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PCSK9 immunization using nanoliposomes: preventive efficacy against hypercholesterolemia and atherosclerosis
Amir Abbas Momtazi-Borojeni1,2, Mahmoud Reza Jaafari3,4, Mohammad Afshar5,6
1Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Introduction:
The aim of the study was to study a nanoliposomal anti-PCSK9 vaccine as a novel approach for cholesterol lowering via PCSK9 inhibition.
Material And Methods:
An immunogenic peptide construct termed immunogenic fused PCSK9-tetanus (IFPT) was displayed on the surface of liposome nanoparticles (L-IFPT) and mixed into alum adjuvant (L-IFPTA+). The manufactured vaccine formulations IFPT, L-IFPT, L-IFPTA+, IFPTA+, and free nanoliposomes were subcutaneously injected four times with bi-weekly intervals in C57BL/6 mice on a severe atherogenic protocol.
Results:
Among the formulations, L-IFPTA+ vaccine was found to elicit the highest IgG response against PCSK9 peptide. The induced PCSK9 antibodies inhibited PCSK9-LDLR interaction through binding to PCSK9 in vaccinated mice. Liver low-density lipoprotein receptor (LDLR) protein was increased in vaccinated mice. L-IFPTA+, L-IFPT and IFPTA+ vaccines reduced total cholesterol by up to -38.13 ±3.8% (p = 0.006), -23 ±4.1% (p = 0.027) and -19.12 ±3% (p = 0.038), and low-density lipoprotein cholesterol (LDL-C) by up to -57 ±7.7% (p = 0.0003), -41.67 ±4.2% (p = 0.03) and -36.11 ±5% (p = 0.02) in hypercholesterolemic mice, respectively, versus control mice after 8 weeks. Long-term assessment indicated that the vaccine formulations could stimulate a long-lasting humoral immune response against PCSK9 peptide, which was associated with a marked reduction of total cholesterol in L-IFPTA+, L-IFPT and IFPTA+ vaccine groups by up to -82.5 ±7.3% (p = 0.002), -70.54 ±6.2% (p = 0.013) and -72.02 ±8.7% (p = 0.004), respectively, and LDL-C by up to -88.14 ±5.6% (p = 0.002), -55.92 ±8.3% (p = 0.003) and 54.81 ±9.3% (p = 0.003), respectively, versus the pre-vaccination time point adjusted to the control group. Anti-inflammatory Th2 cells and IL-4 cytokine were considerably increased in splenocytes of vaccinated mice.
Conclusions:
L-IFPTA+ vaccine can induce long-lasting, functional and safe PCSK9-specific antibodies in hypercholesterolemic C57BL/6 mice, providing a long-term protective impact on dyslipidemia and atherosclerosis.
Insights
A novel nanoliposomal anti-PCSK9 vaccine (L-IFPTA+) effectively lowers cholesterol by inhibiting PCSK9. This vaccine induces a long-lasting immune response, offering a promising new approach for managing dyslipidemia and atherosclerosis.
Area of Science:
- Immunology
- Cardiovascular Science
- Nanotechnology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism.
- Inhibiting PCSK9 is a validated strategy for lowering low-density lipoprotein cholesterol (LDL-C).
- Novel vaccine-based approaches are being explored for sustained PCSK9 inhibition.
Purpose of the Study:
- To develop and evaluate a nanoliposomal vaccine targeting PCSK9 for cholesterol reduction.
- To assess the immunogenicity and efficacy of the nanoliposomal anti-PCSK9 vaccine in a mouse model of hypercholesterolemia.
Main Methods:
- An immunogenic peptide construct (IFPT) was displayed on nanoliposomes (L-IFPT) and formulated with alum adjuvant (L-IFPTA+).
- Vaccine formulations were administered to C57BL/6 mice on an atherogenic diet via subcutaneous injection.
- Humoral immune response, PCSK9-LDLR interaction, lipid levels, and immune cell profiles were analyzed.
Main Results:
- The L-IFPTA+ vaccine induced a robust IgG response against PCSK9, inhibiting PCSK9-LDLR binding and increasing liver LDLR expression.
- Vaccination significantly reduced total cholesterol and LDL-C levels in hypercholesterolemic mice.
- Long-term studies demonstrated sustained reductions in cholesterol and LDL-C, accompanied by an increase in Th2 cells and IL-4.
Conclusions:
- The nanoliposomal anti-PCSK9 vaccine (L-IFPTA+) is effective in inducing long-lasting, functional, and safe PCSK9-specific antibodies.
- This vaccine approach shows potential for long-term management of dyslipidemia and atherosclerosis.
- The study highlights a promising new therapeutic strategy for hypercholesterolemia.
