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

Juliana Falivene,Gabriela Calamante,Beatriz Perdiguero,María Magdalena Gherardi,Cynthia Maeto,María Fernanda Pascutti,Ana María Rodríguez,Mariano Esteban,María Paula Del Médico Zajac,Carmen E Gómez,Adriano Boasso

doi:10.1371/journal.pone.0032220

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.

Highlights

Modified Vaccinia virus Ankara (MVA), an attenuated strain of Vaccinia virus, was obtained following extensive serial passages on primary chicken embryo fibroblasts (CEFs) [1]
Our following aim was to evaluate the loss of function of IL-18 bp in the mutant virus demonstrating that Modified Vaccinia Ankara (MVA) C12L gene encodes a protein with a biological activity directly correlated with IL-18
The loss of function of this activity in MVADC12L was demonstrated by the fact that if rIL-18 was incubated with supernatants from CEFs infected with mutant MVADC12L, the inhibition observed was abolished (Fig. 1C)

Summary

Introduction

Modified Vaccinia virus Ankara (MVA), an attenuated strain of Vaccinia virus, was obtained following extensive serial passages on primary chicken embryo fibroblasts (CEFs) [1]. During this process of attenuation, MVA underwent deletion of 31 kbp (15%) of its genome, as compared to its parental strain, including a number of genes that contribute to viral evasion from host immune responses and that determine virus host range [2,3]. The aim of this study was to evaluate cellular immune responses (CIR) induced by an IL-18 binding protein gene (C12L) deleted vector (MVADC12L)

Objectives

Methods

Results

Conclusion