred in 14/138(10.1%) cases and systemic reactions in 7/138(5.1%). None of the vaccinated children developed any severe neurological or systemic complications from vaccination.DPT and pertussis vaccine contain equal amounts (about 5 000 million cells/ml vaccine) of the Bordetella pertussis strains 18 530 and 1 772 and aluminium hydroxy phosphate as adjuvant. One dose vaccine was 0.5 ml.