gB-MTQ-Ferritin nanoparticle vaccine induces antigen-focused B-T cell synergy against genital HSV-2 challenge

The development of effective vaccines against mucosally transmitted pathogens like herpes simplex virus type 2 (HSV-2) remains an urgent global health challenge. We present a structure-engineered nanovaccine platform that conjugates MTQ-stabilized HSV-2 glycoprotein B (gB) trimers to ferritin nanoparticles via SpyCatcher/SpyTag-mediated bioconjugation. This design achieves three critical advancements: (1) preservation of native-like trimeric conformation through MTQ motif stabilization, (2) site-specific antigen orientation via covalent coupling chemistry, and (3) size-tunable lymphatic trafficking (12.5 → 50.8 nm). In BALB/c mouse models, the nanovaccine induced 15-fold higher antigen-specific IgG titers and 1.54-fold elevated neutralizing antibody responses compared to gB-MTQ formulations, while maintaining balanced Th1/Th2 polarization. Mechanistic profiling revealed 1.43-fold expansion of germinal center B cells and 3-fold enhanced CD4⁺ T follicular helper cell activation versus conventional subunit vaccines. These coordinated humoral-cellular responses translated to 90% survival against lethal HSV-2 challenge, with complete viral clearance by day 14 post-infection and 19% reduction in genital pathology scores compared to monomeric controls. These findings establish a paradigm for next-generation HSV-2 subunit vaccines, where engineered nanoscale architectures bridge the gap between antigen precision and robust immunity, offering a promising vaccine against HSV-2.