title: Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine.
abstract: New subunit vaccine formulations with increased potency are of interest to improve immune responses against poorly immunogenic antigens, to avoid vaccine shortages in pandemic situations, and to promote dose-sparing of potent adjuvant molecules that can cause unacceptable side effects in prophylactic vaccination. Here we report strong class-switched, high avidity humoral immune responses elicited by a vaccine system based on poly(lactide-co-glycolide) micro- or nano-particles enveloped by PEGylated phospholipid bilayers, with protein antigens covalently anchored to the lipid surface and lipophilic adjuvants inserted in the bilayer coating. Strikingly, these particles elicited high endpoint antigen-specific IgG titers (>10(6)) sustained for over 100 days after two immunizations with as little as 2.5 ng of antigen. At such low doses, the conventional adjuvant alum or the molecular adjuvants monophosphoryl lipid A (MPLA) or α-galactosylceramide (αGC) failed to elicit responses. Co-delivery of antigen with MPLA or αGC incorporated into the particle bilayers in a pathogen-mimetic fashion further enhanced antibody titers by ~12-fold. MPLA provided the highest sustained IgG titers at these ultra-low antigen doses, while αGC promoted a rapid rise in serum IgG after one immunization, which may be valuable in emergencies such as disease pandemics. The dose of αGC required to boost the antibody response was also spared by particulate delivery. Lipid-enveloped biodegradable micro- and nano-particles thus provide a potent dose-sparing platform for vaccine delivery.
authors.affiliation: Department of Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4307, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bershteyn
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Hanson
authors.forename: Monica P
authors.initials: MP
authors.lastname: Crespo
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: Adrienne V
authors.initials: AV
authors.lastname: Li
authors.forename: Heikyung
authors.initials: H
authors.lastname: Suh
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D032701:Biomimetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D007074:Immunoglobulin G / Q000097:blood*; D019344:Lactic Acid / Q000008:administration & dosage; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D008055:Lipids / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage*; D010047:Ovalbumin / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D005699:Galactosylceramides; D007074:Immunoglobulin G; D008050:Lipid A; D008055:Lipids; D022223:Vaccines, Subunit; C493154:alpha-galactosylceramide; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; C048436:monophosphoryl lipid A