Modeling Pre-Existing Immunity to Adenovirus in Rodents: Immunological Requirements for Successful Development of a Recombinant Adenovirus Serotype 5-Based Ebola Vaccine

Abstract

Pre-existing immunity (PEI) to human adenovirus serotype 5 (Ad5) worldwide is the primary limitation to routine clinical use of Ad5-based vectors in immunization platforms. Using systemic and mucosal PEI induction models in rodents (mice and guinea pigs), we assessed the influence of PEI on the type of adaptive immune response elicited by an Ad5-based vaccine for Ebola with respect to immunization route. Splenocytes isolated from vaccinated animals revealed that immunization by the same route in which PEI was induced significantly compromised Ebola Zaire glycoprotein (ZGP)-specific IFN-γ+ CD8+ T cells and ZGP-specific multifunctional CD8+ T cell populations. ZGP-specific IgG1 antibody levels were also significantly reduced and a sharp increase in serum anti-Ad5 neutralizing antibody (NAB) titers noted following immunization. These immune parameters correlated with poor survival after lethal challenge with rodent-adapted Ebola Zaire virus (ZEBOV). Although the number of IFN-γ+ CD8+ T cells was reduced in animals given the vaccine by a different route from that used for PEI induction, the multifunctional CD8+ T cell response was not compromised. Survival rates in these groups were higher than when PEI was induced by the same route as immunization. These results suggest that antigen-specific multi-functional CD8+ T cell and Th2 type antibody responses compromised by PEI to Ad5 are required for protection from Ebola. They also illustrate that methods for induction of PEI used in pre-clinical studies must be carefully evaluated for successful development of novel Ad5-based vaccines.

Novel chimpanzee adenovirus-vectored respiratory mucosal tuberculosis vaccine: overcoming local anti-human adenovirus immunity for potent TB protection

“…However, it is noteworthy that in the majority of previous studies, preexisting anti-AdHu5 immunity was generated by systemic AdHu5 infection. As AdHu5 virus is a respiratory pathogen in humans and recent evidence suggests a differential immune-regulatory effect by the mucosal route of induction of anti-AdHu5 immunity, 61,62 in this study we generated preexisting anti-AdHu5 immunity by respiratory route of wild-type AdHu5 infection that generated anti-Ad5-neutralizing antibody titers in both the lung and circulation, similar to the levels seen in humans. 62 Thus, this method is not only clinically relevant but is also relevant to the investigation of AdCh-based respiratory mucosal TB vaccination strategies.…”

Immunogenicity of adenovirus-vector vaccine targeting hepatitis B virus: non-clinical safety assessment in non-human primates

“…Several studies have been conducted on the application of gene therapies using Ad5-based vaccines for the treatment of cancer or chronic virus infections, which have shown that the immunogenicity responses specific for Ad proteins and for transgene-encoded proteins induced by vaccines could have a significant impact on the efficacy of a recombinant Ad vaccine [23][24][25]. Thus, an essential aspect to ensure the efficacy of virus-vector drugs is to comprehensively and accurately evaluate their immunogenicity.…”

Immunology and evolvement of the adenovirus prime, MVA boost Ebola virus vaccine

“…This species difference in vaccine efficacy may relate to fundamental mechanistic differences in infection or immune protection for each animal model, or could simply reflect more subtle requirements for the level or balance of specific immune responses. While not predictive of protection in primates, rodent models were crucial for identifying functional genetic vector systems, targeting immunogenic virus proteins, and defining potential immune correlates of protection [2,[4][5][6].…”