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Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates.
Francica, Joseph R; Laga, Richard; Lynn, Geoffrey M; Muzíková, Gabriela; Androvic, Ladislav; Aussedat, Baptiste; Walkowicz, William E; Padhan, Kartika; Ramirez-Valdez, Ramiro Andrei; Parks, Robert; Schmidt, Stephen D; Flynn, Barbara J; Tsybovsky, Yaroslav; Stewart-Jones, Guillaume B E; Saunders, Kevin O; Baharom, Faezzah; Petrovas, Constantinos; Haynes, Barton F; Seder, Robert A.
Afiliación
  • Francica JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Laga R; Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • Lynn GM; Avidea Technologies, Inc., Baltimore, Maryland, United States of America.
  • Muzíková G; Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • Androvic L; Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • Aussedat B; Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
  • Walkowicz WE; Department of Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
  • Padhan K; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Ramirez-Valdez RA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Parks R; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
  • Schmidt SD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Flynn BJ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Tsybovsky Y; Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
  • Stewart-Jones GBE; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Saunders KO; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
  • Baharom F; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Petrovas C; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Haynes BF; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
  • Seder RA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Biol ; 17(6): e3000328, 2019 06.
Article en En | MEDLINE | ID: mdl-31206510
Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic "star" nanoparticles based on biocompatible N-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: VIH-1 / Vacunas contra el SIDA / Nanopartículas Límite: Animals Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: VIH-1 / Vacunas contra el SIDA / Nanopartículas Límite: Animals Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos