Mejoramiento de una vacuna génica contra el Herpesvirus Bovino-1, uso de adyuvantes: Liposoma MAN?1-2MAN, CD40 ligando, MontanideTM GEL01 PR y Galectina-8
Bovine Herpesvirus type 1 (BoHV-1) has a worldwide distribution, causes various symptoms in cattle, is responsible for economic losses in the cattle industry and is recognized as an important component of the Bovine Respiratory Complex Disease (BRCD).\nAlthough inactivated and modified live virus (M...
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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_6737 https://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6737.dir/6737.PDF |
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| Sumario: | Bovine Herpesvirus type 1 (BoHV-1) has a worldwide distribution, causes various symptoms in cattle, is responsible for economic losses in the cattle industry and is recognized as an important component of the Bovine Respiratory Complex Disease (BRCD).\nAlthough inactivated and modified live virus (MVL) vaccines are currently used, there are certain disadvantages in their use. In the case of inactivated vaccines, they do not provide complete protection and are generally poor in inducers of cellular immunity, while MVL have the risk of reversion to virulence, induction of abortions in pregnant cows and re-excretion of the vaccine strain by immunosuppression of cattle. The manipulation of the virus and the costs associated with its production are important points. On the other hand, DNA vaccines allow the differenciation infected to vaccinated animals (DIVA), are easy to produce, easy to transport and allow inducing humoral and cellular immune responses against specific antigens of the virus of interest.\nIn previous works, the use of a DNA-based vaccine encoding the truncated version of BoHV-1 glycoprotein D (pCIgD) together with chemical adjuvants to enhance DNA transfection has been shown to induce good levels of humoral and cellular immunity in the murine model, and partial protection in bovines.\nTo improve protection, the aim of this work is the evaluation of pCIgD in combination with different chemical and molecular adjuvants, first in mice and then in the natural host of the infection.\nThe adjuvants used were, first, a liposome decorated with MAN?1-2MAN molecules capable of specifically targeting its cargo to dendritic cell (DC) surface receptors called DC-SIGN. Then, a plasmid encoding the CD40L sequence that would allow triggering different responses by its interaction with CD40 present on DCs and other cells. Also, Galectin-8 (Gal-8) whose binding to cell surface glyco-receptors induces multiple cellular responses such as proliferation, differentiation, cytokine secretion among others, and the inclusion of the commercial adjuvant Montanide GEL01 PR. This latter, improves DNA transfection, recruits cells to the inoculation site and maintains the immune response for a longer period of time due to its "depot" effect.\nThe results showed that the use of the different adjuvants together with the DNA vaccine increased the immune response in both animal models. In humoral immunity, significant differences were obtained when total antibody titers, isotypes and neutralizing antibodies in serum and antibodies in mucosal were analyzed. Regarding cellular immunity, there was a significant increase in the proliferative response against BoHV-1 in animals vaccinated with the adjuvants compared to the response induced in animals vaccinated with pCIgD. In addition, upregulation of CD40, MHCII and CD86 molecules on the surface of bovine dendritic cells (DCs) was observed when cells were stimulated and activated with the adjuvants of the vaccine formulations.\nWhen virus challenge was performed, bovines vaccinated with the adjuvants elicited better protection, which was evidenced by lower viral excretion and clinical symptomatology. Undoubtedly, each adjuvant contributed to enhance the vaccine response due to its different chemical and/or molecular properties.\nThese adjuvants were formulated for the first time with a DNA vaccine and the results could be useful to design and improve a vaccine for the control of Infectious Bovine Rhinotracheitis (IBR). |
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