Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses

J Immunol Res. 2015:2015:280238. doi: 10.1155/2015/280238. Epub 2015 Aug 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic*
  • Adsorption
  • Alum Compounds*
  • Animals
  • Antibody Formation / immunology*
  • Antigens, Bacterial / immunology
  • Bronchoalveolar Lavage Fluid / immunology
  • Disease Models, Animal
  • Female
  • Hypersensitivity / immunology
  • Hypersensitivity / metabolism
  • Immunization
  • Immunoglobulin E / blood
  • Immunoglobulin E / immunology
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Ovalbumin / immunology
  • Poly I-C / immunology
  • Poly I-C / pharmacology
  • Tetanus Antitoxin / immunology
  • Tetanus Toxoid / immunology*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism
  • Toll-Like Receptor 3 / antagonists & inhibitors
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Adjuvants, Immunologic
  • Alum Compounds
  • Antigens, Bacterial
  • Lipopolysaccharides
  • Tetanus Antitoxin
  • Tetanus Toxoid
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Immunoglobulin E
  • Ovalbumin
  • Poly I-C