title: Coinjection with CpG-containing immunostimulatory oligodeoxynucleotides reduces the pathogenicity of a live vaccine against cutaneous Leishmaniasis but maintains its potency and durability.
abstract: 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.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Mendez
authors.forename: Khaled
authors.initials: K
authors.lastname: Tabbara
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.forename: Daniela
authors.initials: D
authors.lastname: Verthelyi
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.forename: David L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D012449:Safety; D012867:Skin / Q000473:pathology; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D016052:Protozoan Vaccines; D016753:Interleukin-10; C041524:aluminum sulfate; D007371:Interferon-gamma