Pre-existing immunity against Ad vectors: Humoral, cellular, and innate response, what's important?

Fausther-Bovendo, Hugues; Kobinger, Gary P

has been on the development of new animal based Ad vectors, especially Ad vectors of simian origin. While most of these vectors are in pre-clinical phases of development, some, including ChAd3 and ChAd63, have reached clinical trials. Selection of alternative Ad serotypes has been mainly driven by the absence of neutralizing Ab against these serotypes in the human population. However, the impact of Ad specific T cells on the efficacy of these vectors has been mainly overlooked. This is in part due to the complex nature of T cell assays that are designed to detect anti-Ad T cell responses. Compared with nAbs assays, T cell assays require complex stimulatory conditions and/or multi-parametric flow cytometry. The study of Ad specific T cell responses are further complicated by the presence of T RM that do not circulate in the blood. Isolation of these T cells usually requires mechanical and/or enzymatic disruption of the tissue of interest. These isolation procedures can affect T cell viability and function, which further complicates analysis of T RM cells. In addition, for obvious ethical reasons, isolation of T RM cells is restricted to animal models for most tissues except the skin and gut. Although harder to obtain, information regarding both Ad specific circulating and tissue resident T cells is necessary for a full understanding of preexisting immunity against Ad vectors and to select the most appropriate Ad vector for clinical use. Therefore, the ability of Ad specific T cells in the target population to cross-react with the Ad vector being developed (chimpanzee, porcine, bovine, ovine) should be systematically investigated.