Immunogenicity and control of pathogenic SIV challenge in macaques vaccinated with a novel HIV prototype vaccine

Orateur : Yahia CHEBLOUNE (PAVAL Lab, NanoBio2, UJF, Grenoble)

The highly active anti-retroviral therapy (HAART) has dramatically reduced the death associated with AIDS and prolonged substantially the lifespan of HIV-1-infected individuals. Despite this spectacular scientific and medical advance HIV-1 epidemic is still growing and the number of individuals living with HIV-1 is increasing. Therefore the race for a safe and effective HIV-1 vaccine that protects human from HIV-1 infection and/or HIV-1-associated pathogenesis is still ongoing. The old strategies of vaccine development have failed to generate such a vaccine. We generated a lentivector DNA vaccine whose genome was derived from a highly pathogenic chimeric SHIV virus. This lentivector was designed to be delivered as DNA in a single immunization protocol and to express all the proteins in in vivo transfected cells. Part of these proteins are used directly as immunogens to stimulate the adaptive immune responses and the other part to assemble as viral particles that undergo a single cycle of replication in target cells in absence of integration of the vaccine DNA genome into that of the host. We demonstrated that this lentivector induces potent immune responses in the mouse models (Moussa et al., 2015). These results enabled our enthusiasm to test the efficacy of this novel prototype vaccine in the non-human primate model. We immunized 6 cynomolgus macaques and kept 6 others as controls and examine longitudinally the immune responses over one year and half prior to challenge all the animals with a pathogenic SIVmac virus. Like in the mouse model, we found that the single immunization with our lentivector DNA induced T cell as well as humoral immune responses as early as one week post-immunization and these responses persisted during all the immunogenicity time study (80 weeks). While no neutralizing Ab was detected at any time of the study, Gag and Env binding antibodies were persistently detected in nearly all immunized animals. Antigen specific CD4+ and CD8+ T cells against all expressed proteins by the vaccine were detected and characterized longitudinally during the 80 weeks post immunization. Both effector and various stages of memory T cells mainly against Gag and Nef antigens were detected, evaluated and characterized (Arrode-Brusés et al., 2014). CD4+ and CD8+ T cells contained not only central memory type of cells but also highly proliferative precursor cells (PHPC) that were characterized by a special assay and finally there are some evidence of T stem cell memory cells specific of our vaccine. At week 81 post-immunization all macaques were injected with a highly pathogenic replication-competent virus as a heterologous challenge. We found that all vaccinated macaques, although not protected against the virus acquisition, efficiently and rapidly controled their virus to barely detectable low level viremia. This control was persistent while most of the control animals developed persistent productive replication of the challenge virus. Altogether, these results provide the first demonstration that a vaccination with a lentivector DNA vaccine alone is capable at inducing vaccine-specific persistent memory T cells that correlate with the protection against the pathogenic virus. This protection is not associated with neutralizing antibodies since, in the immunogenicity phase as well as during more than 20 weeks post-challenge, no neutralizing antibody activity was detected either against the vaccine or against the challenge viruses.

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