Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide. Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable driver of ASCVD, and PCSK9 has become an important therapeutic target because it regulates hepatic LDL receptor recycling and circulating LDL-C levels. Although PCSK9-targeting monoclonal antibodies and siRNA therapies can substantially lower LDL-C, their cost and need for repeated administration have motivated efforts to develop longer-lasting and more accessible approaches.
In a new preclinical study published in Life Metabolism, Hongliang Sun, Zhuang Li, Xinli Hu and colleagues, led by Prof. Ruiping Xiao at Peking University, report a structure-guided peptide vaccine candidate targeting PCSK9. The study asked whether a precisely selected PCSK9 B-cell epitope, coupled to a heterologous T-helper epitope, could induce sustained anti-PCSK9 antibodies and reduce hypercholesterolemia and atherosclerosis in animal models.
The researchers designed the vaccine by analyzing PCSK9−antibody complex structures from the Protein Data Bank and AlphaFold3-guided modeling to identify conserved, antibody-facing epitope regions of PCSK9 (Figure 1). Among three candidate constructs, one peptide vaccine, termed PVC3 and formulated with CpG plus alum adjuvant, generated the strongest PCSK9-specific antibody response.
In mice, PVC3 induced durable anti-PCSK9 antibody responses, with antibody titers maintained for up to 24 weeks. The vaccine also induced antibody responses in guinea pigs and rhesus macaques. In the mouse safety assessments, the investigators observed no overt systemic toxicity, no major histopathological abnormalities in examined organs, and no detectable T-cell response to the PCSK9 B-cell epitope alone, supporting a favorable preclinical safety profile.
The functional effects were tested in two hypercholesterolemic mouse models. In an AAV-hPCSK9D374Y-induced model, vaccination inhibited the rise in LDL-C and total cholesterol after AAV challenge and reduced hepatic lipid accumulation. In ApoE-deficient mice, a model that develops spontaneous hypercholesterolemia and atherosclerotic lesions, PVC3 attenuated LDL-C elevation by 29% at week 4 and 20% at week 14 relative to controls. It also reduced aortic lesion area and decreased the necrotic-core fraction in aortic-root plaques, indicating reduced atherosclerotic burden in this mouse model.
The non-human primate findings were more cautious. In healthy rhesus macaques, PVC3 induced robust anti-PCSK9 antibodies and showed no apparent liver, kidney, or autoimmune safety signals in the assays performed, but it did not significantly alter LDL-C, total cholesterol, HDL-C, or triglyceride levels compared with controls. This result suggests that lipid-lowering efficacy may depend on disease context and will need further testing in dyslipidemic larger-animal models.
Overall, the study provides a structure-guided proof of concept for active immunization against PCSK9. By combining rational epitope selection with a peptide vaccine format, the work identifies PVC3 as a candidate that can induce sustained anti-PCSK9 immunity and reduce lipid and atherosclerotic endpoints in mouse models. At the same time, the authors emphasize that further optimization is required, including evaluation in dyslipidemic non-human primate models and mechanistic assays of LDL receptor protection, circulating free PCSK9, and PCSK9-neutralizing activity. As a preclinical study, these findings do not establish efficacy or safety in humans, but they outline a development path for PCSK9-targeted vaccines as potential long-term options for ASCVD risk management.

DOI：10.1093/lifemeta/loag013/8694677