A STING-adjuvanted outer membrane vesicle nanoparticle vaccine vs. Klebsiella pneumoniae elicits broad capsule type cross-protection

Abstract Klebsiella pneumoniae (Kp) is a leading cause of hospital- and community-acquired infections and is increasingly resistant to last-line antibiotics, positioning it as a World Health Organization-designated priority pathogen. Vaccine development has been hindered by the extensive diversity of Kp exopolysaccharide capsules. We developed a cellular nanoparticle (CNP) platform in which bacterial outer membrane vesicles (OMVs) are stably coated onto a STING (stimulator of interferon genes)-adjuvanted nanoparticle core (CNP-KpSTING). The resulting ∼100-nm nanoparticles are homogenous and optimized for recruitment and activation of antigen-presenting cells in draining lymph nodes. CNP-KpSTING vaccination elicited robust antibody responses, enhanced neutrophil-mediated bacterial clearance, and conferred cross-protection against heterologous Kp capsule types in vitro and in lethal pneumonia models. Passive transfer of post-vaccination sera reduced bacterial burden and inflammatory cytokines in the lungs of infected mice. These findings establish CNP-KpSTING as a versatile platform that addresses key antigenic barriers inherent to Kp and support OMV-CNPs as a promising foundation for broadly protective vaccines against multidrug-resistant Gram-negative pathogens.