Structure-based programming of lymph-node targeting in molecular vaccines

An amphiphile vaccine consisting of a peptide antigen or adjuvant cargo linked to a lipophilic tail is shown to have improved potency and safety in mice by targeting the lymph nodes. Subunit vaccines that target lymph nodes Vaccines based on purified peptides, proteins or polysaccharides, together with molecular adjuvants designed to boost the immune response, are potentially safer and easier to manufacture than the alternatives. Generally however, such 'subunit' vaccines elicit weaker immune responses than those using live attenuated pathogens. Darrell Irvine and colleagues demonstrate a simple chemical strategy for the molecular targeting of subunit vaccines to lymphoid organs following parenteral injection. They designed an amphiphilic vaccine consisting of a peptide antigen or adjuvant cargo linked to a lipophilic tail. The resulting CpG-DNA/peptide amph-vaccine showed substantially increased anti-tumour efficacy with reduced toxicity compared to the parent compounds. In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes 1 , 2 . Here we translate this ‘albumin hitchhiking’ approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.