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

References

• Agmon-Levin N, Arango MT, Kivity S, Katzav A, Gilburd B, Blank M, Tomer N, Volkov A, Barshack I, Chapman J, et al. 2014. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model. J Autoimmun. 54:21–32.
   PubMed Web of Science ®Google Scholar
• Agoston DV. 2017. How to translate time? The temporal aspect of human and rodent biology. Front Neurol. 8:92.
   PubMed Web of Science ®Google Scholar
• Andersson HK, Hullberg A, Malmgren L, Lundström K, Rydhmer L, Squires J. 1999. Sexual maturity in entire male pigs: environmental effects, relations to skatole level and female puberty. Null. 49(2):103–112.
   Google Scholar
• Andreollo NA, Santos E d, Araújo MR, Lopes LR. 2012. Rat’s age versus human’s age: what is the relationship? Arq Bras Cir Dig. 25(1):49–51.
   PubMedGoogle Scholar
• Angrand L, Elnar AA, Authier FJ, Gherardi RK, Crépeaux G. 2020. [Aluminium adjuvant exposure through vaccines in France in 2018]. Ann Pharm Fr. 78(2):111–128.
   PubMed Web of Science ®Google Scholar
• Asín J, Molín J, Pérez M, Pinczowski P, Gimeno M, Navascués N, Muniesa A, de Blas I, Lacasta D, Fernández A, et al. 2019 May. Granulomas following subcutaneous injection with aluminum adjuvant-containing products in sheep. Vet Pathol. 56(3):418–428.
   PubMed Web of Science ®Google Scholar
• Asín J, Pascual-Alonso M, Pinczowski P, Gimeno M, Pérez M, Muniesa A, de Pablo-Maiso L, de Blas I, Lacasta D, Fernández A, et al. 2020. Cognition and behavior in sheep repetitively inoculated with aluminum adjuvant-containing vaccines or aluminum adjuvant only. J Inorg Biochem. 203(110934):110934.
   PubMedGoogle Scholar
• Authier F-J, Sauvat S, Christov C, Chariot P, Raisbeck G, Poron MF, Yiou F, Gherardi R. 2006. AlOH3-adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background. Neuromuscul Disord. 16(5):347–352.
   PubMed Web of Science ®Google Scholar
• Badran G, Angrand L, Masson JD, Crépeaux G, David MO. 2022. Physico-chemical properties of aluminum adjuvants in vaccines: implications for toxicological evaluation. Vaccine. 40(33):4881–4888.
   PubMedGoogle Scholar
• Baylor NW, Egan W, Richman P. 2002. Aluminum salts in vaccines–US perspective. Vaccine. 20(3):S18–S23.
   PubMedGoogle Scholar
• Bégué P, Girard M, Bazin H, Bach J-F. 2012. Les adjuvants vaccinaux: quelle actualité en 2012? Bull L’Acad Natl Méd. 196(6):1177–1181.
   Google Scholar
• Berlyne GM, Yagil R, Ari JB, Weinberger G, Knopf E, Danovitch GM. 1972. Aluminium toxicity in rats. Lancet. 1(7750):564–568.
   PubMed Web of Science ®Google Scholar
• Boretti A. 2021. Reviewing the association between aluminum adjuvants in the vaccines and autism spectrum disorder. J Trace Elem Med Biol. 66:126764.
   PubMed Web of Science ®Google Scholar
• Brewer JM, Conacher M, Satoskar A, Bluethmann H, Alexander J. 1996. In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to freund’s complete adjuvant, but continues to induce T helper 2 cytokine production. Eur J Immunol. 26(9):2062–2066.
   PubMed Web of Science ®Google Scholar
• Bruce M, Streifel KM, Boosalis CA, Heuer L, González EA, Li S, Harvey DJ, Lein PJ, Van de Water J. 2019. Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain. J Neuroinflamm. 16(1):200.
