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

Garber, David; O'Mara, Leigh A.; Gangadhara, Sailaja; McQuoid, Monica; Zhang, Xiugen; Zheng, Rui; Gill, Kiran; Verma, Meena; Yu, Tianwei; Johnson, Brent A.; Li, Bing; Derdeyn, Cynthia A.; Ibegbu, Chris; Altman, John D.; Hunter, Eric; Feinberg, Mark B.

doi:10.1128/jvi.00246-12

Cited by 35 publications

(47 citation statements)

References 85 publications

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“…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). Moreover, NYVAC vectors with a single deletion of a VACV gene encoding a TLR inhibitor (A46R [83]) and with single or double deletions in VACV genes encoding type I and II IFN binding proteins (B19R and B8R, respectively [84][85][86]) were also able to enhance the immune responses to HIV-1 antigens in mice.…”

Section: Discussionmentioning

confidence: 97%

“…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.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

García-Arriaza

Gómez

Sorzano

et al. 2014

J Virol

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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

García-Arriaza

Gómez

Sorzano

et al. 2014

J Virol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 HIV-1-specific CD4 and CD8 T cell immune responses were further increased by MVA vectors with deletions of two ( A41L / B16R [54]; or C6L / K7R ; Garcia-Arriaza, submitted) or four [IL-18 binding protein (MVA008L; C12L ), Toll/IL-1 receptor homolog (MVA159R; A46R ), CC-chemokine binding protein (MVA153L; B7R ) and secreted IL-1β receptor (MVA184R; B16R )] immunomodulatory genes [59], while an additional fifth deletion of the uracyl-DNA glycosylase gene (MVA101R) decreased the responses [59]. Similarly, NYVAC vectors with single or double deletions in VACV genes B19R and B8R encoding type I and type II IFN binding proteins, respectively, increased the immune responses to HIV antigens in the mouse model [61].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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Viruses have developed strategies to counteract signalling through Toll-like receptors (TLRs) that are involved in the detection of viruses and induction of proinflammatory cytokines and IFNs. Vaccinia virus (VACV) encodes A46 protein which disrupts TLR signalling by interfering with TLR: adaptor interactions. Since the innate immune response to viruses is critical to induce protective immunity, we studied whether deletion of A46R gene in a NYVAC vector expressing HIV-1 Env, Gag, Pol and Nef antigens (NYVAC-C) improves immune responses against HIV-1 antigens. This question was examined in human macrophages and in mice infected with a single A46R deletion mutant of the vaccine candidate NYVAC-C (NYVAC-C-ΔA46R). The viral gene A46R is not required for virus replication in primary chicken embryo fibroblast (CEF) cells and its deletion in NYVAC-C markedly increases TNF, IL-6 and IL-8 secretion by human macrophages. Analysis of the immune responses elicited in BALB/c mice after DNA prime/NYVAC boost immunization shows that deletion of A46R improves the magnitude of the HIV-1-specific CD4 and CD8 T cell immune responses during adaptive and memory phases, maintains the functional profile observed with the parental NYVAC-C and enhances anti-gp120 humoral response during the memory phase. These findings establish the immunological role of VACV A46R on innate immune responses of macrophages in vitro and antigen-specific T and B cell immune responses in vivo and suggest that deletion of viral inhibitors of TLR signalling is a useful approach for the improvement of poxvirus-based vaccine candidates.

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“…While MVA appears to be exceptionally safe, efforts are being made to improve immunogenicity and vaccine production. Two main approaches have been taken to improve immune responses by MVA: deletion of remaining host defense or other genes [29–33] and insertion of cytokine genes [34, 35]. Efforts to improve vaccine production include the replacement of primary chick embryo fibroblasts with avian suspension cell lines [36, 37].…”

Section: 7 Discussionmentioning

confidence: 99%

Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants

Melamed

Wyatt

Kastenmayer

et al. 2013

Vaccine

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Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production.

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

Cited by 35 publications

References 85 publications

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

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

Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants

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