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

Fausther-Bovendo, Hugues; Kobinger, Gary P

Adenovirus (Ad) derived vectors have been shown to successfully elicit strong cellular and humoral immune responses in rodents, non-human primates (NHP) as well as in humans after a single injection. [4] [5] [6] [7] In preclinical studies, among all human Ad vectors tested, those derived from human adenovirus serotype 5 (HAd5) have emerged as the gold standard for immunization due to their superior immunogenicity. As a result, earlier clinical trials were almost exclusively performed using HAd5 vectors. 8 However, although HAd5 vectors were highly efficacious in pre-clinical studies, they did not perform as anticipated in clinical trials due to pre-existing HAd5 immunity in the participants from natural exposure. Adenoviruses are some of the pathogens that can cause the common cold and a significant proportion of the human population have antibodies against these viruses due to past infections naturally acquired in the community, notably during childhood. 9 ,10 These natural exposures can be responsible for long-lasting immunity (pre-existing immunity) that can interfere with HAd-based vaccines. In a phase I trial, individuals with pre-existing HAd5 immunity mounted lower immune responses compared with participants without pre-existing immunity. 5 Pre-existing immunity to HAd5 was even associated with undesirable effects beyond neutralization of the benefits intended from vaccination. The negative impact of pre-existing HAd5 immunity was illustrated in the infamous STEP trial during which a lower frequency of individuals with high HAd5 Ab titers developed a cellular response to the transgenes (HIV Gag, Pol and Nef). Furthermore, pre-existing HAd5 immunity was associated with an increase in HIV acquisition in vaccinated participants in comparison to the placebo. 7 Pre-existing HAd5 immunity was not taken into account in pre-clinical studies as animals used in these studies, such as mice and NHPs, are not naturally infected by HAd5 or other human Ads. In contrast, the percentage of the African, European and American population with neutralizing antibodies (nAbs) against HAd5 has been documented to be between 65-100, 61 and 37-70%, respectively. [11] [12] [13] [14] Since realizing the negative impact of pre-existing Ad immunity in early clinical trials, better understanding and ultimately circumventing pre-existing immunity has been a major focus in the development of new Ad based vaccines. In order to reach these goals, pre-existing immunity has been artificially generated in animal models by immunization with HAd vectors either lacking a foreign gene or encoding an irrelevant one. In addition, in order to determine the contribution of Ad specific T cells and Ab in pre-existing immunity, T cells or serum from Ad immune animals can be transferred in na€ ıve ones. This review will first summarize the contributions of the different arms of the immune system toward pre-existing immunity against Ad vectors. Then, the mechanisms of evasion of the main strategies developed to circumvent pre-existing Ad immunity will be reviewed.