Improving the MVA Vaccine Potential by Deleting the Viral Gene Coding for the IL-18 Binding Protein

Abstract

BackgroundModified 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).Methodology/Principal FindingsBALB/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/SignificanceThis 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.

Deletion of the Vaccinia Virus N2L Gene Encoding an Inhibitor of IRF3 Improves the Immunogenicity of Modified Vaccinia Virus Ankara Expressing HIV-1 Antigens

“…Several MVA deletion mutants containing deletions in different immunomodulatory VACV genes have been generated and analyzed in mice (42,62,63,(78)(79)(80) and nonhuman primates (81,82). These studies revealed that MVA vectors with deletions of single VACV genes encoding inhibitors of the type I IFN signaling pathway (C6L [42]), apoptosis (F1L [80]), and IL-18 binding protein (C12L [79]) or the uracyl-DNA glycosylase gene (UDG [82]) enhanced the overall immune responses to HIV-1 antigens.…”

“…These studies revealed that MVA vectors with deletions of single VACV genes encoding inhibitors of the type I IFN signaling pathway (C6L [42]), apoptosis (F1L [80]), and IL-18 binding protein (C12L [79]) or the uracyl-DNA glycosylase gene (UDG [82]) enhanced the overall immune responses to HIV-1 antigens. (81), but an additional fifth deletion of the uracil-DNA glycosylase gene (MVA101R) decreased the responses (81).…”

Deletion of the Vaccinia Virus Gene A46R, Encoding for an Inhibitor of TLR Signalling, Is an Effective Approach to Enhance the Immunogenicity in Mice of the HIV/AIDS Vaccine Candidate NYVAC-C

“…A number of MVA deletion mutants in viral immune modulators have been generated to date and tested in mice [54,55,56,57,58] and macaques [59,60]. These studies have shown that MVA recombinant viruses with a single deletion of viral genes encoding inhibitors of type 1 IFN signalling pathway ( C6L [55]), apoptosis ( F1L [56]), IL-18 binding protein ( C12L [57]) or the uracyl-DNA glycosylase gene ( UDG [60]), enhanced the overall immune responses to HIV-1 antigens.…”

The Canarypox Virus Vector ALVAC Induces Distinct Cytokine Responses Compared to the Vaccinia Virus-Based Vectors MVA and NYVAC in Rhesus Monkeys

“…Differences in immune gene upregulation and induced immune phenotypes were further seen following MVA and NYVAC infections in vitro and in vivo (27)(28)(29)(30). Further studies showed increased innate stimulation by these vectors following expanded deletion of their immune regulatory gene repertoire, highlighting the role of the immune gene repertoire of poxvirus vectors in their innate stimulatory phenotypes (31)(32)(33)(34). However, far less is known about the innate immune profile of ALVAC and its immune regulatory genes (35).…”