Design and delivery of a cryptic PrP(C) epitope for induction of PrP(Sc)-specific antibody responses.

Abstract

Transmissible spongiform encephalopathies (TSEs) depend on misfolding of a normal cellular protein (PrP(C)) to an infectious conformation (PrP(Sc)). Targeting PrP(Sc) may represent an effective strategy for immunotherapy while avoiding consequences associated with immune responses to self-proteins. A weakly immunogenic epitope of PrP(C) (YYR), which induces PrP(Sc)-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 PrP(Sc) 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 PrP(Sc)-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.