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In prion diseases, PrPc, a widely expressed protein, is transformed into a pathogenic form called PrPSc, which is in itself infectious. Antibodies directed against PrPc have been shown to inhibit PrPc to PrPSc conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrPderived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrPc makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad) encoding human PrP (hPrP) or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs). Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DCmediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrPc. Frequencies of PrPspecific IFNγ-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3+ T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrPSc replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses. [ABSTRACT FROM AUTHOR]

Highlights: [•] Structural capsid proteins of bluetongue virus were expressed as soluble proteins in bacteria. [•] Soluble bacterially expressed VP2 raise strong neutralising antibodies (NAbs) in Balb/c and IFNAR−/− mice. [•] Immunised IFNAR−/− are protected from lethal challenge with a homologous live BTV but not with a heterologous serotype. [•] Alternative to live or inactivated vaccines, particularly if viruses do not grow in cell culture. [•] Exclusion of antigens such as VP7 is DIVA-compatible. [Copyright &y& Elsevier]

Abstract: Prion diseases are caused by the transconformation of the host cellular prion protein PrPc into an infectious neurotoxic isoform called PrPSc. While vaccine-induced PrP-specific CD4+ T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8+ cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrPc-specific CTL was evaluated by stimulating a CD8+ T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2Db and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNγ secreting CD8+ T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8+ T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3+ T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNγ-secreting CD8+ T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8+ T cells interact with prions into the CNS during the clinical phase of the disease. [Copyright &y& Elsevier]