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Infection and Immunity, August 2005, p. 4714-4722, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4714-4722.2005

Conditions Influencing the Efficacy of Vaccination with Live Organisms against Leishmania major Infection

Khaled S. Tabbara ,^, Nathan C. Peters, Farhat Afrin,^, Susana Mendez, Sylvie Bertholet, Yasmine Belkaid, and David L. Sacks^*

Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 26 January 2005/ Returned for modification 8 March 2005/ Accepted 18 March 2005

Numerous experimental vaccines have been developed with the goal of generating long-term cell-mediated immunity to the obligate intracellular parasite Leishmania major, yet inoculation with live, wild-type L. major remains the only successful vaccine in humans. We examined the expression of immunity at the site of secondary, low-dose challenge in the ear dermis to determine the kinetics of parasite clearance and the early events associated with the protection conferred by vaccination with live L. major organisms in C57BL/6 mice. Particular attention was given to the route of vaccination. We observed that the rapidity, strength, and durability of the memory response following subcutaneous vaccination with live parasites in the footpad are even greater than previously appreciated. Antigen-specific gamma interferon (IFN-)-producing T cells infiltrate the secondary site by 1.5 weeks, and viable parasites are cleared as early as 2.5 weeks following rechallenge, followed by a rapid drop in IFN-⁺ CD4⁺ cell numbers in the site. In comparison, intradermal vaccination with live parasites in the ear generates immunity that is delayed in effector cell recruitment to the rechallenge site and in the clearance of parasites from the site. This compromised immunity was associated with a rapid recruitment of interleukin-10 (IL-10)-producing CD4⁺ T cells to the rechallenge site. Treatment with anti-IL-10-receptor or anti-CD25 antibody enhanced early parasite clearance in ear-vaccinated mice, indicating that chronic infection in the skin generates a population of regulatory cells capable of influencing the level of resistance to reinfection. A delicate balance of effector and regulatory T cells may be required to optimize the potency and durability of vaccines against Leishmaniasis and other intracellular pathogens.

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* 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: W. A. Petri, Jr.

K.S.T., N.C.P., and F.A. contributed equally to this work.

Present address: Arabian Gulf University, College of Medicine, Manama, Bahrain.

Present address: Centre for Biotechnology, Jamia Mamdard, Hamdard University, New Delhi, India.

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Infection and Immunity, August 2005, p. 4714-4722, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4714-4722.2005

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