Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

Abstract

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation.

Keywords: apolipoprotein B100; atherosclerosis; autoantigens; cardiovascular disease; cholesteryl ester transfer protein; immunization; low-density lipoprotein cholesterol; proprotein convertase subtilisin/kexin type 9; vaccination.

Figure 1

Schematic representation of adaptive immune cell involvement in the progression of atherosclerosis. In early atherosclerosis stages, Tregs accumulate in arterial walls, interacting with APCs like dendritic cells and macrophages, releasing anti-inflammatory cytokines (IL-10, TGF-β) to maintain immune tolerance and reduce inflammation. Circulating T cells also migrate to plaques, attracted by chemotactic signals (CCL5, CXCL16) from platelets and immune cells. As the disease progresses, APCs present atherosclerosis-related antigens to naïve T cells in regional lymph nodes, driving T cell polarization into pro-inflammatory Th cells and CTLs. These activated T cells return to plaques, exacerbating local inflammation. In advanced stages, Th1 cells dominate, secreting IFN-γ and TNF-α to promote plaque growth and instability. B cells modulate disease progression: B1 cells secrete protective IgM antibodies, while B2 cells release IgG antibodies, contributing to atherosclerosis progression. Overall, the adaptive immune response shifts from protective to pathogenic, driving plaque progression and vascular damage [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. Abbreviations: APCs: antigen-presenting cells; B1 cells: B cell subtype 1; B2 cells: B cell subtype 2; CCL5: chemokine (C-C motif) ligand 5; CTLs: cytotoxic T lymphocytes; CXCL16: chemokine (C-X-C motif) ligand 16; DCs: dendritic cells; IFN-γ: interferon gamma; IgG: immunoglobulin G; IgM: immunoglobulin M; IL-10: interleukin-10; Mfs: macrophages; MHC: major histocompatibility complex; T cells: T lymphocytes; TGF-β: transforming growth factor beta; Th cells: T helper cells; TNF: tumor necrosis factor; Tregs: regulatory T cells. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/x00b831, assessed on 24 November 2024.

Figure 2

Experimental vaccine models targeting lipids to reduce inflammation in atherosclerosis. This figure depicts four distinct experimental vaccine strategies designed to mitigate the inflammation and progression of atherosclerosis by modulating immune responses. (A) OxLDL-C-pulsed dendritic cell transfer: LDLr−/− mice were treated with mature DCs pulsed with oxLDL-C before atherosclerosis induction via Western-type diet feeding. This approach promoted oxLDL-C-specific T cells and IgG production, diminishing foam cell recruitment and inflammation [84]. (B) PAM nanoparticle vaccine: PAM nanoparticles were used to deliver the p210 peptide in ApoE−/− mice models. This vaccine suppressed CD4⁺ and CD8⁺ effector T cells and shifted macrophage phenotypes, collectively reducing atherosclerotic burden and showing translational potential [99]. (C) Nanoliposome-based PCSK9-TP vaccine: A nanoliposome vaccine conjugated with PCSK9 and tetanus-derived peptides (IFPT peptide) was tested in atherosclerotic mice. The vaccine stimulated anti-inflammatory CD4⁺ Th2 cells and IL-4 secretion, promoting atheroprotective immune responses [121]. (D) Oral TT/CETP vaccine in rabbits: A combined oral vaccine targeting TT and CETP upregulated anti-inflammatory cytokines IL-10 and TGF-β while suppressing pro-inflammatory cytokines TNF-α and IFN-γ [133]. Abbreviations: ApoE: apolipoprotein E; CETP: cholesteryl ester transfer protein; DC: dendritic cell; IFN-γ: interferon-gamma; IL: interleukin; LDLr: low-density lipoprotein receptor; oxLDL-C: oxidized low-density lipoprotein cholesterol; PAM: poly(amino acid)-based; PCSK9: proprotein convertase subtilisin/kexin type 9; TGF-β: transforming growth factor-beta; Th2: T-helper type 2; TNF-α: tumor necrosis factor-alpha; TP: tetanus peptide; TT: tetanus toxoid. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/f60u021, assessed on 24 November 2024.

Figure 3

Primary vaccination targets in atherosclerosis. Abbreviations: ADAMTS-7: A disintegrin and metalloproteinase with thrombospondin motifs 7; ANGII: angiotensin II; ANGPTL3: angiopoietin-like protein 3; ApoB100: apolipoprotein B100; ApoCIII: apolipoprotein CIII; CETP: cholesteryl ester transfer protein; HSP: heat shock protein; IgG: immunoglobulin G; LDL-C: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/f98n410, assessed on 24 November 2024.