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1.
J Control Release ; 244(Pt A): 98-107, 2016 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-27847326

RESUMO

For nearly a century, aluminum salts have been the most widely used vaccine adjuvant formulation, and have thus established a history of safety and efficacy. Nevertheless, for extremely challenging disease targets such as tuberculosis or HIV, the adjuvant activity of aluminum salts may not be potent enough to achieve protective efficacy. Adsorption of TLR ligands to aluminum salts facilitates enhanced adjuvant activity, such as in the human papilloma virus vaccine Cervarix®. However, some TLR ligands such as TLR7/8 agonist imidazoquinolines do not efficiently adsorb to aluminum salts. The present report describes a formulation approach to solving this challenge by developing a lipid-based nanosuspension of a synthetic TLR7/8 ligand (3M-052) that facilitates adsorption to aluminum oxyhydroxide via the structural properties of the helper lipid employed. In immunized mice, the aluminum oxyhydroxide-adsorbed formulation of 3M-052 enhanced antibody and TH1-type cellular immune responses to vaccine antigens for tuberculosis and HIV.


Assuntos
Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Óxido de Alumínio/química , Imidazóis/química , Nanopartículas/química , Quinolinas/química , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Vacinas contra a AIDS/imunologia , Adsorção , Animais , Estabilidade de Medicamentos , Humanos , Imidazóis/imunologia , Imunidade Celular , Imunidade Humoral , Ligantes , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Quinolinas/imunologia , Propriedades de Superfície , Vacinas contra a Tuberculose/imunologia
2.
Vaccine ; 34(46): 5629-5635, 2016 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-27670072

RESUMO

In order for vaccines to induce efficacious immune responses against mucosally transmitted pathogens, such as HIV-1, activated lymphocytes must efficiently migrate to and enter targeted mucosal sites. We have previously shown that all-trans retinoic acid (ATRA) can be used as a vaccine adjuvant to enhance mucosal CD8+ T cell responses during vaccination and improve protection against mucosal viral challenge. However, the ATRA formulation is incompatible with most recombinant vaccines, and the teratogenic potential of ATRA at high doses limits its usage in many clinical settings. We hypothesized that increasing in vivo production of retinoic acid (RA) during vaccination with a DNA vector expressing retinaldehyde dehydrogenase 2 (RALDH2), the rate-limiting enzyme in RA biosynthesis, could similarly provide enhanced programming of mucosal homing to T cell responses while avoiding teratogenic effects. Administration of a RALDH2- expressing plasmid during immunization with a HIVgag DNA vaccine resulted in increased systemic and mucosal CD8+ T cell numbers with an increase in both effector and central memory T cells. Moreover, mice that received RALDH2 plasmid during DNA vaccination were more resistant to intravaginal challenge with a recombinant vaccinia virus expressing the same HIVgag antigen (VACVgag). Thus, RALDH2 can be used as an alternative adjuvant to ATRA during DNA vaccination leading to an increase in both systemic and mucosal T cell immunity and better protection from viral infection at mucosal sites.


Assuntos
Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos , Imunidade nas Mucosas , Retinal Desidrogenase/imunologia , Vacinas de DNA/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Família Aldeído Desidrogenase 1 , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Proteínas do Vírus da Imunodeficiência Humana/administração & dosagem , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Imunização/métodos , Memória Imunológica , Camundongos , Plasmídeos , Retinal Desidrogenase/administração & dosagem , Retinal Desidrogenase/genética , Tretinoína/imunologia , Tretinoína/metabolismo , Vacinas de DNA/administração & dosagem , Vacínia/imunologia , Vacínia/prevenção & controle , Vaccinia virus/genética
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