Desarrollo de vectores adenovirales genéticamente optimizados como candidatos vacunales frente al Virus de la Fiebre Aftosa
Despite the success of adenovirus vectors (Ad5) as vaccine candidates for several Foot-and-mouth Disease (FMDV) strains, reproducible and trustworthy results have been difficult to achieve for the epidemiologically relevant O1/Campos strain. In this work, we hypothesized that enhanced expression of...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
2022
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6706 https://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6706.dir/6706.PDF |
| Aporte de: |
| Sumario: | Despite the success of adenovirus vectors (Ad5) as vaccine candidates for several Foot-and-mouth Disease (FMDV) strains, reproducible and trustworthy results have been difficult to achieve for the epidemiologically relevant O1/Campos strain. In this work, we hypothesized that enhanced expression of FMDV capsid proteins and their self-association into virus-like particles (VLP) would improve the efficacy of an Ad5-O1/C vaccine. We generated the Ad5[PVP2]INV which contains an optimized cassette inserted in a leftward orientation relative to the Ad5 genome and the substitutions S93F/Y98F within VP2, predicted to stabilize FMDV particles. Cells infected with Ad5[PVP2]INV showed an ?14-fold increase of FMDV protein expression than the unmodified Ad5[P]. FMDV-like particles expressed by Ad5[PVP2]INV, which displayed similar thermostability to naturally-generated empty particles, were observed by electron microscopy. Infection of mouse dendritic cells with Ad5[PVP2]INV induced a higher upregulation of CD80 and CD86 than Ad5[P], in a dose-dependent kinetics. Inoculation of Ad5[PVP2]INV promoted higher total and neutralizing O1/C antibodies titers, as compared to Ad5[P], and protected 94 % of mice from homologous challenge. In conclusion, increased protein expression and stabilization of in situ generated VLP improved the performance of an Ad5-O1/Campos vaccine in a well-supported model, providing optimistic expectations to be tested in target animals. |
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