High‐capacity adenoviral vectors circumvent the limitations of ΔE1 and ΔE1/ΔE3 adenovirus vectors to induce multispecific transgene product‐directed CD8 T‐cell responses

Kron, Matthias W.; Engler, Tatjana; Schmidt, Erika; Schirmbeck, Reinhold; Kochanek, Stefan; Kreppel, Florian

doi:10.1002/jgm.1629

Cited by 21 publications

(17 citation statements)

References 45 publications

(79 reference statements)

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“…Enhancing processing of GagL 85-93 through the amino acid substitution in the Gag C1K construct apparently improves its rank in the immunodominance hierarchy. Similar suppression of immune responses to transgene epitopes by adenovirus epitopes has recently been described (15). Epitope competition is also a possible explanation for the considerably higher levels of GagL 85-93 -specific CD8 ϩ T cells induced by the TxnGagL vaccine.…”

supporting

confidence: 73%

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization

Gödel¹,

Windmann²,

Dietze³

et al. 2012

J Virol

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While Friend retrovirus-infected mice readily mount a vigorous CD8؉ T cell response to the leader-gag-derived peptide GagL 85-93 , no GagL 85-93 -specific T cells were detectable in mice immunized against Friend virus (FV) with viral vectors or DNA vaccines. By exchanging one epitope-flanking amino acid or using a scaffold protein we were able to demonstrate for the first time the induction of GagL 85-93 -specific CD8 ؉ T cells by genetic vaccination and show their high protective effect against FV challenge infection. The Gag polyprotein p65 of Friend murine leukemia virus (FMuLV) consists of the structural proteins p15, p12, p30, and p10, which are the main components of the viral capsid. Usage of an alternative start codon upstream of the gag open reading frame adds a leader region to the Gag polyprotein, resulting in the glycosylated protein gp85 gag (12). The leader region of gp85 gag contains an immunodominant CD8 ϩ T cell epitope of Friend virus (FV) (9), and in acutely FV-infected mice up to 15% of the activated CD8 ϩ T cells are GagL 85-93 specific (26). Despite the immunodominance of this epitope in natural FV infection, no induction of GagL 85-93 -specific CD8 ϩ T cells could be detected after immunization of mice with adenovirus (Ad)-based vectors encoding leader-gag (3). Similarly, in mice genetically immunized by plasmid DNA encoding leader-gag, no GagL 85-93 -specific CD8 ϩ T cells could be detected before FV challenge (11), and in vaccination studies with vaccinia virus-based vectors encoding different parts of p65 gag or gp85 gag , no difference in protection was seen whether or not the leader region was included in the vaccine (19). Thus, although the FV model has been used extensively for the development of new concepts for vaccination against retroviruses, none of the genetic vaccines utilized in the past were able to induce CD8 ϩ T cell responses against the immunodominant GagL 85-93 epitope of FV. Therefore, the goal of this study was to develop a genetic vaccine capable of inducing GagL 85-93 -specific immunity.Two factors critically influence if a peptide sequence can be presented as an epitope on a major histocompatibility complex (MHC): the ability to bind to a certain MHC allele and the efficiency of proteasomal degradation resulting in that peptide. Interestingly, neither property is predicted for the immunodominant GagL 85-93 epitope in H-2D b mice using the prediction tools Net-MHC (17) and NetChop (20). As the tyrosine flanking the GagL 85-93 epitope C terminally (C ϩ 1) in the native sequence has been described to be unfavorable for proteasomal degradation (16), inefficiency of processing might be an explanation for the lack of CD8 ϩ T cell immunity after genetic immunization. To overcome this problem, we exchanged the Cϩ1 tyrosine with lysine, since for the resulting protein, leader-gag C1K , proteasomal cleavage after Leu 93 is predicted (20).As an alternative approach, we constructed an adenoviral vector encoding a fusion protein of the murine cellular protein thioredoxin (Txn)...

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supporting

confidence: 73%

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization

Gödel¹,

Windmann²,

Dietze³

et al. 2012

J Virol

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“…Loss of expression was also observed when using HDAd b-Gal vectors in lung (Toietta et al, 2003). Weaver and colleagues clearly demonstrated that HDAds are able to elicit significant transgene-directed T cell and antibody responses (Weaver et al, 2009); whereas Kron and colleagues have shown that HDAd vectors efficiently induced multispecific transgene product-directed CD8 + cytotoxic T lymphocytes (Kron et al, 2011). Furthermore, it has been shown that interferon-c, which would be produced in the course of the T cell-mediated immune response, can inhibit the CMV promoter (Harms and Splitter, 1995).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Transduction by Helper-Dependent Adenoviral Vectors via Intraductal Delivery

