Liver Immunity-Guided Discovery of Capsule-Permeable Protein Antigens Against Bacterial Sepsis

The capsules of invasive bacteria shield underlying antigens, limit immune clearance and hinder vaccine noncapsular antigen discovery. To address this, we developed Liver-based Vaccine Antigen Capture (L-VAC), a functional platform integrating antibody-mediated screening with in vivo visualization of hepatic bacterial clearance in mice. Applying L-VAC to Streptococcus pneumoniae identified multiple capsule-permeable proteins that induce rapid hepatic clearance of blood-borne bacteria. Immunization with these proteins, especially in a multivalent formulation, conferred broad cross-serotype protection. Spatial analyses revealed that only the proteins localized at or near the capsular surface are targetable for vaccine-induced pathogen capture in the liver sinusoids. These findings establish L-VAC as a sensitive and reliable approach for identifying protective protein antigens capable of overcoming capsule barriers, offering a promising strategy to develop broadly protective vaccines against multidrug-resistant encapsulated pathogens.