title: Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil.
abstract: Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.|Department of Obstetrics and Gynecology, Sheba Medical Center, 52621, Tel Hashomer, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Inbar
authors.affiliation: Sagol School of Neuroscience, Tel Aviv University, 69978, Ramat Aviv, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978, Ramat Aviv, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.|Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada.
authors.forename: Lucija
authors.initials: L
authors.lastname: Tomljenovic
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.|Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogota, 111221, Colombia.
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Arango
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Deri
authors.affiliation: Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.|Department of Neurology and Sagol Neuroscience Center, The Sheba Medical Center, 52621, Tel Hashomer, Israel.
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Blank
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, 52621, Israel, Israel. shoenfel@post.tau.ac.il.|Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel-Aviv University, 69978, Ramat Aviv, Israel. shoenfel@post.tau.ac.il.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects*; D000277:Adjuvants, Pharmaceutic / Q000009:adverse effects*; D000536:Aluminum Hydroxide / Q000009:adverse effects*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001522:Behavior, Animal / Q000187:drug effects; D036022:Capsid Proteins / Q000276:immunology; D005260:Female; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 / Q000009:adverse effects*; D008124:Locomotion / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology; D021641:Recognition, Psychology / Q000187:drug effects; D013550:Swimming
chemical_list: D000276:Adjuvants, Immunologic; D000277:Adjuvants, Pharmaceutic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D001323:Autoantibodies; D036022:Capsid Proteins; C114580:HPV L1 protein, Human papillomavirus; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D009856:Oncogene Proteins, Viral; D000536:Aluminum Hydroxide
keywords: ASIA syndrome; Aluminum; Autoantibodies; Autoimmunity; Gardasil; Neuroinflammation