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

Publication ,  Journal Article
Francica, JR; Laga, R; Lynn, GM; Mužíková, G; Androvič, L; Aussedat, B; Walkowicz, WE; Padhan, K; Ramirez-Valdez, RA; Parks, R; Schmidt, SD ...
Published in: PLoS Biol
June 2019

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.

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Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

June 2019

Volume

17

Issue

6

Start / End Page

e3000328

Location

United States

Related Subject Headings

  • Primates
  • Peptides
  • Nanoparticles
  • Mice, Inbred BALB C
  • Mice
  • Macaca mulatta
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Envelope Protein gp120
 

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Francica, J. R., Laga, R., Lynn, G. M., Mužíková, G., Androvič, L., Aussedat, B., … Seder, R. A. (2019). Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates. PLoS Biol, 17(6), e3000328. https://doi.org/10.1371/journal.pbio.3000328
Francica, Joseph R., Richard Laga, Geoffrey M. Lynn, Gabriela Mužíková, Ladislav Androvič, Baptiste Aussedat, William E. Walkowicz, et al. “Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates.PLoS Biol 17, no. 6 (June 2019): e3000328. https://doi.org/10.1371/journal.pbio.3000328.
Francica JR, Laga R, Lynn GM, Mužíková G, Androvič L, Aussedat B, et al. Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates. PLoS Biol. 2019 Jun;17(6):e3000328.
Francica, Joseph R., et al. “Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates.PLoS Biol, vol. 17, no. 6, June 2019, p. e3000328. Pubmed, doi:10.1371/journal.pbio.3000328.
Francica JR, Laga R, Lynn GM, Mužíková G, Androvič L, Aussedat B, Walkowicz WE, Padhan K, Ramirez-Valdez RA, Parks R, Schmidt SD, Flynn BJ, Tsybovsky Y, Stewart-Jones GBE, Saunders KO, Baharom F, Petrovas C, Haynes BF, Seder RA. Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates. PLoS Biol. 2019 Jun;17(6):e3000328.
Journal cover image

Published In

PLoS Biol

DOI

EISSN

1545-7885

Publication Date

June 2019

Volume

17

Issue

6

Start / End Page

e3000328

Location

United States

Related Subject Headings

  • Primates
  • Peptides
  • Nanoparticles
  • Mice, Inbred BALB C
  • Mice
  • Macaca mulatta
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Envelope Protein gp120