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Systems Biology Can Uncover Signatures of Vaccination Immune Response

NEW YORK (GenomeWeb News) – A team of American and French researchers used systems biology to identify gene signatures predicting human immune responses to the yellow fever vaccine, YF-17D. The work appeared in an advanced online publication in Nature Immunology yesterday.
Using high-throughput gene expression measurements, multiplex analysis of cytokines and chemokines, and multi-parameter flow cytometry, investigators tested samples taken from more than a dozen individuals in the days and weeks following their yellow fever vaccination. Computational modeling allowed them to come up with signatures predicting CD8+ T-cell and neutralizing antibody responses to YF-17D — insights into vaccine immunogenicity that may inform future vaccine research and development.
“The identification of gene signatures that correlate with, and are capable of predicting, the magnitudes of the antigen-specific CD8+ T-cell and neutralizing antibody responses provides the first methodological evidence that vaccine-induced immune responses can indeed be predicted,” senior author Bali Pulendran, an immunologist and virologist at the Emory Vaccine Center in Atlanta, and his colleagues wrote.
The yellow fever vaccine, which was developed in the 1930s, has been administered to more than 600 million people around the world. Because it is among the most effective vaccines to date — protecting 80 to 90 percent of the individuals who receive it — the researchers reasoned that YF-17D could serve as a good model for studying the early immune response to vaccination.
In an effort to explore the innate immune responses to yellow fever vaccination, Pulendran and his co-workers first followed 15 individuals who were vaccinated with YF-17D, analyzing blood samples at baseline as well as one, three, seven, and 21 days after the vaccination.
A 24-plex Luminex assay assessing the protein cytokines in individuals’ blood indicated that vaccination induces the cytokines IP-10 and IL-α. Meanwhile, transcriptional profiling of peripheral blood mononuclear cells using the Affymetrix Human Genome U133 Plus 2.0 Array turned up 97 genes that were up- or down-regulated in more than 60 percent of the subjects tested following their vaccination with YF-17D.
In an independent study of ten individuals, the researchers came up with 125 genes that appear to be modulated by YF-17D — including 65 that had already been uncovered in the initial study. The Gene Ontology terms associated with the 65 shared genes suggested the differentially regulated genes tend to govern immunological responses, cell motility, and biopolymer metabolism.
Transcription factor binding site analysis on these genes revealed a statistical over-representation of interferon-stimulated response element, interferon regulatory factor 7 binding site, and sterol regulatory element-binding protein 1 binding site.
And when the team used Ingenuity Pathways analysis combined with transcription factor motif information, they turned up a closely interacting network containing 50 genes involved in processes such as interferon function, viral recognition, and antiviral immunity.
The expression of some genes shifted as early as one or three days after vaccination. But gene expression changes peaked a week after vaccination — particularly for genes involved in interferon and innate antiviral response. In general, the authors noted, “YF-17D vaccination induced a gene signature characteristic of viral infection.”
Nevertheless, they did not find a correlation between the expression of these genes and CD8+ T-cell response. When they specifically looked for a gene expression signature for predicting CD8+ T-cell response in the 15-person trial, the researchers found 839 genes, many of which were involved in metabolism and immunological response.
Using one classification method, the researchers found that at least 48 genes are necessary to accurately classify subjects as either high- or low-CD8+ T-cell responders. With another classification method, they turned up eight independent signature sets containing two or three genes that were each about 90 predictive. In particular, several of the signatures contained EIF2AK4 and SLC2A6, genes involved in regulating protein synthesis and glucose transport and glycolysis, respectively.
Finally, the investigators looked for genetic signatures that could be used to predict individuals’ neutralizing antibody response, again using unsupervised principal component analysis several weeks after vaccination to relate gene expression to antibody responses. In that case, they found that the B-cell growth factor receptor TNFRSF17 is often involved in predictive signatures.
“Our results indicated that several innate immune mechanisms are induced by YF-17D and that several innate immune signatures can be used to predict the strength of the adaptive immune response,” the authors wrote.

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