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Infection and Immunity, September 2003, p. 5121-5129, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.5121-5129.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Coinjection with CpG-Containing Immunostimulatory Oligodeoxynucleotides Reduces the Pathogenicity of a Live Vaccine against Cutaneous Leishmaniasis but Maintains Its Potency and Durability

Susana Mendez,1,{dagger} Khaled Tabbara,1 Yasmine Belkaid,1 Sylvie Bertholet,1 Daniela Verthelyi,2 Dennis Klinman,3 Robert A. Seder,4 and David L. Sacks1*

Laboratory of Parasitic Diseases,1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health,4 Division of Therapeutic Proteins,2 Section of Retroviral Immunology, Cellular Immunology Section, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208923

Received 13 March 2003/ Returned for modification 5 June 2003/ Accepted 19 June 2003

The inoculation of live, nonattenuated Leishmania major to produce a lesion in a selected site that heals, referred to as leishmanization, is to date the only vaccine against leishmaniasis that has proven to be effective in humans. Its use has been restricted or abandoned entirely, however, due to safety concerns. In an attempt to develop a leishmanization protocol that minimizes pathology while maintaining long-term protection, live parasites were coinjected with CpG-containing immunostimulatory oligodeoxynucleotides (CpG ODNs) alone or in combination with whole-cell lysates of heat-killed L. major promastigotes bound to alum (ALM). C57BL/6 mice infected intradermally by using L. major plus CpG ODN with or without ALM developed few or no dermal lesions and showed an early containment of parasite growth, while mice infected with L. major with or without ALM developed sizable dermal lesions that required up to 10 weeks to heal. The CpG ODNs provoked a transient inflammation that included an early recruitment and accumulation of gamma interferon-producing CD4+ lymphocytes in the site. Attenuation of the live vaccine did not compromise its ability to confer long-term immunity, as mice receiving L. major and CpG ODN plus ALM were totally protected against reinfection with L. major for up to 6 months. By comparison, the immunity elicited by two efficient nonlive vaccines began to wane by 6 months. Our results suggest that immune modulation using CpG ODNs might be a practical approach to improving the safety of a highly effective live vaccine that has already been widely applied.

* Corresponding author. Mailing address: NIAID, Laboratory of Parasitic Diseases, Bldg. 4, Rm. 126, Center Dr. MSC 0425, Bethesda, MD 20892-0425. Phone: (301) 496-0577. Fax: (301) 480-3708. E-mail: dsacks{at}nih.gov.

Editor: J. M. Mansfield

{dagger} Present address: Department of Microbiology and Tropical Medicine, George Washington University, Washington, DC 20052.

Infection and Immunity, September 2003, p. 5121-5129, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.5121-5129.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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