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Journal of Virology, August 2008, p. 7492-7503, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.02743-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Induction of Broad CD4+ and CD8+ T-Cell Responses and Cross- Neutralizing Antibodies against Hepatitis C Virus by Vaccination with Th1-Adjuvanted Polypeptides Followed by Defective Alphaviral Particles Expressing Envelope Glycoproteins gpE1 and gpE2 and Nonstructural Proteins 3, 4, and 5{triangledown} ,{dagger}

Yinling Lin,* Taewoo Kwon, John Polo, Yi-Fei Zhu, Stephen Coates, Kevin Crawford, Christine Dong, Mark Wininger, John Hall, Mark Selby, Doris Coit, Angelica Medina-Selby, Colin McCoin, Philip Ng, Debbie Drane, David Chien, Jang Han, Michael Vajdy, and Michael Houghton{ddagger}

Novartis Vaccine and Diagnostic, Inc., Emeryville, California 94608

Received 26 December 2007/ Accepted 19 May 2008

Broad, multispecific CD4+ and CD8+ T-cell responses to the hepatitis C virus (HCV), as well as virus-cross-neutralizing antibodies, are associated with recovery from acute infection and may also be associated in chronic HCV patients with a favorable response to antiviral treatment. In order to recapitulate all of these responses in an ideal vaccine regimen, we have explored the use of recombinant HCV polypeptides combined with various Th1-type adjuvants and replication-defective alphaviral particles encoding HCV proteins in various prime/boost modalities in BALB/c mice. Defective chimeric alphaviral particles derived from the Sindbis and Venezuelan equine encephalitis viruses encoding either the HCV envelope glycoprotein gpE1/gpE2 heterodimer (E1E2) or nonstructural proteins 3, 4, and 5 (NS345) elicited strong CD8+ T-cell responses but low CD4+ T helper responses to these HCV gene products. In contrast, recombinant E1E2 glycoproteins adjuvanted with MF59 containing a CpG oligonucleotide elicited strong CD4+ T helper responses but no CD8+ T-cell responses. A recombinant NS345 polyprotein also stimulated strong CD4+ T helper responses but no CD8+ T-cell responses when adjuvanted with Iscomatrix containing CpG. Optimal elicitation of broad CD4+ and CD8+ T-cell responses to E1E2 and NS345 was obtained by first priming with Th1-adjuvanted proteins and then boosting with chimeric, defective alphaviruses expressing these HCV genes. In addition, this prime/boost regimen resulted in the induction of anti-E1E2 antibodies capable of cross-neutralizing heterologous HCV isolates in vitro. This vaccine formulation and regimen may therefore be optimal in humans for protection against this highly heterogeneous global pathogen.

* Corresponding author. Mailing address: 4 Captain Dr. 411, Emeryville, CA 94608-2916. Phone: (510) 923-8170. Fax: (510) 923-2586. E-mail: yinlilin918{at}yahoo.com

{triangledown} Published ahead of print on 28 May 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Epiphany Biosciences Inc., 1 California St., Suite 2800, San Francisco, CA 94111.

Journal of Virology, August 2008, p. 7492-7503, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.02743-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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