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Improving the MVA vaccine potential by deleting the viral gene coding for the IL-18 binding protein.

Falivene J, Del Médico Zajac MP, Pascutti MF, Rodríguez AM, Maeto C, Perdiguero B, Gómez CE, Esteban M, Calamante G, Gherardi MM - PLoS ONE (2012)

Bottom Line: 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.This 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.

View Article: PubMed Central - PubMed

Affiliation: Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

ABSTRACT

Background: Modified 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 findings: BALB/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/significance: This 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.

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Related in: MedlinePlus

MVAΔC12L induced strengthened cellular responses against recombinant HIV antigens compared to MVA after DNA/MVA immunizations.(A) Description of the different vectors employed in the DNA/MVA immunization schemes applied, each group consisted of three to four BALB/c mice. (B) Seven days after the boost, specific-CD8+ T-cell responses against NefBF (homologous) or NefB (heterologous) peptides were evaluated in the spleen. (C) Ten days after the boost specific responses against HIV-1 subtype C antigens were evaluated in the spleen. To the left it is depicted the responses found against the total pool of peptides analyzed, in the right panel it can be seen the detailed analysis showing the pool of peptides targeted comprising the different HIV antigens that are expressed from the vectors. The magnitude of the response was measured by IFN-γ Elispot assay after 24 hr stimulation. Background (RPMI control) subtracted results are depicted as mean IFN-γ spot forming units (SFU) per 106 splenocytes ± SD. Statistically significant differences: *p<0.05, **p<0.01, ***p<0.001.
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pone-0032220-g008: MVAΔC12L induced strengthened cellular responses against recombinant HIV antigens compared to MVA after DNA/MVA immunizations.(A) Description of the different vectors employed in the DNA/MVA immunization schemes applied, each group consisted of three to four BALB/c mice. (B) Seven days after the boost, specific-CD8+ T-cell responses against NefBF (homologous) or NefB (heterologous) peptides were evaluated in the spleen. (C) Ten days after the boost specific responses against HIV-1 subtype C antigens were evaluated in the spleen. To the left it is depicted the responses found against the total pool of peptides analyzed, in the right panel it can be seen the detailed analysis showing the pool of peptides targeted comprising the different HIV antigens that are expressed from the vectors. The magnitude of the response was measured by IFN-γ Elispot assay after 24 hr stimulation. Background (RPMI control) subtracted results are depicted as mean IFN-γ spot forming units (SFU) per 106 splenocytes ± SD. Statistically significant differences: *p<0.05, **p<0.01, ***p<0.001.

Mentions: For these experiments, immunizations based on DNA prime/MVA boost schemes were applied, but now employing recombinant MVA vectors expressing NefBF [38] or a recombinant MVA expressing codon-optimized Env as a monomeric gp120 and a polyprotein Gag-Pol-Nef from clade C (referred as MVA-C) [39]. The immunization schemes are described in Figure 8A. Fig. 8B–C shows the HIV specific responses detected 7–10 days after the last immunization. When the NefBF antigen was used, it can be clearly seen that if the booster dose was MVAΔC12L-NefBF, the reactivity against NefBF peptides (overlapping peptides representing the entire protein) was significantly improved (Fig. 8B), and even more, a higher -albeit not significant- level of cross-reactivity against B peptides was also found in mice that received the DNA-NefBF/MVAΔC12L-NefBF scheme.


Improving the MVA vaccine potential by deleting the viral gene coding for the IL-18 binding protein.

Falivene J, Del Médico Zajac MP, Pascutti MF, Rodríguez AM, Maeto C, Perdiguero B, Gómez CE, Esteban M, Calamante G, Gherardi MM - PLoS ONE (2012)

MVAΔC12L induced strengthened cellular responses against recombinant HIV antigens compared to MVA after DNA/MVA immunizations.(A) Description of the different vectors employed in the DNA/MVA immunization schemes applied, each group consisted of three to four BALB/c mice. (B) Seven days after the boost, specific-CD8+ T-cell responses against NefBF (homologous) or NefB (heterologous) peptides were evaluated in the spleen. (C) Ten days after the boost specific responses against HIV-1 subtype C antigens were evaluated in the spleen. To the left it is depicted the responses found against the total pool of peptides analyzed, in the right panel it can be seen the detailed analysis showing the pool of peptides targeted comprising the different HIV antigens that are expressed from the vectors. The magnitude of the response was measured by IFN-γ Elispot assay after 24 hr stimulation. Background (RPMI control) subtracted results are depicted as mean IFN-γ spot forming units (SFU) per 106 splenocytes ± SD. Statistically significant differences: *p<0.05, **p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285208&req=5

pone-0032220-g008: MVAΔC12L induced strengthened cellular responses against recombinant HIV antigens compared to MVA after DNA/MVA immunizations.(A) Description of the different vectors employed in the DNA/MVA immunization schemes applied, each group consisted of three to four BALB/c mice. (B) Seven days after the boost, specific-CD8+ T-cell responses against NefBF (homologous) or NefB (heterologous) peptides were evaluated in the spleen. (C) Ten days after the boost specific responses against HIV-1 subtype C antigens were evaluated in the spleen. To the left it is depicted the responses found against the total pool of peptides analyzed, in the right panel it can be seen the detailed analysis showing the pool of peptides targeted comprising the different HIV antigens that are expressed from the vectors. The magnitude of the response was measured by IFN-γ Elispot assay after 24 hr stimulation. Background (RPMI control) subtracted results are depicted as mean IFN-γ spot forming units (SFU) per 106 splenocytes ± SD. Statistically significant differences: *p<0.05, **p<0.01, ***p<0.001.
Mentions: For these experiments, immunizations based on DNA prime/MVA boost schemes were applied, but now employing recombinant MVA vectors expressing NefBF [38] or a recombinant MVA expressing codon-optimized Env as a monomeric gp120 and a polyprotein Gag-Pol-Nef from clade C (referred as MVA-C) [39]. The immunization schemes are described in Figure 8A. Fig. 8B–C shows the HIV specific responses detected 7–10 days after the last immunization. When the NefBF antigen was used, it can be clearly seen that if the booster dose was MVAΔC12L-NefBF, the reactivity against NefBF peptides (overlapping peptides representing the entire protein) was significantly improved (Fig. 8B), and even more, a higher -albeit not significant- level of cross-reactivity against B peptides was also found in mice that received the DNA-NefBF/MVAΔC12L-NefBF scheme.

Bottom Line: 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.This 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.

View Article: PubMed Central - PubMed

Affiliation: Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

ABSTRACT

Background: Modified 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 findings: BALB/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/significance: This 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.

Show MeSH
Related in: MedlinePlus