Early spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice

As the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to the inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits the understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity. We, therefore, utilized a mouse model to investigate the spatiotemporal evolution of the immune response within the first 24 hours following intramuscular adenovirus serotype 26 (Ad26) vector vaccination in tissues. We show that the Ad26 vaccine-elicited innate immune response commences by 1 hour and rapidly evolves in tissues and blood within the first 24 hours, as reflected by the detection of cytokines, chemokines, cellular responses, and transcriptomic pathways. Furthermore, serum levels of IL-6, MIG, MIP-1α, MIP-1β, and TNF-α at 6 hours post-vaccination correlated with the frequency of vaccine-elicited memory CD8⁺ T cell responses evaluated at 60 days post-vaccination in blood and tissues. Taken together, our data suggest that the immune response to Ad26 vector vaccination commences quickly in tissues by 1 hour and that events by as early as 6 hours post-vaccination can shape vaccine-elicited CD8⁺ T cell responses at later memory time points.IMPORTANCEPrior studies have largely concentrated on innate immune activation in peripheral blood following vaccination. In this study, we report the detailed spatial and temporal innate immune activation in tissues following Ad26 vaccination in mice. We observed rapid innate activation not only in peripheral blood but also in draining lymph nodes and at the site of inoculation. Our findings provide a more detailed picture of the host response to vaccination than previously reported.