Immunization using ApoB-100 peptide–linked nanoparticles reduces atherosclerosis

Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAMs) as a vaccine formulation to reduce atherosclerosis in B6.129P2-Apoetm1Unc/J (ApoE-/-) mice and P210's potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge to future clinical testing. P210 provoked T cell activation and memory response in PBMCs of patients with ASCVD. Dendritic cell uptake of P210-PAM and its costaining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAMs dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model. Our data support experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.