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Journal of Virology, August 2001, p. 7330-7338, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7330-7338.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Delivery of Multiple Epitopes by Recombinant Detoxified Adenylate Cyclase of Bordetella pertussis Induces Protective Antiviral Immunity

Catherine Fayolle,1 Adriana Osickova,2 Radim Osicka,2 Thomas Henry,1 Marie-Jésus Rojas,1 Marie-Françoise Saron,3 Peter Sebo,2 and Claude Leclerc1,*

Unité de Biologie des Régulations Immunitaires1 and Unité d'Histopathologie,3 Institut Pasteur, Paris, France, and Cell and Molecular Microbiology Division, Institute of Microbiology, Academy of Sciences, 142 20 Prague, Czech Republic2

Received 20 December 2000/Accepted 15 May 2001

CyaA, the adenylate cyclase toxin from Bordetella pertussis, can deliver its N-terminal catalytic domain into the cytosol of a large number of eukaryotic cells and particularly into professional antigen-presenting cells. We have previously identified within the primary structure of CyaA several permissive sites at which insertion of peptides does not alter the ability of the toxin to enter cells. This property has been exploited to design recombinant CyaA toxoids capable of delivering major histocompatibility complex (MHC) class I-restricted CD8+ T-cell epitopes into antigen-presenting cells and to induce specific CD8+ cytotoxic T-lymphocyte (CTL) responses in vivo. Here we have explored the capacity of the CyaA vector carrying several different CD8+ T-cell epitopes to prime multiple CTL responses. The model vaccine consisted of a polyepitope made of three CTL epitopes from lymphocytic choriomeningitis virus (LCMV), the V3 region of human immunodeficiency virus gp120, and chicken ovalbumin, inserted at three different sites of the catalytic domain of genetically detoxified CyaA. Each of these epitopes was processed on delivery by CyaA and presented in vitro to specific T-cell hybridomas. Immunization of mice by CyaA toxoids carrying the polyepitope lead to the induction of specific CTL responses for each of the three epitopes, as well as to protection against a lethal viral challenge. Moreover, mice primed against the vector by mock CyaA or a recombinant toxoid were still able to develop strong CTL responses after subsequent immunization with a recombinant CyaA carrying a foreign CD8+ CTL epitope. These results highlight the potency of the adenylate cyclase vector for induction of protective CTL responses with multiple specificity and/or broad MHC restriction.

* Corresponding author. Mailing address: Unité de Biologie des Régulations Immunitaires, Institut Pasteur, 25 rue du docteur Roux, 75724 Paris Cedex 15, France. Phone: 33-1 45.68.86.18. Fax: 33-1 45.68.85.40. E-mail: cleclerc{at}pasteur.fr.

Journal of Virology, August 2001, p. 7330-7338, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7330-7338.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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