   PubMed Web of Science ®Google Scholar
• Cain DW, Sanders SE, Cunningham MM, Kelsoe G. 2013. Disparate adjuvant properties among three formulations of “alum”. Vaccine. 31(4):653–660.
   PubMed Web of Science ®Google Scholar
• Champion JA, Mitragotri S. 2009. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 26(1):244–249.
   PubMed Web of Science ®Google Scholar
• Crépeaux G, Authier F-J, Exley C, Luján L, Gherardi RK. 2020. The role of aluminum adjuvants in vaccines raises issues that deserve independent, rigorous and honest science. J Trace Elem Med Biol. 62:126632.
   PubMed Web of Science ®Google Scholar
• Crépeaux G, Eidi H, David M-O, Baba-Amer Y, Tzavara E, Giros B, Authier F-J, Exley C, Shaw CA, Cadusseau J, et al. 2017. Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity. Toxicology. 375:48–57.
   PubMed Web of Science ®Google Scholar
• Crépeaux G, Eidi H, David M-O, 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.
   PubMed Web of Science ®Google Scholar
• Day MJ, Horzinek MC, Schultz RD, Squires RA, Vaccination Guidelines Group (VGG) of the World Small Animal Veterinary Association (WSAVA). 2016. WSAVA Guidelines for the vaccination of dogs and cats. J Small Anim Pract. 57(1):E1–E45.
   PubMed Web of Science ®Google Scholar
• de Miguel R, Asín J, Rodríguez-Largo A, Molín J, Echeverría I, de Andrés D, Pérez M, de Blas I, Mold M, Reina R, et al. 2020. Detection of aluminum in lumbar spinal cord of sheep subcutaneously inoculated with aluminum-hydroxide containing products. J Inorg Biochem. 204:110871.
   PubMed Web of Science ®Google Scholar
• de Miguel R, Asín J, Rodríguez-Largo A, Echeverría I, Lacasta D, Pinczowski P, Gimeno M, Molín J, Fernández A, de Blas I, et al. 2021. Growth performance and clinicopathological analyses in lambs repetitively inoculated with aluminum-hydroxide containing vaccines or aluminum-hydroxide only. Animals. 11(1):146.
   Web of Science ®Google Scholar
• Di Pasquale A, Preiss S, Tavares Da Silva F, Garçon N. 2015. Vaccine adjuvants: from 1920 to 2015 and beyond. Vaccines. 3(2):320–343.
   PubMed Web of Science ®Google Scholar
• Dutta S, Sengupta P. 2016. Men and mice: relating their ages. Life Sci. 152:244–248.
   PubMed Web of Science ®Google Scholar
• Dutta S, Sengupta P. 2018. Rabbits and men: relating their ages. J Basic Clin Physiol Pharmacol. 29(5):427–435.
   PubMedGoogle Scholar
• Eickhoff TC, Myers M. 2002. Workshop summary. Aluminum in vaccines. Vaccine. 20(3):S1–S4.
   PubMedGoogle Scholar
• Eidi H, David M-O, Crépeaux G, Henry L, Joshi V, Berger M-H, Sennour M, Cadusseau J, Gherardi RK, Curmi PA. 2015. Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant particle biodisposition. BMC Med. 13(1):144
   PubMedGoogle Scholar
• Eidi H, Yoo J, Bairwa SC, Kuo M, Sayre EC, Tomljenovic L, Shaw CA. 2020. Early postnatal injections of whole vaccines compared to placebo controls: differential behavioural outcomes in mice. J Inorg Biochem. 212:111200.
   PubMed Web of Science ®Google Scholar
• Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. 2008. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 453(7198):1122–1126.
   PubMed Web of Science ®Google Scholar
• Exley C. 2013. Human exposure to aluminium. Environ Sci Process Impacts. 15(10):1807–1816.
   PubMed Web of Science ®Google Scholar
• Exley C. 2020. An aluminium adjuvant in a vaccine is an acute exposure to aluminium. J Trace Elem Med Biol. 57:57–59.
