Biopersistence and brain translocation of aluminum adjuvants of vaccines
Romain Kroum Gherardi *, Housam Eidi , Guillemette Cr?peaux, Fran?ois Jerome Authier and
Josette Cadusseau
Facult? de M?decine and Facult? des Sciences et Technologie, INSERM U955 Team 10, Universit? Paris Est-Cr?teil, Cr?teil, France
Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological
adjuvant of vaccines. Concerns linked to the use of alum particles emerged following
recognition of their causative role in the so-called macrophagic myofasciitis (MMF)
lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome.MMF
revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably
susceptible individuals, stressing the previous fundamental misconception of its
biodisposition.We previously showed that poorly biodegradable aluminum-coated particles
injected into muscle are promptly phagocytosed in muscle and the draining lymph nodes,
and can disseminate within phagocytic cells throughout the body and slowly accumulate in
brain.This strongly suggests that long-term adjuvant biopersistence within phagocytic cells
is a prerequisite for slow brain translocation and delayed neurotoxicity. The understanding
of basic mechanisms of particle biopersistence and brain translocation represents a major
health challenge, since it could help to define susceptibility factors to develop chronic
neurotoxic damage. Biopersistence of alum may be linked to its lysosome-destabilizing
effect, which is likely due to direct crystal-induced rupture of phagolysosomal membranes.
Macrophages that continuously perceive foreign particles in their cytosol will likely reiterate,
with variable interindividual efficiency, a dedicated form of autophagy (xenophagy)
until they dispose of alien materials. Successful compartmentalization of particles within
double membrane autophagosomes and subsequent fusion with repaired and re-acidified
lysosomes will expose alum to lysosomal acidic pH, the sole factor that can solubilize alum
particles. Brain translocation of alum particles is linked to a Trojan horse mechanism previously
described for infectious particles (HIV, HCV), that obeys to CCL2, signaling the major
inflammatory monocyte chemoattractant.
Keywords: alum, vaccine adjuvants, macrophagic myofasciitis, neurotoxicity, genetics, monocytes, CCL2, MCP1
