The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for use as vaccines and therapeutics relatively straightforward in comparison with other viral vectors. In this review we summarize the structure and life cycle of the adenovirus and focus on the use of adenovirus-based vectors in vaccines against infectious diseases and cancers. Strategies to overcome the problem of preexisting antiadenovirus immunity, which can hamper the immunogenicity of adenovirus-based vaccines, are discussed. When armed with tumor-associated antigens, replication-deficient and oncolytic adenoviruses can efficiently activate an antitumor immune response. We present concepts on how to use adenoviruses as therapeutic cancer vaccines and consider some of the strategies used to further improve antitumor immune responses. Studies that explore the prospect of adenoviruses as vaccines against infectious diseases and cancer are underway, and here we give an overview of the latest developments.

Adenovirus-based vaccines for fighting infectious diseases and cancer : progress in the field

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed.

Emerging therapeutic approaches in the management of retinal angiogenesis and edema

Purpose To determine whether the duration of transgene expression from an alternate adenovector serotype, Ad35, can provide advantages over an Ad5 serotype vector following a single intravitreal (IVT) administration. Methods To assess the transgene expression profile, mice received one IVT injection of Ad5- or Ad35-based vectors expressing green fluorescent protein (GFP), luciferase or pigment epithelium-derived factor (PEDF). At specified time points following vector administration, eyes were monitored for GFP expression, or eyes were harvested and assayed for adenovector genomes, luciferase activity or PEDF levels. Ad35-based vector in vivo biologic activity was investigated using a mouse model of laser-induced choroidal neovascularization (CNV). On Day 0, mice received one IVT injection of Ad5.PEDF or Ad35.PEDF (HI-RGD) followed by laser-induced CNV on Day 28. Fourteen days later, animals were perfused with fluorescein-labeled dextran and CNV lesion size quantitated in choroidal flat mounts. Results These studies demonstrate that following a single IVT adenovector administration: 1) gene expression is prolonged following administration of an Ad35 compared to an Ad5-based vector; 2) the amount of vector genomes in the eye remain constant out to 60 days post injection of both Ad5 and Ad35-based vectors; and 3) an Ad35.PEDF (HI-RGD) vector inhibits CNV in a mouse model at 42 days post injection. Conclusions These studies show that transgene and genome levels are prolonged in the eye following 1 IVT injection of an Ad35-based vector. Moreover, therapeutic gene levels from 1 IVT administration of Ad35.PEDF (HI-RGD) vector block abnormal blood vessel growth in a laser-induced CNV mouse model.

/pdf/alternate-serotype-adenovector-provides-long-term-1tg13xovuv.pdf

Alternate serotype adenovector provides long-term therapeutic gene expression in the eye.

The CMV promoter drives high transgene expression and is one of the most commonly used promoters for gene transfer. Tissue-specific mammalian promoters provide an alternative, and it would be useful to have a system to directly compare them to viral promoters free from potential confounding vector-related effects. In this study, we describe how electroporation after subretinal injection of plasmid DNA can be used to perform comparative quantitative analysis of promoter activities. Luciferase assay of eyecup homogenates was carried out after coinjection/electroporation of pGL2, a plasmid containing the promoter fragment of interest coupled to the firefly luciferase gene, and pRL-CMV, a plasmid containing the CMV promoter coupled to the Renilla luciferase gene for normalization. This technique was used to compare activity of different fragments of the 5′-upstream region of the vitelliform macular dystrophy 2 (VMD2) gene, which is selectively expressed in the retinal pigmented epithelial (RPE) cells, and results indicated positive regulatory elements between −104 and −154 bp and between −424 and −585 bp. Addition of a fragment from intron 1 reduced the activity of the −585/+38 bp fragment by 75%. Deletion analysis implicated a 342 bp region near the 5′-end of intron 1 in the repression. Results of transient transfections in two cell lines that constitutively express VMD2 were similar, and results in transgenic mice were consistent, providing validation for promoter analysis by in vivo electroporation. We then explored the time course of expression of the −585/+38 VMD2 promoter fragment and found that compared to cassettes driven by CMV or SV40 promoters, which showed peak luciferase activity on day 2 followed by a rapid decrease in activity, the VMD2 promoter fragment showed lower activity initially, but the activity was sustained for up to 56 days (longest time point measured). A promoter fragment from another RPE-specific gene, Rpe65, showed a similar pattern of sustained expression for at least 112 days. These data indicate that nonviral gene transfer can be used to quantitatively evaluate the activity of promoter fragments independent of influence from viral vectors. A potentially important finding using this new technique is the demonstration that relatively sustained passenger gene expression can be achieved with nonviral gene transfer using mammalian rather than viral promoters.

