Structure-guided PCSK9 epitope vaccine effectively lowers LDL-C and attenuates atherosclerosis in animal models

High levels of low-density lipoprotein cholesterol (LDL-C) are a primary driver of atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating LDL-C by promoting LDL-R degradation, making it a key therapeutic target. While existing monoclonal antibodies targeting PCSK9 are clinically effective, their substantial cost and requirement for frequent, repeated administration limit widespread patient access and adherence, highlighting a critical need for more scalable and convenient alternatives.

Researchers developed a peptide-based vaccine by identifying specific B-cell epitopes from PCSK9-antibody complexes, leveraging Protein Data Bank (PDB) structural data and AlphaFold3 prediction. These epitopes were then fused with a heterologous T-helper epitope. The vaccine was formulated with CpG plus alum adjuvant and administered to mice (in both prophylactic and therapeutic models), guinea pigs, and rhesus macaques. Key endpoints included assessing the induction of anti-PCSK9 antibody responses, changes in LDL-C levels, hepatic lipid accumulation, and the progression of atherosclerotic plaques. Systemic toxicity and autoimmunity were also monitored.

The novel peptide-based PCSK9 vaccine consistently induced strong and durable anti-PCSK9 antibody responses across all tested species, including mice, guinea pigs, and rhesus macaques. This robust immune activation translated into significant physiological benefits in preclinical models. In both prophylactic and therapeutic mouse models, the vaccine significantly reduced LDL-C levels. > The vaccine also effectively attenuated hepatic lipid accumulation, indicating a direct impact on liver cholesterol metabolism. Furthermore, the intervention mitigated the progression of atherosclerotic plaques, demonstrating its potential to slow the underlying disease process of ASCVD. Importantly, comprehensive evaluations in these animal models revealed no signs of systemic toxicity or autoimmunity, suggesting a favorable safety profile for this vaccine approach.