Evaluation of human adenovirus-based vectors for immunization in consideration of seroprevalence, immunogenicity and effects of pre-existing immunity

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Adenovirus-based vectors are popular tools for experimental vaccine development; however, their application in humans can be problematic if vectors are based, as they historically were, on high-prevalent human adenovirus types such as Ad5. Therefore, many efforts have been made to develop alternative vectors. In preliminary experiments, we could show that pre-existing immunity against the adenovirus-based vector can impair the transgene-specific CD8+ T cell response, but it can also have a positive impact on the induction of transgene-specific antibody responses. In preliminary experiments, we have already tested the antibody reactivity of 245 human sera of a student cohort against 30 human adenovirus types in direct comparison to Ad5. We were able to identify a number of adenovirus types that were significantly less prevalent in comparison to Ad5. In the proposed project, we would like to evaluate 10 human adenovirus types that we selected based on their low seroprevalence in the student cohort for their potential as vaccine vectors. In the first project part, we will determine antibody and CD8+ T cell responses against the human adenovirus types in mouse experiments, including an analysis of cross-reactive immune responses. In further experiments, we will construct vectors encoding Friend virus Gag and test them in vitro for their efficacy in stimulating CD8+ T cell proliferation and activating antigen-presenting cells. The best vectors will then be used in vivo for the evaluation of CD8+ T cell responses and protection from Friend virus challenge infection. Furthermore, we will experimentally address the hypotheses that the genomic stimulatory TLR motif content or capsid proteins are determining an adenovirus type’s immunogenicity. In the last part of the proposed project, we will analyse the mechanisms underlying the pre-immunity-mediated enhancement of antibody responses, and we will establish a cohort-like adenovirus immunity to evaluate the effectiveness of an optimized immunization protocol using the new vectors under realistic conditions of pre-existing immunity.We expect that the results of this proposed project will yield important new insights for the development of new effective adenovirus-based vectors for vaccine development.