Aluminium hydroxide (alum) has long been added as an adjuvant of vaccines. It consists of nanoparticles forming aggregates. Unexpectedly long-lasting biopersistence of alum aggregates were found within immune cells of patients with chronic fatigue, cognitive dysfunction, myalgias and dysimmunity [1Gherardi R.K., Coquet M., Chérin P., Authier F.J., Laforêt P., Bélec L., et al. Macrophagic myofasciitis: an emerging entity Lancet 1998 ;  352 (9125) : 347-352 [cross-ref]

Cliquez ici pour aller à la section Références, 2Gherardi R.K., Coquet M., Cherin P., Belec L., Moretto P., Dreyfus P.A., et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle Brain 2001 ;  124 (Pt 9) : 1821-1831 [cross-ref]

Cliquez ici pour aller à la section Références]. We documented in mice slow translocation of alum aggregates captured by monocyte-lineage cells from the injected muscle to brain [3Khan Z., Combadière C., Authier F.J., Itier V., Lux F., Exley C., et al. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain BMC Med 2013 ;  11 : 99 [cross-ref]

Cliquez ici pour aller à la section Références, 4Eidi H., David M.O., Crépeaux G., Henry L., Joshi V., Berger M.H., et al. Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant particle biodisposition BMC Med 2015 ;  13 : 144 [cross-ref]

Cliquez ici pour aller à la section Références, 5Crépeaux G., Eidi H., David M.O., Tzavara E., Giros B., Exley C., et al. Highly delayed systemic translocation of aluminum-based adjuvant in CD1 mice following intramuscular injections J Inorg Biochem 2015 ;  15 : 30031-30033[pii: S0162-0134].

Cliquez ici pour aller à la section Références]. Herein, brain function and aluminium (Al) concentration were examined long after injections.

Alhydrogel^® was injected in TA muscle in adult female CD1 mice at 3 doses ranging from 133 to 800μg Al/kg. Eight validated tests were used to evaluate cognitive and motor performances 180 days after injection. Brains were collected for Al level determination and Iba-1 immunohistochemistry.

A most unusual neuro-toxicological pattern limited to lower doses of alum was observed. Neurobehavioral changes, including decreased activity levels and altered anxiety-like behaviour, were documented in animals exposed to the two lowest doses (133 and 200μg Al/kg) but not at the highest dose (800μg Al/kg), compared to controls. Consistently, cerebral Al levels were increased in animals exposed to the lowest doses. Microglial cell increase was found in amygdala of the 200μg Al/kg group. Interestingly, the injected suspensions corresponding to the two lowest doses contained much smaller aggregates (1.50–1.75μm) compared to the highest dose (4.70μm).

Alum particles injected in muscle may induce neurotoxic effects and Al cerebral accumulation six months after injection in mice. Neurotoxic effects are restricted to low concentration suspensions forming small particle aggregates. Such bacteria-sized aggregates are known to be selectively captured by monocyte-lineage cells. This study strongly suggests that, in contrast to “the dose makes the poison” paradigm of classical toxicology, alum toxicology obeys the specific rules of small particle toxicology, thus deserving in depth revaluation. (This study was supported by ANSM).