   PubMed Web of Science ®Google Scholar
• Exley C, Siesjö P, Eriksson H. 2010. The immunobiology of aluminium adjuvants: how do they really work? Trends Immunol. 31(3):103–109.
   PubMed Web of Science ®Google Scholar
• 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(12–13):1314–1318.
   PubMed Web of Science ®Google Scholar
• Franchi L, Núñez G. 2008. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 38(8):2085–2089.
   PubMed Web of Science ®Google Scholar
• Gallagher CM, Goodman MS. 2010. Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997–2002. J Toxicol Environ Health A. 73(24):1665–1677.
   PubMed Web of Science ®Google Scholar
• Geifman N, Rubin E. 2013. The mouse age phenome knowledgebase and disease-specific inter-species age mapping. PLOS One. 8(12):e81114.
   PubMed Web of Science ®Google Scholar
• Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, Pellissier JF, Chariot P, Authier FJ. 2001. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain. 124(9):1821–1831.
   PubMed Web of Science ®Google Scholar
• Gherardi RK, Crépeaux G, Authier F-J. 2019. Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system. Autoimmun Rev. 18(7):691–705.
   PubMed Web of Science ®Google Scholar
• Ghimire TR, Benson RA, Garside P, Brewer JM. 2012. Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. Immunol Lett. 147(1–2):55–62.
   PubMed Web of Science ®Google Scholar
• Glenny AT, Pope CG, Waddington H, Wallace V. 1926a. The antigenic value of toxoid precipitated by potassium alum. J Pathol Bacteriol. 29:38–45.
   Google Scholar
• Glenny AT, Pope CG, Waddington H, Wallace U. 1926b. Immunological notes. XVII–XXIV. J Pathol. 29(1):31–40.
   Google Scholar
• Glenny AT, Buttle GAH, Stevens MF. 1931. Rate of disappearance of diphtheria toxoid injected into rabbits and guinea pigs: toxoid precipitated with Alum. J Pathol. 34(2):267–275.
   Google Scholar
• Goto N, Akama K. 1982. Histopathological studies of reactions in mice injected with aluminum-adsorbed tetanus toxoid. Microbiol Immunol. 26(12):1121–1132.
   PubMed Web of Science ®Google Scholar
• Graves KL, Mordhorst BR, Wright EC, Hale BJ, Stalder KJ, Keating AF, Ross JW. 2020. Identification of measures predictive of age of puberty onset in gilts. Transl Anim Sci. 4(1):285–292.
   PubMed Web of Science ®Google Scholar
• Hem SL. 2002. Elimination of aluminum adjuvants. Vaccine. 20(3):S40–S43.
   PubMedGoogle Scholar
• Hem SL, Hogenesch H. 2007. Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Rev Vaccines. 6(5):685–698.
   PubMed Web of Science ®Google Scholar
• Hernán MA, Jick SS, Olek MJ, Jick H. 2004. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology. 63(5):838–842.
   PubMed Web of Science ®Google Scholar
• HogenEsch H. 2013. Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol 3:406.
   PubMed Web of Science ®Google Scholar
• HogenEsch H, Dunham A, Burlet E, Lu F, Mosley Y-YC, Morefield G. 2017. Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant. J Appl Toxicol. 37(2):222–230.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Hsiao I-L, Huang Y-J. 2011. Effects of various physicochemical characteristics on the toxicities of ZnO and TiO nanoparticles toward human lung epithelial cells. Sci Total Environ. 409(7):1219–1228.
   PubMed Web of Science ®Google Scholar
• Hühn D, Kantner K, Geidel C, Brandholt S, De Cock I, Soenen SJH, Rivera Gil P, Montenegro J-M, Braeckmans K, Müllen K, et al. 2013. Polymer-coated nanoparticles interacting with proteins and cells: focusing on the sign of the net charge. ACS Nano. 7(4):3253–3263.
   PubMed Web of Science ®Google Scholar
• Inbar R, Weiss R, Tomljenovic L, Arango MT, Deri Y, Shaw CA, Chapman J, Blank M, Shoenfeld Y. 2017. Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol Res. 65(1):136–149.
