title: Deletion of A44L, A46R and C12L Vaccinia Virus Genes from the MVA Genome Improved the Vector Immunogenicity by Modifying the Innate Immune Response Generating Enhanced and Optimized Specific T-Cell Responses.
abstract: MVA is an attenuated vector that still retains immunomodulatory genes. We have previously reported its optimization after deleting the C12L gene, coding for the IL-18 binding-protein. Here, we analyzed the immunogenicity of MVA vectors harboring the simultaneous deletion of A44L, related to steroid synthesis and A46R, a TLR-signaling inhibitor (MVAΔA44L-A46R); or also including a deletion of C12L (MVAΔC12L/ΔA44L-A46R). The absence of biological activities of the deleted genes in the MVA vectors was demonstrated. Adaptive T-cell responses against VACV epitopes, evaluated in spleen and draining lymph-nodes of C57Bl/6 mice at acute/memory phases, were of higher magnitude in those animals that received deleted MVAs compared to MVAwt. MVAΔC12L/ΔA44L-A46R generated cellular specific memory responses of higher quality characterized by bifunctionality (CD107a/b⁺/IFN-γ⁺) and proliferation capacity. Deletion of selected genes from MVA generated innate immune responses with higher levels of determining cytokines related to T-cell response generation, such as IL-12, IFN-γ, as well as IL-1β and IFN-β. This study describes for the first time that simultaneous deletion of the A44L, A46R and C12L genes from MVA improved its immunogenicity by enhancing the host adaptive and innate immune responses, suggesting that this approach comprises an appropriate strategy to increase the MVA vaccine potential.
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. piaholgado@gmail.com.
authors.forename: María Pía
authors.initials: MP
authors.lastname: Holgado
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. juliana.falivene@gmail.com.
authors.forename: Juliana
authors.initials: J
authors.lastname: Falivene
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. cynthiamayumi85@gmail.com.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Maeto
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. mfernandezamigo.19@gmail.com.
authors.forename: Micaela
authors.initials: M
authors.lastname: Amigo
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. fpascutti@yahoo.com.ar.
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: Pascutti
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. mb_vecchione@hotmail.com.|Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina. mb_vecchione@hotmail.com.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Vecchione
authors.affiliation: Unidad de Microanálisis y Métodos Físicos Aplicados a Química Orgánica (UMYMFOR), Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina. andrea.bruttomesso@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bruttomesso
authors.affiliation: Instituto de Biotecnología, CICVyA-INTA Castelar, Buenos Aires 1686, Argentina. calamante.gabriela@inta.gob.ar.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Calamante
authors.affiliation: Instituto de Biotecnología, CICVyA-INTA Castelar, Buenos Aires 1686, Argentina. delmedicozajac.maria@inta.gob.ar.
authors.forename: María Paula
authors.initials: MP
authors.lastname: Del Médico-Zajac
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Facultad de Medicina, Ciudad de Buenos Aires 1121, Argentina. mmgherardi@gmail.com.
authors.forename: María Magdalena
authors.initials: MM
authors.lastname: Gherardi
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D007113:Immunity, Innate; D008198:Lymph Nodes / Q000276:immunology; D008810:Mice, Inbred C57BL; D017384:Sequence Deletion; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: C413651:A46R protein, vaccinia virus; D000956:Antigens, Viral; C469545:C12L protein, vaccinia virus; D016207:Cytokines; D000939:Epitopes; D014764:Viral Proteins
keywords: MVA; T-cell response; vaccine