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A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees

Abstract

Three percent of the world's population is chronically infected with the hepatitis C virus (HCV) and at risk of developing liver cancer. Effective cellular immune responses are deemed essential for spontaneous resolution of acute hepatitis C and long-term protection. Here we describe a new T-cell HCV genetic vaccine capable of protecting chimpanzees from acute hepatitis induced by challenge with heterologous virus. Suppression of acute viremia in vaccinated chimpanzees occurred as a result of massive expansion of peripheral and intrahepatic HCV-specific CD8+ T lymphocytes that cross-reacted with vaccine and virus epitopes. These findings show that it is possible to elicit effective immunity against heterologous HCV strains by stimulating only the cellular arm of the immune system, and suggest a path for new immunotherapy against highly variable human pathogens like HCV, HIV or malaria, which can evade humoral responses.

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Figure 1: Time course and magnitude of HCV-specific CD8+ and CD4+ T-cell responses by IFN-γ ICS during immunization and after challenge.
Figure 2: HCV-specific cytotoxic T lymphocyte (CTL) activity in vaccinated chimpanzees.
Figure 3: Intrahepatic HCV-specific CD8+ T-cell response in vaccinated chimpanzees.
Figure 4: Magnitude of intrahepatic HCV specific CD8+ T-cell response in vaccinated and control chimpanzees.
Figure 5: Kinetics of HCV RNA, alanine aminotransferase (ALT), gamma-glutamil transpeptidase (GGT) and HCV-specific antibody response in vaccinated and control chimpanzees.

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Acknowledgements

We acknowledge R.H. Purcell and J. Bukh for provision of the H77 viral inoculum; J. Burns and L. Kierstead for assistance with the intrahepatic lymphocyte cultures; P. Sczerba for clinical chemistry; C.M. Walker and R.H. Purcell for discussion; J. Fontenot, D. Hasselschwert, N. Smith and the staff at the New Iberia Research Center for the care of chimpanzees and samples and M. Emili for artwork. We also thank C.M. Rice, D. Mathis, J.W. Mattaj and G. Migliaccio for critical reading of the manuscript. This paper is dedicated to the memory of Elisabetta Sporeno, who will be missed by all her colleagues. This work was supported in part by Ministero dell'Istruzione, dell'Università e della Ricerca-MIUR (project “Vaccino per l'epatite C”, Legge n. 488/1992).

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Correspondence to Alfredo Nicosia.

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Supplementary information

Supplementary Fig. 1

Representative IFN-γ ICS with PBMCs from two vaccinated chimpanzees. (PDF 166 kb)

Supplementary Fig. 2

HCV-specific T-cell proliferation by BrdU assay in vaccinated chimpanzees. (PDF 27 kb)

Supplementary Fig. 3

Kinetics of HCV RNA, amino acid substitution and epitope recognition for chimpanzee 96A022. (PDF 108 kb)

Supplementary Table 1 (PDF 22 kb)

Supplementary Methods (PDF 47 kb)

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Folgori, A., Capone, S., Ruggeri, L. et al. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 12, 190–197 (2006). https://doi.org/10.1038/nm1353

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