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

From Stock Bottle to Vaccine: Elucidating the Particle Size Distributions of Aluminum Adjuvants Using Dynamic Light Scattering.

The physicochemical properties of aluminum salts are key determinants of their resultant adjuvanticity in vivo when administered as part of a vaccine. While there are links between particle size and the efficacy of the immune response, the limited literature directly characterizing the PSD of aluminum adjuvants has stymied the elucidation of such a relationship for these materials. Hence, this comparative study was undertaken to monitor the PSD of aluminum adjuvants throughout the process of vaccine formulation using DLS. A significant proportion of the stock suspensions was highly agglomerated (>9 μm) and Alhydrogel® exhibited the smallest median size (2677 ± 120 nm) in comparison to Adju-Phos® or Imject alum® (7152 ± 308 and 7294 ± 146 nm respectively) despite its large polydispersity index (PDI). Dilution of these materials induced some degree of disaggregation within all samples with Adju-Phos® being the most significantly affected. The presence of BSA caused the median size of Alhydrogel® to increase but these trends were not evident when model vaccines were formulated with either Adju-Phos® or Imject alum®. Nevertheless, Alhydrogel® and Adju-Phos® exhibited comparable median sizes in the presence of this protein (4194 ± 466 and 4850 ± 501 nm respectively) with Imject alum® being considerably smaller (2155 ± 485 nm). These results suggest that the PSD of aluminum adjuvants is greatly influenced by dilution and the degree of protein adsorption experienced within the vaccine itself. The size of the resultant antigen-adjuvant complex may be important for its immunological recognition and subsequent clearance from the injection site

An interaction of β-amyloid with aluminium in vitro

AbstractWe have used circular dichroism spectroscopy to confirm that, in a membrane-mimicking solvent, AβP(1–40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and β-amyloid and may have important implications for the pathogenesis of Alzheimer's disease

Qualitative study of patient views on a 'telephone-first' approach in general practice in England: speaking to the GP by telephone before making face-to-face appointments.

This is the final version. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVE: To understand patients' views on a 'telephone-first' approach, in which all appointment requests in general practice are followed by a telephone call from the general practitioner (GP). DESIGN: Qualitative interviews with patients and carers. SETTING: Twelve general practices in England. PARTICIPANTS: 43 patients, including 30 women, nine aged over 75 years, four parents of young children, five carers, five patients with hearing impairment and two whose first language was not English. RESULTS: Patients expressed varied views, often strongly held, ranging from enthusiasm for to hostility towards the 'telephone-first' approach. The new system suited some patients, avoiding the need to come into the surgery but was problematic for others, for example, when it was difficult for someone working in an open plan office to take a call-back. A substantial proportion of negative comments were about the operation of the scheme itself rather than the principles behind it, for example, difficulty getting through on the phone or being unable to schedule when the GP would phone back. Some practices were able to operate the scheme in a way that met their patients' needs better than others and practices varied significantly in how they had implemented the approach. CONCLUSIONS: The 'telephone-first' approach appears to work well for some patients, but others find it much less acceptable. Some of the reported problems related to how the approach had been implemented rather than the 'telephone-first' approach in principle and suggests there may be potential for some of the challenges experienced by patients to be overcome.National Institute for Health Researc

Aluminium in Brain Tissue in Multiple Sclerosis.

Multiple sclerosis (MS) is a devastating and debilitating neurodegenerative disease of unknown cause. A consensus suggests the involvement of both genetic and environmental factors of which the latter may involve human exposure to aluminium. There are no data on the content and distribution of aluminium in human brain tissue in MS. The aluminium content of brain tissue from 14 donors with a diagnosis of MS was determined by transversely heated graphite furnace atomic absorption spectrometry. The location of aluminium in the brain tissue of two donors was investigated by aluminium-specific fluorescence microscopy. The aluminium content of brain tissue in MS was universally high with many tissues bearing concentrations in excess of 10 μg/g dry wt. (10 ppm) and some exceeding 50 ppm. There were no statistically significant relationships between brain lobes, donor age or donor gender. Aluminium-specific fluorescence successfully identified aluminium in brain tissue in both intracellular and extracellular locations. The association of aluminium with corpora amylacea suggests a role for aluminium in neurodegeneration in MS