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Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL

Gene Therapy volume 11, pages 1617–1626 (2004)Cite this article

Abstract

Recombinant adenoviral vectors (AdV) have been used experimentally as vaccines to present antigenic transgenes in vivo. However, administration of first-generation vectors (FG-AdV) is often limited by their induction of antiviral immunity. To address this limitation, helper-dependent vectors (HD-AdV) were developed that lack viral coding regions. While the administration of HD-AdV results in long-term gene expression in vivo, their utility as immunogens has never been examined. Direct vaccination with 108 blue-forming units (BFU) of HD-AdV injected into C57BL/6 mice lead to superior transgene-specific CTL and antibody responses when compared to the same amount of a FG-AdV. The antibody responses to viral antigens were high in response to both the vectors. As a mechanism to reduce viral exposure, dendritic cells (DC) were transduced with HD-AdV in vitro and then used as a cell-based vaccine. DC transduced with HD-AdV expressed higher levels of transgene-specific mRNA and up to 1200-fold higher levels of transgene protein than did DC transduced with a FG-AdV. In addition, HD-AdV-transduced DC stimulated superior transgene-specific CTL responses when administered in vivo, an effect that was further enhanced by maturing the DC with LPS prior to administration. In contrast to direct immunization with HD-AdV, vaccination with HD-AdV-transduced DC was associated with limited antibody responses against the AdV. We conclude that HD-AdV stimulates superior transgene-specific immune responses when compared to a FG-AdV, and that immunization with a DC-based vaccine maintains this efficacy while limiting antiviral reactivity.

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Acknowledgements

Supported by grants from the Tobacco-Related Disease Research Program of California (SKB, 10KT-0086; MDR, #7RT-0040); the American Lung Association of California (SKB); the UCLA Gene Therapy Program (SMK); and the UCLA Lung Cancer SPORE (NIH/NCI 1 P50 CA090388).

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Authors and Affiliations

  1. Pulmonary & Critical Care Medicine, UCLA School of Medicine, Los Angeles, CA, USA

    A Harui, M D Roth, S M Kiertscher & S K Basak

  2. Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, Los Angeles, CA, USA

    K Mitani

  3. Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA, USA

    M D Roth, S M Kiertscher & K Mitani

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Harui, A., Roth, M., Kiertscher, S. et al. Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL. Gene Ther 11, 1617–1626 (2004). https://doi.org/10.1038/sj.gt.3302332

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