A cholesterol-lowering VLP vaccine that targets PCSK9

• DOI: 10.1016/j.vaccine.2015.09.044
• Publication Date: 2015-09-26T15:26:32Z
• Authors: Erin Crossey; Marcelo J.A. Amar; Maureen Sampson; Julianne Peabody; John T. Schiller; Bryce Chackerian; Alan T. Remaley
• Keywords: Male; 0301 basic medicine; Drug Carriers; Mice, Inbred BALB C; 0303 health sciences; 3. Good health; 03 medical and health sciences; Cholesterol; Treatment Outcome; Immunoglobulin G; Animals; Macaca; Bacteriophages; Female; Proprotein Convertases; Vaccines, Virus-Like Particle; Phospholipids; Triglycerides; Autoantibodies

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated virus-like particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies.