Volume 87, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive -specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude antigen–driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36–71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Greenblatt CL, , 1988. Cutaneous leishmaniasis: the prospects for a killed vaccine. Parasitol Today 4: 5354.[Crossref] [Google Scholar]
  2. Antunes CM, Mayrink W, Magalhaes PA, Costa CA, Melo MN, Dias M, Michalick MS, Williams P, Lima AO, Vieira JB, , 1986. Controlled field trials of a vaccine against New World cutaneous leishmaniasis. Int J Epidemiol 15: 572580.[Crossref] [Google Scholar]
  3. Khalil EA, El Hassan AM, Zijlstra EE, Mukhtar MM, Ghalib HW, Musa B, Ibrahim ME, Kamil AA, Elsheikh M, Babiker A, Modabber F, , 2000. Autoclaved Leishmania major vaccine for prevention of visceral leishmaniasis: a randomised, double-blind, BCG-controlled trial in Sudan. Lancet 356: 15651569.[Crossref] [Google Scholar]
  4. Mayrink W, da Costa CA, Magalhaes PA, Melo MN, Dias M, Lima AO, Michalick MS, Williams P, , 1979. A field trial of a vaccine against American dermal leishmaniasis. Trans R Soc Trop Med Hyg 73: 385387.[Crossref] [Google Scholar]
  5. Momeni AZ, Jalayer T, Emamjomeh M, Khamesipour A, Zicker F, Ghassemi RL, Dowlati Y, Sharifi I, Aminjavaheri M, Shafiei A, Alimohammadian MH, Hashemi-Fesharki R, Nasseri K, Godal T, Smith PG, Modabber F, , 1999. A randomised, double-blind, controlled trial of a killed L. major vaccine plus BCG against zoonotic cutaneous leishmaniasis in Iran. Vaccine 17: 466472.[Crossref] [Google Scholar]
  6. Sharifi I, FeKri AR, Aflatonian MR, Khamesipour A, Nadim A, Mousavi MR, Momeni AZ, Dowlati Y, Godal T, Zicker F, Smith PG, Modabber F, , 1998. Randomised vaccine trial of single dose of killed Leishmania major plus BCG against anthroponotic cutaneous leishmaniasis in Bam, Iran. Lancet 351: 15401543.[Crossref] [Google Scholar]
  7. Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, Sisk E, Hertzfowler C, Quail MA, Harris D, Rajandream M-A, Davies RM, Aert R, Andersson B, Anupama A, Attipoe P, Bason N, Bauser C, Beck A, Beverley SM, Bianchettin G, Borzym K, Bothe G, Bruschi CV, Collins M, Cadag E, Ciarloni L, Clayton C, Coulson RMR, Cronin A, Cruz AC, De Gaudenzi J, Dobson DE, Duesterhoeft A, Fazelina G, Fosker N, Frasch AC, Fraser A, Fuchs M, Gabel C, Goble C, Goffeau A, Hilbert H, Horn D, Huang Y, Klages S, Knights A, Kube M, Larke N, Litvin L, Lord A, Louie T, Marra M, Masuy D, Matthews K, Michaeli S, Mottram JC, Mueller-Auer S, Munden H, Nelson S, Nilsson D, Norbertczak H, Oliver K, O'Neill S, Pentony M, Pohl TM, Price C, Purnelle B, Rabbinowitsch E, Reinhardt R, Rieger M, Rinta J, Robben J, Robertson L, Ruiz J, Rutter S, Saunders D, Schaefer M, Schein J, Schwartz DC, Seeger K, Seyler A, Sharp S, Shin H, Sivam D, Squares R, Squares S, Tosato V, Tram A-N, Vogt C, Volckaert G, Wambutt R, Warren T, Wedler H, Woodward J, Zhou S, Zimmermann W, Smith DF, Blackwell JM, Stuart KD, Barrell B, Myler PJ, , 2005. The genome of the kinetoplastid parasite, Leishmania major . Science 309: 436442.[Crossref] [Google Scholar]
  8. Stober C, Lange U, Roberts MT, Gilbmartin B, Francis R, Almeida R, Peacock CS, McCann S, Blackwell JM, , 2006. From genome to vaccines for leishmaniasis: screening 100 novel vaccine candidates against murine Leishmania major infection. Vaccine 24: 26022614.[Crossref] [Google Scholar]
  9. Campos-Neto A, Porrozzi R, Greeson K, Coler RN, Webb JR, Seiky YA, Reed SG, Grimaldi G, Jr, 2001. Protection against cutaneous leishmaniasis induced by recombinant antigens in murine and nonhuman primate models of the human disease. Infect Immun 69: 41034108.[Crossref] [Google Scholar]
