Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Philip J.m Brouwer ,John P Moore,Neil P King,Jonathan L Torres,Andrew B Ward,Joel D Allen,Anila Yasmeen,Rajesh P Ringe,Max Crispin,Per Johan Klasse,Celia C Labranche ,David C Montefiori,Gabriel Ozorowski,Aleksandar Antanasijevic,Tom P L Bijl,Marlon De Gast,Marit J Van Gils,Judith A Burger,Rashmi Ravichandran,Rogier W Sanders

doi:10.1038/s41541-021-00285-9

Abstract

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.

Highlights

The immune evasion mechanisms and profound sequence diversity of human immunodeficiency virus-1 (HIV-1) make the development of a vaccine that can induce persistent and broad protection one of the greatest challenges in vaccinology today
Thermal melting experiments by nanoscale differential scanning fluorimetry (NanoDSF) showed that 16055 SOSIP-I53-50NPs displayed a typical two-phase melting profile with an unfolding peak at 76 °C for the SOSIP trimers and a second peak at 87 °C for the I53-50NP core (Supplementary Fig. 2)
Particles remained intact over the duration of resulting 16055 SOSIP.v5.2 construct was expressed in 293F cells this experiment (Supplementary Fig. 2)

Summary

Introduction

The immune evasion mechanisms and profound sequence diversity of human immunodeficiency virus-1 (HIV-1) make the development of a vaccine that can induce persistent and broad protection one of the greatest challenges in vaccinology today. To cope with the extensive diversity of globally circulating strains it is widely agreed that an effective vaccine will need to induce broadly neutralizing antibodies (bNAbs)[1–3]. The development of recombinant immunogens that closely resemble the native trimeric conformation of Env, such as those based on the SOSIP design, have accelerated HIV-1 vaccine development by enabling the elicitation of autologous NAb responses in various animal models[2,6]. Consistent induction of bNAbs has so far not been achieved, several immunization regimens have been able to elicit antibodies with an encouraging still inadequate degree of neutralization breadth[11,12]

Methods

Results

Conclusion