A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
© 2024. The Author(s).

Immunogenic biologics trigger an anti-drug antibody (ADA) response in patients that reduces efficacy and increases adverse reactions. Our laboratory has shown that targeting protein antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a strategy to increase delivery of otherwise immunogenic biologics to the liver via conjugation to a synthetic mannose polymer, p(Man). This delivery leads to reduced antigen-specific T follicular helper cell and B cell responses resulting in diminished ADA production, which is maintained throughout subsequent administrations of the native biologic. We find that p(Man)-antigen treatment impairs the ADA response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten immunodominance or control by T regulatory cells. We identify increased T cell receptor signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment via transcriptomic analyses. This modular platform may enhance tolerance to biologics, enabling long-term solutions for an ever-increasing healthcare problem.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

The development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.
© 2023. The Author(s).

Allergen-specific IgE antibodies mediate allergic pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. We report a population of type 2 polarized MBCs defined as CD23 hi , IL-4Rα hi , CD32 low at the transcriptional and surface protein levels. These “MBC2s” are enriched in IgG1 and IgG4-expressing cells, while constitutively expressing germline transcripts for IgE. Allergen-specific B cells from patients with allergic rhinitis and food allergy were enriched in MBC2s. MBC2s generated allergen specific-IgE during sublingual immunotherapy, thereby identifying these cells as the primary reservoir of IgE. The identification of MBC2s provides insights into the maintenance of IgE memory, which is detrimental in allergic diseases, but which could be beneficial in protection against venoms and helminths. One-Sentence Summary Identification of a novel memory B cell subset which holds allergen specific IgE memory.

Multiple sclerosis (MS) is an inflammatory, demyelinating CNS disease believed to be mediated by CD4 T cells specific for CNS self-antigens. CD8 T cells are also implicated in MS but their function is not well understood. MS lesions are heterogeneous and may reflect variation in the contribution of different types of lymphocytes. Understanding how lymphocytes with different effector functions contribute to MS is essential to develop effective therapies. We investigated how T cells expressing an MHC class I-restricted transgenic TCR specific for myelin basic protein (MBP) contribute to CNS autoimmunity using the mouse model of MS, experimental autoimmune encephalomyelitis. Virus infection triggered cytotoxic TCR-transgenic CD8 T cells to initiate acute experimental autoimmune encephalomyelitis in an IFN-γ- and perforin-dependent manner. Unexpectedly, spontaneous CNS autoimmunity developed in the TCR-transgenic mice that was accelerated by IFN-γ-deficiency. Spontaneous disease was associated with CD4 T cells that develop via endogenous TCR rearrangements but retain specificity for the MHC class I-restricted MBP epitope. The CD4 T cells produced TNF-α without other inflammatory cytokines and caused lesions with striking similarity to active MS lesions. Surprisingly, B cells were the predominant cell type that cross-presented MBP, and their depletion halted disease progression. This work provides a new model of spontaneous CNS autoimmunity with unique similarities to MS that is mediated by T cells with a distinct effector phenotype.
Copyright © 2022 by The American Association of Immunologists, Inc.