Abstract / Summary
Mycoplasma pneumoniae (MP), a major cause of community-acquired pneumonia, poses an escalating public health concern due to the increasing prevalence of macrolide-resistant strains, underscoring the urgent need for an effective vaccine. Here, we designed and constructed four multi-target chimeric mucosal vaccine candidates (MpCVs) by integrating key immunogenic domains from the major adhesion-associated proteins P1, P30, P40/90, and P116. These chimeric antigens exhibited favorable predicted antigenicity and non-allergenicity. Intranasal administration of MpCVs, particularly the lead candidate MpCV-R2, elicited stronger mucosal IgA and systemic IgG antibody responses than a simple antigen mixture. MpCV-R2 showed serum/BALF-mediated inhibition of MP adhesion in vitro and markedly reduced pulmonary MP genomic burden and associated lung pathology after challenge, including a macrolide-resistant clinical isolate. Furthermore, MpCV-R2 promoted antigen-specific B-cell activation and supported lung tissue-resident memory T-cell formation, while facilitating early control of pulmonary infection and modulating the local cytokine milieu. Collectively, these findings identify MpCV-R2 as a promising multi-target mucosal vaccine candidate for further development against MP infection.