Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates

作者：Joseph R. Francica, Richard Laga, Geoffrey M. Lynn, Gabriela Mužíková, Ladislav Androvič, Baptiste Aussedat, William E. Walkowicz, Kartika Padhan, Ramiro A. Ramirez-Valdez, Robert Parks, Stephen D. Schmidt, Barbara J. Flynn, Yaroslav Tsybovsky, Guillaume B. E. Stewart-Jones, Kevin O. Saunders, Faezzah Baharom, Constantinos Petrovas, Barton F. Haynes, Robert A. Seder · 发表于：PLoS Biology · 年份：2019 · DOI：10.1371/journal.pbio.3000328 · 被引用次数：38 · 研究领域：HIV Research and Treatment、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

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 trim...