Augmenting the Immune Response against a Stabilized HIV-1 Clade C Envelope Trimer by Silica Nanoparticle Delivery.

David Peterhoff,Martin F Bachmann,Jan M Sobczak,Stefanie Thalhauser,Alexandra Hauser,Quentin Sattentau,Mona O Mohsen,Christoph Voigt,Nicole Seifert,Ralf Wagner,Miriam Breunig,Song Ding,Patrick Neckermann

doi:10.3390/vaccines9060642

Abstract

The delivery of HIV-1 envelope (Env) trimer-based immunogens on the surface of nanoparticles holds promise to promote immunogenicity with the aim of inducing a potent, durable and broad neutralizing antibody (bnAb) response. Towards that goal, we examined the covalent conjugation of Env to 100 nm and 200 nm silica nanoparticles (SiNPs) to optimize conjugation density and attachment stability. Env was redesigned to enable site-specific cysteine-mediated covalent conjugation while maintaining its structural integrity and antigenicity. Env was anchored to different sized SiNPs with a calculated spacing of 15 nm between adjacent trimers. Both particle sizes exhibited high in vitro stability over a seven-day period. After attachment, 100 nm particles showed better colloidal stability compared to 200 nm particles. Importantly, the antigenic profile of Env was not impaired by surface attachment, indicating that the quaternary structure was maintained. In vitro Env uptake by dendritic cells was significantly enhanced when Env was delivered on the surface of nanoparticles compared to soluble Env. Furthermore, multivalent Env displayed efficiently activated B cells even at Env concentrations in the low nanomolar range. In mice, antibody responses to nanoparticle-coupled Env were stronger compared to the free protein and had equivalent effects at lower doses and without adjuvant.

Highlights

The sequence diversity of HIV-1 poses a huge challenge to the development of a prophylactic vaccine [1,2]
One possible route to this ultimate goal is the induction of broadly neutralizing antibodies. broad neutralizing antibody (bnAb) naturally occur after a prolonged co-evolution in the infected host, and they recognize conserved epitopes of the HIV-1 envelope glycoprotein and interfere with its function as a viral membrane fusion machine [4,5]
We addressed critical design parameters required for efficient nanoparticulate delivery of Env-based immunogens

Summary

Introduction

The sequence diversity of HIV-1 poses a huge challenge to the development of a prophylactic vaccine [1,2]. Substantial progress has been made in the development of soluble and stabilized Env-based immunogens that provide an optimized antigenic profile and are recognized by several bnAbs, but not by non-neutralizing antibodies (nnAbs) [6]. Immunization with these Env variants has so far failed to induce neutralization breadth, and the immunogenicity of the heavily glycosylated stabilized Env trimers is rather weak [7,8,9]. This begs the question, how can we boost immunogenicity and elicit the production of bnAbs

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Results

Conclusion