A new study from Ralph Steinmans's laboratory indicates that targeting DNA vaccines to dendritic cells can substantially boost their immunogenicity. The approach involves fusing the antigen of interest (in this study, HIV-1 Gag) with a single chain antibody targeting the dendritic cell receptor DEC205 (also called CD205). Combined with delivery via electroporation, the researchers report that the approach boosted vaccine potency 100-fold in a mouse challenge system. Steinman recently won a Lasker award for his work on dendritic cells; writing about his work in Nature Medicine, he noted sadly that most of the research he conducted (and on which the Lasker award was based) would probably not have been funded if the NIH grant payline had been at the low level it is today:
"The vision of Mary Lasker was to urge the government to sponsor basic research to understand and treat disease. Her vision remains critical to meet ongoing challenges to the scientific enterprise. One challenge is our declining ability to support independent scientists. I probably could not have carried out my research under the current funding environment for basic research, because many of my grant applications only ranked in the top quartile, whereas funding by the US National Institutes of Health is currently only sufficient for less than 10% of basic proposals."
In another recent paper, Jinyan Liu and colleagues show that electroporation alone results in a 77-fold enhancement in the recruitment of dendritic cells to the site of DNA vaccine inoculation, likely accounting for the significant enhancements in immunogenicity that have been reported using this delivery method. The question mark hanging over viral vectors due to the Merck HIV vaccine results is likely to refocus attention on these and other strategies for improving DNA vaccine immunogenicity.
J Clin Invest. 2008 Apr 1;118(4):1427-1436. (free full text access)
Nchinda G, Kuroiwa J, Oks M, Trumpfheller C, Park CG, Huang Y, Hannaman D, Schlesinger SJ, Mizenina O, Nussenzweig MC, Uberla K, Steinman RM.
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York, USA. Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany. The Aaron Diamond AIDS Research Center, New York, New York, USA. Ichor Medical Systems, San Diego, California, USA. Laboratory of Molecular Immunology, Chris Browne Center for Immunology, The Rockefeller University, New York, New York, USA.
DNA vaccines promote an immune response by providing antigen-encoding DNA to the recipient, but the efficacy of such vaccines needs improving. Many approaches have considerable potential but currently induce relatively weak immune responses despite multiple high doses of DNA vaccine. Here, we asked whether targeting vaccine antigens to DCs would increase the immunity and protection that result from DNA vaccines. To determine this, we generated a DNA vaccine encoding a fusion protein comprised of the vaccine antigen and a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Following vaccination of mice, the vaccine antigen was expressed selectively by DCs, which were required for the increased efficacy of MHC class I and MHC class II antigen presentation relative to a control scFv DNA vaccine. In addition, a DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein induced 10-fold higher antibody levels and increased numbers of IFN-gamma-producing CD4(+) and CD8(+) T cells. After a single i.m. injection of the DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein, mice were protected from an airway challenge with a recombinant vaccinia virus expressing the HIV gag p41, even with 1% of the dose of nontargeted DNA vaccine. The efficacy of DNA vaccines therefore may be enhanced by inclusion of sequences such as single-chain antibodies to target the antigen to DCs.
J Virol. 2008 Mar 19 [Epub ahead of print]
Liu J, Kjeken R, Mathiesen I, Barouch DH.
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Inovio Biomedical, San Diego, CA 92121.
In vivo electroporation (EP) has been shown to augment the immunogenicity of plasmid DNA vaccines, but its mechanism of action has not been fully characterized. In this study, we show that in vivo EP augmented cellular and humoral immune responses to an HIV-1 Env DNA vaccine in mice and allowed a 10-fold reduction in vaccine dose. This enhancement was durable for over 6 months, and re-exposure to antigen resulted in anamnestic effector and central memory CD8+ T lymphocyte responses. Interestingly, in vivo EP also recruited large mixed cellular inflammatory infiltrates to the site of inoculation. These infiltrates contained 45-fold increased numbers of macrophages and 77-fold increased numbers of dendritic cells as well as 2- to 6-fold increased numbers of B and T lymphocytes as compared with infiltrates following DNA vaccination alone. These data suggest that recruiting inflammatory cells including APCs to the site of antigen production substantially improves the immunogenicity of DNA vaccines. Combining in vivo EP with plasmid chemokine adjuvants that similarly recruited antigen-presenting cells (APCs) to the injection site, however, did not result in synergy.
Comments