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Influenza Vaccine Response Expression Signature Identified in Young Adults

NEW YORK (GenomeWeb) – A gene expression signature present in the blood prior to vaccination might help to predict influenza vaccination response — at least in individuals under 35 years old, new research suggests.

Investigators with the Human Immunology Project Consortium (HIPC) and Center for Human Immunology used array-based expression profiling and RNA sequencing to track blood gene expression patterns before and after influenza vaccination in several cohorts comprised of individuals across the age spectrum.

The team's findings, published online today in Science Immunology, highlighted more than a dozen genes and three interconnected gene modules with expression levels that coincided with vaccination response and related antibody activity in individuals younger than 35 years old.

"These results point to the prospect of predicting antibody responses before vaccination and provide insights into the biological mechanisms underlying vaccination responses," the authors wrote.

Interestingly, though, enhanced expression of some of the same genes — including genes involved in inflammatory immunity — heralded poorer antibody response after vaccination in older adults.

"[W]e found that baseline differences, both at the gene and module level, were inversely correlated between young and older participants," corresponding author Steven Kleinstein, a computational biology and bioinformatics, pathology, and immunobiology researcher at Yale University, said in a statement.

The investigators began by bringing together pre- and post-vaccination antibody titer measurements for more than 500 individuals from four cohorts — focusing on individuals younger than 35 or over 60 years old — who were tested at a sites across the US as vaccinations were given for five consecutive flu seasons beginning 2008-2009.

The post-vaccination transcriptional patterns in these participants were assessed with array-based profiling or RNA sequencing on whole blood or peripheral blood mononuclear cells from the participants, the researchers explained. For 275 of the individuals, they also had access to genome-wide transcriptome profiles for blood samples collected moments after the flu vaccine jab.

Using an analytical framework dubbed the Quantitative Set Analysis for Gene Expression, or QuSAGE, in combination with a pipeline designed to bring together datasets representing multiple cohorts, the team searched for genes and gene sets with distinct expression patterns before and after vaccination in these individuals.

The search led to a pre-vaccination blood gene expression signature associated with vaccine response in the under-35s — a set that included nine genes with higher-than-usual expression in participants showing robust flu vaccine response and six genes with muted baseline expression in those with pronounced antibody activity after vaccination.

For their subsequent validation analysis, the researchers focused on the nine genes with enhanced expression in the young flu vaccine responders. There, they saw significant ties between expression of vaccine response and seven genes from the signature that had been measured in two additional cohorts. The validation stage of the study also highlighted three gene modules associated with antigen activity in the younger participants.

But blood expression patterns in the older study participants were more difficult to link to vaccine response. In particular, the team had trouble pinpointing genes showing enhanced expression in vaccine responders. Moreover, some of the genes with elevated expression in younger vaccine responders were linked to poorer vaccine response in the over-60 participants receiving the flu vaccine.

"We found an inverse correlation between the effect size of signatures in young and older individuals," the authors explained. "Although the presence of an inflammatory gene signature, for example, was associated with better antibody responses in young individuals, it was associated with worse responses in older individuals."

The study's authors are making data from the study available to other researchers on the HIPC's ImmuneSpace site and through ImmPort, an effort funded by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and US Health and Human Services for sharing and analyzing immunology-related data.

"In addition to potentially enabling the prediction of antibody responses before vaccination in the clinic and in vaccine trials, these results provide hypotheses on potential biological mechanisms underlying successful influenza vaccination responses and how these mechanisms could change with age," Kleinstein and colleagues wrote."