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Modulation of the Immune Response Induced by Gene Electrotransfer of a Hepatitis C Virus DNA Vaccine in Nonhuman Primates

Stefania Capone^1,*, Immacolata Zampaglione^1,*, Alessandra Vitelli^*, Monica Pezzanera^*, Lisa Kierstead, Janine Burns, Lionello Ruggeri^*, Mirko Arcuri^*, Manuela Cappelletti^*, Annalisa Meola^*, Bruno Bruni Ercole^*, Rosalba Tafi^*, Claudia Santini^*, Alessandra Luzzago^*, Tong-Ming Fu, Stefano Colloca^*, Gennaro Ciliberto^*, Riccardo Cortese^*, Alfredo Nicosia^*, Elena Fattori^* and Antonella Folgori^2,*

^* Istituto di Ricerche di Biologia Molecolare, "P. Angeletti," Rome, Italy; and Merck Research Laboratories, West Point, PA 19486

Induction of multispecific, functional CD4⁺ and CD8⁺ T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4⁺ and CD8⁺ cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN- ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4⁺ T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-⁺CD8⁺ and CD4⁺ T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ S.C. and I.Z. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Antonella Folgori, Technology Department, Istituto di Ricerche di Biologia Molecolare, via Pontina Kilometer 30600, 00040 Rome, Italy. E-mail address: antonella_folgori{at}merck.com

³ Abbreviations used in this paper: HCV, hepatitis C virus; B-LCL, B lymphoblastoid cell line; CMI, cellular-mediated immunity; GET, gene electrotransfer; ICS, intracellular staining; SFC, spot-forming cell; SI, stimulation index; T, time.

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