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Enhancement of DNA Vaccine Potency by Linkage of Antigen Gene to an HSP70 Gene¹

Departments of Oncology [C-H. C., D. M. P., T-C. W.], Pathology [T-L. W., C-F. H., Y. Y., T-C. W.], Obstetrics and Gynecology [T-C. W.], and Molecular Microbiology and Immunology [T-C. W.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287; Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02139 [R. A. Y.]; Department of Biology [R. A. Y.] and Center for Cancer Research [R. A. Y.], Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan [C-H. C.]

Nucleic acid vaccines represent an attractive approach to generating antigen-specific immunity because of their stability and simplicity of delivery. However, there is still a need to increase the potency of DNA vaccines. Using human papillomavirus type 16 E7 as a model antigen, we evaluated the effect of linkage to Mycobacterium tuberculosis heat shock protein 70 (HSP70) on the potency of antigen-specific immunity generated by naked DNA vaccines. We found that vaccines containing E7-HSP70 fusion genes increased the frequency of E7-specific CD8+ T cells by at least 30-fold relative to vaccines containing the wild-type E7 gene. More importantly, this fusion converted a less effective vaccine into one with significant potency against established E7-expressing tumors. Surprisingly, E7-HSP70 fusion vaccines exclusively targeted CD8+ T cells; immunological and antitumor effects were completely CD4-independent. These results indicate that fusion of HSP70 to an antigen gene may greatly enhance the potency of DNA vaccines via CD8-dependent pathways.

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