   PubMed Web of Science ®Google Scholar
• [IOM] Institute of Medicine. 2012. Adverse effects of vaccines: evidence and causality. Washington (DC): The National Academies Press.
   Google Scholar
• Ivanovski I, Fletcher MW, Ivanovski A, Nikolić D, Ivanovski P. 2019. Do the vaccines harm? J Trace Elem Med Biol. 55:107–109.
   PubMed Web of Science ®Google Scholar
• Keith LS, Jones DE, Chou CH. 2002. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine. 20:S13–S17.
   PubMed Web of Science ®Google Scholar
• Khan Z, Combadière C, Authier FJ, Itier V, Lux F, Exley C, Mahrouf-Yorgov M, Decrouy X, Moretto P, Tillement O, et al. 2013. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMC Med. 11(99):99.
   PubMedGoogle Scholar
• Kivity S, Arango M-T, Molano-González N, Blank M, Shoenfeld Y. 2017. Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior in mice. Immunol Res. 65(1):99–105.
   PubMed Web of Science ®Google Scholar
• Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J. 2008. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol. 181(6):3755–3759.
   PubMed Web of Science ®Google Scholar
• Lacasta D, Ferrer LM, Ramos JJ, González JM, Ortín A, Fthenakis GC. 2015. Vaccination schedules in small ruminant farms. Vet Microbiol. 181(1–2):34–46.
   PubMed Web of Science ®Google Scholar
• Lee JH, Ju JE, Kim BI, Pak PJ, Choi EK, Lee HS, Chung N. 2014. Rod-shaped iron oxide nanoparticles are more toxic than sphere-shaped nanoparticles to murine macrophage cells. Environ Toxicol Chem. 33(12):2759–2766.
   PubMed Web of Science ®Google Scholar
• Li H, Huang T, Wang Y, Pan B, Zhang L, Zhang Q, Niu Q. 2020. Toxicity of alumina nanoparticles in the immune system of mice. Nanomedicine. 15(9):927–946.
   PubMed Web of Science ®Google Scholar
• Li H, Nookala S, Re F. 2007. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J Immunol. 178(8):5271–5276.
   PubMed Web of Science ®Google Scholar
• Li H, Willingham SB, Ting JP-Y, Re F. 2008. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J Immunol. 181(1):17–21.
   PubMed Web of Science ®Google Scholar
• Li Q, Qi F, Yang J, Zhang L, Gu H, Zou J, Yuan Q, Yao Z. 2015. Neonatal vaccination with bacillus Calmette-Guérin and hepatitis B vaccines modulates hippocampal synaptic plasticity in rats. J Neuroimmunol. 288:1–12.
   PubMed Web of Science ®Google Scholar
• Li X, Aldayel AM, Cui Z. 2014. Aluminum hydroxide nanoparticles show a stronger vaccine adjuvant activity than traditional aluminum hydroxide microparticles. J Control Release. 173:148–157.
   PubMed Web of Science ®Google Scholar
• Li X, Hufnagel S, Xu H, Valdes SA, Thakkar SG, Cui Z, Celio H. 2017. Aluminum (Oxy) hydroxide nanosticks synthesized in bicontinuous reverse microemulsion have potent vaccine adjuvant activity. ACS Appl Mater Interfaces. 9(27):22893–22901.
   PubMed Web of Science ®Google Scholar
• Lima H, Jacobson LS, Goldberg MF, Chandran K, Diaz-Griffero F, Lisanti MP, Brojatsch J. 2013. Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle. 12(12):1868–1878.
   PubMed Web of Science ®Google Scholar
• Lindblad EB. 2004. Aluminium adjuvants–in retrospect and prospect. Vaccine. 22(27–28):3658–3668.
   PubMed Web of Science ®Google Scholar
• Lu F, Hogenesch H. 2013. Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine. 31(37):3979–3986.
