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Related Experiment Video

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Engineering chimeric PCSK9 for a vaccine against atherosclerosis.

Špela Malenšek1,2, Duško Lainšček1,3, Hana Esih1,2

  • 1Department of Synthetic Biology and Immunology, National Institute of Chemistry, 1000 Ljubljana, Slovenia.

Molecular Therapy. Methods & Clinical Development
|August 18, 2025
PubMed
Summary

A novel chimeric vaccine targeting proprotein convertase 9 (PCSK9) effectively reduces cholesterol and atherosclerosis in mice. This approach overcomes immune tolerance, offering a promising long-term strategy for cardiovascular disease prevention.

Keywords:
ApoE−/− micePCSK9 vaccineT-cell cytotoxicityatherosclerosisautologous vaccinehypercholesterolemiaplasmid vaccineprotein design

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Area of Science:

  • Immunology
  • Cardiovascular Science
  • Vaccine Development

Background:

  • Cardiovascular diseases, particularly atherosclerosis, are a leading global cause of mortality.
  • Lowering serum low-density lipoprotein cholesterol (LDL-C) is crucial for reducing cardiovascular risk.
  • Targeting proprotein convertase 9 (PCSK9) is an effective strategy, with current methods including genome editing and monoclonal antibodies.

Purpose of the Study:

  • To develop a novel vaccine strategy against PCSK9 to overcome challenges of immunogenicity and B cell tolerance.
  • To create a chimeric PCSK9 vaccine that elicits a strong humoral immune response while minimizing T cell reactivity against self-antigens.
  • To evaluate the long-term efficacy of this chimeric vaccine in an atherosclerosis mouse model.

Main Methods:

  • Design and development of a chimeric PCSK9 construct maintaining surface epitopes but lacking natural T cell epitopes.
  • Vaccination of mice with the chimeric PCSK9 construct.
  • Assessment of humoral immunity (PCSK9-specific antibodies) and T cell reactivity.
  • Evaluation of therapeutic effects in an established atherosclerosis mouse model, measuring circulating PCSK9, cholesterol levels, and atherosclerotic burden in the aorta.

Main Results:

  • The chimeric PCSK9 vaccine successfully elicited PCSK9-specific antibodies, comparable to human vaccines, with reduced T cell reactivity.
  • Vaccination led to sustained reduction in circulating PCSK9 and cholesterol levels for over 20 weeks in the atherosclerosis model.
  • A significant decrease in atherosclerotic disease burden within the aorta was observed, demonstrating therapeutic improvement.

Conclusions:

  • A rationally designed chimeric PCSK9 vaccine can overcome immune tolerance and generate a potent humoral immune response.
  • This vaccine strategy offers a promising, long-lasting therapeutic approach for atherosclerosis by targeting endogenous PCSK9.
  • The study provides proof-of-concept for designing vaccines against self-antigens for treating chronic diseases.