Effectiveness and immunogenicity of a nanoemulsion protein subunit vaccine against Pseudomonas aeruginosa: investigation in diet-induced obese mice.

Pseudomonas aeruginosa (Pa) is an opportunistic pathogen threatening individuals with obesity, a condition associated with chronic meta-inflammation and altered immunity. In this study, we evaluate the immunogenicity and protective efficacy of a nanoemulsion-based subunit vaccine (L-PaF/ME/BECC) targeting Pa in a diet-induced obese mouse model. Mice fed a high-fat diet (HFD; 60% fat) were compared to those on a low-fat diet (LFD; 10% fat) or regular chow (3% to 4% fat) to assess differences in vaccine responsiveness. Our results show that while L-PaF induces robust immune responses across all groups, HFD-fed mice exhibit significantly impaired antibody quality, including reduced IgA, IgG1, and IgG3 titers. These deficiencies were associated with impaired germinal center B-cell and T follicular helper cell responses, along with reduced CXCR5 and PD-1 modulation. In contrast, LFD-fed mice displayed preserved germinal center architecture and enhanced class-switched antibody production. This immune impairment extended to the lung-resident memory B cell in HFD mice, whereas LFD mice maintained a functional response. Despite compromised humoral immunity, HFD mice showed an expansion of lung tissue-resident memory T (Trm) cells postvaccination. FTY720 treatment showed that early secondary protection against Pa was maintained in the absence of circulating T-cell recruitment, consistent with a dominant contribution of lung-resident immune mechanisms during this early recall phase. Together, these findings suggest that lung Trm-associated immunity may partially compensate for obesity-associated defects in humoral responses and highlight the importance of vaccine strategies that promote tissue-localized T-cell immunity in metabolically compromised hosts.