title: Nanoparticles decorated with viral antigens are more immunogenic at low surface density.
abstract: There is an urgent need to develop protective vaccines for high priority viral pathogens. One approach known to enhance immune responses to viral proteins is to display them on a nanoparticle (NP) scaffold. However, little is known about the effect of protein density on the B cell response to antigens displayed on NPs. To address this question HIV-1 Envelope (Env) and influenza hemagglutinin (HA) were displayed on a polystyrene-based NP scaffold at various densities - corresponding to mean antigen distances that span the range encountered on naturally occurring virions. Our studies revealed that NPs displaying lower densities of Env or HA more efficiently stimulated antigen-specific B cells in vitro, as measured by calcium flux, than did NPs displaying higher antigen densities. Similarly, NPs displaying a low density of Env or HA also elicited higher titers of antigen-specific serum IgG in immunized BALB/c mice (including elevated titers of hemagglutination-inhibiting antibodies), as well as an increased frequency of antigen-specific antibody secreting cells in the lymph node, spleen and bone marrow. Importantly, our studies showed that the enhanced B cell response elicited by the lower density NPs is likely secondary to more efficient development of follicular helper CD4 T cells and germinal center B cells. These findings demonstrate that the density of antigen on a NP scaffold is a critical determinant of the humoral immune response elicited, and that high density display does not always result in an optimal response.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Brewer
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, United States; David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: DiPiazza
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Acklin
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642, United States.
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, United States; David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, United States.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Sant
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, United States. Electronic address: stephen_dewhurst@urmc.rochester.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
mesh_terms: D000327:Adsorption; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D005260:Female; D015497:HIV-1 / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007114:Immunization; D009980:Influenza A virus / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D011137:Polystyrenes / Q000737:chemistry; D012996:Solutions; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011137:Polystyrenes; D012996:Solutions; D054299:env Gene Products, Human Immunodeficiency Virus; D002118:Calcium
keywords: Antigen density; Antigen display; Envelope; HIV; Hemagglutinin; Humoral immunity; Influenza; Nanoparticle