   PubMed Web of Science ®Google Scholar
• Luján L, Pérez M, Salazar E, Álvarez N, Gimeno M, Pinczowski P, Irusta S, Santamaría J, Insausti N, Cortés Y, et al. 2013. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol Res. 56(2–3):317–324.
   PubMed Web of Science ®Google Scholar
• Lyons-Weiler J, Ricketson R. 2018. Reconsideration of the immunotherapeutic pediatric safe dose levels of aluminum. J Trace Elem Med Biol. 48:67–73.
   PubMed Web of Science ®Google Scholar
• Mannhalter JW, Neychev HO, Zlabinger GJ, Ahmad R, Eibl MM. 1985. Modulation of the human immune response by the non-toxic and non-pyrogenic adjuvant aluminium hydroxide: effect on antigen uptake and antigen presentation. Clin Exp Immunol. 61(1):143–151.
   PubMed Web of Science ®Google Scholar
• Marrack P, McKee AS, Munks MW. 2009. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 9(4):287–293.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Matsiko A. 2020. Alum adjuvant discovery and potency nature materials. https://www.nature.com/articles/d42859-020-00011-w?sf245768437=1
   Google Scholar
• McDougall SA, Heath MD, Kramer MF, Skinner MA. 2016. Analysis of aluminium in rat following administration of allergen immunotherapy using either aluminium or microcrystalline-tyrosine-based adjuvants. Bioanalysis. 8(6):547–556.
   PubMed Web of Science ®Google Scholar
• Miller NZ. 2016. Aluminum in childhood vaccines is unsafe. J Amer Physic Surg. 21(4):9.
   Google Scholar
• Mitkus RJ, King DB, Hess MA, Forshee RA, Walderhaug MO. 2011. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine. 29(51):9538–9543.
   PubMed Web of Science ®Google Scholar
• Mold M, Shardlow E, Exley C. 2016. Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations. Sci Rep. 6(1):31578.
   PubMedGoogle Scholar
• Mold M, Umar D, King A, Exley C. 2018. Aluminium in brain tissue in autism. J Trace Elem Med Biol. 46:76–82.
   PubMed Web of Science ®Google Scholar
• Morefield GL, Sokolovska A, Jiang D, HogenEsch H, Robinson JP, Hem SL. 2005. Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine. 23(13):1588–1595.
   PubMed Web of Science ®Google Scholar
• Morford LL, Bowman CJ, Blanset DL, Bøgh IB, Chellman GJ, Halpern WG, Weinbauer GF, Coogan TP. 2011. Preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals: strategy, challenges, current practices. Birth Defects Res B Dev Reprod Toxicol. 92(4):359–380.
   PubMedGoogle Scholar
• Morris G, Puri BK, Frye RE. 2017. The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved? Metab Brain Dis. 32(5):1335–1355.
   PubMed Web of Science ®Google Scholar
• Nies I, Hidalgo K, Bondy SC, Campbell A. 2020. Distinctive cellular response to aluminum based adjuvants. Environ Toxicol Pharmacol. 78:103404.
   PubMed Web of Science ®Google Scholar
• OECD. 1997. Test No. 424: neurotoxicity study in rodents, OECD guidelines for the testing of chemicals, section 4. Paris: OCDE.
   Google Scholar
• OECD. 2007. Test No. 426: developmental neurotoxicity study, OECD guidelines for the testing of chemicals, section 4. Paris: OCDE.
   Google Scholar
• Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA. 2007. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromolecular Med. 9(1):83–100.
   PubMed Web of Science ®Google Scholar
• Ramon G. 1926. Procédés pour accroitre la production des antitoxines. Ann Inst Pasteur. 40:1–10.
   Google Scholar
• Ramon G. 1925. Sur l’augmentation anormale de l’antitoxine chez les chevaux producteurs de serum antidiphterique. Bull Soc Centr Med Vet. 101:227–234.
   Google Scholar
• Rosenblum H, Shoenfeld Y, Amital H. 2011. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect Dis Clin North Am. 25(4):851–863.
