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Infection and Immunity, May 2001, p. 3041-3047, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3041-3047.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Improved Immunogenicity and Protective Efficacy of
a Tuberculosis DNA Vaccine Encoding Ag85 by Protein
Boosting
Audrey
Tanghe,1
Sushila
D'Souza,1
Valérie
Rosseels,1
Olivier
Denis,1
Thomas H. M.
Ottenhoff,2
Wilfried
Dalemans,3
Carl
Wheeler,4 and
Kris
Huygen1,*
Pasteur Institute of Brussels, Mycobacterial
Immunology, B1180 Brussels,1 and
SmithKline Beecham Biologicals, B1330
Rixensart,3 Belgium; Leiden University
Medical Center, ZA 2333, Leiden, The
Netherlands2; and Vical
Incorporated, San Diego, California 921214
Received 9 November 2000/Returned for modification 14 November
2000/Accepted 8 February 2001
C57BL/6 mice were vaccinated with plasmid DNA encoding Ag85 from
Mycobacterium tuberculosis, with Ag85 protein in
adjuvant, or with a combined DNA prime-protein boost regimen. While DNA immunization, as previously described, induced robust Th1-type cytokine
responses, protein-in-adjuvant vaccination elicited very poor cytokine
responses, which were 10-fold lower than those observed with DNA
immunization alone. Injection of Ag85 DNA-primed mice with 30 to 100 µg of purified Ag85 protein in adjuvant increased the interleukin-2
and gamma interferon (IFN-
) response in spleen two- to fourfold.
Further, intracellular cytokine analysis by flow cytometry also showed
an increase in IFN-
-producing CD4+ T cells in
DNA-primed-protein-boosted animals, compared to those that received
only the DNA vaccination. Moreover, these responses appeared to be
better sustained over time. Antibodies were readily produced by all
three methods of immunization but were exclusively of the
immunoglobulin G1 (IgG1) isotype following protein immunization in
adjuvant and preferentially of the IgG2a isotype following DNA and DNA
prime-protein boost vaccination. Finally, protein boosting increased
the protective efficacy of the DNA vaccine against an intravenous
M. tuberculosis H37Rv challenge infection, as measured
by CFU or relative light unit counts in lungs 1 and 2 months after
infection. The capacity of exogenously given protein to boost the
DNA-primed vaccination effect underlines the dominant role of Th1-type
CD4+ helper T cells in mediating protection.
*
Corresponding author. Mailing address: Mycobacterial
Immunology, Pasteur Institute of Brussels, 642 Engelandstraat, B1180 Brussels, Belgium. Phone: 32.2.373.33.70. Fax: 32.2.373.33.67. E-mail:
khuygen{at}pasteur.be.
Infection and Immunity, May 2001, p. 3041-3047, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3041-3047.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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