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

Fausther-Bovendo, Hugues; Kobinger, Gary P

Although ChAd vectors appear very promising, cross-reacting pre-existing cellular immunity against Ad should not be overlooked. Indeed, in vitro, HAd specific T cells cross-react with ChAd vectors, such as ChAd6 and 7. 34 Similarly, Ad specific T cells from a human cohort recognize HAd5, HAd4 as well as simian derived Ad (SAd-24/ChAd68 and SAd-32) to a similar extent. 33 This could be expected due to the close phylogenetic proximity between human and chimpanzee Ad, 46,70 more specifically to the highly conserved hexon C-terminal sequences that are recognized by Ad cross-reactive T cells. [27] [28] [29] [30] 33 The inhibitory role of Ad specific T cells on ChAd vectors was confirmed in animal models. In rare occasion, such as in the mouse model of malaria infection, pre-existing immunity to HAd5 reduced protection mediated by ChAd7 or ChAd 9 immunization. 66 However, in most animal models, although ChAd induced protection was not impacted by pre-existing HAd5 immunity, 46, 63, 65, 71 ChAd induced immune responses tend to be lower in the presence of pre-existing immunity to HAd5. It is worth noting that the animal models mentioned above might underestimate the importance of cellular immunity. In pre-clinical studies, preexisting immunity is usually generated by a single injection with a replication deficient Ad vector. 46, 63, 65, 71 This artificial preexisting immunity may not recapitulate the potent Ad specific T cell response observed in humans following repeated exposure to replication competent Ad that initiate productive infections. Indeed, in primates, multiple exposures of replication competent Ad over time gives rise to polyfunctional and highly potent T cells.