Aluminium in plasma and tissues after intramuscular injection of adjuvanted human vaccines in rats

Abstract

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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References

  1. Bagi CM, Berryman E, Moalli MR (2011) Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery. Comp Med 61:76–85

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Barak MM, Lieberman DE, Hublin JJ (2013) Of mice, rats and men: trabecular bone architecture in mammals scales to body mass with negative allometry. J Struct Biol 183:123–131

    Article  PubMed  Google Scholar 

  3. Barrett JS, Della Casa Alberighi O, Läer S, Meibohm B (2012) Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther 92:40–49

    CAS  Article  PubMed  Google Scholar 

  4. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407–484

    CAS  Article  PubMed  Google Scholar 

  5. Crépeaux G, Eidi H, David MO, Tzavara E, Giros B, Exley C, Curmi PA, Shaw CA, Gherardi RK, Cadusseau J (2015) Highly delayed systemic translocation of aluminum-based adjuvant in CD1 mice following intramuscular injections. J Inorg Biochem 152:199–205

    Article  CAS  PubMed  Google Scholar 

  6. FDA/CDER guidance for industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers (2005) https://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf. Accessed 13 Sept 2019

  7. Flarend RE, Hem SL, White JL, Elmore D, Suckow MA, Rudy AC, Dandashli EA (1997) In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine 15:1314–1318

    CAS  Article  PubMed  Google Scholar 

  8. Gherardi RK, Eidi H, Crépeaux G, Authier FJ, Cadusseau J (2015) Biopersistence and brain translocation of aluminum adjuvants of vaccines. Front Neurol 6:4

    Article  PubMed  PubMed Central  Google Scholar 

  9. He P, Zou Y, Hu Z (2015) Advances in aluminum hydroxide-based adjuvant research and its mechanism. Hum Vaccin Immunother 11:477–488

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hellström HO, Mjöberg B, Mallmin H, Michaëlsson K (2005) The aluminum content of bone increases with age, but is not higher in hip fracture cases with and without dementia compared to controls. Osteoporos Int 16:1982–1988

    Article  CAS  PubMed  Google Scholar 

  11. Hellström HO, Mjöberg B, Mallmin H, Michaëlsson K (2006) No association between the aluminium content of trabecular bone and bone density, mass or size of the proximal femur in elderly men and women. BMC Musculoskelet Disord 7:69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hem SL, HogenEsch H (2007) Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Rev Vaccines 6:685–698

    CAS  Article  PubMed  Google Scholar 

  13. Hirayama M, Iijima S, Iwashita M, Akiyama S, Takaku Y, Yamazaki M, Omori T, Yumoto S, Shimamura T (2011) Aging effects of major and trace elements in rat bones and their mutual correlations. J Trace Elem Med Biol 25:73–84

    CAS  Article  PubMed  Google Scholar 

  14. HogenEsch H, O’Hagan DT, Fox CB (2018) Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. NPJ Vaccines 3:51

    Article  PubMed  PubMed Central  Google Scholar 

  15. HogenEsch H (2013) Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol 3:406

    Article  PubMed  PubMed Central  Google Scholar 

  16. House E, Esiri M, Forster G, Ince PG, Exley C (2012) Aluminium, iron and copper in human brain tissues donated to the Medical research council’s cognitive function and ageing study. Metallomics 4:56–65

    CAS  Article  PubMed  Google Scholar 

  17. Immunization Safety Review (2001) Thimerosal-containing vaccines and neurodevelopmental disorders. Institute of Medicine (US) Immunization safety Review Committee. National Academies Press (US), Washington

    Google Scholar 

  18. Immunization Safety Review (2004) Vaccines and Autism. Institute of Medicine (US) Immunization safety review committee. Washington (DC): National Academies Press (US)

  19. Klein GL (2019) Aluminum toxicity to bone: A multisystem effect? Osteoporos Sarcopenia 5:2–5

    Article  PubMed  PubMed Central  Google Scholar 

  20. Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J et al (2007) Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 10(Suppl 1):1–269

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Lin WT, Chen RC, Lu WW, Liu SH, Yang FY (2015) Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer’s disease rat model. Sci Rep 5:9671

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Lu H, Rosenbaum S (2014) Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther 19:262–276

    PubMed  PubMed Central  Google Scholar 

  23. Masson JD, Crépeaux G, Authier FJ, Exley C, Gherardi RK (2018) Critical analysis of reference studies on the toxicokinetics of aluminum-based adjuvants. J Inorg Biochem 181:87–95

    CAS  Article  PubMed  Google Scholar 

  24. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31

    Article  PubMed  PubMed Central  Google Scholar 

  25. Netterlid E, Hindsén M, Siemund I, Björk J, Werner S, Jacobsson H, Güner N, Bruze M (2013) Does allergen-specific immunotherapy induce contact allergy to aluminium? Acta Derm Venereol 93:50–56

    CAS  Article  PubMed  Google Scholar 

  26. O’Flaherty EJ (1991) Physiologically based models for bone-seeking elements. I. Rat skeletal and bone growth. Toxicol Appl Pharmacol 111:299–312

