Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5–0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0–80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5–12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14–0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.
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The authors thank Barbara Verhoeven for her technical assistance and Daniela Golomb for preparation of the treatment formulations.
The project was funded by the German Ministry of Health (ZMVI1-2515-FSB-772).
Conflict of interest
Author Jennifer D. Oduro declares that she is employee at preclinics GmbH, a contract research organization that has received payment for conducting the animal study. All other authors declare that they have no conflict of interest.
All applicable international, national institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution (preclinics GmbH, Germany) at which the studies were conducted.
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Weisser, K., Göen, T., Oduro, J.D. et al. Aluminium in plasma and tissues after intramuscular injection of adjuvanted human vaccines in rats. Arch Toxicol 93, 2787–2796 (2019). https://doi.org/10.1007/s00204-019-02561-z
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