title: Heterologous priming-boosting with DNA and vaccinia virus expressing kinetoplastid membrane protein-11 induces potent cellular immune response and confers protection against infection with antimony resistant and sensitive strains of Leishmania (Leishmania) donovani.
abstract: BACKGROUND
  Emergence of resistance against commonly available drugs poses a major threat in the treatment of visceral leishmaniasis (VL), particularly in the Indian subcontinent. Absence of any licensed vaccine against VL emphasizes the urgent need to develop an effective alternative vaccination strategy.
  
  
  METHODS
  We developed a novel heterologous prime boost immunization strategy using kinetoplastid membrane protein-11 (KMP-11) DNA priming followed by boosting with recombinant vaccinia virus (rVV) expressing the same antigen. The efficacy of this vaccination regimen in a murine and hamster model of visceral leishmaniasis caused by both antimony resistant (Sb-R) and sensitive (Sb-S) Leishmania (L.) donovani is examined.
  
  
  RESULTS
  Heterologous prime-boost (KMP-11 DNA/rVV) vaccination was able to protect mice and hamsters from experimental VL induced by both Sb-S and Sb-R-L. (L.) donovani isolates. Parasite burden is kept significantly low in the vaccinated groups even after 60 days post-infection in hamsters, which are extremely susceptible to VL. Protection in mice is correlated with strong cellular and humoral immune responses. Generation of polyfunctional CD8(+) T cell was observed in vaccinated groups, which is one of the most important prerequisite for successful vaccination against VL. Protection was accompanied with generation of antigen specific CD4(+) and CD8(+) cells that produced effector cytokines such as IFN-γ, IL-2 and TNF-α. KMP-11-DNA/rVV vaccination also developed strong cytotoxic response and reversed T-cell impairment to induce antigen specific T cell proliferation.
  
  
  CONCLUSIONS
  KMP-11 is a unique antigen with high epitope density. Heterologous prime boost vaccination activates CD4(+) and CD8(+) T-cell mediated immunity to confer resistance to VL. This immunization method also produces high quality T-cells secreting multiple effector cytokines thus enhancing durability of the immune response. Thus the vaccination regime as described in the present study could provide a potent strategy for future anti-leishmanial vaccine development.
authors.affiliation: Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Guha
authors.forename: Shantanabha
authors.initials: S
authors.lastname: Das
authors.forename: June
authors.initials: J
authors.lastname: Ghosh
authors.forename: Kshudiram
authors.initials: K
authors.lastname: Naskar
authors.forename: Ashok
authors.initials: A
authors.lastname: Mandala
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Dujardin
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
mesh_terms: D000818:Animals; D000965:Antimony / Q000494:pharmacology*; D006224:Cricetinae; D045142:Cross-Priming; D016207:Cytokines / Q000276:immunology; D004351:Drug Resistance; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology; D007893:Leishmania donovani / Q000187:drug effects / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016052:Protozoan Vaccines / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; C090009:kinetoplastid membrane protein 11, Leishmania donovani; D000965:Antimony