Protective-Antigen Scaffold Nanoparticle Vaccine Overcomes Carrier-Induced Suppression and Immunosenescence to Protect against Pseudomonas aeruginosa Pneumonia

Multidrug-resistant Pseudomonas aeruginosa (PA) causes severe infections, with severe burden especially in older adults. Vaccines remain effective and are urgently needed despite immunosenescence. Self-assembling nanoparticles can enhance vaccine immunogenicity, but their translational use is constrained by the useless anticarrier immunity and carrier-induced epitope suppression (CIES). Herein, we developed a protective-antigen-based nanoparticle platform in which the PA chaperonin GroEL, an intrinsically self-assembling protective antigen, serves as the scaffold for a fusion immunogen reGroEL-PO, which displays the PcrV-OprI antigen (rePO). In mice, pre-existing anti-GroEL immunity did not blunt responses but enhanced anti-rePO immunity. Mechanistically, reGroEL-PO increased antigen uptake by antigen-presenting cells, promoted dendritic-cell maturation and accelerated both humoral and cellular immunity. In addition, reGroEL-PO elicited immune responses and conferred protection in adult and aged mice. These data demonstrate reGroEL-PO as a PA vaccine candidate and illustrate a nanoparticle design that leverages protective carriers and circumvents CIES effects.