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

Fausther-Bovendo, Hugues; Kobinger, Gary P

In addition to chimpanzee Ad vectors, bovine, porcine, ovine, canine and fowl derived Ad vectors are currently in preclinical stages of development. 72 NAbs against these vectors, including porcine Ad serotype 3 (PAd3), bovine Ad serotype 3 (BAd3) and Ovine Ad serotype 7 (OAd7), have not been detected in the human population. 73, 74 Similar to simian Ad vectors, cross-nAbs against PAd3 and BAd3 were not generated by mice immunized with HAd5. 25 Furthermore, little to no CD4 and CD8 T cells cross-reactive against PAd3 and BAd3 were detected in HAd5 immunized mice. 75 Finally, immunization with either BAd3 or Pad3-based vaccines protected both na€ ıve and HAd5 preimmune mice against influenza virus challenge. Both humoral and cellular immune responses were not impacted by pre-existing HAd5 immunity. 76, 77 Similarly, transgene expression and cellular responses were not affected in HAd5 pre-immune mice after OAd7 and OAdV injection, respectively. 73, 78 However, although promising results were obtained in rodents using non-primate Ad-derived vectors including BAd, PAd and OAd, their usefulness needs to be ultimately confirmed in humans. Whether Ad cross-reactive T cells can react with BAd and Pad still needs to be assessed as the cellular immune response is heavily influenced by MHC alleles, which are different in mice and humans. 75 Varying immunization routes In addition to using alternative Ad serotypes, pre-existing immunity has been overcome by varying the route of immunization. Indeed, mice with pre-existing HAd5 immunity generated by intranasal or intramuscular immunization did not experience reduced humoral responses upon subsequent oral immunization. 79 Similarly, in the NHP model of Ebola virus, HAd5 mediated protection after intranasal/intratracheal immunization was not impacted by pre-existing HAd5 immunity generated by intramuscular (IM) injection of an irrelevant HAd5 vector. 80 The lack of impact despite pre-existing immunity may be due to evasion from tissue resident Ad specific T cells.