Immune Recognition of Gene Transfer Vectors: Focus on Adenovirus as a Paradigm

Abstract

Recombinant Adenovirus (Ad) based vectors have been utilized extensively as a gene transfer platform in multiple pre-clinical and clinical applications. These applications are numerous, and inclusive of both gene therapy and vaccine based approaches to human or animal diseases. The widespread utilization of these vectors in both animal models, as well as numerous human clinical trials (Ad-based vectors surpass all other gene transfer vectors relative to numbers of patients treated, as well as number of clinical trials overall), has shed light on how this virus vector interacts with both the innate and adaptive immune systems. The ability to generate and administer large amounts of this vector likely contributes not only to their ability to allow for highly efficient gene transfer, but also their elicitation of host immune responses to the vector and/or the transgene the vector expresses in vivo. These facts, coupled with utilization of several models that allow for full detection of these responses has predicted several observations made in human trials, an important point as lack of similar capabilities by other vector systems may prevent detection of such responses until only after human trials are initiated. Finally, induction of innate or adaptive immune responses by Ad vectors may be detrimental in one setting (i.e., gene therapy) and be entirely beneficial in another (i.e., prophylactic or therapeutic vaccine based applications). Herein, we review the current understanding of innate and adaptive immune responses to Ad vectors, as well some recent advances that attempt to capitalize on this understanding so as to further broaden the safe and efficient use of Ad-based gene transfer therapies in general.

Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2

“…27,28 Our present and previously published data have demonstrated that expression of EAT-2 during initial antigen presentation enhanced the production of proinflammatory cytokines and chemokines, as well as upregulated the expression of co-stimulatory molecules on the surface of APCs. 34,58 In this study, we focused on the kinetics and amplitude of cytokine and chemokine production levels following rAd5-EAT2 administration in vivo . Significantly, EAT-2 overexpression enhances the soluble proinflammatory repertoire by enhancing the production of the Th1-type-skewing cytokines (IFNγ, IL-12 and IL-1α) while minimizing the induction of Th2-type-enhancing cytokines (IL-10) and chemokines (EOTAXIN and KC).…”

Modeling Pre-Existing Immunity to Adenovirus in Rodents: Immunological Requirements for Successful Development of a Recombinant Adenovirus Serotype 5-Based Ebola Vaccine

“…Approximately 45% of the healthy adult population in the United States and India, 72% in China and 80% in South Africa, Gambia and Thailand have serological evidence of PEI to Ad5 in the context of measurable anti-Ad5 neutralizing antibody (NAB) titers in the circulation 12–15 . This may manifest as high levels of pro-inflammatory cytokines at the time the vaccine is given, a humoral antibody response that neutralizes the adenovirus, or a cellular immune response that targets and destroys cells expressing adenoviral antigens 11, 16 .…”

Stimulation of Innate Immunity byIn VivoCyclic di-GMP Synthesis Using Adenovirus

“…Adenovirus vectors transduce large fragments of DNA into a wide range of cells in order to synthesize proteins in vivo, and gene expression can be modulated and even localized to specific cell types. Unlike that for other types of viral delivery systems, the DNA delivered by adenovirus vectors does not integrate into the genome and thus the danger of insertional mutagenesis is circumvented (22). Adenovirus vectors have been shown to induce innate immunity, which is partially due to induction of the STING DNA recognition pathway (23).…”