    Article  PubMed  Google Scholar 

  27. Ogasawara Y, Sakamoto T, Ishii K, Takahashi H, Tanabe S (2002) Effects of the administration routes and chemical forms of aluminum on aluminum accumulation in rat brain. Biol Trace Elem Res 86:269–278

    CAS  Article  PubMed  Google Scholar 

  28. Ph. Eur. 9.6, Monograph 0153: Vaccines for human use (07/2018)

  29. Powell BS, Andrianov AK, Fusco PC (2015) Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes. Clin Exp Vaccine Res 4:23–45

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Priest ND (2004) The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J Environ Monit 6:375–403

    CAS  Article  PubMed  Google Scholar 

  31. Seeber SJ, White JL, Hem SL (1991) Solubilization of aluminum-containing adjuvants by constituents of interstitial fluid. J Parenter Sci Technol 45:156–159

    CAS  PubMed  Google Scholar 

  32. Shardlow E, Mold M, Exley C (2018) Unraveling the enigma: elucidating the relationship between the physicochemical properties of aluminium-based adjuvants and their immunological mechanisms of action. Allergy Asthma Clin Immunol 14:80. https://doi.org/10.1186/s13223-018-0305-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Sharma V, McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157:907–921

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Steinhausen C (1997) Untersuchung der Aluminiumbiokinetik mit 26Al und Beschleunigermassenspektrometrie. Dissertation, Technical University of Munich, Germany

  35. Sun X, Liu J, Zhuang C, Yang X, Han Y, Shao B et al (2016) Aluminum trichloride induces bone impairment through TGF-β1/Smad signaling pathway. Toxicology 371:49–57

    CAS  Article  PubMed  Google Scholar 

  36. Sun X, Cao Z, Zhang Q, Liu S, Xu F, Che J et al (2015) Aluminum trichloride impairs bone and downregulates Wnt/β-catenin signaling pathway in young growing rats. Food Chem Toxicol 86:154–162

    CAS  Article  PubMed  Google Scholar 

  37. Valtulini S, Macchi C, Ballanti P, Cherel Y, Laval A, Theaker JM, Bak M, Ferretti E, Morvan H (2005) Aluminium hydroxide-induced granulomas in pigs. Vaccine 23:3999–4004

    CAS  Article  PubMed  Google Scholar 

  38. Van Landeghem GF, D’Haese PC, Lamberts LV, Djukanovic L, Pejanovic S, Goodman WG et al (1998) Low serum aluminum values in dialysis patients with increased bone aluminum levels. Clin Nephrol 50:69–76

    PubMed  Google Scholar 

  39. Veiga M, Bohrer D, Banderó CR, Oliveira SM, do Nascimento PC, Mattiazzi P et al (2013) Accumulation, elimination, and effects of parenteral exposure to aluminum in newborn and adult rats. J Inorg Biochem 128:215–220

    CAS  Article  PubMed  Google Scholar 

  40. Verdier F, Burnett R, Michelet-Habchi C, Moretto P, Fievet-Groyne F, Sauzeat E (2005) Aluminium assay and evaluation of the local reaction at several time points after intramuscular administration of aluminium containing vaccines in the Cynomolgus monkey. Vaccine 23:1359–1367

    CAS  Article  PubMed  Google Scholar 

  41. Walker VR, Sutton RA, Meirav O, Sossi V, Johnson R, Klein J et al (1994) Tissue disposition of 26aluminium in rats measured by accelerator mass spectrometry. Clin Invest Med 17:420–425

    CAS  PubMed  Google Scholar 

  42. Weisser K, Göen T, Oduro JD, Wangorsch G, Hanschmann KMO, Keller-Stanislawski B (2019) Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats. Arch Toxicol 93:37–47

    CAS  Article  PubMed  Google Scholar 

  43. Weisser K, Stübler S, Matheis W, Huisinga W (2017) Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products. Regul Toxicol Pharmacol 88:310–321

    CAS  Article  PubMed  Google Scholar 

  44. WHO Expert Committee on Biological Standardization, sixty-sixth report. Geneva: World Health Organization; 2016 (WHO technical report series; no. 999)

  45. WHO (2012) Global advisory committee for vaccine safety“(GACVS), Report of Meeting Held 6–7 June 2012. WHO Weekly Epidemiological Record

  46. Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 88:159–167

    CAS  Article  PubMed  Google Scholar 

  47. Yumoto S, Nagai H, Imamura M, Matsuzaki H, Hayashi K, Masuda A et al (1997) 26Al uptake and accumulation in the rat brain. Nucl Instrum Methods Phys Res B 123:279–282

    CAS  Article  Google Scholar 

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Acknowledgements

The authors thank Barbara Verhoeven for her technical assistance and Daniela Golomb for preparation of the treatment formulations.

Funding

The project was funded by the German Ministry of Health (ZMVI1-2515-FSB-772).

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Correspondence to Karin Weisser.

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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.

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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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Keywords

  • Aluminium
  • Adjuvants
  • Systemic availability
  • Rats
  • Intramuscular
  • Vaccine