Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations

Aleksandar Antanasijevic,Torben Schiffner,Jacob T. Martin,Chiamaka A. Enemuo,George Ueda,Yury Choe,Kimberly M. Cirelli,Talar Tokatlian,Andrew B. Ward,Shane Crotty,Sergey Menis,Jeffrey Copps,Diane G. Carnathan,Guido Silvestri,Federico Viviano,Darrell J. Irvine,Galit Alter,William R. Schief,David Baker,Etse H. Gebru,Stephanie Fischinger,Neil P. King,Benjamin Cossette ,Christopher A. Cottrell

doi:10.1038/s41541-020-00223-1

Abstract

Following immunization, high-affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble human immunodeficiency virus (HIV) envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here, we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single LN within two days after immunization. Imaging of LNs collected seven days postimmunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent GCs. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with ICs or nanoparticles.

Highlights

The development of immunogens/immunization regimens capable of eliciting broadly neutralizing antibodies that can recognize diverse viral strains is thought to be an important approach to achieve an effective human immunodeficiency virus (HIV) vaccine[1,2]
Nanoparticle trimer immunogens accumulate in follicles of nonhuman primates (NHPs) following immunization We designed an experiment to compare antigen trafficking of soluble BG505 SOSIP MD39 trimer[9] and BG505 SOSIP-T33_dn[2] nanoparticle immunogen in rhesus macaques
The immunogen dose was normalized based on the total amount of BG505 SOSIP (100 and 142 μg per dose per animal for free trimer and nanoparticle, respectively)

Summary

Introduction

The development of immunogens/immunization regimens capable of eliciting broadly neutralizing antibodies (bNAbs) that can recognize diverse viral strains is thought to be an important approach to achieve an effective human immunodeficiency virus (HIV) vaccine[1,2]. Optimizing immunization strategies to promote high-affinity antibody responses against trimer immunogens remains an important goal. Soluble immunogens are rapidly bound by antibodies present in the tissue, forming immune complexes (ICs) that can subsequently traffic into lymphatic vessels and downstream draining LNs. In antigen-naive animals, IC formation can be mediated by natural pentameric IgM (nIgM) that binds antigen with low affinity but moderate to high avidity[14,15]. Non-antigen-specific, naive B cells capture IC–C3d complexes from the basolateral surface of SCS macrophages using complement receptor 2 and deposit them onto the surface of follicular dendritic cells (FDCs), where they are subsequently available to participate in Published in partnership with the Sealy Center for Vaccine Development the GC reaction[17]. FDCs serve as antigen depots that are capable of storing and displaying antigen for months[19]

Methods

Results

Conclusion