Bacillus Calmette-Guérin (BCG) is an attenuated vaccine widely used for tuberculosis prevention. While BCG has long been perceived as an intracellular candidate vector for delivering antigens against infectious diseases and cancers, challenges persist in inducing durable immune responses, particularly high-titer neutralizing antibodies (Nabs). Here we show that displaying antigens in the surface of BCG is a promising strategy to induce long-lasting Nabs production and T-cell responses. We constructed a recombinant BCG expressing the SARS-CoV-2 receptor-binding domain (RBD) antigen on its cell wall, termed CW-rBCG::RBD, which achieved an antigen yield approaching 850 nanograms per 107 colony-forming unit. Compared with both the parental BCG and the RBD protein subunit vaccine (RBDAS01), intravenous administration of CW-rBCG::RBD followed by a booster dose significantly enhanced Nab production and increased the frequencies of RBD-specific central memory T cells (Tcm) and T follicular helper (Tfh) cells in the spleen. In mice primed with a single dose of CW-rBCG::RBD and boosted with RBDAS01, we also observed elevated Nab titers and detectable levels of RBD-specific IgG2a antibodies at 8 weeks post-priming, responses that were not observed in the BCG-primed or RBDAS01-only groups. Furthermore, subcutaneous co-administration of CW-rBCG::RBD and RBDAS01 sustained Nab production for up to 31 weeks and maintained higher Tfh and Tcm cell frequencies compared to both BCG co-administration with RBDAS01 and RBDAS01 alone. These findings highlight an effective strategy for optimizing BCG-based vaccination and immunotherapy platforms. Subject terms: recombinant BCG; immune response; vaccines; cell wall; SARS-CoV-2 RBD.
© 2025. The Author(s).

Progranulin (PGRN) plays a critical role in bronchial asthma and the function of various immune cells. However, the mechanisms by which PGRN influences B-cell receptor (BCR) signaling and immunoglobulin E(IgE) production are not fully understood. The study aimed to elucidate the molecular mechanisms through which PGRN affects BCR signaling, B-cell differentiation, and IgE production. A PGRN knockout mouse model, along with techniques including flow cytometry, the creation of a bone marrow chimeric mouse model, total internal reflection fluorescence (TIRF), and Western blot (WB) analysis is employed, to investigate the link between PGRN and various aspects of B-cell biology. It is discovered that the absence of PGRN in mice alters peripheral B-cell subpopulations, promotes IgE class switching in a cell-intrinsic manner, and affects B-cell subpopulations. Additionally, PGRN modulates B-cell functions by regulating BCR signaling pathways, metabolic processes, and the actin cytoskeleton during early B-cell activation. Significantly, PGRN deficiency results in diminished production of NP-specific antibodies. Moreover, it is found that PGRN inhibits B-cell activation and IgE production through the PGRN-IFITM3-STAT1 signaling pathway. The findings provide new strategies for the targeted treatment of bronchial asthma, highlighting the crucial role of PGRN in B-cell signaling and IgE production.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

IκB kinase (IKK)α controls noncanonical NF-κB signaling required for lymphoid organ development. We showed previously that lymph node formation is ablated in IkkαLyve-1 mice constitutively lacking IKKα in lymphatic endothelial cells (LECs). We now reveal that loss of IKKα in LECs leads to the formation of BALT in the lung. Tertiary lymphoid structures appear only in the lungs of IkkαLyve-1 mice and are not present in any other tissues, and these highly organized BALT structures form after birth and in the absence of inflammation. Additionally, we show that IkkαLyve-1 mice challenged with influenza A virus (IAV) exhibit markedly improved survival and reduced weight loss compared with littermate controls. Importantly, we determine that the improved morbidity and mortality of IkkαLyve-1 mice is independent of viral load and rate of clearance because both mice control and clear IAV infection similarly. Instead, we show that IFN-γ levels are decreased, and infiltration of CD8 T cells and monocytes into IkkαLyve-1 lungs is reduced. We conclude that ablating IKKα in LECs promotes BALT formation and reduces the susceptibility of IkkαLyve-1 mice to IAV infection through a decrease in proinflammatory stimuli.
Copyright © 2024 The Authors.

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).

Nanoparticle vaccines based on H. pylori ferritin are increasingly used as a vaccine platform for many pathogens, including RSV, influenza, and SARS-CoV-2. They have been found to elicit enhanced, long-lived B cell responses. The basis for improved efficacy of ferritin nanoparticle vaccines remains unresolved, including whether recruitment of CD4 T cells specific for the ferritin component of these vaccines contributes to cognate help in the B cell response. Using influenza HA-ferritin nanoparticles as a prototype, we have performed an unbiased assessment of the CD4 T cell epitope composition of the ferritin particles relative to that contributed by influenza HA using mouse models that express distinct constellations of MHC class II molecules. The role that these CD4 T cells play in the B cell responses was assessed by quantifying follicular helper cells (TFH), germinal center (GC) B cells, and antibody secreting cells. When mice were immunized with equimolar quantities of soluble HA-trimers and HA-Fe nanoparticles, HA-nanoparticle immunized mice had an increased overall abundance of TFH that were found to be largely ferritin-specific. HA-nanoparticle immunized mice had an increased abundance of HA-specific isotype-switched GC B cells and HA-specific antibody secreting cells (ASCs) relative to mice immunized with soluble HA-trimers. Further, there was a strong, positive correlation between CD4 TFH abundance and GC B cell abundance. Thus, availability of helper CD4 T cell epitopes may be a key additional mechanism that underlies the enhanced immunogenicity of ferritin-based HA-Fe-nanoparticle vaccines.
© 2022. The Author(s).