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Introduction: Elevated levels of serum LDL-cholesterol (LDL-C) and triglycerides have independently been found to confer increased risk of early cardiovascular disease (CVD). Naturally occurring loss-of-function mutations in two host proteins that are involved in lipid metabolism, Proprotein convertase subtilisin/kexin type 9 (PSCK9) and Apolipoprotein C-III (ApoC3), have been associated with low serum lipids and reduced rates of CVD without any evident medical complications. We generated vaccines targeting PCSK9 and ApoC3 using a flexible virus-like particle (VLP)-based vaccine platform technology. Display of antigens at high valency on the surface of VLPs is an effective technique for enhancing the immunogenicity of antigens, even self-antigens such as PSCK9 and ApoC3. In preclinical studies, we demonstrated that vaccination against PSCK9 lowers serum lipids in mice and non-human primates and vaccination against ApoC3 lowers serum triglyceride levels in mice.
Methods: Peptides derived from PCSK9 or ApoC3 were displayed on bacteriophage VLPs. Animals were immunized with VLPs and antibodies against PCSK9 or ApoC3 and plasma lipid levels were measured. In macaques, we assessed the effectiveness of vaccination in conjunction with statin therapy to evaluate synergistic effects.
Results: Vaccines targeting PCSK9 and ApoC3 induced high titer antibody responses against the targets. Mice immunized against PCSK9 had significantly lower total cholesterol (28% reduction) and triglycerides (51% reduction) in comparison to controls. Immunized macaques that also received a statin had 30-40% decrease in LDL-C, whereas LDL-C levels decreased only 5% in macaques that only received a statin. Mice immunized against ApoC3 had 30-40% reduction in triglyceride levels relative to pre-vaccination levels.
Discussion: These data demonstrate that host-immunity to PCSK9 or ApoC3 and concomitant reduction in serum lipid levels can be achieved using VLP-based vaccines. A vaccine-based approach may be a compelling alternative to monoclonal-based therapeutics.
Poster Hall, Hall C
Saturday, March 18, 2017, 9:45 a.m.-10:30 a.m.
Session Title: Updates on Risk Factors for Cardiovascular Disease
Abstract Category: 32. Prevention: Clinical
Presentation Number: 1187-054
- 2017 American College of Cardiology Foundation