RESUMO
Meningitis and sepsis caused by serogroup B meningococcus are two severe diseases that still cause significant mortality. To date there is no universal vaccine that prevents these diseases. In this work, five antigens discovered by reverse vaccinology were expressed in a form suitable for large-scale manufacturing and formulated with adjuvants suitable for human use. The vaccine adjuvanted by aluminum hydroxide induced bactericidal antibodies in mice against 78% of a panel of 85 meningococcal strains representative of the global population diversity. The strain coverage could be increased to 90% and above by the addition of CpG oligonucleotides or by using MF59 as adjuvant. The vaccine has the potential to conquer one of the most devastating diseases of childhood.
Assuntos
Vacinas Meningocócicas/imunologia , Neisseria meningitidis Sorogrupo B/imunologia , Animais , Anticorpos/imunologia , Antígenos de Bactérias/imunologia , Modelos Animais de Doenças , Humanos , Meningite Meningocócica/imunologia , Meningite Meningocócica/microbiologia , Meningite Meningocócica/prevenção & controle , Camundongos , Microscopia Eletrônica de Transmissão , Neisseria meningitidis Sorogrupo B/classificação , Neisseria meningitidis Sorogrupo B/ultraestrutura , RatosRESUMO
Previous work had shown that the immunogenicity of conjugate vaccine against group C meningococci (CRM-MenC) is enhanced when it is delivered intranasally (inl) with mucosal adjuvants, such as mutants of the Escherichia coli enterotoxin (LT), and with delivery systems such as chitosan derivatives. We show, in mice, that the concomitant use of limiting doses of the fully nontoxic LTK63 mutant as a mucosal adjuvant and of the trimethyl derivative of chitosan as a delivery system allows the reduction of each of the components for the induction of antibody and bactericidal responses to CRM-MenC conjugate vaccine delivered inl at titers similar to or higher than those induced by parenteral immunization. These data could affect the design of efficacious mucosal vaccines and their safety.
Assuntos
Quitina/análogos & derivados , Quitosana , Meningite Meningocócica/imunologia , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis Sorogrupo C/imunologia , Adjuvantes Imunológicos , Administração Intranasal , Animais , Modelos Animais de Doenças , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Cholera toxin and Escherichia coli heat-labile enterotoxin are powerful mucosal adjuvants but their high toxicity hampers their use in humans. Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine.
