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

Fausther-Bovendo, Hugues; Kobinger, Gary P

Tissue resident memory T cells (T RM ) are memory CD8 T cells which, unlike effector memory CD8 T (T EM ) cells that circulate between blood and extra-lymphoid organs, do not circulate and remain confined to the tissue where the original infection occurred (For reviews see refs. [81] [82] [83] ). T RM have been shown to induce better protection compared with T EM . Using parabiotic mice, skin resident T cells were shown to confer better protection against vaccinia virus skin infection compared with circulating memory T cells. 84 Similarly, T RM induced a greater viral load reduction after skin and vaginal infection with Herpes simplex virus (HSV) compared with T EM. 85 In addition, T RM were still detectable in tissues after effector memory T cells were no longer visible in circulation. 86 Tissue specificity of T RM is mainly determined during priming by tissue derived migratory dendritic cells (DC). Migratory DCs from different tissues induce T RM with different homing molecules and therefore different tissue specificity. 83 Various immunization routes result in antigen (Ag) presentation by distinct tissue derived migratory DC and therefore, generation of T RM with different tissue specificity (Fig. 3) . In the Richardson and colleagues study, IM injection probably did not generate T RM in the lung. Subsequent airway immunizations (intranasal/ intratracheal) would be affected by the previously generated Ad specific T EM in the circulation but not by T RM, which would be absent from the lung. The ability to detect Ad specific T cells in human colon biopsies as well as in NHP gut (Ileum, colon and rectum) is supporting the existence of Ad specific T RM . 33 However, there are limitations in using different immunization routes to circumvent Ad pre-existing immunity. There are limited routes of immunization including intradermal, oral, intranasal/intratracheal, IM, sublingual and intravenous (IV). The latter may not be the best route for Ad vector immunization as one fatality has been reported in a gene therapy clinical trial. 87 Furthermore, the route of natural Ad infections has to be considered in order to determine where putative Ad specific T RM are to be located in humans. Natural Ad infections mainly target the respiratory tract, and to lower extend the eye, gut and urinary tract of infected individuals. 9,40 Therefore, Ad specific T RM may be present in the lung and gastro-intestinal tract of Ad immune individuals, which may affect intranasal/intratracheal and oral immunizations, respectively. This will need to be evaluated experimentally in the future.