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Aluminum compounds are the most widely used adjuvants in veterinary and human vaccines. Despite almost a century of use and substantial advances made in recent decades about their fate and biological effects, the exact mechanism of their action has been continuously debated, from the initial "depot-theory" to the direct immune system stimulation, and remains elusive. Here we investigated the early in vitro response of primary human PBMCs obtained from healthy individuals to aluminum oxyhydroxide (the most commonly used adjuvant) and a whole vaccine, in terms of internalization, conventional and non-conventional autophagy pathways, inflammation, ROS production, and mitochondrial metabolism. During the first four hours of contact, aluminum oxyhydroxide particles, with or without adsorbed vaccine antigen, (1) were quickly recognized and internalized by immune cells; (2) increased and balanced two cellular clearance mechanisms, i.e. canonical autophagy and LC3-associated phagocytosis; (3) induced an inflammatory response with TNF-α production as an early event; (4) and altered mitochondrial metabolism as assessed by both decreased maximal oxygen consumption and reduced mitochondrial reserve, thus potentially limiting further adaptation to other energetic requests. Further studies should consider a multisystemic approach of the cellular adjuvant mechanism involving interconnections between clearance mechanism, inflammatory response and mitochondrial respiration., (© 2023. The Author(s).)

Objectives: Aluminum-containing vaccine adjuvants stimulate an adequate immune response to vaccination. The safety and rapid elimination of these molecules, a guarantee of their safe use for several decades, have been challenged by a growing number of studies over the last 20 years. Evaluation of exposure to aluminum adjuvants of an individual is thus essential. The current review answers the following questions: what is the exposure of aluminum adjuvants of an individual vaccinated in France? What are the factors of variation?, Methods: To evaluate the immunization exposure to aluminum for a vaccinee in France, we used the 2018 vaccination schedule and the Social Security database for vaccines reimbursed that year. French mandatory and recommended vaccines for an individual who does not travel abroad and has no particular professional obligations have been taken into account., Results: Our results show that an individual following the vaccination requirements and recommendations of 2018 receives between 2545 and 7735μg of Al 3+ during his lifetime, and at least 50% before the age of 1year. Exposure varies with age, weight, sex, and choice of administered vaccines., Conclusion: Vaccines with higher doses of aluminum are mainly injected at the beginning of life. Women receive a proportionately larger dose than men. The most reimbursed vaccines are often those with the highest amount of aluminum salts., (Copyright © 2020 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

We reviewed the three toxicokinetic reference studies commonly used to suggest that aluminum (Al)-based adjuvants are innocuous. A single experimental study was carried out using isotopic 26Al (Flarend et al., Vaccine, 1997). This study used aluminum salts resembling those used in vaccines but ignored adjuvant uptake by cells that was not fully documented at the time. It was conducted over a short period of time (28days) and used only two rabbits per adjuvant. At the endpoint, Al elimination in the urine accounted for 6% for Al hydroxide and 22% for Al phosphate, both results being incompatible with rapid elimination of vaccine-derived Al in urine. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to an oral "minimal risk level" (MRL) extrapolated from animal studies. Keith et al. (Vaccine, 2002) used a high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (Vaccine, 2011) only considered solubilized Al, with erroneous calculations of absorption duration. Systemic Al particle diffusion and neuro-inflammatory potential were omitted. The MRL they used was both inappropriate (oral Al vs. injected adjuvant) and still too high (1mg/kg/d) regarding recent animal studies. Both paucity and serious weaknesses of reference studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including both neonatal and adult exposures, to ensure their safety and restore population confidence in Al-containing vaccines., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.

Macrophagic myofasciitis (MMF), a condition newly recognized in France, is manifested by diffuse myalgias and characterized by highly specific myopathological alterations which have recently been shown to represent an unusually persistent local reaction to intramuscular injections of aluminium-containing vaccines. Among 92 MMF patients recognized so far, eight of them, which included the seven patients reported here, had a symptomatic demyelinating CNS disorder. CNS manifestations included hemisensory or sensorimotor symptoms (four out of seven), bilateral pyramidal signs (six out of seven), cerebellar signs (four out of seven), visual loss (two out of seven), cognitive and behavioural disorders (one out of seven) and bladder dysfunction (one out of seven). Brain T(2)-weighted MRI showed single (two out of seven) or multiple (four out of seven) supratentorial white matter hyperintense signals and corpus callosum atrophy (one out of seven). Evoked potentials were abnormal in four out of six patients and CSF in four out of seven. According to Poser's criteria for multiple sclerosis, the diagnosis was clinically definite (five out of seven) or clinically probable multiple sclerosis (two out of seven). Six out of seven patients had diffuse myalgias. Deltoid muscle biopsy showed stereotypical accumulations of PAS (periodic acid-Schiff)-positive macrophages, sparse CD8+ T cells and minimal myofibre damage. Aluminium-containing vaccines had been administered 3-78 months (median = 33 months) before muscle biopsy (hepatitis B virus: four out of seven, tetanus toxoid: one out of seven, both hepatitis B virus and tetanus toxoid: two out of seven). The association between MMF and multiple sclerosis-like disorders may give new insights into the controversial issues surrounding vaccinations and demyelinating CNS disorders. Deltoid muscle biopsy searching for myopathological alterations of MMF should be performed in multiple sclerosis patients with diffuse myalgias.

Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated ‘autoimmune/inflammatory syndrome induced by adjuvants’ (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain. [ABSTRACT FROM AUTHOR]