RESUMEN
The current anthrax vaccine imparts protective immunity by generating a humoral immune response against a single antigen, the PA exotoxin subunit. While this response neutralizes the two anthrax exotoxins and protects the recipient from toxin-related mortality, the recipient is not protected from spore germination, infection, and/or bacteremia. Moreover, protective immunity against PA must be generated via a lengthy injection schedule and maintained by a yearly booster. In an effort to improve upon the current vaccine formulation, we screened six of seven known virulence factors encoded by Bacillus anthracis epigenetic elements pXO1 and pXO2 as well as the major surface proteins EA1 and SAP. Screening was carried out in conjunction with a plasmid-based technology known for its ability to generate type 1 and type 2 T-helper responses. Long-term high level antibody titers were generated against the products of eag (EA1), sap (SAP), and the capA capsule synthesis subunit in vivo. Further analysis of PA- and EA1-vaccinated mice demonstrated antigen-specific type 1 helper responses including IFN-gamma secretion and lysis of EA1- or PA-loaded macrophages; further, an EA1 T-cell epitope was identified. The results demonstrate that anthrax antigens other than PA might be suitable for the generation of durable immune responses against anthrax.
Asunto(s)
Vacunas contra el Carbunco/inmunología , Carbunco/inmunología , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Toxinas Bacterianas/inmunología , Exotoxinas/inmunología , Plásmidos/inmunología , Células TH1/inmunología , Células Th2/inmunología , Vacunación , Animales , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/genética , Epigénesis Genética , Exotoxinas/genética , Femenino , Interferón gamma/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Subunidades de Proteína/genética , Subunidades de Proteína/inmunología , Especificidad de la Especie , Vacunas Sintéticas/inmunologíaRESUMEN
We describe the use of retrogen plasmid-based vaccine technology to break tolerance and to generate a robust, dose-dependent antibody response against the self cancer antigen, survivin. We further demonstrate that this phenomenon is due to the incorporation of the survivin antigen into the retrogen system rather than to some peculiarity unique to survivin. In contrast to other genetic immunization methods designed to produce antibody responses, the retrogen system results in a broad range of antibody isotypes, indicative of both a Th-1 and a Th-2 CD4+ response. Additional evidence of a Th-1 response is demonstrated by tumor growth inhibition in a mouse model of colon cancer metastasis. We speculate that this cost-effective technology could one day bolster or even supplant the use of monoclonal antibodies in the targeting of cell surface cancer antigens.