Researchers at Peking University have developed a peptide vaccine targeting PCSK9 that produced sustained antibody responses for up to 24 weeks and reduced LDL cholesterol by up to 29 percent in hypercholesterolaemic mice. The findings were published in the journal Life Metabolism and provide proof…
Scientists at Peking University have engineered a peptide vaccine that targets proprotein convertase subtilisin/kexin type 9, commonly known as PCSK9. This protein plays a central role in managing low-density lipoprotein cholesterol, or LDL-C, which is often referred to as bad cholesterol. The research team, led by Professor Ruiping Xiao, designed the vaccine using a structure-guided approach, selecting a specific PCSK9 B-cell epitope and combining it with a heterologous T-helper epitope to stimulate a sustained immune response. Their findings appear in the journal Life Metabolism.
Atherosclerotic cardiovascular disease, abbreviated as ASCVD, remains one of the leading causes of death worldwide. Elevated LDL-C is a major modifiable risk factor for this condition, and PCSK9 has become an attractive therapeutic target because it regulates the recycling of LDL receptors in the liver, thereby influencing circulating cholesterol levels. Currently available PCSK9-targeting treatments include monoclonal antibodies and small interfering RNA, or siRNA, therapies. These can significantly reduce LDL-C, but their high cost and the need for repeated injections have prompted researchers to search for longer-lasting alternatives.
To develop the vaccine, the Peking University team performed structural analysis of PCSK9-antibody complexes obtained from the Protein Data Bank, combined with AlphaFold3 modelling. This allowed them to identify conserved regions of the protein most likely to trigger an effective antibody response. From this analysis, they created three peptide vaccine candidates. One construct, designated PVC3, produced the strongest PCSK9-specific antibody response when formulated with CpG and alum adjuvants.
In mouse studies, PVC3 generated anti-PCSK9 antibodies that remained detectable for up to 24 weeks. Similar antibody responses were also observed in guinea pigs and rhesus macaques. The vaccine was then evaluated in two mouse models of hypercholesterolaemia. In one model, vaccination prevented the sharp rise in LDL-C and total cholesterol that normally follows induction of disease, and it also reduced fat accumulation in the liver. In ApoE-deficient mice, which naturally develop high cholesterol and atherosclerotic plaques, PVC3 reduced LDL-C levels by 29 percent after four weeks and by 20 percent after 14 weeks, compared with untreated controls. Additionally, the vaccine reduced the size of aortic lesions and decreased the proportion of necrotic tissue within arterial plaques, indicating a reduction in overall atherosclerotic burden.
Safety assessments conducted in mice found no evidence of systemic toxicity or significant tissue abnormalities. Researchers also detected no T-cell response to the PCSK9 B-cell epitope alone, supporting what they described as a favourable preclinical safety profile. Results in non-human primates were more measured. Although healthy rhesus macaques developed strong anti-PCSK9 antibody responses and showed no signs of liver, kidney, or autoimmune toxicity during the study, the vaccine did not significantly change LDL-C, total cholesterol, HDL-C, or triglyceride levels compared with controls. The researchers suggest this may reflect differences between healthy animals and those with lipid disorders, highlighting the need for further testing in dyslipidaemic non-human primate models.
While these findings provide proof of concept for an active vaccine against PCSK9, the authors stress that additional research is required before any potential clinical application. Future work will focus on optimising the vaccine, investigating its mechanism of action, and evaluating its effectiveness in larger animal models with abnormal cholesterol levels. As a preclinical study, the research does not demonstrate efficacy or safety in humans. However, it offers an important step towards the development of long-lasting PCSK9-targeted vaccines that could provide a more accessible approach to reducing the risk of atherosclerotic cardiovascular disease.
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