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Interferon and inflammasome networks are associated with lower neutralizing antibody responses to Yellow Fever vaccination

ABSTRACT: The immune response to vaccines is critically dependent on multiple host and environmental factors including acute and chronic infections as well as metabolic and/or pathophysiological states of the host. In this study, we used computational systems biology to analyze a cohort of Ugandan subjects following immunization with the Yellow Fever vaccine (YF-17D) to identify pre-vaccination molecular and cellular mechanisms that are associated with the response to the vaccine. By integrating gene expression profiling, cell subset phenotyping and cytokine measurements, we highlight the upregulated levels of interferon-regulated, and inflammasome genes and proteins at the time of vaccination as negative correlates of the antibody response to the YF-17D vaccine. We show that this innate immune response is associated with higher levels of genes that interact with bacterial components and with increased frequencies of Tr1 CD39+ IL-10 producing cells. Our results provide a framework to define the influence of environmental parameters present prior to vaccination on the response to vaccines in human populations

ORGANISM(S): Homo sapiens

PROVIDER: GSE125921 | GEO | 2019/01/31

REPOSITORIES: GEO

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Project description:The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed evaluation of safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a system biology approach to compare hematological, biochemical, transcriptomic, innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans, but with slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques (by Day 7 [D7]), but titers >10 were reached in both species by D14 post-vaccination and were not significantly different by D28 (PRNT50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; p = 0.821). Changes in neutrophils, NK cells, monocytes, T and B cell frequency were higher in cynomolgus macaques and persisted for four weeks versus less than two weeks in humans. Low levels of systemic inflammatory cytokines (IL-1Ra, IL-8, MIP-1α, IP-10, MCP-1 or VEGF) were detected in either or both species, but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3–D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques (28% [5/18]) but generally absent in humans (except one participant [5%; 1/20]). Importance: Cynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans, and suggest a key role for type I IFN.

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Interferon and inflammasome networks are associated with lower neutralizing antibody responses to Yellow Fever vaccination

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