Human AdV-20-42-42, a Promising Novel Adenoviral Vector for Gene Therapy and Vaccine Product Development

Abstract

Pre-existing immune responses towards adenoviral vector limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest to vectorize novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton-base which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver and spleen and triggered robust inflammatory immune response. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination. IMPORTANCE Adenoviral vectors are currently under investigation for a broad range of therapeutic indications in diverse fields, such as oncology and gene therapy, as well as for vaccination both for human and veterinary use. A wealth of data shows that pre-existing immune responses may limit the use of a vector. Particularly in the current climate of global pandemic, there is a need to expand the toolbox with novel adenoviral vectors for vaccine development. Our data demonstrates that we have successfully vectorized a novel adenovirus type candidate with low seroprevalence. The cell transduction data and antigen-specific immune responses induced in vivo demonstrate that this vector is highly promising for the development of gene therapy and vaccine products.

Building a Scaffold for Arteriovenous Fistula Maturation: Unravelling the Role of the Extracellular Matrix

“…Both cross-linking and microfibril-assembly of collagen, elastin, and fibrillin are known to be influenced by intrinsic redox regulation, affecting the protein’s cysteine residues and MMP-2 and MMP-9 [ 159 ]. Moreover, adenoviral-delivered gene therapy is a well-studied delivery method in vein grafts and AVFs [ 160 , 161 , 162 ] and could be employed to target LOX, MMPs, or TIMPs.…”

The use of adenoviral vectors in gene therapy and vaccine approaches

“…It has a tropism to cells with CD46 receptor rather than cells expressing CAR (coxsackie and adenovirus receptor), but this can be overcome by construction of a chimeric Ad35 expressing the Ad5 fiber knob ( Nanda et al, 2005 ). Several other adenoviruses with low seroprevalence have been engineered into non-replicative adenoviral vectors, such as: Ad11 ( Holterman et al, 2004 ); Ad41 ( Lemiale et al, 2007 ); Ad56 ( Duffy et al, 2018 ); Ad19a, which transduces dendritic cells ( Ragonnaud et al, 2018 ); Ad20-42-42, which is related to type 42 but with a penton base derived from type 20 and tropism to both CAR and CD46 receptors ( Ballmann et al, 2021 ); Ad26, Ad48 and Ad50 are rare types, the Ad26 vector was shown to be the most immunogenic and more interesting in vaccine development ( Abbink et al, 2007 ). Ad26 uses sialic acid as a primary target in the cell ( Baker et al, 2019 ).…”