Engineering chimeric PCSK9 for a vaccine against atherosclerosis

Cardiovascular diseases, especially atherosclerosis, are the major cause of death in the modern era. In most cases, amelioration is achieved by decreasing the concentration of LDL cholesterol in blood, using statins or monoclonal antibodies targeting PCSK9, which are highly efficient, but are costly and requires bimonthly administration. Vaccination against PCSK9 represents an attractive alternative with potentially long-lasting efficiency, but has to overcome the challenge of autoimmune reactivity against an endogenous protein to prevent healthy tissue damage. We developed an autologous chimeric vaccine against PCSK9, which triggers a B cell immune response to produce neutralizing antibodies but avoids induction of self antigen mediated T cell cytotoxicity. We demonstrated in atherosclerosis murine model that vaccination generated an adequate humoral immune response with the effect persistent over 24°weeks, observed in lower circulating PCSK9, lower cholesterol and reduced atherosclerotic disease burden in the aortas. This is a proof of concept study for a therapeutic amelioration of atherosclerosis, which also provides a perspective on the rational design of a vaccine against endogenous proteins.