Manganese salts function as potent adjuvants

Cell Mol Immunol. 2021 May;18(5):1222-1234. doi: 10.1038/s41423-021-00669-w. Epub 2021 Mar 25.


Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2'3'-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.

Keywords: Manganese (Mn2+); NLRP3; adjuvant; antigen presentation; cGAS-STING.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antigen Presentation / drug effects
  • Antiviral Agents / pharmacology
  • Cancer Vaccines / immunology
  • Cell Line
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Humans
  • Interleukin-1 / biosynthesis
  • Interleukin-18 / biosynthesis
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Manganese / pharmacology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Nucleotidyltransferases / metabolism
  • Protein Subunits / metabolism
  • Salts / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology


  • Adjuvants, Immunologic
  • Antiviral Agents
  • Cancer Vaccines
  • Interleukin-1
  • Interleukin-18
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Subunits
  • Salts
  • Sting1 protein, mouse
  • Manganese
  • Nucleotidyltransferases
  • cGAS protein, mouse