Estimating the best PCSK9 vaccine design for atherosclerosis based on mouse models: A frequentist network meta-analysis

Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) plays a crucial role in regulating the plasma levels of low-density lipoprotein cholesterol (LDL-C) and low-density lipoprotein receptor (LDLR). In contrast, vaccines have been developed to induce PCSK9-specific antibodies, which could improve dyslipidemia in atherosclerotic animal models. The aim of this study was to determine the best PCSK9 vaccine design for improving dyslipidemia and atherosclerosis in animal studies. Methods: A systematic search was performed on PubMed, Scopus, and Web of Science for studies published as of August 2024. Studies that developed a PCSK9 vaccine and reported its efficacy in mouse models were included. A random-effects model was used to conduct a frequentist network meta-analysis. The standardized mean difference (SMD) and 95% confidence interval (CI) were used as size effects. Heterogeneity in the model was judged based on the I2 values. Results: Six studies, published between 2014 and 2024, were included. There were 8 vaccine designs developed using different peptides, carriers, and delivery systems. Vaccines prepared with human PCSK9-003 epitope peptide (F-A-Q-S-I-P-W-N) with Qb virus-like particles consistently appeared to be the best vaccine design for the reduction of total cholesterol (p<0.001), LDL-C (p=0.002), and triglycerides (p=0.024). The heterogeneity was low for total cholesterol and LDL-C (I2 = 16% and 0%, respectively) and moderate for triglycerides (I2 =64%). Conclusion: Vaccines prepared from the PCSK9-003 epitope peptide (F-A-Q-S-I-P-W-N) conjugated with Qb virus-like particles are suggested to be promising for atherosclerosis treatment by reducing LDL-C and improving other lipid profiles. PROSPERO: CRD42024596892.