title: Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy.
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.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Siefert
authors.affiliation: Department of Molecular and Cellular Physiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Chemical and Environmental Engineering, Yale University, New Haven, CT 06520, USA; Department of Immunobiology, Yale University, New Haven, CT 06520, USA. Electronic address: tarek.fahmy@yale.edu.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D001428:Bacterial Vaccines / Q000276:immunology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives / Q000737:chemistry; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001428:Bacterial Vaccines; C408982:CPG-oligonucleotide; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; D000069452:Pathogen-Associated Molecular Pattern Molecules; D051193:Toll-Like Receptors; C048436:monophosphoryl lipid A
keywords: Biomimetic; Cellular immunity; Nanoparticle; PAMP; TLR; Vaccine