Morró

Teichenne²,

Jiménez³

et al. 2014

Human Gene Therapy

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Pancreatic gene transfer could be useful to treat several diseases, such as diabetes mellitus, cystic fibrosis, chronic pancreatitis, or pancreatic cancer. Helper-dependent adenoviral vectors (HDAds) are promising tools for gene therapy because of their large cloning capacity, high levels of transgene expression, and long-term persistence in immunocompetent animals. Nevertheless, the ability of HDAds to transduce the pancreas in vivo has not been investigated yet. Here, we have generated HDAds carrying pancreas-specific expression cassettes, that is, driven either by the elastase or insulin promoter, using a novel and convenient plasmid family and homologous recombination in bacteria. These HDAds were delivered to the pancreas of immunocompetent mice via intrapancreatic duct injection. HDAds, encoding a CMV-GFP reporter cassette, were able to transduce acinar and islet cells, but transgene expression was lost 15 days postinjection in correlation with severe lymphocytic infiltration. When HDAds encoding GFP under the control of the specific elastase promoter were used, expression was detected in acinar cells, but similarly, the expression almost disappeared 30 days postinjection and lymphocytic infiltration was also observed. In contrast, long-term transgene expression (>8 months) was achieved with HDAds carrying the insulin promoter and the secretable alkaline phosphatase as the reporter gene. Notably, transduction of the liver, the preferred target for adenovirus, was minimal by this route of delivery. These data indicate that HDAds could be used for pancreatic gene therapy but that selection of the expression cassette is of critical importance to achieve long-term expression of the transgene in this tissue.

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“…In mice, where all compared adenoviruses could not replicate, the removed targets for vector elimination in HC vectors prolonged transgene expression and facilitated the diversity of transgene directed responses [33]. In monkeys, replication competence of the vector results in an extended transgene expression together with an ongoing infectious response [32,34].…”

Section: Advantages Of Replication-competent Adenovirus Compared Tmentioning

confidence: 99%

“…The added benefit of robustly stimulating the innate immune system with an RC vector has the disadvantage of the expression of all vectors’ genes and competition with the transgene for induction of immune responses. Since the immunodominance of the vector genes over the transgene is already a problem with FG vaccines [31,33], this problem can only be more pronounced in RC vaccines (Figure 2C).…”

Section: Advantages Of Replication-competent Adenovirus Compared Tmentioning

confidence: 99%

“…Whereas the majority of studies are using relatively simple FG or RC adenovirus vector systems, the comparison with complete virus gene-deleted vectors in mice (HC vectors) indicates that vector gene competition is an important parameter [31,33] (Figure 2D). Essentially, the rabies vaccine is, in this review, hypothesized to work by the combination of replication competence and transgene immunodominance.…”

Section: Advantages Of Replication-competent Adenovirus Compared Tmentioning

confidence: 99%

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Future Prospects for the Development of Cost-Effective Adenovirus Vaccines

Fougeroux¹,

Holst²

2017

IJMS

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Vaccination is one of the most efficient tools for disease prevention, and a continuously growing field of research. However, despite progress, we still need more efficient and cost-effective vaccines that would improve access to those in need. In this review, we will describe the status of virus-vectored vaccine technology with a focus on adenoviral-based vaccines. Adenovirus (Ad) vaccines have proven to be efficient in military vaccinations against Ad4 and Ad7 and as highly efficient vectored vaccines against rabies. The question of how other adenovirus-based vaccines can become as efficient as the rabies vaccine is the underlying theme in this review. Here, we will first give an overview of the basic properties of vectored vaccines, followed by an introduction to the characteristics of adenoviral vectors and previously tested modifications of the vector backbone and expression cassettes, with a focus on how they can contribute to increased vaccine cost-effectiveness. Finally, we will highlight a few successful examples of research that have attempted to improve the use of adenoviral-based vaccines by improving the transgene immunogenicity.

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High‐capacity adenoviral vectors circumvent the limitations of ΔE1 and ΔE1/ΔE3 adenovirus vectors to induce multispecific transgene product‐directed CD8 T‐cell responses

Cited by 21 publications

References 45 publications

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization

Pancreatic Transduction by Helper-Dependent Adenoviral Vectors via Intraductal Delivery

Future Prospects for the Development of Cost-Effective Adenovirus Vaccines

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High‐capacity adenoviral vectors circumvent the limitations of ΔE1 and ΔE1/ΔE3 adenovirus vectors to induce multispecific transgene product‐directed CD8 T‐cell responses

Cited by 21 publications

References 45 publications

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8+T Cells by Adenovirus-Based Immunization

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8+T Cells by Adenovirus-Based Immunization

Pancreatic Transduction by Helper-Dependent Adenoviral Vectors via Intraductal Delivery

Future Prospects for the Development of Cost-Effective Adenovirus Vaccines

Contact Info

Product

Resources

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Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization

Modification of One Epitope-Flanking Amino Acid Allows for the Induction of Friend Retrovirus-Specific CD8⁺T Cells by Adenovirus-Based Immunization