Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever

Schäfer, Björn Malte; Holzer, Georg W.; Joachimsthaler, Alexandra; Coulibaly, Sogue; Schwendinger, Michael G.; Crowe, Brian A.; Kreil, Thomas R.; Barrett, Perry; Falkner, Falko G.

doi:10.1371/journal.pone.0024505

Cited by 25 publications

(25 citation statements)

References 65 publications

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“…A potentially safer Vero cell-derived inactivated vaccine was evaluated in phase I clinical trial (Monath et al, 2011). Candidate experimental vaccines also include NS1 protein vaccine (Schlesinger et al, 1986), as well as the modified vaccinia Ankara and the D4R-defective vaccinia viruses expressing 17D prME protein (Schafer et al, 2011). In this study, we configured recently developed iDNA® approach (Tretyakova et al, 2014; Tretyakova et al, 2013) to prepare a novel experimental vaccine for YFV.…”

Section: Discussionmentioning

confidence: 99%

Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice

et al. 2014

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Yellow fever (YF) causes an acute hemorrhagic fever disease in tropical Africa and Latin America. To develop a novel experimental YF vaccine, we applied iDNA infectious clone technology. The iDNA represents plasmid that encodes the full-length RNA genome of 17D vaccine downstream from a cytomegalovirus (CMV) promoter. The vaccine was designed to transcribe the full-length viral RNA and to launch 17D vaccine virus in vitro and in vivo. Transfection with 10ng of iDNA plasmid was sufficient to start replication of vaccine virus in vitro. Safety of the parental 17D and iDNA-derived 17D viruses was confirmed in AG129 mice deficient in receptors for IFN-α/β/γ. Finally, direct vaccination of BALB/c mice with a single 20µg dose of iDNA plasmid resulted in seroconversion and elicitation of virus-specific neutralizing antibodies in animals. We conclude that iDNA immunization approach combines characteristics of DNA and attenuated vaccines and represents a promising vaccination strategy for YF.

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Section: Discussionmentioning

confidence: 99%

Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice

et al. 2014

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“…8K). The discrepancy between downregulation of MHC-I and that of MHC-II may provide an indication of why recombinant MVA induces stronger CD8 ϩ than CD4 ϩ T cell responses (4,67) (Fig. 4 and 7).…”

Section: Discussionmentioning

confidence: 99%

Modified Vaccinia Virus Ankara-Based Vaccine Vectors Induce Apoptosis in Dendritic Cells Draining from the Skin via both the Extrinsic and Intrinsic Caspase Pathways, Preventing Efficient Antigen Presentation

Guzman¹,

Cubillos‐Zapata²,

Cottingham

et al. 2012

J Virol

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Dendritic cells (DC) are potent antigen-presenting cells and central to the induction of immune responses following infection or vaccination. The collection of DC migrating from peripheral tissues by cannulation of the afferent lymphatic vessels provides DC which can be used directly ex vivo without extensive in vitro manipulations. We have previously used bovine migrating DC to show that recombinant human adenovirus 5 vectors efficiently transduce afferent lymph migrating DEC-205 + CD11c + CD8 − DC (ALDC). We have also shown that recombinant modified vaccinia virus Ankara (MVA) infects ALDC in vitro , causing downregulation of costimulatory molecules, apoptosis, and cell death. We now show that in the bovine system, modified vaccinia virus Ankara-induced apoptosis in DC draining from the skin occurs soon after virus binding via the caspase 8 pathway and is not associated with viral gene expression. We also show that after virus entry, the caspase 9 pathway cascade is initiated. The magnitude of T cell responses to mycobacterial antigen 85A (Ag85A) expressed by recombinant MVA-infected ALDC is increased by blocking caspase-induced apoptosis. Apoptotic bodies generated by recombinant MVA (rMVA)-Ag85A-infected ALDC and containing Ag85A were phagocytosed by noninfected migrating ALDC expressing SIRPα via actin-dependent phagocytosis, and these ALDC in turn presented antigen. However, the addition of fresh ALDC to MVA-infected cultures did not improve on the magnitude of the T cell responses; in contrast, these noninfected DC showed downregulation of major histocompatibility complex class II (MHC-II), CD40, CD80, and CD86. We also observed that MVA-infected ALDC promoted migration of DEC-205 + SIRPα + CD21 + DC as well as CD4 + and CD8 + T cells independently of caspase activation. These in vitro studies show that induction of apoptosis in DC by MVA vectors is detrimental to the subsequent induction of T cell responses.

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“…Delivery of YFV antigens by live-attenuated, recombinant vaccinia constructs was shown to be feasible in the late 1990s[73]. A recent effort used the replication-deficient modified vaccinia virus Ankara (MVA) and d4R defective vaccinia virus (dVV) to vector the 17D prM/M-E antigen protected mice from intracerebral challenge with 17D when administered in a single dose (17D substrains, though highly attenuated in humans, are virulent for mice when directly introduced to the brain) [74]. The study not only demonstrated protection and immunogenicity of the constructs, but also high apparent safety in mice, as the vaccines themselves were not neurotropic when administered at doses exceeding the that required to induce protection.…”

Section: New Yfv Vaccine Candidate Technologies and Monitoring Of Safetymentioning

confidence: 99%

Current status and future prospects of yellow fever vaccines

Beck

Barrett²

2015

Expert Review of Vaccines

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Summary Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized for historically immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be life-long. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease.

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Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever

Cited by 25 publications

References 65 publications

Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice

Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice

Modified Vaccinia Virus Ankara-Based Vaccine Vectors Induce Apoptosis in Dendritic Cells Draining from the Skin via both the Extrinsic and Intrinsic Caspase Pathways, Preventing Efficient Antigen Presentation

Current status and future prospects of yellow fever vaccines

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