PROJECT SUMMARY Over 30% of the adult population of the United States has elevated levels of low-density lipoprotein cholesterol (LDL-C), a condition that is correlated with an increased risk of coronary heart disease and stroke. Lifestyle modifications and treatment with statins can be sufficient for the treatment of mildly elevated LDL-C, but a substantial percentage of patients on statins fail to meet recommended LDL-C goals. Thus, new approaches are needed to control LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a molecule that modulates expression of the LDL receptor (LDL-R). Naturally occurring mutations that reduce the activity of PCSK9 are associated with decreased LDL-C levels and reduced risk of cardiovascular disease. More recently, it has been shown in clinical trials that PCSK9-targeted monoclonal antibodies (mAbs) can dramatically reduce LDL-C levels. The goal of this proposal is develop an active vaccination strategy to target PCSK9, as an alternative to mAb therapy. To do this we will use a virus-like particle (VLP) nanoparticle platform, which we have used previously to elicit high-titer antibody responses against PCSK9 and other self- antigen targets. In Aim 1 we will engineer VLP-based vaccines targeting different epitopes in PCSK9, and compare their immunogenicity and ability to reduce lipid levels in mice. In Aim 2 we will test candidate vaccine in hypercholesterolemic and atherosclerotic mouse models. In Aim 3 we will assess the immunogenicity and functionality of our lead PCSK9-VLP vaccine in non-human primates, and test its compatibility with statins. The long-term goal of this research is to generate effective vaccines that target human PCSK9 and reduce LDL-C, as a novel vaccine-based therapeutic treatment for heart disease.