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

Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant.
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Francica JR, Lynn GM, Laga R, Joyce MG, Ruckwardt TJ, Morabito KM, Chen M, Chaudhuri R, Zhang B, Sastry M, Druz A, Ko K, Choe M, Pechar M, Georgiev IS, Kueltzo LA, Seymour LW, Mascola JR, Kwong PD, Graham BS, Seder RA,


Francica JR, Lynn GM, Laga R, Joyce MG, Ruckwardt TJ, Morabito KM, Chen M, Chaudhuri R, Zhang B, Sastry M, Druz A, Ko K, Choe M, Pechar M, Georgiev IS, Kueltzo LA, Seymour LW, Mascola JR, Kwong PD, Graham BS, Seder RA, (click to view)

Francica JR, Lynn GM, Laga R, Joyce MG, Ruckwardt TJ, Morabito KM, Chen M, Chaudhuri R, Zhang B, Sastry M, Druz A, Ko K, Choe M, Pechar M, Georgiev IS, Kueltzo LA, Seymour LW, Mascola JR, Kwong PD, Graham BS, Seder RA,

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Bioconjugate chemistry 2016 Sep 2227(10) 2372-2385

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.

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