   PubMed Web of Science ®Google Scholar
• Roth J, Sandbulte M. 2021. The role of veterinary vaccines in livestock production, animal health and public health. In: Metwally S, Viljoen G, El Idrissi A, editors. Veterinary vaccines: principles and applications. Hoboken (NJ): Wiley Blackwell. 1–10.
   Google Scholar
• RUMA Guidelines. 2022. Vaccines – responsible use of medicines in agriculture alliance. [accessed 2022 Mar 21]. https://www.ruma.org.uk/vaccines/.
   Google Scholar
• Seeber SJ, White JL, Hem SL. 1991. Predicting the adsorption of proteins by aluminium-containing adjuvants. Vaccine. 9(3):201–203.
   PubMed Web of Science ®Google Scholar
• Segal L, Wilby OK, Willoughby CR, Veenstra S, Deschamps M. 2011. Evaluation of the intramuscular administration of Cervarix™ vaccine on fertility, pre- and post-natal development in rats. Reprod Toxicol. 31(1):111–120.
   PubMed Web of Science ®Google Scholar
• Seneff S, Davidson R, Liu J. 2012. Empirical data confirm autism symptoms related to aluminum and acetaminophen exposure. Basel: MDPI Publishing [Internet] [accessed 2019 Jul 12]. https://dspace.mit.edu/handle/1721.1/77575.
   Google Scholar
• Sengupta P. 2013. The laboratory rat: relating its age with human’s. Int J Prev Med. 4(6):624–630.
   PubMedGoogle Scholar
• Sengupta P, Dutta S. 2020. Mapping the age of laboratory rabbit strains to human. Int J Prev Med. 11(194):194.
   PubMedGoogle Scholar
• Al-Shakhshir R, Regnier F, White JL, Hem SL. 1994. Effect of protein adsorption on the surface charge characteristics of aluminium-containing adjuvants. Vaccine. 12(5):472–474.
   PubMed Web of Science ®Google Scholar
• Shardlow E, Linhart C, Connor S, Softely E, Exley C. 2021. The measurement and full statistical analysis including Bayesian methods of the aluminium content of infant vaccines. J Trace Elem Med Biol. 66:126762.
   PubMed Web of Science ®Google Scholar
• Shardlow E, Mold M, Exley C. 2016. From stock bottle to vaccine: elucidating the particle size distributions of aluminum adjuvants using dynamic light scattering. Front Chem. 4:48.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Shaw CA, Li Y, Tomljenovic L. 2013. Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes. J Inorg Biochem. 128:237–244.
   PubMed Web of Science ®Google Scholar
• Shaw CA, Petrik MS. 2009. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem. 103(11):1555–1562.
   PubMed Web of Science ®Google Scholar
• Shaw CA, Tomljenovic L. 2013. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res. 56(2–3):304–316.
   PubMed Web of Science ®Google Scholar
• Sheth SKS, Li Y, Shaw CA. 2018. Is exposure to aluminium adjuvants associated with social impairments in mice? A pilot study. J Inorg Biochem. 181:96–103.
   PubMed Web of Science ®Google Scholar
• Shoenfeld Y, Agmon-Levin N. 2011. “ASIA” – autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 36(1):4–8.
   PubMed Web of Science ®Google Scholar
• Sokolovska A, Hem SL, HogenEsch H. 2007. Activation of dendritic cells and induction of CD4+ T cell differentiation by aluminum-containing adjuvants. Vaccine. 25(23):4575–4585.
   PubMed Web of Science ®Google Scholar
• Spickler AR, Roth JA. 2003. Adjuvants in veterinary vaccines: modes of action and adverse effects. J Vet Intern Med. 17(3):273–281.
   PubMed Web of Science ®Google Scholar
• Sukhanova A, Bozrova S, Sokolov P, Berestovoy M, Karaulov A, Nabiev I. 2018. Dependence of nanoparticle toxicity on their physical and chemical properties. Nanoscale Res Lett. 13(1):44.
