Comparative analysis of the impact of 40 adenovirus types on dendritic cell activation and CD8+ T cell proliferation capacity for the identification of favorable immunization vector candidates

Abstract

For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8+ T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8+ T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8+ T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.

The Immune System—A Double-Edged Sword for Adenovirus-Based Therapies

“…As briefly touched upon before, different species and serotypes of Ads are considered to have different immunogenicity [ 2 , 41 , 229 ]. Johnson et al showed that in PBMCs from healthy donors, HAdV-D28 and HAdV-B35, lead to increased death of APCs.…”

“…A comprehensive study by Wang et al in 2023 evaluated 39 different serotypes covering all the Ad human species for their potential suitability as vaccine vectors. They specifically focused on CD8+ T cell and DC activation, as well as cytokine expression in their in vitro assays, and predicted HAdV-C1, HAdV-D8, HAdV-B7, HAdV-F41, HAdV-D33, HAdV-C2, HAdV-A31, HAdV-B3, and HAdV-D65 to be particularly useful if vectorised [ 229 ]. As they were looking for high immunogenicity in potential vaccine vectors, it will be interesting to see if these predictions hold true and if viruses they scored with lower immunogenicity ratings may be advantageous in engineering vectors with increased immune evasion in the future.…”