Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect

Brandler, Samantha; Lepelley, Alice; Desdouits, Marion; Guivel‐Benhassine, Florence; Ceccaldi, Pierre‐Emmanuel; Lévy, Yves; Schwartz, Olivier; Moris, Arnaud

doi:10.1128/jvi.02329-09

Cited by 37 publications

(52 citation statements)

References 63 publications

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“…This was first evidenced by Drillien et al (17) in human DCs and then by Liu et al (32) in murine bone marrow-derived DCs. Maturation of human DCs by an MVAbased HIV vaccine was also very recently reported (8). The results presented in this work confirm and extend these previous publications by demonstrating that MVA induces increases in costimulatory molecules CD83 and CD86 and in HLA-DR expression, although these effects were observed within a narrow window of MOIs of 1 to 3 PFU/cell, coinciding with the recent results observed for murine DCs (36).…”

Section: Discussionsupporting

confidence: 92%

“…It has been described that, as part of their immune evasion mechanisms, replicative strains of vaccinia virus inhibit the maturation of DCs and thus their ability to stimulate the proliferation of allogeneic T cells (19). As reported before (8,17,32) and confirmed here, MVA is able to induce maturation of DCs; however, the ability of MVA-infected DCs to activate T cells remains controversial. Drillien et al found that human DCs infected directly with MVA did not induce a significant number of IFN-␥-producing T cells in a syngeneic ELISPOT assay (17).…”

Section: Mva-infected Dcs Are Able To Activate and Induce Ifn-␥ Produsupporting

confidence: 80%

“…A previous report indicated that infection of monocyte-derived DCs with MVA led to a moderate increase in cell surface CD80 and CD83, a more marked increase in CD86, and low levels of TNF-␣ and IL-6 secretion (17). Additionally, in a recently published paper by Brandler et al, an MVA vector expressing HIV genes was shown to induce upregulation of maturation markers to an extent similar to that induced by LPS (8). Our first aim was to extend these observations, examining the effect of MVA infection on both the expression of costimulatory and MHC molecules and the production of chemokines and cytokines in order to characterize in more depth the maturation profile induced by MVA on DCs.…”

Section: Resultsmentioning

confidence: 95%

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Interplay between Modified Vaccinia Virus Ankara and Dendritic Cells: Phenotypic and Functional Maturation of Bystander Dendritic Cells

Pascutti

Rodrı́guez

Falivene

et al. 2011

J Virol

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Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus strain, currently under evaluation as a vaccine vector in various clinical settings. It has been reported that human dendritic cells (DCs) mature after infection with MVA, but reports on the functionality of DCs have so far been controversial. In this work, we studied the phenotype and functionality of MVA-infected DCs. As previously reported, we found that human monocyte-derived DCs upregulated CD86 and HLA-DR in response to MVA infection. Moreover, infected DCs produced a broad array of chemokines and cytokines and were able to activate and induce gamma interferon (IFN-␥) production both in CD4؉ and in CD8 ؉ allogeneic T cells and in specific autologous peripheral blood lymphocytes (PBLs). Analysis of DC maturation following infection with a recombinant green fluorescent protein (GFP)-expressing MVA revealed that upregulation of CD86 expression was mainly observed in GFP neg (bystander) cells. While GFP pos (infected) DCs produced tumor necrosis factor alpha (TNF-␣), they were unable to produce CXCL10 and were less efficient at inducing IFN-␥ production in CEF-specific autologous PBLs. Maturation of bystander DCs could be achieved by incubation with supernatant from infected cultures or with apoptotic infected cells. Type I IFNs were partially responsible for the induction of CXCL10 on bystander DCs. Our findings demonstrate for the first time that, in MVA-infected DC cultures, the leading role with respect to functionality and maturation characteristics is achieved by the bystander DCs.

