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

Fausther-Bovendo, Hugues; Kobinger, Gary P

Low seroprevalence human Ad Due to the importance of nAbs in dampening Ad vector efficacy, Ad vectors were developed using human Ad with low seroprevalence in the human population. Among these vectors, both HAd35 and HAd26 vectors have been tested and shown to be safe in phase I clinical trials. [54] [55] [56] However, compared with HAd5, human serotype vectors based on low seroprevalence, including Ad35 and Ad26, have shown lower immunogenicity 12,46,57-59 and protection efficacy in the non-human primate (NHP) model of Ebola virus infection, 45 therefore questioning their clinical utility. In addition to lower immunogenicity, the protection efficacy of vectors based on low seroprevalence serotypes will probably also suffer from pre-existing Ad specific T cells. Although HAd5 specific neutralizing Ab do not cross-react with HAd35, 60 HAd2 specific T cells, which are common in the human population, were able to cross-react with HAd35. Furthermore, HAd35 cross-reactive T cells were detected in individuals that lack nAbs against HAd35. 61 Animal derived adenoviruses Due to the lower immunogenicity of low seroprevalence HAd derived vectors, attention shifted toward the development of vectors based on animal Ad. Among these, chimpanzee derived Ad vector (ChAd) are the most studied. NAbs against simian Ad vectors are relatively rare. For example, nAbs against ChAd7 are detected in less than 15% of American, European, Chinese and African populations. The frequency of nAbs against ChAd6 are similar in these populations except in Africa where it peaks below 40%. 14,46,62 Furthermore, unlike rare human Ad serotypes, ChAd have demonstrated great efficacy in pre-clinical studies including ChAd7 in a mouse model of EBOV infection, 63 ChAd68 (SAd-24) in a NHP model of rabies, 64, 65 ChAd63, ChAd7 or ChAd9 in combination with modified vaccinia Ankara (MVA) boost in a malaria mouse model, 66, 67 and ChAdOx1 in a rodent model of Rift Valley Fever (RVF). 68 In addition, in Phase I clinical trials against Malaria and HCV, ChAd63 46 and ChAd3, 69 respectively, were found to be safe and able to generate robust, broad and polyfunctional T cell responses against the transgene.