Design and delivery of a cryptic PrPC epitope for induction of PrPSc-specific antibody responses

Transmissible spongiform encephalopathies (TSEs) depend on misfolding of a normal cellular protein (PrPC) to an infectious conformation (PrPSc). Targeting PrPSc may represent an effective strategy for immunotherapy while avoiding consequences associated with immune responses to self-proteins. A weakly immunogenic epitope of PrPC (YYR), which induces PrPSc-specific antibodies, is used as a starting point for vaccine development. Through optimization of epitope, as well as formulation/delivery, we enhance immunogenicity while retaining PrPSc specificity. In particular, QVYYRPVDQYSNQN, presented by a leukotoxin carrier protein, emerges as a strong vaccine candidate. A vaccine representing this construct induces consistent and sustained serum PrPSc-specific IgG antibody responses following two vaccinations. Antigen specific antibodies are also present within cerebral spinal fluid and mucosal secretions. These characteristics provide a foundation for development of a TSE vaccine.