Strategies to overcome host immunity to adenovirus vectors in vaccine development

Thacker, Erin E.; Timares, Laura; Matthews, Qiana L.

doi:10.1586/erv.09.29

Cited by 91 publications

(68 citation statements)

References 207 publications

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“…This initiated interest in the development of nonhuman AdVs, including FAdVs, which are an attractive choice both as vaccine vectors for poultry (15,16) and as gene therapy vectors. The optimization of delivery routes and application regimens of AdV vectors are also needed to counteract the limitations of HAdV-based vaccines (21). Moreover, oral administration of AdV vectors is better able to avoid systemic neutralizing antibodies than are other routes of administration (29,30).…”

Section: Discussionmentioning

confidence: 99%

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Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Deng

Sharif

Nagy

2013

Clin Vaccine Immunol

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Fowl adenoviruses (FAdVs) are a potential alternative to human adenovirus-based vaccine vectors. Our previous studies demonstrated that a 2.4-kb region at the left end of the FAdV-9 genome is nonessential for virus replication and is suitable for the insertion or replacement of transgenes. Our in vivo study showed that the virus FAdV-9⌬4, lacking six open reading frames (ORFs) at the left end of its genome, replicates less efficiently than wild-type FAdV-9 (wtFAdV-9) in chickens that were infected intramuscularly. However, the fecal-oral route is the natural route of FAdV infection, and the oral administration of a vaccine confers some advantages compared to administration through other routes, especially when developing an adenovirus as a vaccine vector. Therefore, we sought to investigate the effects of FAdV-9 in orally inoculated chickens. In the present study, we orally inoculated specific-pathogen-free (SPF) chickens with FAdV-9 and FAdV-9⌬4 and assessed virus shedding, antibody response, and viral genome copy number and cytokine gene expression in tissues. Our data showed that FAdV-9⌬4 replicated less efficiently than did wtFAdV-9, as evidenced by reduced virus shedding in feces, lower viral genome copy number in tissues, and lower antibody response, which are consistent with the results of the intramuscular route of immunization. Furthermore, we found that both wtFAdV-9 and FAdV-9⌬4 upregulated the mRNA expression of alpha interferon (IFN-␣), IFN-␥, and interleukin-12 (IL-12). In addition, there was a trend toward downregulation of IL-10 gene expression caused by both viruses. These findings indicate that one or more of the six deleted ORFs contribute to modulating the host response against virus infection as well as virus replication in vivo.

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Section: Discussionmentioning

confidence: 99%

“…All these studies suggest the importance of the left-end genes of the FAdV-9 genome in virus replication, immune response modulation, and vector design. Moreover, the optimization of delivery routes and regimens is important for overcoming the potential limitations of AdV-based vaccines for both human and animal applications (21).…”

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confidence: 99%

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Deng

Sharif

Nagy

2013

Clin Vaccine Immunol

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“…However, the use of viral vectors in medical applications presents some concerns because of their potential to alter the host genome by random integration of viral genes into the host genome (Fischer et al, 2011). Immunogenicity produced by viral proteins is another problem limiting the use of viral vectors (Thacker et al, 2009). Retroviral vectors do integrate into the host DNA to replicate and express the genes that they carry.…”

Section: Introductionmentioning

confidence: 99%

In vitro transcription and validation of human pancreatic transcription factors’ mRNAs

Akinci¹,

Yildiz²,

Ünal³

et al. 2017

Turk J Biol

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Direct reprogramming of pancreatic beta cells is of great interest due to its possible use in diabetes treatment. Various studies have demonstrated direct reprogramming of insulin expressing beta cells from other somatic cells by overexpressing important pancreatic transcription factors through viral vectors. However, concerns about using viral vectors in the clinic have prompted scientists to find new approaches for gene delivery and expression. In vitro synthesis and transfection of mRNAs is a safer strategy for ectopic gene expression. In this study we aimed to design and in vitro synthesize human pancreatic transcription factors' mRNAs: Pdx1, Ngn3, and MafA. We also aimed to assess their expression efficiency in cultured cells. First we ligated the open reading frames of these genes to modified 5′ and 3′ UTRs. Ligation products were then cloned into a plasmid and subjected to in vitro transcription to get their corresponding mRNAs. Modified mRNAs were subsequently examined for their quality, quantity, and protein translation efficiency. In vitro-transcribed mRNAs were successfully transfected to the human fibroblast cells. Efficiently translated proteins were correctly localized into the nucleus. It is concluded that pancreatic mRNAs designed and in vitro-transcribed in this study can be used in further direct beta cell reprogramming studies.

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“…The adenovirus (Ad) expression system, one of the most widely-used viral expression systems, shows more advan-tages than other systems, such as easy construction, higher efficiency of gene transfer, higher titers and induction of humoral, mucosal and cellular immune responses (Benihoud et al, 1999;Douglas, 2007;Ferreira et al, 2005;Kovesdi et al, 1997;Thacker et al, 2009). Adenovirus vector system expressing PCV2 Cap protein has been studied, but has limited immune efficiency (Wang et al, 2006(Wang et al, , 2007.…”

Section: Introductionmentioning

confidence: 99%

Modified recombinant adenoviruses increase porcine circovirus 2 capsid protein expression and induce enhanced immune responses in mice

Li¹,

Huang²,

Liu³

et al. 2016

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Summary. -Porcine circovirus type 2 (PCV2) is the primary viral pathogen of porcine circovirus associated disease (PCVAD) and vaccination is an important method to prevent and control the disease. The expression of PCV2 capsid protein (Cap) in adenovirus vector system has been investigated, but the poor immune responses limit its application. In this study, transcriptional enhancer element largest intron of the human cytomegalovirus (Intron A) and woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) were applied to increase the immunogenicity of PCV2 Cap adenovirus-based vaccine. Western blot and indirect immunofluorescence assay (IFA) analysis showed that modified adenoviruses with Intron A and WPRE alone or both could significantly increase the expression of Cap compared to the unmodified adenoviruses. Furthermore, the humoral and cellular immune responses of the constructed recombinant adenoviruses were evaluated in mice. Indirect ELISA, virus neutralizing test and western blot showed that modified adenoviruses elicited higher humoral immune responses than unmodified adenovirus, and Intron A-WPRE-modified virus immunized group had better immune response than the others. Besides, the results of lymphocyte proliferation response and cytokines release assay showed that enhanced cellular immune responses were induced by modified adenoviruses. These results demonstrated that Intron A and WPRE significantly improved the expression of the Cap protein in adenovirus vector system and enhanced the immune responses in mice, making the adenovirus vector system more applicable against PCV2.Keywords: modified recombinant adenoviruses; porcine circovirus type 2; capsid protein; immune responses * Corresponding author. E-mail: dwtong@nwsuaf.edu.cn; phone: +86-29-8709-1622. Abbreviations: iELISA = indirect enzyme-linked immunosorbent assay; PCV2 = porcine circovirus type 2; PCVAD = porcine circovirus associated disease; VN = virus neutralization assay; WPRE = woodchuck hepatitis virus post-transcriptional regulatory element

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Strategies to overcome host immunity to adenovirus vectors in vaccine development

Cited by 91 publications

References 207 publications

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

Oral Inoculation of Chickens with a Candidate Fowl Adenovirus 9 Vector

In vitro transcription and validation of human pancreatic transcription factors’ mRNAs

Modified recombinant adenoviruses increase porcine circovirus 2 capsid protein expression and induce enhanced immune responses in mice

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