Editors' ChoiceVaccine Development

The Skeleton Key for Intracellular Pathogens: Nanoparticles and Pulmonary Vaccination

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Science Translational Medicine  16 Nov 2011:
Vol. 3, Issue 109, pp. 109ec186
DOI: 10.1126/scitranslmed.3003416

Since 1796, when Edward Jenner inoculated a boy with pus from a cowpox pustule and rendered him immune to smallpox, investigators have sought better vaccines to ward off pathogens. Whereas many vaccines generate strong antibody responses, the ability to produce robust cellular immune responses has been challenging because soluble (free) antigens do not readily enter the pathway for recognition by cytotoxic T lymphocytes (CTLs, also known as CD8+ T cells). These lymphocytes are key for immunity to intracellular pathogens such as influenza and Mycobacterium tuberculosis; they recognize and kill infected cells and alert other cells. Now, with the goal of inducing CTLs that protect against influenza, Nembrini and colleagues demonstrate in a mouse model that pulmonary vaccination with nanoparticle (NP)–conjugated antigen broadly elicits cellular immune responses.

To generate CTL responses, an antigen must be taken up by antigen-presenting cells, processed, and presented to T cells via a major histocompatibility complex (MHC) molecule. To access this pathway, the researchers developed a NP-based platform in which an antigen of interest is coupled to a 30-nm particle by a disulfide link. After the antigen-NP is engulfed by the presenting cell, the antigen is unlinked in the reductive environment of the endosome and loaded onto the MHC molecule. In this study, NP-linked ovalbumin (a model antigen) was delivered to the lung with an immunostimulatory adjuvant.

First, the investigators confirmed that the vaccine was preferentially taken up by dendritic cells, which are an important type of antigen-presenting cell. Mice vaccinated with NP-linked ovalbumin had greater frequencies of antigen-specific CD8+ T cells in the blood and spleen than did those vaccinated with unlinked ovalbumin; the splenic T cells displayed effector function when stimulated ex vivo. Mice evaluated 50 days after NP-ovalbumin vaccination demonstrated elevated frequencies of antigen-specific effector memory CD8+ T cells, which provide immunity in tissues such as the lung. Last, NP-ovalbumin–vaccinated mice, challenged with a recombinant strain of influenza that expresses an ovalbumin epitope, showed a 10-fold increased frequency of antigen-specific CD8+ T cells in the lung and complete protection against morbidity resulting from infection with recombinant influenza.

Although this vaccine platform has only been validated in an animal model to date, Nambrini et al. have demonstrated an innovative method for vaccine delivery, with strong translational potential for targeting other intracellular organisms.

C. Nembrini et al., Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination. Proc. Natl. Acad. Sci. U.S.A. 1 November 2011 (10.1073/pnas.1104264108). [Abstract]

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