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

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.

SUBMITTER: Rollier CS

PROVIDER: S-EPMC7109070 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Rollier Christine S CS Spencer Alexandra J AJ Sogaard Karen Colbjorn KC Honeycutt Jared J Furze Julie J Bregu Migena M Gilbert Sarah C SC Wyllie David D Hill Adrian V S AVS

Scientific reports 20200331 1

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. ...[more]

PMID: 32235848

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Project description:Replication-deficient chimpanzee adenovirus (ChAd) vectors represent an attractive vaccine platform and are thus employed as vaccine candidates against several infectious diseases. Since inducing effective immunity depends on the interplay between innate and adaptive immunity, a deeper understanding of innate immune responses elicited by intramuscularly injected ChAd vectors in tissues can advance the platform's development. Using different candidate vaccines based on the Group C ChAd type 155 (ChAd155) vector, we characterized early immune responses in injected muscles and draining lymph nodes (dLNs) from mice, and complemented these analyses by evaluating cytokine responses and gene expression patterns in peripheral blood from ChAd155-injected macaques. In mice, vector DNA levels gradually decreased post-immunization, but local transgene mRNA expression exhibited two transient peaks [at 6 h and Day (D)5], which were most obvious in dLNs. This dynamic pattern was mirrored by the innate responses in tissues, which developed as early as 1-3 h (cytokines/chemokines) or D1 (immune cells) post-vaccination. They were characterized by a CCL2- and CXCL9/10-dominated chemokine profile, peaking at 6 h (with CXCL10/CCL2 signals also detectable in serum) and D7, and clear immune-cell infiltration peaks at D1/D2 and D6/D7. Experiments with a green fluorescent protein-expressing ChAd155 vector revealed infiltrating hematopoietic cell subsets at the injection site. Cell infiltrates comprised mostly monocytes in muscles, and NK cells, T cells, dendritic cells, monocytes, and B cells in dLNs. Similar bimodal dynamics were observed in whole-blood gene signatures in macaques: most of the 17 enriched immune/innate signaling pathways were significantly upregulated at D1 and D7 and downregulated at D3, and clustering analysis revealed stronger similarities between D1 and D7 signatures versus the D3 signature. Serum cytokine responses (CXCL10, IL1Ra, and low-level IFN-α) in macaques were predominantly observed at D1. Altogether, the early immune responses exhibited bimodal kinetics with transient peaks at D1/D2 and D6/D7, mostly with an IFN-associated signature, and these features were remarkably consistent across most analyzed parameters in murine tissues and macaque blood. These compelling observations reveal a novel aspect of the dynamics of innate immunity induced by ChAd155-vectored vaccines, and contribute to ongoing research to better understand how adenovectors can promote vaccine-induced immunity.

Dataset Information

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

Publications

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

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