Fig. 3

Developmental trajectory of peptide vaccines. Upper panel: Early clinical peptide vaccine formulations combining minimal CD8 ⁺ T-cell epitopes with adjuvants such as incomplete Freund’s adjuvant (IFA), creating an antigen “depot” at the injection site. However, this leads to antigen presentation by nonprofessional APCs, causing sustained chronic inflammation at the injection site. Antigen-specific T cells accumulate at the injection site and undergo tolerance and dysfunction. Middle panel: Many current clinical trials use synthetic long peptides (SLPs) mixed with Toll-like receptor (TLR) agonists, such as polyICLC. SLPs promote antigen presentation by professional APCs and may contain CD4 ⁺ T-cell epitopes, which help recruit CD4⁺ T cells to assist in CD8 ⁺ T-cell priming. This improves T-cell priming and effector T-cell generation. However, owing to the small size of TLR agonists and SLPs, most of the injected reagents leak into the circulation, with limited antigen and adjuvant uptake by APCs. Additionally, some TLR agonists can induce systemic proinflammatory responses, resulting in toxicity. Lower panel: New-generation peptide vaccines use particulate delivery systems for antigens and adjuvants, which improve lymphoid tissue targeting. Antigens and adjuvants can be designed to self-assemble into nanometer-scale complexes or be incorporated into lipid-based nanoparticles, which are preferentially taken up by APCs. This design allows for the efficient codelivery of antigens and adjuvants, reducing systemic inflammatory responses and inducing robust T-cell responses. However, large-scale production and quality control of lipid nanoparticle-based vaccines remain significant challenges. Another strategy involves conjugating peptides or adjuvants to moieties that bind albumin, which increases APC uptake and enhances T-cell responses