Nanotechnology-based cardiovascular vaccines

University Of California, San Diego, La Jolla CA

Investigators

Abstract

4Summary3 Cardiovascular disease (CVD) is the number one cause of death worldwide. The underlying cause is athero- sclerosis, which progresses to thrombosis and leads to myocardial infarction, stroke, and pulmonary embolism. The main drugs used for CVD management are statins and anti-coagulants, but they have side effects, must be taken as a lifelong therapy, and there is a lack of patient compliance in primary prevention. Immunothera- peutic approaches with atheroprotective antibodies are promising; however, the need for lifelong treatment means that passive immunotherapy is unsuitable for most patients due to the high costs per dose. To over- come these challenges, we propose a CVD vaccine that targets S100A9 or S100A9 and PCSK9 to sim- ultaneously target inflammation or cholesterol metabolism. S100A9 and its heterodimer S100A8/9 regu- late myeloid cell function and control inflammation. We have shown that knockout of S100A9 attenuates ather- osclerosis in mouse models. S100A9 deficiency is protective but has no effect on hemostasis. Given the role of S100A8/9 in CVD pathogenesis, we propose a vaccine that targets S100A9. Plant virus like particles (VLPs) derived from cowpea mosaic virus (CPMV) will display S100A9 and/or PCSK9 epitopes and deliver them to innate immune cells, activating the latter by binding to pattern recognition receptors (PRRs). Our proposal builds on extensive supporting data validating S100A9 as a target, and demonstrating the efficacy of plant vi- rus-based vaccines. We will develop S100A9-CPMV vaccine candidates and assay whether anti-S100A9 anti- bodies reduce S100A9 serum levels, inflammatory cytokines, and cholesterol, ultimately to achieve atheropro- tective effects in a mouse model of atherosclerosis. We will test efficacy in this model, as well as safety and mechanism of action (Aim 1). Because CVD is a multifactorial disease, we will develop a multi-target vaccine that targets S100A9 and cholesterol checkpoints such as PCKS9 – this is expected to increase efficacy of the approach through combined attenuation of inflammation and reduction of cholesterol (Aim 2). Finally, S100A9 is linked to cancer as well as CVD. We will therefore test the efficacy, safety, and mechanism of action of our approach in high-risk models: mice undergoing chemotherapy using healthy mice and tumor-bearing athero- sclerosis models. Synergistic effects of the S100A9 vaccine candidate will be assessed. We will also investi- gate the effects of aging and the circadian cycle on the efficacy and safety of the vaccine (Aim 3).