  10. Mougneau E, Altare F, Wakil AE, Zheng S, Coppola T, Wang Z-E, Waldmann R, Locksley RM, Glaichenhaus N, , 1995. Expression cloning of a protective Leishmania antigen. Science 268: 563566.[Crossref] [Google Scholar]
  11. Levick MP, Tetaud E, Fairlamb AH, Blackwell JM, , 1998. Identification and characterisation of a functional peroxidoxin from Leishmania major . Mol Biochem Parasitol 96: 125137.[Crossref] [Google Scholar]
  12. Stober C, Lange U, Roberts MTM, Alcami A, Blackwell JM, , 2005. IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection. J Immunol 175: 25172514.[Crossref] [Google Scholar]
  13. Dondji B, Perez-Jimenez E, Goldsmith-Pestana K, Esteban M, McMahon-Pratt D, , 2005. Prime-boost vaccination using the LACK antigen protects against murine visceral leishmaniasis. Infect Immun 73: 52865289.[Crossref] [Google Scholar]
  14. Jeronimo SM, Duggal P, Ettinger NA, Nascimento ET, Monteiro GR, Cabral AP, Pontes NN, Lacerda HG, Queiroz PV, Gomes CE, Pearson RD, Blackwell JM, Beaty TH, Wilson ME, , 2007. Genetic predisposition to self-curing infection with the protozoan Leishmania chagasi: a genomewide scan. J Infect Dis 196: 12611269.[Crossref] [Google Scholar]
  15. Jeronimo SM, Oliveira RM, Mackay S, Costa RM, Sweet J, Nascimento ET, Luz KG, Fernandes MZ, Jernigan J, Pearson RD, , 1994. An urban outbreak of visceral leishmaniasis in Natal, Brazil. Trans R Soc Trop Med Hyg 88: 386388.[Crossref] [Google Scholar]
  16. Jeronimo SM, Holst AK, Jamieson SE, Francis R, Martins DR, Bezerra FL, Ettinger NA, Nascimento ET, Monteiro GR, Lacerda HG, Miller EN, Cordell HJ, Duggal P, Beaty TH, Blackwell JM, Wilson ME, , 2007. Genes at human chromosome 5q31.1 regulate delayed-type hypersensitivity responses associated with Leishmania chagasi infection. Genes Immun 8: 539551.[Crossref] [Google Scholar]
  17. Howie BN, Donnelly P, Marchini J, , 2009. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529.[Crossref] [Google Scholar]
  18. Reed SG, Badaro R, Masur H, Carvalho EM, Lorenco R, Lisboa A, Teixeira R, Johnson WD, Jr Jones TC, , 1986. Selection of a skin test antigen for American visceral leishmaniasis. Am J Trop Med Hyg 35: 7985. [Google Scholar]
  19. Jeronimo SM, Teixeira MJ, Sousa A, Thielking P, Pearson RD, Evans TG, , 2000. Natural history of Leishmania (Leishmania) chagasi infection in northeastern Brazil: long-term follow-up. Clin Infect Dis 30: 608609.[Crossref] [Google Scholar]
  20. Braz RF, Nascimento ET, Martins DR, Wilson ME, Pearson RD, Reed SG, Jeronimo SM, , 2002. The sensitivity and specificity of Leishmania chagasi recombinant K39 antigen in the diagnosis of American visceral leishmaniasis and in differentiating active from subclinical infection. Am J Trop Med Hyg 67: 344348. [Google Scholar]
  21. Jeronimo SM, Duggal P, Braz RF, Cheng C, Monteiro GR, Nascimento ET, Martins DR, Karplus TM, Ximenes MF, Oliveira CC, Pinheiro VG, Pereira W, Peralta JM, Sousa J, Medeiros IM, Pearsoni RD, Burns TL, Pugh EW, Wilson ME, , 2004. An emerging peri-urban pattern of infection with Leishmania chagasi, the protozoan causing visceral leishmaniasis in northeast Brazil. Scand J Infect Dis 36: 443449.[Crossref] [Google Scholar]
  22. Badaro R, Benson D, Eulalio MC, Freire M, Cunha S, Netto EM, Pedral-Sampaio D, Madureira C, Burns JM, Houghton RL, David JR, Reed SG, , 1996. rK39: a cloned antigen of Leishmania chagasi that predicts active visceral leishmaniasis. J Infect Dis 173: 758761.[Crossref] [Google Scholar]
  23. Burns JM, Jr Shreffler WG, Benson DR, Ghalib HW, Badaro R, Reed SG, , 1993. Molecular characterization of a kinesin-related antigen of Leishmania chagasi that detects specific antibody in African and American visceral leishmaniasis. Proc Natl Acad Sci USA 90: 775779.[Crossref] [Google Scholar]
