A cholesterol-lowering VLP vaccine that targets PCSK9. Issue 43 (26th October 2015)

• Record Type: Journal Article
• Authors: Crossey, Erin; Amar, Marcelo J.A.; Sampson, Maureen; Peabody, Julianne; Schiller, John T.; Chackerian, Bryce; Remaley, Alan T.
• Is Part Of: Vaccine. Volume 33:Issue 43(2015)
• Page Start: 5747
• Page End: 5755
• Publication Date: 2015-10-26
• Subjects: PCSK9 -- Vaccine -- Virus-like particles -- LDL Cholesterol; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2015.09.044
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: PCSK9 is a molecule that controls the metabolism of low-density lipoprotein cholesterol (LDL-C). We have generated virus-like particles based vaccines that induce high-titer antibodies against PCSK9. Vaccination of mice with PCSK9-VLPs resulted in reduced lipid levels. Macaques vaccinated with PCSK9-VLPs and coadministered statins had significant reduction in LDL-C levels. Vaccination against PCSK9 may be an alternative to monoclonal antibody-based therapies. Abstract: 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.