   PubMed Web of Science ®Google Scholar
• Thakkar SG, Xu H, Li X, Cui Z. 2018. Uric acid and the vaccine adjuvant activity of aluminium (oxy)hydroxide nanoparticles. J Drug Target. 26(5–6):474–480.
   PubMed Web of Science ®Google Scholar
• Tohyama S, Kobayashi E. 2019. Age-appropriateness of porcine models used for cell transplantation. Cell Transplant. 28(2):224–228.
   PubMed Web of Science ®Google Scholar
• Tomljenovic L, Shaw CA. 2011. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J Inorg Biochem. 105(11):1489–1499.
   PubMed Web of Science ®Google Scholar
• Ulanova M, Tarkowski A, Hahn-Zoric M, Hanson LA. 2001. The Common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism. Infect Immun. 69(2):1151–1159.
   PubMed Web of Science ®Google Scholar
• 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(30):3999–4004
   PubMed Web of Science ®Google Scholar
• Varela-Martínez E, Bilbao-Arribas M, Abendaño N, Asín J, Pérez M, de Andrés D, Luján L, Jugo BM. 2020. Whole transcriptome approach to evaluate the effect of aluminium hydroxide in ovine encephalon. Sci Rep. 10(1):15240.
   PubMed Web of Science ®Google Scholar
• 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(11):1359–1367.
   PubMed Web of Science ®Google Scholar
• Vogel FR. 2000. Improving vaccine performance with adjuvants. Clin Infect Dis. 30(3):S266–S270.
   PubMedGoogle Scholar
• Vogel F, Hem SL. 2004. Immunologic adjuvants. In: Vaccines. Philadelphia (PA): Saunders Elsevier; p. 69–79.
   Google Scholar
• Wang X, Yang J, Xing Z, Zhang H, Wen Y, Qi F, Zuo Z, Xu J, Yao Z. 2018. IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL-4 receptor in the hippocampus. Cytokine. 110:137–149.
   PubMed Web of Science ®Google Scholar
• Weisser K, Göen T, Oduro JD, Wangorsch G, Hanschmann KO, Keller-Stanislawski B. 2019. Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats. Arch Toxicol. 93(1):37–47.
   PubMed Web of Science ®Google Scholar
• Weisser K, Göen T, Oduro JD, Wangorsch G, Hanschmann KO, Keller-Stanislawski B. 2020. Aluminium from adjuvanted subcutaneous allergen immunotherapeutics in rats is mainly detected in bone. Allergy. 75(1):215–217.
   PubMed Web of Science ®Google Scholar
• Wen Y, Shi Y. 2016. Alum: an old dog with new tricks. Emerg Microbes Infect. 5:e25.
   PubMed Web of Science ®Google Scholar
• Wise LD, Wolf JJ, Kaplanski CV, Pauley CJ, Ledwith BJ. 2008. Lack of effects on fertility and developmental toxicity of a quadrivalent HPV vaccine in Sprague-Dawley rats. Birth Defects Res B Dev Reprod Toxicol. 83(6):561–572.
   PubMedGoogle Scholar
• Yang J, Qi F, Yang Y, Yuan Q, Zou J, Guo K, Yao Z. 2016. Neonatal hepatitis B vaccination impaired the behavior and neurogenesis of mice transiently in early adulthood. Psychoneuroendocrinology. 73:166–176.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Ding Y, He K, Li H, Gao F, Moehling TJ, Wu X, Duncan J, Niu Q. 2018. Exposure to alumina nanoparticles in female mice during pregnancy induces neurodevelopmental toxicity in the offspring. Front Pharmacol. 9(253):253.
   PubMedGoogle Scholar
• Zhang QL, Li MQ, Ji JW, Gao FP, Bai R, Chen CY, Wang ZW, Zhang C, Niu Q. 2011. In vivo toxicity of nano-alumina on mice neurobehavioral profiles and the potential mechanisms. Int J Immunopathol Pharmacol. 24(1):23S–29S.
   PubMed Web of Science ®Google Scholar