Opportunities for an atherosclerosis vaccine: From mice to humans

Abstract

Atherosclerosis, the major underlying cause of cardiovascular diseases (CVD), is the number one killer globally. The disease pathogenesis involves a complex interplay between metabolic and immune components. Although lipid-lowering drugs such as statins curb the risks associated with CVD, significant residual inflammatory risk remains. Substantial evidence from experimental models and clinical studies has established the role of inflammation and immune effector mechanisms in the pathogenesis of atherosclerosis. Several stages of the disease are affected by host-mediated antigen-specific adaptive immune responses that play either protective or proatherogenic roles. Therefore, strategies to boost an anti-atherogenic humoral and T regulatory cell response are emerging as preventative or therapeutic strategies to lowering inflammatory residual risks. Vaccination holds promise as an efficient, durable and relatively inexpensive approach to induce protective adaptive immunity in atherosclerotic patients. In this review, we discuss the status and opportunities for a human atherosclerosis vaccine. We describe (1) some of the immunomodulatory therapeutic interventions tested in atherosclerosis (2) the immune targets identified in pre-clinical and clinical investigations (3) immunization strategies evaluated in animal models (4) past and ongoing clinical trials to examine the safety and efficacy of human atherosclerosis vaccines and (5) strategies to improve and optimize vaccination in humans (antigen selection, formulation, dose and delivery).

Keywords: Antigen-specific; Atherosclerosis; Immunomodulation; Peptide-based vaccine; Tregs.

Figure 1.. Approaches to atherosclerosis vaccines.

A: Antibody-based vaccines may target PCSK9, CETP or other proteins. The antigenic protein is engineered, possibly using a carrier protein (tan). MHC-II-restricted T cell epitopes induce a CD4 T cell response that, in the presence of IL-6 and IL-27, can result in follicular helper TFH cells, characterized by the transcription factor Bcl6 (orange). In germinal centres, TFH cells provide help to B cells, induce antibody isotype switch from IgM to IgG and support the maturation of B cells to long-lived IgG-secreting plasma cells (green). Without T cell help, B cells can mature into IgM-producing plasma cells (tan). B: Self-reactive Tregs can be targeted when self- peptides are administered through an appropriate route and formulated in a suitable adjuvant. After vaccination, antigen-specific peptides are presented to naïve self-reactive T cells through MHC class II on APCs. This results in activation of antigen-specific Tregs. Activated Tregs suppress effector T cells by cell contact-dependent mechanisms and by secreting anti-inflammatory cytokines, such as IL-10, IL-35, and TGFβ. ApoB: apolipoprotein B, APC: antigen-presenting cell, T_FH: T follicular cell, Treg: regulatory T cell, Teff: T effector cell, MHC: major histocompatibility complex, TCR: T cell receptor.

Figure 2.. Overview of vaccine design development.

The triangle illustrates the stages required for the development of effective atheroprotective vaccines – the technologies (left, mauve), pre-clinical studies (right, green), antigen discovery (center, yellow) and vaccine formulation, toxicology and clinical studies (top, blue).