Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys

Abstract

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.

SARS-CoV-2 vaccines: Lights and shadows

“…In this context, viral vector vaccines might trigger a further enhancement of the immune reactions against Spike proteins by engaging a stronger innate responses also mediated by cytokines, chemokines and immune cells [21] . Such immune reaction appears to mimic an active COVID-19 disease.…”

“…Nonetheless, the use of animal adenovirus may decrease the preexisting vector immunity observed using a human viral vector [4] . The early innate response to Adenovirus vector generally starts 1-3 hours to 1 day post-vaccination through cytokines/chemokines and immune cells, with final enhancement of the immune reactions against Spike proteins [21] .…”

Immunological mechanisms of vaccine-induced protection against COVID-19 in humans

“…Alternatively, it is possible that there are non-adaptive (that is, innate) immune mechanisms that are responsible for this early protection after vaccination, for example via type I or type III interferons 57 , 71 , 72 , with the possibility of a ‘trained immunity’-type effect that has been described for the Bacillus Calmette–Guérin (BCG) vaccine in the COVID-19 context 74 . Both BNT162b2 and mRNA-1273, as well as the adenoviral-vectored vaccine ChAdOx1 nCoV-19, have been shown to induce type I interferon, thus potentially inducing pathogen-agnostic protection 75 – 77 . Unfortunately, given the urgency of the situation, the trials of the currently licensed COVID-19 vaccines did not include a vector control (such as scrambled mRNA or simian adenovirus without the S protein), and therefore the role of pathogen-agnostic immunity in humans cannot be assessed with the currently available data; however, antigen non-specific stimulation of type I interferon pathways has been demonstrated with other formulations of mRNA in animal models 78 , 79 .…”

Cytokine Responses to Adenovirus and Adenovirus Vectors

“…In mice, after intramuscular vaccine administration, IFN-α and CXCL10 are detected three hours post vector injection in the local draining lymph nodes but not in the muscle tissue [ 26 ]. Six hours post-vaccination, these proteins can be detected not only in the draining lymph nodes but also in muscle tissue surrounding the injection site [ 12 , 26 ].…”