Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant

Bioconjug Chem. 2016 Oct 19;27(10):2372-2385. doi: 10.1021/acs.bioconjchem.6b00370. Epub 2016 Sep 22.

Abstract

Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, TH1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Animals
  • Antibodies, Neutralizing
  • Chemistry Techniques, Synthetic
  • Drug Delivery Systems / methods
  • Female
  • Mice, Inbred Strains
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Polymers / chemistry*
  • Respiratory Syncytial Virus Vaccines / administration & dosage
  • Respiratory Syncytial Virus Vaccines / immunology
  • Respiratory Syncytial Virus Vaccines / pharmacology*
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 8 / agonists
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / chemistry
  • Viral Fusion Proteins / administration & dosage*
  • Viral Fusion Proteins / chemistry

Substances

  • Adjuvants, Immunologic
  • Antibodies, Neutralizing
  • F protein, human respiratory syncytial virus
  • Polymers
  • Respiratory Syncytial Virus Vaccines
  • TLR7 protein, human
  • TLR8 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Vaccines, Synthetic
  • Viral Fusion Proteins