Exploiting albumin as a mucosal vaccine chaperone for robust generation of lung-resident memory T cells

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Science Immunology  19 Mar 2021:
Vol. 6, Issue 57, eabd8003
DOI: 10.1126/sciimmunol.abd8003

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Chaperoned vaccine primes pulmonary TRMs

Lung-dwelling tissue-resident memory T cells (TRMs) protect the lower respiratory system after exposure to previously encountered viral pathogens. Using a previously established amphiphilic vaccine formulation that binds avidly to albumin, Rakhra et al. investigated whether coordinated delivery to the lung mucosa of peptide antigen adjuvanted with a CpG oligonucleotide improved the generation of vaccine antigen-specific CD8+ pulmonary TRMs in mice compared with subcutaneous delivery. Intratracheal vaccine administration of the amphiphilic vaccine resulted in a substantial increase in cytokine-producing CD8+ TRMs in the lung and enhanced T cell–mediated protection against both virus and tumor cell challenges. These findings lay the groundwork for further development of amphiphilic mucosal vaccines delivered via an aerosol for induction of robust TRM-based immunity to viruses that threaten the human respiratory health.


Tissue-resident memory T cells (TRMs) can profoundly enhance mucosal immunity, but parameters governing TRM induction by vaccination remain poorly understood. Here, we describe an approach exploiting natural albumin transport across the airway epithelium to enhance mucosal TRM generation by vaccination. Pulmonary immunization with albumin-binding amphiphile conjugates of peptide antigens and CpG adjuvant (amph-vaccines) increased vaccine accumulation in the lung and mediastinal lymph nodes (MLNs). Amph-vaccines prolonged antigen presentation in MLNs over 2 weeks, leading to 25-fold increased lung-resident T cell responses over traditional immunization and enhanced protection from viral or tumor challenge. Mimicking such prolonged exposure through repeated administration of soluble vaccine revealed that persistence of both antigen and adjuvant was critical for optimal TRM induction, mediated through T cell priming in MLNs after prime, and directly in the lung tissue after boost. Thus, vaccine persistence strongly promotes TRM induction, and amph-conjugates may provide a practical approach to achieve such kinetics in mucosal vaccines.

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