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Infection and Immunity, September 2000, p. 4877-4883, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Recombinant Mycobacterium bovis BCG Expressing Pertussis Toxin Subunit S1 Induces Protection against an Intracerebral Challenge with Live Bordetella pertussis in Mice

Ivan P. Nascimento,1,2 Waldely O. Dias,1 Rogerio P. Mazzantini,1 Eliane N. Miyaji,1 Marcia Gamberini,1 Wagner Quintilio,1 Vera C. Gebara,1 Diva F. Cardoso,3,dagger Paulo L. Ho,1 Isaias Raw,1 Nathalie Winter,4 Brigitte Gicquel,4,5 Rino Rappuoli,6 and Luciana C. C. Leite1,*

Centro de Biotecnologia,1 and Immunopatologia,3 Instituto Butantan, and Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo,2 São Paulo, São Paulo, Brazil; Laboratoire du BCG4 and Unité de Génétique Mycobactérienne,5 Institut Pasteur, Paris, France; and IRIS, Chiron SpA, Siena, Italy6

Received 10 February 2000/Returned for modification 30 March 2000/Accepted 6 June 2000

The recent development of acellular pertussis vaccines has been a significant improvement in the conventional whole-cell diphtheria-pertussis-tetanus toxoid vaccines, but high production costs will limit its widespread use in developing countries. Since Mycobacterium bovis BCG vaccination against tuberculosis is used in most developing countries, a recombinant BCG-pertussis vaccine could be a more viable alternative. We have constructed recombinant BCG (rBCG) strains expressing the genetically detoxified S1 subunit of pertussis toxin 9K/129G (S1PT) in fusion with either the beta -lactamase signal sequence or the whole beta -lactamase protein, under control of the upregulated M. fortuitum beta -lactamase promoter, pBlaF*. Expression levels were higher in the fusion with the whole beta -lactamase protein, and both were localized to the mycobacterial cell wall. The expression vectors were relatively stable in vivo, since at two months 85% of the BCG recovered from the spleens of vaccinated mice maintained kanamycin resistance. Spleen cells from rBCG-S1PT-vaccinated mice showed elevated gamma interferon (IFN-gamma ) and low interleukin-4 (IL-4) production, as well as increased proliferation, upon pertussis toxin (PT) stimulation, characterizing a strong antigen-specific Th1-dominant cellular response. The rBCG-S1PT strains induced a low humoral response against PT after 2 months. Mice immunized with rBCG-S1PT strains displayed high-level protection against an intracerebral challenge with live Bordetella pertussis, which correlated with the induction of a PT-specific cellular immune response, reinforcing the importance of cell-mediated immunity in the protection against B. pertussis infection. Our results suggest that rBCG-expressing pertussis antigens could constitute an effective, low-cost combined vaccine against tuberculosis and pertussis.

* Corresponding author. Mailing address: Centro de Biotecnologia, Instituto Butantan, Av. Vital Brasil 1500, 05503-900 São Paulo, SP, Brazil. Phone: 55-11-813-7222, ext. 2242. Fax: 55-11-815-1505. E-mail: lccleite{at}quim.iq.usp.br.

dagger Deceased December 1999.

Infection and Immunity, September 2000, p. 4877-4883, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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