Structure-guided design of a PCSK9 epitope vaccine with efficacy against hyperlipidemia and atherosclerosis

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating low-density lipoprotein cholesterol (LDL-C) levels and has emerged as an attractive target for atherosclerotic cardiovascular disease (ASCVD) therapy. While monoclonal antibodies targeting PCSK9 have demonstrated clinical efficacy, their high cost and need for repeated administration limit widespread use. In this study, we developed a peptide-based vaccine by identifying B-cell epitopes from PCSK9–antibody complexes using the Protein Data Bank (PDB) structural data and AlphaFold3 prediction, and fusing them with a heterologous T-helper epitope. The vaccine induced strong and durable anti-PCSK9 antibody responses in mice, guinea pigs, and rhesus macaques when formulated with the CpG plus alum adjuvant. The vaccine significantly reduced LDL-C levels and attenuated hepatic lipid accumulation in both prophylactic and therapeutic mouse models. Moreover, it mitigated the progression of atherosclerotic plaques. The vaccine also demonstrated no signs of systemic toxicity or autoimmunity in animal models. These findings indicate that the vaccine is a safe, effective, and scalable approach for controlling hypercholesterolemia and preventing ASCVD through active immunization against PCSK9.