Abstract
Chronic wasting disease (CWD) is a fatal neurodegenerative disease that affects cervids in North America and now Europe. No effective measures are available to control CWD. We hypothesized that active vaccination with homologous and aggregation-prone recombinant prion protein (PrP) could overcome self-tolerance and induce autoantibody production against the cellular isoform of PrP (PrPC), which would be protective against CWD infection from peripheral routes. Five groups of transgenic mice expressing elk PrP (TgElk) were vaccinated with either the adjuvant CpG alone or one of four recombinant PrP immunogens: deer dimer (Ddi); deer monomer (Dmo); mouse dimer (Mdi); and mouse monomer (Mmo). Mice were then challenged intraperitoneally with elk CWD prions. All vaccinated mice developed ELISA-detectable antibody titers against PrP. Importantly, all four vaccinated groups survived longer than the control group, with the Mmo-immunized group exhibiting 60% prolongation of mean survival time compared with the control group (183 versus 114 days post-inoculation). We tested for prion infection in brain and spleen of all clinically sick mice. Notably, the attack rate was 100% as revealed by positive CWD signals in all tested tissues when assessed with Western blotting, real-time quaking-induced conversion, and immunohistochemistry. Our pilot study in reindeer indicated appreciable humoral immune responses to Mdi and Ddi immunogens, and the post-immune sera from the Ddi-vaccinated reindeer mitigated CWD propagation in a cell culture model (CWD-RK13). Taken together, our study provides very promising vaccine candidates against CWD, but further studies in cervids are required to investigate vaccine efficacy in the natural CWD hosts.
Highlights
Chronic wasting disease (CWD) is a fatal neurodegenerative disease that affects cervids in North America and Europe
We used multimeric and aggregationprone recombinant prion protein (PrP), as our lab had already provided a proof-of-principle that this approach can induce a robust humoral immunity against PrPC, both mouse and cervid [21, 28, 29], and protect some immunized mice against scrapie challenge [23]. We tested these recombinant immunogens for their potential to induce immune responses in transgenic mice expressing elk PrP (TgElk) and in reindeer, and we studied the vaccination effect in TgElk mice against CWD challenge
We used TgElk mice as a mouse model for CWD. These mice are homozygous for elk PrP, with a 2.5-fold higher expression of PrPC in the brain compared with WT mice [33]
Summary
PrPSc, scrapie isoform of the prion protein; PrPC, cellular isoform of the prion protein; CpG, 5Ј-cytosine-phosphate-guanine3Ј; CWD, chronic wasting disease; PrP, recombinant prion protein; Tg, transgenic; Ddi, deer dimer; Dmo, deer monomer; Mdi, mouse dimer; Mmo, mouse monomer; PK, proteinase K; BH, brain homogenate; SH, spleen homogenate; HRP, horseradish peroxidase; NaPTA, sodium phosphotungstic acid; IHC, immunohistochemistry; RT-QuIC, real-time– quaking-induced conversion assay; H&E, hematoxylin and eosin; dpi, days post-inoculation. A recent study described a potential CWD vaccine consisting of a nonreplicating human adenovirus that expresses a truncated rabies glycoprotein G fused with postulated disease-specific epitopes, named the rigid loop region (hAd5:tgG-RL) This vaccine was successful in inducing humoral immune responses, both systemic and mucosal, upon oral immunization of white-tailed deer [32]. Our objective in this study was to develop a CWD vaccine that overcomes self-tolerance and induces self-antibodies against cervid prion protein to impede peripheral prion infection For this purpose, we used multimeric and aggregationprone recombinant PrPs (both mouse and deer), as our lab had already provided a proof-of-principle that this approach can induce a robust humoral immunity against PrPC, both mouse and cervid [21, 28, 29], and protect some immunized mice against scrapie challenge [23]. We tested these recombinant immunogens for their potential to induce immune responses in transgenic mice expressing elk PrP (TgElk) and in reindeer, and we studied the vaccination effect in TgElk mice against CWD challenge
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