RESUMO
PURPOSE: To test the safety and immunogenicity of an orally delivered avian influenza vaccine. The vaccine has a non-replicating adenovirus type 5 vector backbone which expresses hemagglutinin from avian influenza and a TLR3 ligand as an adjuvant. METHODS: Forty-two subjects were randomized into 3 groups dosed with either 1×10(10), 1×10(9), or 1×10(8) IU of the vaccine administered in capsules. Twelve subjects were vaccinated with identical capsules containing placebo. A portion of the 1×10(9) dose group were immunized a second time 4 weeks after the first immunization. The safety of the vaccine was assessed by measuring the frequency and severity of adverse events in placebo versus vaccine treated subjects. IFN-γ and granzyme B ELISpot assays were used to assess immunogenicity. RESULTS: The vaccine had a positive safety profile with no treatment emergent adverse events reported above grade 1, and with an adverse event frequency in the treated groups no greater than placebo. Antigen specific cytotoxic and IFN-γ responses were induced in a dose dependent manner and cytotoxic responses were boosted after a second vaccination. CONCLUSION: This first in man clinical trial demonstrates that an orally delivered adenovirus vectored vaccine can induce immune responses to antigen with a favorable safety profile. CLINICAL TRIAL REGISTRATION NUMBER: NCT01335347.
Assuntos
Adenoviridae/genética , Portadores de Fármacos/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Linfócitos T/imunologia , Receptor 3 Toll-Like/agonistas , Administração Oral , Adulto , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , ELISPOT , Feminino , Vetores Genéticos , Granzimas/metabolismo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/genética , Influenza Humana/prevenção & controle , Interferon gama/metabolismo , Masculino , Placebos/administração & dosagem , Receptor 3 Toll-Like/genéticaRESUMO
An oral gene-based avian influenza vaccine would allow rapid development and simplified distribution, but efficacy has previously been difficult to achieve by the oral route. This study assessed protection against avian influenza virus challenge using a chimeric adenovirus vector expressing hemagglutinin and a double-stranded RNA adjuvant. Immunized ferrets and mice were protected upon lethal challenge. Further, ferrets immunized by the peroral route induced cross-clade neutralizing antibodies, and the antibodies were selective against hemagglutinin, not the vector. Similarly, experiments in mice demonstrated selective immune responses against HA with peroral delivery and the ability to circumvent preexisting vector immunity.
Assuntos
Adenoviridae/genética , Adjuvantes Imunológicos/administração & dosagem , Portadores de Fármacos , Vetores Genéticos , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , RNA de Cadeia Dupla/administração & dosagem , Adjuvantes Imunológicos/genética , Administração Oral , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Reações Cruzadas , Modelos Animais de Doenças , Furões , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Virus da Influenza A Subtipo H5N1/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , RNA de Cadeia Dupla/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
Adenoviral vaccines delivered orally have been used for decades to prevent respiratory illness, but are now being seriously explored again as a platform technology to make vaccines against a variety of pathogens. Years of use in military populations as a preventative measure for adenoviral infection have demonstrated the safety of oral administration of adenovirus. The advantages of using this approach as a platform technology for vaccines include rapid development and distribution, as well as ease of administration. Recent discoveries may allow this platform approach to reach the clinic within a few years.
