Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy

Biomaterials. 2016 Aug;97:85-96. doi: 10.1016/j.biomaterials.2016.03.039. Epub 2016 Apr 1.

Abstract

Antigen-presenting cells (APCs) sense microorganisms via pathogen-associated molecular patterns (PAMPs) by both extra- and intracellular Toll-like Receptors (TLRs), initiating immune responses against invading pathogens. Bacterial PAMPs include extracellular lipopolysaccharides and intracellular unmethylated CpG-rich oligodeoxynucleotides (CpG). We hypothesized that a biomimetic approach involving antigen-loaded nanoparticles (NP) displaying Monophosphoryl Lipid A (MPLA) and encapsulating CpG may function as an effective "artificial bacterial" biomimetic vaccine platform. This hypothesis was tested in vitro and in vivo using NP assembled from biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer, surface-modified with MPLA, and loaded with CpG and model antigen Ovalbumin (OVA). First, CpG potency, characterized by cytokine profiles, titers, and antigen-specific T cell responses, was enhanced when CpG was encapsulated in NP compared to equivalent concentrations of surface-presented CpG, highlighting the importance of biomimetic presentation of PAMPs. Second, NP synergized surface-bound MPLA with encapsulated CpG in vitro and in vivo, inducing greater pro-inflammatory, antigen-specific T helper 1 (Th1)-skewed cellular and antibody-mediated responses compared to single PAMPs or soluble PAMP combinations. Importantly, NP co-presentation of CpG and MPLA was critical for CD8(+) T cell responses, as vaccination with a mixture of NP presenting either CpG or MPLA failed to induce cellular immunity. This work demonstrates a rational methodology for combining TLR ligands in a context-dependent manner for synergistic nanoparticulate vaccines.

Keywords: Biomimetic; Cellular immunity; Nanoparticle; PAMP; TLR; Vaccine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antibody Formation / drug effects
  • Bacterial Vaccines / immunology*
  • Biomimetic Materials / pharmacology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Humans
  • Immunity, Cellular / drug effects
  • Lipid A / analogs & derivatives
  • Lipid A / chemistry
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Oligodeoxyribonucleotides / pharmacology
  • Pathogen-Associated Molecular Pattern Molecules / metabolism*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Toll-Like Receptors / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Vaccines
  • CPG-oligonucleotide
  • Lipid A
  • Oligodeoxyribonucleotides
  • Pathogen-Associated Molecular Pattern Molecules
  • Toll-Like Receptors
  • monophosphoryl lipid A