Sustained expression after nonviral ocular gene transfer using mammalian promoters

Development of an effective HIV/AIDS vaccine remains a big challenge, largely due to the enormous HIV diversity which propels immune escape. Thus novel vaccine strategies are targeting multiple variants of conserved antibody and T cell epitopic regions which would incur a huge fitness cost to the virus in the event of mutational escape. Besides immunogen design, the delivery modality is critical for vaccine potency and efficacy, and should be carefully selected in order to not only maximize transgene expression, but to also enhance the immuno-stimulatory potential to activate innate and adaptive immune systems. To date, five HIV vaccine candidates have been evaluated for efficacy and protection from acquisition was only achieved in a small proportion of vaccinees in the RV144 study which used a canarypox vector for delivery. Conversely, in the STEP study (HVTN 502) where human adenovirus serotype 5 (Ad5) was used, strong immune responses were induced but vaccination was more associated with increased risk of HIV acquisition than protection in vaccinees with pre-existing Ad5 immunity. The possibility that pre-existing immunity to a highly promising delivery vector may alter the natural course of HIV to increase acquisition risk is quite worrisome and a huge setback for HIV vaccine development. Thus, HIV vaccine development efforts are now geared toward delivery platforms which attain superior immunogenicity while concurrently limiting potential catastrophic effects likely to arise from pre-existing immunity or vector-related immuno-modulation. However, it still remains unclear whether it is poor immunogenicity of HIV antigens or substandard immunological potency of the safer delivery vectors that has limited the success of HIV vaccines. This article discusses some of the promising delivery vectors to be harnessed for improved HIV vaccine efficacy.

/pdf/the-influence-of-delivery-vectors-on-hiv-vaccine-efficacy-4uoxaebu3a.pdf

The influence of delivery vectors on HIV vaccine efficacy.

We have generated hexon-modified adenovirus serotype 5 (Ad5) vectors that are not neutralized by Ad5-specific neutralizing antibodies in mice. These vectors are attractive for the advancement of vaccine products because of their potential for inducing robust antigen-specific immune responses in people with prior exposure to Ad5. However, hexon-modified Ad5 vectors displayed an approximate 10-fold growth defect in complementing cells, making potential vaccine costs unacceptably high. Replacing hypervariable regions (HVRs) 1, 2, 4, and 5 with the equivalent HVRs from Ad43 was sufficient to avoid Ad5 preexisting immunity and retain full vaccine potential. However, the resulting vector displayed the same growth defect as the hexon-modified vector carrying all 9 HVRs from Ad43. The growth defect is likely due to a defect in capsid assembly, since DNA replication and late protein accumulation were normal in these vectors. We determined that the hexon-modified vectors have a 32°C cold-sensitive phenotype and selected revertants that restored vector productivity. Genome sequencing identified a single base change resulting in a threonine-to-methionine amino acid substitution at the position equivalent to residue 342 of the wild-type protein. This mutation has a suppressor phenotype (SP), since cloning it into our Ad5 vector containing all nine hypervariable regions from Ad43, Ad5.H(43m-43), increased yields over the version without the SP mutation. This growth improvement was also shown for an Ad5-based hexon-modified vector that carried the hexon hypervariable regions of Ad48, indicating that the SP mutation may have broad applicability for improving the productivity of different hexon-modified vectors.

Identification of a Suppressor Mutation That Improves the Yields of Hexon-Modified Adenovirus Vectors

Activation of Gene Expression from Silenced Adenovector Genomes

Repeat Dosing of Adenovector in the Eye

Ocular Sublocalization and Pharmacokinetics of Expression of Pigment Epithelium-Derived Factor in Murine Eyes Following Adenovirus-Based Intravitreous Gene Delivery

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Identification of a Suppressor Mutation That Improves the Yields of Hexon-Modified Adenovirus Vectors

Activation of Gene Expression from Silenced Adenovector Genomes

Repeat Dosing of Adenovector in the Eye

Ocular Sublocalization and Pharmacokinetics of Expression of Pigment Epithelium-Derived Factor in Murine Eyes Following Adenovirus-Based Intravitreous Gene Delivery