Modification of Adenovirus vaccine vector-induced immune responses by expression of a signalling molecule

Christine S Rollier,David Wyllie,Karen Colbjorn Sogaard,Adrian V S Hill,Jared Honeycutt,Sarah C Gilbert,Julie Furze,Alexandra J Spencer,Migena Bregu

doi:10.1038/s41598-020-61730-8

Christine S Rollier, David Wyllie + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-61730-8

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Abstract

Adenoviral vectors are being developed as vaccines against infectious agents and tumour-associated antigens, because of their ability to induce cellular immunity. However, the protection afforded in animal models has not easily translated into primates and clinical trials, underlying the need for improving adenoviral vaccines-induced immunogenicity. A Toll-like receptor signalling molecule, TRAM, was assessed for its ability to modify the immune responses induced by an adenovirus-based vaccine. Different adenovirus vectors either expressing TRAM alone or co-expressing TRAM along with a model antigen were constructed. The modification of T-cell and antibody responses induced by TRAM was assessed in vivo in mice and in primates. Co-expression of TRAM and an antigen from adenoviruses increased the transgene-specific CD8+ T cell responses in mice. Similar effects were seen when a TRAM expressing virus was co-administered with the antigen-expressing adenovirus. However, in primate studies, co-administration of a TRAM expressing adenovirus with a vaccine expressing the ME-TRAP malaria antigen had no significant effect on the immune responses. While these results support the idea that modification of innate immune signalling by genetic vectors modifies immunogenicity, they also emphasise the difficulty in generalising results from rodents into primates, where the regulatory pathway may be different to that in mice.

Highlights

Adenoviral vectors are being developed as vaccines against infectious agents and tumour-associated antigens, because of their ability to induce cellular immunity
Bi-cistronic AdHu5 vectors and chimpanzee adenovirus serotypes serotype 63 (ChAd63) vectors encoding a model transgene of interest, driven by a human EF1α promoter, were constructed including cassettes allowing inflammatory signalling components to be expressed under the control of a CMV promoter (Fig. 1a), while the antigen was driven by an hEF1α promoter, a strong mammalian promoter[12]
That the pro-inflammatory response was not observed in cells infected with control viruses, in which the only difference is the absence of the TRIF-related adaptor molecule (TRAM) gene, or with a vector containing a different transgene (TAK1), provides evidence of the transgene-specific modification of the signalling response in the cells

Summary

Introduction

Adenoviral vectors are being developed as vaccines against infectious agents and tumour-associated antigens, because of their ability to induce cellular immunity. A Toll-like receptor signalling molecule, TRAM, was assessed for its ability to modify the immune responses induced by an adenovirus-based vaccine. In primate studies, co-administration of a TRAM expressing adenovirus with a vaccine expressing the ME-TRAP malaria antigen had no significant effect on the immune responses While these results support the idea that modification of innate immune signalling by genetic vectors modifies immunogenicity, they emphasise the difficulty in generalising results from rodents into primates, where the regulatory pathway may be different to that in mice. Adenovirus based vaccine vectors induce both innate and adaptive immune responses in mammalian hosts[2,3,4] They continue to be developed because of their well-recognised ability to induce potent cellular as well as humoral responses against transgenic antigens from target pathogens. We investigated immune responses elicited by adenovirus vaccine immunization, with and without TRAM expression, in both murine and non-human primate models

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