Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination

Chiara Nembrini, Armando Stano, Karen Y. Dane, Marie Ballester, André J. Van Der Vlies, Benjamin J. Marsland, Melody A. Swartz, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

The ability of vaccines to induce memory cytotoxic T-cell responses in the lung is crucial in stemming and treating pulmonary diseases caused by viruses and bacteria. However, most approaches to subunit vaccines produce primarily humoral and only to a lesser extent cellular immune responses. We developed a nanoparticle (NP)-based carrier that, upon delivery to the lung, specifically targets pulmonary dendritic cells, thus enhancing antigen uptake and transport to the draining lymph node; antigen coupling via a disulfide link promotes highly efficient cross-presentation after uptake, inducing potent protective mucosal and systemic CD8 + T-cell immunity. Pulmonary immunization with NP-conjugated ovalbumin (NP-ova) with CpG induced a threefold enhancement of splenic antigen-specific CD8 + T cells displaying increased CD107a expression and IFN-γ production compared with immunization with soluble (i.e., unconjugated) ova with CpG. This enhanced response was accompanied by a potent Th17 cytokine profile in CD4 + T cells. After 50 d, NP-ova and CpG also led to substantial enhancements in memory CD8 + T-cell effector functions. Importantly, pulmonary vaccination with NP-ova and CpG induced as much as 10-fold increased frequencies of antigen-specific effector CD8 + T cells to the lung and completely protected mice from morbidity following influenza-ova infection. Here, we highlight recruitment to the lung of a long-lasting pool of protective effector memory cytotoxic T-cells by our disulfide-linked antigen-conjugated NP formulation. These results suggest the reduction-reversible NP system is a highly promising platform for vaccines specifically targeting intracellular pathogens infecting the lung.

Original languageEnglish (US)
Pages (from-to)E989-E997
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number44
DOIs
StatePublished - Nov 1 2011

Keywords

  • Adjuvant
  • Antigen conjugation
  • Antigen trafficking
  • Prophylactic
  • T lymphocyte

ASJC Scopus subject areas

  • General

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    Nembrini, C., Stano, A., Dane, K. Y., Ballester, M., Van Der Vlies, A. J., Marsland, B. J., Swartz, M. A., & Hubbell, J. A. (2011). Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination. Proceedings of the National Academy of Sciences of the United States of America, 108(44), E989-E997. https://doi.org/10.1073/pnas.1104264108