Front. Neurol., 05 February 2015; FULL article @ journal.frontiersin.org:
Biopersistence and brain translocation of aluminum adjuvants of vaccinesimageRomain Kroum Gherardi*
, imageHousam Eidi, imageGuillemette Crépeaux, imageFrançois Jerome Authier
and imageJosette Cadusseau
* Faculté de Médecine and Faculté des Sciences et Technologie, INSERM U955 Team 10, Université Paris Est-Créteil, Créteil, 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.
Billions of humans have been vaccinated and marked regression or eradication of several severe infectious diseases was observed. Nowadays, the potential applications of vaccines extend far beyond prevention of infectious diseases, and vaccination is considered to be a most promising weapon against a variety of different conditions. Vaccine safety has been regarded as excellent at the level of the population (1
), but adverse effects have also been reported (2
Concerns about the use of aluminum adjuvants have emerged following (i) recognition of their role at the origin of the so-called macrophagic myofasciitis (MMF) lesion in 2001 (3
), which revealed fundamental misconception of their adjuvant effect and pointed out their unexpectedly long-lasting biopersistence (4
); and (ii) demonstration of their apparent capacity to migrate in lymphoid organs and then disseminate throughout the body within monocyte-lineage cells and progressively accumulate in the brain (5
The present paper will review these emerging characteristics of alum adjuvant particles that raise concerns about innocuity of this widely used compound.