INBIRS   24491
INSTITUTO DE INVESTIGACIONES BIOMEDICAS EN RETROVIRUS Y SIDA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Immunogenicity Potential of MVA Vectors after Removal of the Immunomodulatory A44L and A46R Viral Genes
Autor/es:
MARIA PIA HOLGADO; JULIANA FALIVENE; MARIA PAULA DEL MEDICO-ZAJAC; CYNTHIA MAETO; ANA MARÍA RODRÍGUEZ; MARÍA FERNANDA PASCUTTI; GABRIELA CALAMANTE; MARÍA MAGDALENA GHERARDI
Lugar:
Barcelona
Reunión:
Congreso; Poster aceptado en el AIDS Vaccine Conference; 2013
Resumen:
Background: Modified Vaccinia Ankara (MVA) still retains
genes involved in host immune response evasion. We have previously reported the optimization
of MVA vaccine potential after the deletion of the C12L gene encoding an IL-18
binding protein. Here we analyze the immunogenicity of MVA vectors harboring the
simultaneous deletion of two viral genes: A44L, implicated in synthesis of steroid hormones and A46R,
which inhibit transduction
signals from TLR receptors (MVAΔA44L-A46R); or with an additional gene deletion:
C12L (MVAΔC12L/ΔA44L-A46R). Methods: C57Bl/6 mice were intramuscularly immunized with wild
type (MVAwt), or deleted MVAs (dMVAs). T-cell responses to VACV (Vaccinia
Virus) epitopes were evaluated at acute and memory phases (7 and 45 days
post-immunization (dpi) respectively). The proportion of IFN-γ and IL-2 producing
cells was measured by ELISPOT. Percentage of cytotoxic CD8-T cells was analyzed
by flow citometry through CD107a/b surface-marker, and memory T-cell responses
by expression of CD44 and CD62L among proliferating (CFSElow) T-cell
populations. Results: Compared with MVAwt at 7dpi both dMVAs induced significant increases in the IFN-γ anti-VACV CD8 and CD4-Tcells (1,5 to
two-fold, p<0,01; 2,5 to five-fold, p<0.01 respectively); and IL-2
anti-VACV CD8-Tcells (up to five-fold higher; p<0,01). Importantly,
increments at 45 dpi in IFN-γ CD8 and CD4-T cell responses were maintained (p<0,05);
regarding anti-VACV IL-2 secreting cells, improvements were of two or four-fold
against CD4 and CD8 peptides (p<0,05). Proliferating anti-VACV CD8-T cells
were incremented from 1% (MVAwt) to 2,8% (MVAΔC12L/ΔA44L-A46R) and significantly this vector elicited a higher proportion of
specific TCM (45,2%) than TEM (43,5%) compared to MVAwt (TCM:19,5%, TEM:63%).
Percentage of specific cytotoxic CD8-T cells that secrete IFN-γ (CD107/IFN-γ),
were also incremented by MVAΔC12L/ΔA44L-A46R.
Conclusions: Simultaneous deletion
of specific viral genes from the MVA genome with inter-related functions as
A46R and C12L, is an adequate strategy to improve the vaccine potential of this
vector.