Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants

J Clin Invest. 2015 Jun;125(6):2532-46. doi: 10.1172/JCI79915. Epub 2015 May 4.

Abstract

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS Vaccines / immunology
  • AIDS Vaccines / pharmacology
  • Adjuvants, Immunologic* / chemistry
  • Adjuvants, Immunologic* / pharmacology
  • Animals
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / chemistry
  • Cyclic GMP / pharmacology
  • Drug Delivery Systems*
  • HIV Envelope Protein gp41 / immunology
  • HIV Envelope Protein gp41 / pharmacology
  • HIV-1 / immunology
  • Lipid A / analogs & derivatives*
  • Lipid A / chemistry
  • Lipid A / pharmacology
  • Lymph Nodes / immunology*
  • Membrane Proteins / agonists*
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles / chemistry*
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology

Substances

  • AIDS Vaccines
  • Adjuvants, Immunologic
  • HIV Envelope Protein gp41
  • Lipid A
  • MPYS protein, mouse
  • Membrane Proteins
  • gp41 protein, Human immunodeficiency virus 1
  • Polyethylene Glycols
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP
  • monophosphoryl lipid A