Clearance, biodistribution, and neuromodulatory effects of aluminum-based adjuvants. Systematic review and meta-analysis: what do we learn from animal studies?

Abstract

Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuromodulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuromodulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.

Keywords:

• Aluminum-based adjuvants
• vaccines
• biopersistence
• clearance
• translocation
• biodistribution
• neurotoxicity
• animal studies

Acknowledgments

The authors thank funders Entraide aux Malades de Myofasciite à Macrophages (E3M), I For Lyme, BioSanté éditions, Agence Nationale pour la Recherche, and the Department of Innovation, Research and University of Aragón (Spain). The authors thank the anonymous reviewers selected by the Editor for the value of their comments, which allow the improvement of this review. We gratefully acknowledge Pr RK Gherardi for his careful proofreading and advice.

Declaration of interest

The authors declare that there are no conflicts of interest. This work was initiated to have a synthesis of all the work published on the topic, for the purpose of disseminating knowledge but also for the purpose of developing future research protocols. None of the authors has been paid specifically for this work, the publication of scientific data being an integral part of our professional missions. The authors have not participated in and do not anticipate participation in any legal, regulatory, or advocacy proceedings related to the contents of the article.

Supplemental material

Supplemental data for this article is available online at https://doi.org/10.1080/10408444.2022.2105688

Notes

1 In all the studies or documents consulted to write the present review, the way of indicating the quantity of aluminum present in a vaccine or a solution may differ, between Al and Al³⁺. We have chosen in this manuscript to cite precisely the references used. When the term aluminum is written in full we have kept the abbreviation Al.