title: Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses.
abstract: Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT) technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Metz
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hoekstra
authors.affiliation: Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Xianwen
authors.initials: X
authors.lastname: Yi
authors.affiliation: Liquidia Technologies, Research Triangle Park, North Carolina, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stone
authors.affiliation: Liquidia Technologies, Research Triangle Park, North Carolina, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: Horvath
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.affiliation: Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.|Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
authors.affiliation: Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Luft
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood* / Q000276:immunology; D002522:Chlorocebus aethiops; D003715:Dengue / Q000276:immunology / Q000517:prevention & control; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D019344:Lactic Acid / Q000737:chemistry; D008198:Lymph Nodes / Q000276:immunology; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000302:isolation & purification; D065288:Serogroup; D013499:Surface Properties; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D022223:Vaccines, Subunit; D014759:Viral Envelope Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid