Inactivation of the viral interleukin 1  receptor improves CD8+ T-cell memory responses elicited upon immunization with modified vaccinia virus Ankara

Abstract

Interleukin 1 (IL1) is an important regulator of inflammatory responses and contributes to host immune defence against infection. Vaccinia virus encodes a viral soluble IL1b receptor (IL1bR), which modulates the acute-phase host response to infection and might influence the induction of immune responses against virus-associated antigens. Here, modified vaccinia virus Ankara (MVA) mutants defective in IL1bR production were produced by insertion of selectable marker gene sequences that precisely deleted the IL1bR coding sequences from the MVA genome (MVA-DIL1bR). Analysis of MVA mutants indicated that deletion of the IL1bR gene did not abrogate the formation of MVA progeny upon tissue culture propagation. After high-dose intranasal infection with MVA-DIL1bR, mice showed no signs of fever or other illness, suggesting that the avirulent phenotype remained preserved for MVA-DIL1bR. Following vaccination of mice, MVA-DIL1bR or non-mutated MVA induced similar acute-phase immune responses. Importantly, when monitored at the memory phase, significantly higher vaccinia virus-specific total CD8 + and HLA-A*0201-binding peptide epitope-specific T-cell responses were found after vaccination of HLA-A*0201-transgenic and non-transgenic mice with MVA-DIL1bR. Moreover, 4-6 months after vaccination, MVA-DIL1bR provided higher levels of protection against lethal respiratory challenge infection with virulent vaccinia virus strain Western Reserve compared with wild-type MVA. These data suggest that deletion of the viral IL1bR gene may be considered a relevant approach to amplify the virus-specific CD8 + memory T-cell response and duration of protective immunity obtained after MVA vaccination.

Deletion of Specific Immune-Modulatory Genes from Modified Vaccinia Virus Ankara-Based HIV Vaccines Engenders Improved Immunogenicity in Rhesus Macaques

“…However, immunogenicity studies in mice of MVA recombinants that harbor a single-gene deletion of MVA184R (78) or MVA153L (18, 21) or a double deletion of these two immune-modulatory genes (32) reported modest effects (2-to 3-fold enhancement) of these gene deletions on the magnitudes of the ensuing T cell responses. The relatively greater effects observed here for our modified vaccines in nonhuman primates may reflect positive contributions of additional gene deletions, speciesspecific differences between rhesus macaques and mice, or a combination of these factors with regard to the modified vaccines' ability to induce a more favorable environment for antigen presentation and/or the expansion of antigen-specific T cells in vivo.…”

“…The biological activities of these factors can be inferred by the fact that deletions of their orthologs from replication-competent strains of vaccinia virus result in altered pathogenic phenotypes in murine models (2,62,74,77,80). Additionally, the observation that MVA recombinants lacking MVA184R and/or MVA153L may elicit modestly augmented CD8 T cell responses in mice indicates that the deletion of immune-modulatory genes from MVA-based vaccines is a relevant approach toward improving vaccine immunogenicity (18,21,32,78).…”

Expression of CCL20 and Granulocyte-Macrophage Colony-Stimulating Factor, but Not Flt3-L, from Modified Vaccinia Virus Ankara Enhances Antiviral Cellular and Humoral Immune Responses

“…80,2006 CYTOKINE AUGMENTATION OF MVA IMMUNOGENICITY 7679 3-fold increases over MVA-NP-immunized mice in the fraction of CD8 ϩ T cells that produced IFN-␥ in response to stimulation with the LCMV-NP 118-126 peptide (Fig. 2C and D).…”

“…and at a dose of 1 ϫ 10 6 PFU per immunization. The murine intraperitoneal infection model is a generally accepted model of poxvirus infection and immunity that has been successfully utilized in studies of poxvirus immunogenicity (29), T-cell epitope mapping (92), and rational enhancement of MVA vector immunogenicity (80). Mice were sacrificed at 7 days, 15 days, and 30 days postinfection (dpi), and spleens were removed for the immune response studies.…”

Mucosal Immunization of Lactating Female Rhesus Monkeys with a Transmitted/Founder HIV-1 Envelope Induces Strong Env-Specific IgA Antibody Responses in Breast Milk

“…After immunization with MVA, CD8 ϩ T-cell memory responses can be improved by the deletion of the viral gene (MVA ORF 184R) encoding the soluble, secreted interleukin-1␤ receptor (IL-1␤R) (28). To take advantage of this phenotype, the IL-1␤R gene in MVA virus A676 was inactivated by the transient marker stabilization procedure using plasmid p2588.…”