Factors Which Contribute to the Immunogenicity of Non-replicating Adenoviral Vectored Vaccines

Abstract

Adenoviral vectors are a safe and potently immunogenic vaccine delivery platform. Non-replicating Ad vectors possess several attributes which make them attractive vaccines for infectious disease, including their capacity for high titer growth, ease of manipulation, safety, and immunogenicity in clinical studies, as well as their compatibility with clinical manufacturing and thermo-stabilization procedures. In general, Ad vectors are immunogenic vaccines, which elicit robust transgene antigen-specific cellular (namely CD8 + T cells) and/or humoral immune responses. A large number of adenoviruses isolated from humans and non-human primates, which have low seroprevalence in humans, have been vectorized and tested as vaccines in animal models and humans. However, a distinct hierarchy of immunological potency has been identified between diverse Ad vectors, which unfortunately limits the potential use of many vectors which have otherwise desirable manufacturing characteristics. The precise mechanistic factors which underlie the profound disparities in immunogenicity are not clearly defined and are the subject of ongoing, detailed investigation. It has been suggested that a combination of factors contribute to the potent immunogenicity of particular Ad vectors, including the magnitude and duration of vaccine antigen expression following immunization. Furthermore, the excessive induction of Type I interferons by some Ad vectors has been suggested to impair transgene expression levels, dampening subsequent immune responses. Therefore, the induction of balanced, but not excessive stimulation of innate signaling is optimal. Entry factor binding or receptor usage of distinct Ad vectors can also affect their in vivo tropism following administration by different routes. The abundance and accessibility of innate immune cells and/or antigen-presenting cells at the site of injection contributes to early innate immune responses to Ad vaccination, affecting the outcome of the adaptive immune response. Although a significant amount of information exists regarding the tropism determinants of the common human adenovirus type-5 vector, very little is known about the receptor usage and tropism of rare species or non-human Ad vectors. Increased understanding of how different facets of the host response to Ad vectors contribute to their immunological potency will be essential for the development of optimized and customized Ad vaccine platforms for specific diseases.

Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection

“…Positive staining was patchy, as would be expected for non-uniform transduction of the lung with the Ad-hACE2 vector. Transduction of epithelial cells, alveolar macrophages and endothelial cells is consistent with the known tropism and target cells for HAdV-C5 based vectors in mice [ 33 , 38 , 39 ]. Although the lowest dose of Ad-hACE2 (7.5×10 7 PFU) appeared to yield a similar distribution of transduction in the lung to the highest dose (2.5×10 8 PFU), the intensity of staining appeared to be dose-dependent with more intense brown staining for hACE2 in the highest dose of Ad-hACE2 (2.5×10 8 PFU).…”

“…Recombinant Ad vectors can be used to transduce a wide-range of cell types, both in vitro and in vivo, and are well-established to facilitate sustained transgene expression when used as a delivery vector (33). Prior studies have demonstrated that Ad-mediated delivery of a functional viral entry receptor into mice, such as the human dipeptidyl peptidase 4 (hDPP4) receptor for Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV), can render them permissive to infection with human viruses, which are otherwise unable to support viral entry using the murine receptor homolog (26,34).…”

Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

“…Some studies using Ad-hACE2 have used IFNAR -/mice, or have blocked IFNAR1 using α-IFNAR1 mAbs, demonstrating that a lack of intact type I IFN response in mice resulted in greater weight loss and exacerbated lung pathology upon SARS-CoV-2 infection (15,33), and concluding that IFN may have protective effects against SARS-CoV-2. However, this should be validated in an additional model for hACE2, as there is evidence that blockade of Type I IFN can affect transgene expression from nonreplicating Ad vectors and T cell responses to the transgene/vector, which could confound results (39,62).…”

“…Recombinant Ad vectors can be used to transduce a wide-range of cell types, both in vitro and in vivo, and are well-established to facilitate sustained transgene expression when used as a delivery vector (39)(40)(41).…”

Viral Related Tools against SARS-CoV-2

“…The use of virus-based vaccines has been studied for many years, although until now only one viral-vector vaccine has been approved for use in humans, the rVSV-ZEBOV-GP indicated against Ebola [ 124 ]. Nevertheless, some of them are in the final steps of the clinical trials [ 125 ]. Despite all the advantages that this kind of vaccines have, they still have some disadvantages such as the pre-existing immunity that can be found against the most common viral-vectors (poxvirus and adenovirus), which might decrease the efficacy of the vaccine [ 126 ], or the lack of proper animal models [ 127 ].…”