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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.

Original publication

DOI

10.1021/acs.bioconjchem.6b00370

Type

Journal article

Journal

Bioconjugate chemistry

Publication Date

10/2016

Volume

27

Pages

2372 - 2385

Addresses

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.

Keywords

Animals, Mice, Inbred Strains, Polymers, Vaccines, Synthetic, Viral Fusion Proteins, Respiratory Syncytial Virus Vaccines, Adjuvants, Immunologic, Drug Delivery Systems, Female, Toll-Like Receptor 7, Toll-Like Receptor 8, Nanoparticles, Antibodies, Neutralizing, Chemistry Techniques, Synthetic