Abstract
New vaccine design approaches would be greatly facilitated by a better understanding of the early systemic changes, and those that occur at the site of injection, responsible for the installation of a durable and oriented protective response. We performed a detailed characterization of very early infection and host response events following the intradermal administration of the modified vaccinia virus Ankara as a live attenuated vaccine model in non-human primates. Integrated analysis of the data obtained from in vivo imaging, histology, flow cytometry, multiplex cytokine, and transcriptomic analysis using tools derived from systems biology, such as co-expression networks, showed a strong early local and systemic inflammatory response that peaked at 24 h, which was then progressively replaced by an adaptive response during the installation of the host response to the vaccine. Granulocytes, macrophages, and monocytoid cells were massively recruited during the local innate response in association with local productions of GM-CSF, IL-1β, MIP1α, MIP1β, and TNFα. We also observed a rapid and transient granulocyte recruitment and the release of IL-6 and IL-1RA, followed by a persistent phase involving inflammatory monocytes. This systemic inflammation was confirmed by molecular signatures, such as upregulations of IL-6 and TNF pathways and acute phase response signaling. Such comprehensive approaches improve our understanding of the spatiotemporal orchestration of vaccine-elicited immune response, in a live-attenuated vaccine model, and thus contribute to rational vaccine development.
Highlights
Vaccine innovation would be aided by a better understanding of the basic mechanisms associated with processes that affect the duration, breadth, and efficiency of the host response, the very early events that can be manipulated by antigen targeting, adjuvants and immune stimulants, dose, and delivery
The eGFP-expressing cells resulting from rMVA infection were tracked in the skin by repeated in vivo imaging using Fibered Confocal Fluorescence Microscopy (FCFM) (Figure 1C)
We used a multimodal analysis strategy to characterize the early steps of the immune response to Modified virus Ankara (MVA) infection, at the local site of injection, in the draining lymph node (LN), and blood
Summary
Vaccine innovation would be aided by a better understanding of the basic mechanisms associated with processes that affect the duration, breadth, and efficiency of the host response, the very early events that can be manipulated by antigen targeting, adjuvants and immune stimulants, dose, and delivery. The innate response in the blood can be triggered as early as 24 h after immunization when using adjuvants such as alum or tolllike receptor (TLR) [9] or after immunization with Modified virus Ankara (MVA) [10,11,12,13]. These works suggest that very early events can have a strong impact to long-term responses to vaccines
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