Engineering chimeric PCSK9 for a vaccine against atherosclerosis.

Cardiovascular diseases, especially atherosclerosis, are the main cause of death in the whole world. The risk can be reduced by lowering the serum low-density lipoprotein cholesterol by targeting proprotein convertase 9 (PCSK9) through genome editing or neutralization by monoclonal antibodies. Vaccination against PCSK9 represents an alternative with potentially long-lasting efficacy, but must overcome the challenge of immunogenicity against the endogenous protein, which can also elicit lower antibody response due to B cell tolerance. In contrast to the previously reported weakly immunogenic PCSK9 peptides, we have developed a designed chimeric PCSK9 that maintains the surface epitopes and elicits a B cell immune response with PCSK9-specific antibodies, comparable to human-based vaccines, but eliminates the natural protein T cell epitopes and impairs self-antigen-mediated T cell cytotoxicity upon vaccination. We demonstrated that vaccination with chimera-based vaccines generates humoral immunity with a decreased T cell reactivity. In an atherosclerosis mouse model, the effect persisted over 20 weeks, as evidenced by a reduction in the circulating PCSK9 and cholesterol and a lower atherosclerotic disease burden in the aorta. This demonstrates a therapeutic improvement in atherosclerosis in an animal model and the proof-of-concept for the rational design of vaccines against endogenous proteins.