title: Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant.
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.
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Joseph R
authors: JR
authors: Francica
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Geoffrey M
authors: GM
authors: Lynn
authors: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic , 162 06 Prague, Czech Republic.
authors: Richard
authors: R
authors: Laga
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: M Gordon
authors: MG
authors: Joyce
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Tracy J
authors: TJ
authors: Ruckwardt
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Kaitlyn M
authors: KM
authors: Morabito
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Man
authors: M
authors: Chen
authors: Vaccine Production Program, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Gaithersburg, Maryland 20878, United States.
authors: Rajoshi
authors: R
authors: Chaudhuri
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Baoshan
authors: B
authors: Zhang
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Mallika
authors: M
authors: Sastry
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Aliaksandr
authors: A
authors: Druz
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Kiyoon
authors: K
authors: Ko
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Misook
authors: M
authors: Choe
authors: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic , 162 06 Prague, Czech Republic.
authors: Michal
authors: M
authors: Pechar
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Ivelin S
authors: IS
authors: Georgiev
authors: Vaccine Production Program, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Gaithersburg, Maryland 20878, United States.
authors: Lisa A
authors: LA
authors: Kueltzo
authors: Department of Oncology, University of Oxford , Oxford OX3 7DQ, U.K.
authors: Leonard W
authors: LW
authors: Seymour
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: John R
authors: JR
authors: Mascola
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Peter D
authors: PD
authors: Kwong
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Barney S
authors: BS
authors: Graham
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Robert A
authors: RA
authors: Seder
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D057134:Antibodies, Neutralizing; D060326:Chemistry Techniques, Synthetic; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D008815:Mice, Inbred Strains; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000737:chemistry; D014760:Viral Fusion Proteins / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; C526850:F protein, human respiratory syncytial virus; D011108:Polymers; D022261:Respiratory Syncytial Virus Vaccines; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014614:Vaccines, Synthetic; D014760:Viral Fusion Proteins