title: Improving the MVA vaccine potential by deleting the viral gene coding for the IL-18 binding protein.
abstract: BACKGROUND
  Modified Vaccinia Ankara (MVA) is an attenuated strain of Vaccinia virus (VACV) currently employed in many clinical trials against HIV/AIDS and other diseases. MVA still retains genes involved in host immune response evasion, enabling its optimization by removing some of them. The aim of this study was to evaluate cellular immune responses (CIR) induced by an IL-18 binding protein gene (C12L) deleted vector (MVAΔC12L).
  
  
  RESULTS
  BALB/c and C57BL/6 mice were immunized with different doses of MVAΔC12L or MVA wild type (MVAwt), then CIR to VACV epitopes in immunogenic proteins were evaluated in spleen and draining lymph nodes at acute and memory phases (7 and 40 days post-immunization respectively). Compared with parental MVAwt, MVAΔC12L immunization induced a significant increase of two to three-fold in CD8(+) and CD4(+) T-cell responses to different VACV epitopes, with increased percentage of anti-VACV cytotoxic CD8(+) T-cells (CD107a/b(+)) during the acute phase of the response. Importantly, the immunogenicity enhancement was also observed after MVAΔC12L inoculation with different viral doses and by distinct routes (systemic and mucosal). Potentiation of MVA's CIR was also observed during the memory phase, in correlation with a higher protection against an intranasal challenge with VACV WR. Of note, we could also show a significant increase in the CIR against HIV antigens such as Env, Gag, Pol and Nef from different subtypes expressed from two recombinants of MVAΔC12L during heterologous DNA prime/MVA boost vaccination regimens.
  
  
  CONCLUSIONS
  This study demonstrates the relevance of IL-18 bp contribution in the immune response evasion during MVA infection. Our findings clearly show that the deletion of the viral IL-18 bp gene is an effective approach to increase MVA vaccine efficacy, as immunogenicity improvements were observed against vector antigens and more importantly to HIV antigens.
authors.affiliation: Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Juliana
authors.initials: J
authors.lastname: Falivene
authors.forename: María Paula
authors.initials: MP
authors.lastname: Del Médico Zajac
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Pascutti
authors.forename: Ana María
authors.initials: AM
authors.lastname: Rodríguez
authors.forename: Cynthia
authors.initials: C
authors.lastname: Maeto
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perdiguero
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Gómez
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.forename: Gabriela
authors.initials: G
authors.lastname: Calamante
authors.forename: María Magdalena
authors.initials: MM
authors.lastname: Gherardi
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002645:Chickens; D005260:Female; D017353:Gene Deletion; D005822:Genetic Vectors; D007156:Immunologic Memory; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18; D007376:Interleukin-2 / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000378:metabolism; D014616:Vaccinia virus / Q000378:metabolism*
chemical_list: D016915:AIDS Vaccines; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D007376:Interleukin-2; C118370:interleukin-18 binding protein; D007371:Interferon-gamma