Modifying antigens or adjuvants with a lipophilic albumin-binding tail promotes lymph node accumulation.

  • Major finding: Modifying antigens or adjuvants with a lipophilic albumin-binding tail promotes lymph node accumulation.

  • Clinical relevance: Antitumor immunity was enhanced by lymph node targeting of tumor antigens.

  • Impact: Lymph node–targeted optimized vaccines may increase T-cell responses and reduce systemic inflammation.

Molecular vaccines consisting of an adjuvant or antigen can initiate stronger antitumor responses when they accumulate in secondary lymphoid organs, but targeted delivery of these vaccines remains a challenge. Because dyes that bind serum albumin are particularly effective as lymph node tracers in patients with cancer, Liu and colleagues hypothesized that compounds with strong albumin binding ability could be exploited as an effective delivery system for molecular vaccines. Given that albumin is a fatty acid transporter, the authors assayed the ability of peptide antigens or oligonucleotide vaccine adjuvants linked to a variety of lipophilic tails for their ability to bind albumin in fetal bovine serum. Diacyl lipid-conjugated cargo bound the most albumin, trafficked from a subcutaneous injection site, and accumulated in lymph nodes at a higher volume and for a longer period of time than soluble cargo and cargo delivered by common vaccine vehicles. Moreover, cargo modified in this manner associated with macrophages and dendritic cells in the lymph node and not in distal tissues, which might reduce tolerance, and significantly enhanced antigen-specific CD8+ T-cell responses and antibody responses with minimal systemic inflammation compared with soluble adjuvants and peptide antigens. To improve the potential broad use of this vaccine therapy, the authors developed a more soluble compound by conjugating a short poly(ethylene glycol) spacer between the albumin-binding domain and cargo peptide or adjuvant. Vaccination of tumor-bearing mice with a modified adjuvant and modified peptide derived from a tumor-specific antigen successfully reduced tumor growth in association with efficient lymph node accumulation and increased CD8+ T-cell expansion and activation. Although it is necessary to assess the autoimmune consequences of this approach, these data indicate that increased lymph node delivery of adjuvants and antigens by conjugation to albumin-binding domains may improve vaccine efficacy and safety.

Liu H, Moynihan KD, Zheng Y, Szeto GL, Li A, Huang B, et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 2014 Feb 16 [Epub ahead of print].