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Infection and Immunity, November 2004, p. 6418-6425, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6418-6425.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Listeria monocytogenes-Based Antibiotic Resistance Gene-Free Antigen Delivery System Applicable to Other Bacterial Vectors and DNA Vaccines

Thorsten Verch, Zhen-Kun Pan, and Yvonne Paterson*

Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania

Received 13 May 2004/ Returned for modification 22 June 2004/ Accepted 2 August 2004

Plasmids represent a powerful tool to rapidly introduce genes into bacteria and help them reach high expression levels. In vaccine development, with live vaccine vectors, this allows greater flexibility and the ability to induce larger antigen amounts through multiple gene copies. However, plasmid retention often requires antibiotic resistance markers, the presence of which has been discouraged in clinical applications by the Food and Drug Administration. Therefore, we developed a Listeria monocytogenes-Escherichia coli shuttle plasmid that is retained by complementation of D-alanine racemase-deficient mutant strains both in vitro and in vivo. Our technology potentially allows the production of antibiotic resistance marker-free DNA vaccines as well as bacterial vaccine vectors devoid of engineered antibiotic resistances. As a proof of concept, we applied the D-alanine racemase complementation system to our Listeria cancer vaccine platform. With a transplantable tumor model, we compared the efficacy of the new Listeria vector to that of an established vector containing a conventional plasmid carrying a tumor-specific antigen. Both vaccine vector systems resulted in long-term regression of established tumors, with no significant difference between them. Thus, the Listeria vaccine vector presented here potentially complies with Food and Drug Administration regulations and could be developed further for clinical use.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania, 323 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 898-3461. Fax: (215) 573-4666. E-mail: Yvonne{at}mail.med.upenn.edu.

Editor: F. C. Fang

Infection and Immunity, November 2004, p. 6418-6425, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6418-6425.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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