Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens.

Benjamin J Read,Chengbo Chen,Shengwei Wu,Neil P King,Darrell J Irvine,Aereas Aung,Daniel Lingwood,Isaac Sappington,John C Kraft,Lori Won,Kelly K Lee,Julia Bals

doi:10.1016/j.celrep.2021.110217

Abstract

SUMMARYNanoparticle (NP) vaccine formulations promote immune responses through multiple mechanisms. We recently reported that mannose-binding lectin (MBL) triggers trafficking of glycosylated HIV Env-immunogen NPs to lymph node follicles. Here, we investigate effects of MBL and complement on NP forms of HIV and other viral antigens. MBL recognition of oligomannose on gp120 nanoparticles significantly increases antigen accumulation in lymph nodes and antigen-specific germinal center (GC) responses. MBL and complement also mediate follicular trafficking and enhance GC responses to influenza, HBV, and HPV particulate antigens. Using model protein nanoparticles bearing titrated levels of glycosylation, we determine that mannose patches at a minimal density of 2.1 × 10−3 mannose patches/nm2 are required to trigger follicular targeting, which increases with increasing glycan density up to at least ~8.2 × 10−3 patches/nm2. Thus, innate immune recognition of glycans has a significant impact on humoral immunity, and these findings provide a framework for engineering glycan recognition to optimize vaccine efficacy.

Highlights

The use of nanoparticles displaying many copies of an antigen on their surface has been a very successful strategy for enhancing humoral responses to vaccine candidates
We recently reported that glycosylated HIV-immunogenbearing nanoparticles accumulate within follicles in a process mediated by mannose-binding lectin (MBL), which triggers complement deposition on the nanoparticle surface, transport to follicular dendritic cells (FDCs), and enhanced germinal center (GC) and serum antibody responses relative to non-accumulating nanoparticles (Tokatlian et al, 2018)
Wild-type (WT) or MBL KO mice were immunized with far-red dye-labeled eOD monomer or eOD-60mer administered subcutaneously with saponin adjuvant, followed by excision of draining inguinal lymph nodes and immediate whole-tissue fluorescence imaging to measure antigen accumulation and persistence in the tissues

Summary

Introduction

The use of nanoparticles displaying many copies of an antigen on their surface has been a very successful strategy for enhancing humoral responses to vaccine candidates. Numerous preclinical studies have found that nanoparticles of a variety of compositions drain efficiently through the lymph, but upon reaching secondary lymphoid tissues remain primarily localized within the subcapsular sinus and the medulla or are seemingly excluded from B cell follicles (Katagiri et al, 2019; Manolova et al, 2008; Moon et al, 2012; Mueller et al, 2015; Reddy et al, 2006; Shukla et al, 2017; Wang et al, 2019). Since interactions with B cells within follicles are essential for the development of high-affinity antibodies, localization of antigen within these regions has the potential to drive more robust humoral responses.

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Discussion

Conclusion