RESUMO
Chronic lung infection by opportunistic pathogens, such as Pseudomonas aeruginosa and members of the Burkholderia cepacia complex, is a major cause of morbidity and mortality in patients with cystic fibrosis. Outer membrane proteins (OMPs) of gram-negative bacteria are promising vaccine antigen candidates. In this study, we evaluated the immunogenicity, protection, and cross-protection conferred by intranasal vaccination of mice with OMPs from B. multivorans plus the mucosal adjuvant adamantylamide dipeptide (AdDP). Robust mucosal and systemic immune responses were stimulated by vaccination of naive animals with OMPs from B. multivorans and B. cenocepacia plus AdDP. Using a mouse model of chronic pulmonary infection, we observed enhanced clearance of B. multivorans from the lungs of vaccinated animals, which correlated with OMP-specific secretory immunoglobulin A responses. Furthermore, OMP-immunized mice showed rapid resolution of the pulmonary infection with virtually no lung pathology after bacterial challenge with B. multivorans. In addition, we demonstrated that administration of B. multivorans OMP vaccine conferred protection against B. cenocepacia challenge in this mouse infection model, suggesting that OMPs provide cross-protection against the B. cepacia complex. Therefore, we concluded that mucosal immunity to B. multivorans elicited by intranasal vaccination with OMPs plus AdDP could prevent early steps of colonization and infection with B. multivorans and also ameliorate lung tissue damage, while eliciting cross-protection against B. cenocepacia. These results support the notion that therapies leading to increased mucosal immunity in the airways may help patients with cystic fibrosis.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Amantadina/análogos & derivados , Proteínas da Membrana Bacteriana Externa/administração & dosagem , Infecções por Burkholderia/prevenção & controle , Complexo Burkholderia cepacia/química , Dipeptídeos/administração & dosagem , Pneumopatias/prevenção & controle , Administração Intranasal , Amantadina/administração & dosagem , Amantadina/imunologia , Animais , Anticorpos Antibacterianos/sangue , Proteínas da Membrana Bacteriana Externa/imunologia , Infecções por Burkholderia/imunologia , Dipeptídeos/imunologia , Modelos Animais de Doenças , Imunização , Pneumopatias/imunologia , Pneumopatias/microbiologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Moraxella catarrhalis causes acute otitis media in children and lower respiratory tract infections in adults and elderly. In children the presence of antibodies against the highly conserved outer membrane protein CD correlates with protection against infection, suggesting that this protein may be useful as a vaccine antigen. However, native CD is difficult to purify, and it is still unclear if recombinant CD (rCD) is a valid alternative. We performed a side-by-side comparison of the immunogenicities and efficacies of vaccine formulations containing native CD and rCD with adamantylamide dipeptide as the mucosal adjuvant. Intranasal vaccination of mice stimulated the production of high CD-specific antibody titers in sera and of secretory immunoglobulin A in mucosal lavages, which cross-recognized both antigens. While vaccination with native CD increased the number of interleukin-2 (IL-2)- and gamma interferon-producing cells, rCD mainly stimulated IL-4-secreting cells. Nevertheless, efficient bacterial clearance was observed in the lungs of challenged mice receiving native CD and in the lungs of challenged mice receiving rCD (96% and 99%, respectively). Thus, rCD is a promising candidate for incorporation in vaccine formulations for use against M. catarrhalis.
Assuntos
Adesinas Bacterianas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Amantadina/análogos & derivados , Vacinas Bacterianas/imunologia , Dipeptídeos/imunologia , Pulmão/microbiologia , Moraxella catarrhalis/imunologia , Infecções por Moraxellaceae/imunologia , Adesinas Bacterianas/genética , Administração Intranasal , Amantadina/administração & dosagem , Amantadina/imunologia , Animais , Anticorpos Antibacterianos/sangue , Vacinas Bacterianas/administração & dosagem , Proliferação de Células , Contagem de Colônia Microbiana , DNA Bacteriano/química , DNA Bacteriano/genética , Dipeptídeos/administração & dosagem , Modelos Animais de Doenças , Imunoglobulina A Secretora/análise , Interferon gama/biossíntese , Interleucinas/biossíntese , Pulmão/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Moraxella catarrhalis/isolamento & purificação , Infecções por Moraxellaceae/microbiologia , Mucosa/imunologia , Baço/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
Nontypeable Haemophilus influenzae (NTHi) is a leading etiologic agent of otitis media in children and recurrent respiratory infections in patients with chronic obstructive pulmonary disease. The highly conserved outer membrane protein P6 constitutes a promising vaccine candidate antigen. However, the small amount of P6 produced by this fastidious microorganism renders large-scale production difficult. Controversial data also exist concerning the suitability of recombinant P6 (rP6) as a vaccine antigen. Therefore, we performed a comparative evaluation of the immunogenicity and efficacy of native P6 and rP6 in mice intranasally vaccinated with adamantylamide dipeptide (AdDP) as an adjuvant. High titers of P6-specific serum antibodies were elicited in mice vaccinated with either native P6 or rP6, which cross-recognized both antigens. However, rP6 stimulated stronger mucosal responses. Mice vaccinated with rP6 were protected against both pulmonary and middle-ear infections (P<.01). This demonstrates that rP6 plus AdDP constitutes a promising vaccine formulation against the most relevant forms of disease caused by NTHi.