title: Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses.
abstract: Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived from Escherichia coli consistently dampened TT-induced Th2 activities without inducing IFNγ or Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted from Salmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines.
authors.affiliation: Department of Immunology, Institute of Biomedical Science, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Bortolatto
authors.affiliation: Department of Immunology, Institute of Biomedical Science, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Mirotti
authors.affiliation: Department of Immunology, Institute of Biomedical Science, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Dunia
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: Department of Immunology, Institute of Biomedical Science, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Eliane
authors.initials: E
authors.lastname: Gomes
authors.affiliation: Department of Immunology, Institute of Biomedical Science, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
authors.forename: Momtchilo
authors.initials: M
authors.lastname: Russo
mesh_terms: D000276:Adjuvants, Immunologic; D000327:Adsorption; D000534:Alum Compounds; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D013743:Tetanus Antitoxin / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000942:Antigens, Bacterial; D008070:Lipopolysaccharides; D013743:Tetanus Antitoxin; D013745:Tetanus Toxoid; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E; D010047:Ovalbumin; D011070:Poly I-C