  24. Stober CB, Lange UG, Roberts MT, Alcami A, Blackwell JM, , 2007. Heterologous priming-boosting with DNA and modified vaccinia virus Ankara expressing tryparedoxin peroxidase promotes long-term memory against Leishmania major in susceptible BALB/c Mice. Infect Immun 75: 852860.[Crossref] [Google Scholar]
  25. Blackwell JM, Jamieson SE, Burgner D, , 2009. HLA and infectious diseases. Clin Microbiol Rev 22: 370385.[Crossref] [Google Scholar]
  26. Mauel J, , 2002. Vaccination against Leishmania infections. Curr Drug Targets Immune Endocr Metabol Disord 2: 201226.[Crossref] [Google Scholar]
  27. Gurunathan S, Prussin C, Sacks DL, Seder RA, , 1998. Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection. Nat Med 4: 14091415.[Crossref] [Google Scholar]
  28. Modabber F, , 2010. Leishmaniasis vaccines: past, present and future. Int J Antimicrob Agents 36 (Suppl 1): S58S61.[Crossref] [Google Scholar]
  29. Jayakumar A, Castilho TM, Park E, Goldsmith-Pestana K, Blackwell JM, McMahon-Pratt D, , 2011. TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T cell responses providing protection against Leishmania (Viannia). PLoS Negl Trop Dis 5: e1204.[Crossref] [Google Scholar]
  30. Barral-Netto M, Badaro R, Barral A, Almeida RP, Santos SB, Badaro F, Pedral-Sampaio D, Carvalho EM, Falcoff E, Falcoff R, , 1991. Tumor necrosis factor (cachectin) in human visceral leishmaniasis. J Infect Dis 163: 853857.[Crossref] [Google Scholar]
  31. Sacks DL, Lal SL, Shrivastava SN, Blackwell JM, Neva FA, , 1987. An analysis of T cell responsiveness in Indian Kala-azar. J Immunol 138: 908913. [Google Scholar]
  32. Gidwani K, Jones S, Kumar R, Boelaert M, Sundar S, , 2011. Interferon-gamma release assay (modified QuantiFERON) as a potential marker of infection for Leishmania donovani, a proof of concept study. PLoS Negl Trop Dis 5: e1042.[Crossref] [Google Scholar]
  33. Follador I, Araujo C, Bacellar O, Araujo CB, Carvalho LP, Almeida RP, Carvalho EM, , 2002. Epidemiologic and immunologic findings for the subclinical form of Leishmania braziliensis infection. Clin Infect Dis 34: E54E58.[Crossref] [Google Scholar]
  34. Novoa R, Bacellar O, Nascimento M, Cardoso TM, Ramasawmy R, Oliveira WN, Schriefer A, Carvalho EM, , 2011. IL-17 and regulatory cytokines (IL-10 and IL-27) in L. braziliensis infection. Parasite Immunol 33: 132136.[Crossref] [Google Scholar]
  35. Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernandez-Vina M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Muller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J, , 2010. Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75: 291455.[Crossref] [Google Scholar]
  36. Costa CH, Peters NC, Maruyama SR, de Brito EC, Jr Santos IK, , 2011. Vaccines for the leishmaniases: proposals for a research agenda. PLoS Negl Trop Dis 5: e943.[Crossref] [Google Scholar]
  37. Goto Y, Bhatia A, Raman VS, Liang H, Mohamath R, Picone AF, Vidal SE, Vedvick TS, Howard RF, Reed SG, , 2011. KSAC, the first defined polyprotein vaccine candidate for visceral leishmaniasis. Clin Vaccine Immunol 18: 11181124.[Crossref] [Google Scholar]
  38. Chakravarty J, Kumar S, Trivedi S, Rai VK, Singh A, Ashman JA, Laughlin EM, Coler RN, Kahn SJ, Beckmann AM, Cowgill KD, Reed SG, Sundar S, Piazza FM, , 2011. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine for use in the prevention of visceral leishmaniasis. Vaccine 29: 35313537.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 21 Mar 2012
  • Accepted : 27 May 2012
  • Published online : 03 Oct 2012

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error