Vaccination Strategies for Atherosclerosis: A Narrative Review of PCSK9, ApoB-100, Modified LDL, and Heat-Shock Protein Targets

Active immunization against atherosclerosis-related self-antigens is intended to produce sustained lipid lowering or antigen-specific immune regulation. This narrative review examines PCSK9, ApoB-100, modified LDL, heat-shock proteins, and CETP, with particular attention to the distinction between experimental efficacy and clinical benefit. Intervention reports are discussed separately from observational associations, passive antibody treatment, and mechanistic hypotheses. Most of the evidence comes from animal models. PCSK9 vaccines have elicited functional antibodies in mice and nonhuman primates, but lipid effects vary across formulations and studies. A randomized Phase I trial in 72 healthy adults demonstrated the immunogenicity of AT04A and AT06A; exploratory, post hoc analyses supported modest LDL-cholesterol lowering with AT04A. That trial did not evaluate cardiovascular events and cannot establish long-term safety. ApoB-100, modified-LDL, and heat-shock-protein immunization have shown model-dependent effects on atherosclerosis, without established clinical efficacy. The proposed clearance of vaccine-generated modified-LDL immune complexes through the asialoglycoprotein receptor remains unproven. Evidence provenance, physiological target functions, and limits of extrapolation are considered throughout. The available evidence supports further target-specific investigation, but not clinical use or the assumption that immunogenicity predicts cardiovascular protection.