Efectos sobre la fertilidad del cerdo de dos candidatos vacunales recombinantes basados en la GnRH

This paper describes for the first time the generation of the K88ab-GnRH hybrid fimbriae, the fusion of N. meningitidis P64k protein (P64k-GnRH), and its evaluation as vaccine candidates to control fertility in mammals. Twenty hybrid male pigs were randomly distributed in four groups: placebos and immunized with K88ab-GnRH, P64k-GnRH and a GnRH analogue (GnRHm1), linked to a tetanus toxoid (TT) T-helper epitope (positive control), respectively. The pigs were immunized at 9-10 weeks of age, using a two-dose scheme, and were sacrificed sixteen weeks later. K88ab-GnRH, P64k-GnRH, and GnRHm1-TT induced higher, similar, and lower testosterone levels in the serum, compared to the placebo, respectively. In the K88ab-GnRH group, the pigs underwent a reduction in testicle size and weight (P < 0.01), and the weight of epididymes compared to the placebo; none of them was able to ejaculate. In the P64k-GnRH group, the pigs had a reduction in testicle weight (P < 0.05), and only one of them was able to ejaculate. The testicles of the pigs immunized with K88ab-GnRH and P64k-GnRH showed structural and functional damage; spermatogenesis was also affected. The accessory sexual glands of the P64k-GnRH group were normal, in contrast to K88ab-GnRH, where interstitial fibrosis was observed. The damage caused by K88ab-GnRH and P64k-GnRH in the target organs evaluated were in all cases lower than the affectations caused by the GnRHm1-TT peptide.En este trabajo se describe, por primera vez, la obtención de la fimbria híbrida K88ab-GnRH, la fusión de la GnRH a la proteína P64k de N. meningitidis (P64k-GnRH) y su evaluación como candidatos vacunales para controlar la fertilidad en mamíferos. Veinte cerdos machos híbridos fueron asignados al azar a cuatro grupos: placebo e inmunizados con K88ab-GnRH, P64k-GnRH y con un péptido análogo de GnRH (GnRHm1), unido a un epítopo T cooperador del toxoide tetánico (TT) (control positivo), respectivamente. Los cerdos se inmunizaron con 9-10 semanas de edad, en un esquema de 2 dosis y se sacrificaron 16 semanas después. K88ab-GnRH, P64k-GnRH y GnRHm1-TT indujeron niveles de testosterona en suero, mayor, similar y menor, comparados con el placebo, respectivamente. En el grupo K88ab-GnRH los cerdos disminuyeron (P < 0,01) el largo y peso de los testículos y el peso de los epidídimos, comparado con el placebo y ninguno llegó a eyacular. En el grupo P64k-GnRH los cerdos disminuyeron el peso de los testículos (P < 0,05), y sólo uno llegó a eyacular. Los testículos de los cerdos inmunizados con K88ab-GnRH y P64k-GnRH mostraron daños estructurales, funcionales y afectación de la espermatogénesis. Las glándulas sexuales accesorias del grupo P64k-GnRH estaban normales a diferencia de K88ab-GnRH, en las que se observó fibrosis intersticial. Los daños provocados por K88ab-GnRH y P64k-GnRH en los órganos diana evaluados, resultaron inferiores en todos los casos, a las afectaciones que generó el péptido GnRHm1-TT

Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin‑releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non‑vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19‑31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti‑GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH‑based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer.The authors would like to thank the Union for International Cancer Control (Geneva, Switzerland; grant no., YY1/09/008/2009) for the fellowship received to support the present study. The authors would also like to thank the researchers at the Trev and Joyce Deeley Research Centre (Victoria, Canada), British Columbia Cancer Research Centre (Vancouver, Canada) and University of Victoria (Victoria, Canada), particularly Professor Brad Nelson, Dr Julian Lum and Dr John Webb, for purchasing the mice and providing the laboratory facilities required to conduct the present study.http://www.spandidos-publications.com/or/2017-02-27am2016Mammal Research Institut

Effects of Two GnRH-based Recombinant Vaccine Candidates on Pig Fertility

This paper describes for the first time the generation of the K88ab-GnRH hybrid fimbria, the fusion of N. meningitidis P64k protein (P64k-GnRH), and its evaluation as vaccine candidates to control fertility in mammals. Twenty hybrid male pigs were randomly distributed in four groups: placebos and immunized with K88ab-GnRH, P64k-GnRH and a GnRH analogue (GnRHm1), linked to a tetanus toxoid (TT) T-helper epitope (positive control), respectively. The pigs were immunized at 9-10 weeks of age, using a two-dose scheme, and were sacrificed sixteen weeks later. K88ab-GnRH, P64k-GnRH, and GnRHm1-TT induced higher, similar, and lower testosterone levels in the serum, compared to the placebo, respectively. In the K88ab-GnRH group, the pigs underwent a reduction in testicle size and weight (P < 0.01), and a reduction in the weight of epididymes compared to the placebo; none of them was able to ejaculate. In the P64k-GnRH group, the pigs had a reduction in testicle weight (P < 0.05), and only one of them was able to ejaculate. The testicles of the pigs immunized with K88ab-GnRH and P64k-GnRH showed structural and functional damage; spermatogenesis was also affected. The accessory sexual glands of the P64k-GnRH group were normal, in contrast to K88ab-GnRH, where interstitial fibrosis was observed. The damage caused by K88ab-GnRH and P64k-GnRH in the target organs evaluated were in all cases lower than the affectations caused by the GnRHm1-TT peptide