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Section: Discussionsupporting

confidence: 92%

Section: Mva-infected Dcs Are Able To Activate and Induce Ifn-␥ Produsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 95%

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Interplay between Modified Vaccinia Virus Ankara and Dendritic Cells: Phenotypic and Functional Maturation of Bystander Dendritic Cells

Pascutti

Rodrı́guez

Falivene

et al. 2011

J Virol

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“…injection of 10 mg/kg ketamine (RhoneMérieux, Lyon, France) during the immunizations and blood sampling. On D 0 (baseline) and D 58 , macaques were injected via the s.c. route with 2 3 1 ml inoculum in regions drained by the two inguinal lymph nodes, which contained a total of 4 3 10 8 PFU recombinant MVA that expresses HIV proteins Gag, Pol, and Nef (MVA HIV-B MVATG17401; Transgene, Illkirch-Graffenstaden, France) (49). Macaque blood was collected into either lithium-heparin tubes (Vacutainer BD) before immunization on D 0 and also at D 8 PB and D 28 PB for PBMC isolation, into K3-EDTA tubes for complete blood count (Greiner Bio-One, Frickenhausen, Germany), or into serum clot activator tubes (Greiner Bio-One) at the indicated additional time points.…”

Section: Mva Inoculation and Macaque Samplingmentioning

confidence: 99%

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Pejoski¹,

Tchitchek²,

Pozo³

et al. 2016

The Journal of Immunology

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Broadening our understanding of the abundance and phenotype of B cell subsets that are induced or perturbed by exogenous Ags will improve the vaccine evaluation process. Mass cytometry (CyTOF) is being used to increase the number of markers that can be investigated in single cells, and therefore characterize cell phenotype at an unprecedented level. We designed a panel of CyTOF Abs to compare the B cell response in cynomolgus macaques at baseline, and 8 and 28 d after the second homologous immunization with modified vaccinia virus Ankara. The spanning-tree progression analysis of density-normalized events (SPADE) algorithm was used to identify clusters of CD20+ B cells. Our data revealed the phenotypic complexity and diversity of circulating B cells at steady-state and significant vaccine-induced changes in the proportions of some B cell clusters. All SPADE clusters, including those altered quantitatively by vaccination, were characterized phenotypically and compared using double hierarchical clustering. Vaccine-altered clusters composed of previously described subsets including CD27hiCD21lo activated memory and CD27+CD21+ resting memory B cells, and subphenotypes with novel patterns of marker coexpression. The expansion, followed by the contraction, of a single memory B cell SPADE cluster was positively correlated with serum anti-vaccine Ab titers. Similar results were generated by a different algorithm, automatic classification of cellular expression by nonlinear stochastic embedding. In conclusion, we present an in-depth characterization of B cell subphenotypes and proportions, before and after vaccination, using a two-step clustering analysis of CyTOF data, which is suitable for longitudinal studies and B cell subsets and biomarkers discovery.

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“…MVA-LEO38-GFP or MVA-LEO160-GFP. Since macrophages are one of the most susceptible cell types to MVA infection (Brandler et al, 2010) and constitute approximately 30% of the total peritoneal cell yield (Ray & Dittel, 2010), only GFP + F4/ 80 high macrophages were analysed (Fig. 3a); both viruses showed similar infective capacity (w80%) (Fig.…”

Section: Promoter Spacer Length and Gfp Antigen Expressionmentioning

confidence: 99%

Modification of promoter spacer length in vaccinia virus as a strategy to control the antigen expression

Pilato

Sánchez-Sampedro

Mejías-Pérez

et al. 2015

Journal of General Virology

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Vaccinia viruses (VACVs) with distinct early promoters have been developed to enhance antigen expression and improve antigen-specific CD8 T-cell responses. It has not been demonstrated how the length of the spacer between the coding region of the gene and its regulatory early promoter motif influences antigen expression, and whether the timing of gene expression can modify the antigen-specific CD4 T-cell response. We generated several recombinant VACVs based on the attenuated modified vaccinia Ankara (MVA) strain, which express GFP or the Leishmania LACK antigen under the control of an optimized promoter, using different spacer lengths. Longer spacer length increased GFP and LACK early expression, which correlated with an enhanced LACK-specific memory CD4 and CD8 T-cell response. These results show the importance of promoter spacer length for early antigen expression by VACV and provide alternative strategies for the design of poxvirus-based vaccines.

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Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect

Cited by 37 publications

References 63 publications

Interplay between Modified Vaccinia Virus Ankara and Dendritic Cells: Phenotypic and Functional Maturation of Bystander Dendritic Cells

Interplay between Modified Vaccinia Virus Ankara and Dendritic Cells: Phenotypic and Functional Maturation of Bystander Dendritic Cells

Identification of Vaccine-Altered Circulating B Cell Phenotypes Using Mass Cytometry and a Two-Step Clustering Analysis

Modification of promoter spacer length in vaccinia virus as a strategy to control the antigen expression

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