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Gene Vaccines[dhelix]

Indresh K. Srivastava, PhD; and Margaret A. Liu, MD
[+] Article, Author, and Disclosure Information

From Chiron Corporation, Emeryville, California; and Transgene, Strasbourg, France.

Acknowledgment: The authors thank Nelle Cronen for editorial assistance.

Potential Financial Conflicts of Interest:Employment: I. Srivistava (Chiron Corp.), M.A. Liu (Bill & Melinda Gates Foundation, Transgene, Chiron Corp., Merck & Co., Inc.); Consultancies: M.A. Liu; Honoraria: M.A. Liu (Bill & Melinda Gates Foundation); Stock ownership or options (other than mutual funds): I. Srivistava (Chiron Corp.), M.A. Liu (Merck & Co., Inc., Chiron Corp.); Grants received: I. Srivistava (Chiron Corp.); Patents received and pending: M.A. Liu (Merck & Co., Inc., Chiron Corp.).

Requests for Single Reprints: Margaret A. Liu, MD, Transgene, 11 rue de Molsheim, 67082 Strasbourg, France; e-mail, liu@transgene.fr.

Current Author Addresses: Dr. Srivastava: Chiron Corporation, 4560 Horton Street, MS 4.3, Emeryville, CA 94608.

Dr. Liu: Transgene, 11 rue de Molsheim, 67082 Strasbourg, France.

Ann Intern Med. 2003;138(7):550-559. doi:10.7326/0003-4819-138-7-200304010-00011
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Gene vaccines are a new approach to immunization and immunotherapy in which, rather than a live or inactivated organism (or a subunit thereof), one or more genes that encode proteins of the pathogen are delivered. The goal of this approach is to generate immunity against diseases for which traditional vaccines and treatments have not worked, to improve vaccines, and to treat chronic diseases. Gene vaccines make use of advances in immunology and molecular biology to more specifically tailor immune responses (cellular or humoral, or both) against selected antigens. They are still under development in research and clinical trials.

The mechanisms for inducing cellular (as opposed to humoral) responses against a particular antigen have been elucidated. Gene vaccines provide a means to generate specific cellular responses while still generating antibodies, if desired. In addition, by delivering only the genes that encode the particular proteins against which a protective or therapeutic immune response is desired, the potential limitations and risks of certain other approaches can be avoided.

This article describes the rationale for, immunologic mechanisms involved in, and design of gene vaccines under development. Preclinical and clinical studies of these vaccines are discussed for various clinical applications, focusing on infectious diseases.


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Figure 1.
Activation of cytolytic T lymphocytes.+(2)

Newly synthesized viral protein in the cytoplasm of an infected cell is degraded into peptides that are transported into the endoplasmic reticulum and then to the Golgi apparatus. Peptides bind to newly synthesized major histocompatibility complex class I molecules; the complex is then expressed on the surface of the cell where, in the presence of appropriate accessory molecules, binding to the T-cell receptor of CD8 cells can occur. This binding results in activation of the cytolytic T lymphocyte. Adapted from McDonnell and Askari , with permission from the Massachusetts Medical Society.

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Figure 2.
Heterosubtypic protection.TopsquarescirclesBottomleftright

. Survival rates among mice immunized against influenza by using a DNA vaccine encoding the nucleoprotein of influenza from the 1934 H1N1 strain ( ). When infected with a lethal dose of influenza from a strain different from the strain from which the vaccine was made, immunized mice had a higher survival rate than did control mice immunized with a control ( ). This protection was mediated by cytolytic T lymphocytes that recognized portions of the nucleoprotein. . The strains from which the DNA vaccine was made ( ) and used to infect ( ) the mice. The influenza nucleoprotein was more highly conserved than the surface proteins. Reproduced with permission from the British Society for Immunology. Donnelly JJ, Ulmer JB, Liu MA. Immunization with polynucleotides. Immunology. 1994; 2:20-6.

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Figure 3.
Mechanism of antigen presentation for generation of cytolytic T cells after DNA vaccination.APC(3)

Studies in bone marrow chimeric mice demonstrated that after immunization with plasmid DNA encoding an antigen, cytolytic T lymphocytes were activated by antigen-presenting cells ( ) that either had been directly transfected by the DNA or had received antigen via cross-priming, in which a non–antigen-presenting cell initially produces the protein encoded by the DNA vaccine, then transfers the antigen in some form to a professional antigen-presenting cell for generation of MHC class I restricted cytolytic T cells. Production of the protein antigen in non–antigen-presenting cells, such as myocytes, cannot result in direct stimulation of cytolytic T cells .

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Figure 4.
Designer gene vaccines.

Sites within a DNA plasmid can be altered to potentially increase the potency of or alter the type of immune responses induced by the DNA vaccine. BGH = bovine growth hormone; CMVintA = cytomegalovirus promoter with the intron A sequence; mRNA = messenger RNA.

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Summary for Patients

Gene Vaccines Offer a Precise and Powerful Approach to Treating Serious Infections

The summary below is from the full report titled “Gene Vaccines.” It is in the 1 April 2003 issue of Annals of Internal Medicine (volume 138, pages 550-559). The authors are I.K. Srivastava and M.A. Liu.


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