Abstract
Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, the potential of a vector to elicit transgene-specific adaptive immune responses is largely dependent on the viral serotype used. HAdV-5 (Human adenovirus C) vectors are more immunogenic than chimpanzee adenovirus vectors from species Human adenovirus E (ChAdOx1 and AdC68) in mice, though the mechanisms responsible for these differences in immunogenicity remain poorly understood. In this study, superior immunogenicity was associated with markedly higher levels of transgene expression in vivo, particularly within draining lymph nodes. To investigate the viral factors contributing to these phenotypes, we generated recombinant ChAdOx1 vectors by exchanging components of the viral capsid reported to be principally involved in cell entry with the corresponding sequences from HAdV-5. Remarkably, pseudotyping with the HAdV-5 fiber and/or penton RGD loop had little to no effect on in vivo transgene expression or transgene-specific adaptive immune responses despite considerable species-specific sequence heterogeneity in these components. Our results suggest that mechanisms governing vector transduction after intramuscular administration in mice may be different from those described in vitro.
Highlights
human adenovirus type 5 (HAdV-5) is a member of species Human adenovirus C (HAdV-C), while most other alternative human serotypes in clinical use are members of species HAdV-B (HAdV-35), or HAdV-D (HAdV-26, HAdV28), and many ChAd vectors are derived from members of HAdV-E (ChAd63, AdC68, ChAdOx1)
HAdV-5 vaccine vectors elicit higher antigen specific immune responses and higher levels of transgene expression in vivo compared to ChAdOx1 vectors
BALB/c mice were vaccinated with HAdV-5 or ChAdOx1 vectors expressing Photinus pyralis luciferase at a dose of 108 infectious units
Summary
HAdV-5 is a member of species Human adenovirus C (HAdV-C), while most other alternative human serotypes in clinical use are members of species HAdV-B (HAdV-35), or HAdV-D (HAdV-26, HAdV28), and many ChAd vectors are derived from members of HAdV-E (ChAd63, AdC68, ChAdOx1). The classical pathway of adenovirus entry involves an initial high affinity interaction between the adenovirus fiber protein and a cell surface receptor such as CAR23,24 or CD4625, followed by a subsequent interaction between a tri-peptide Arg-Gly-Asp (RGD) motif on the viral penton base and cellular α v integrins to facilitate clathrin-dependent endocytosis[26,27,28]. Both the adenovirus fiber and the flexible penton RGD loop exhibit considerable sequence heterogeneity between viral species. We assess the contribution of these key viral sequences to the differences in immunogenicity and transgene expression between HAdV-5 and ChAdOx1 vector vaccines, to facilitate rational design of improved vector platforms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
