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Study Detects Vaccine Response Signatures that Differ with Age, Adverse Events

NEW YORK (GenomeWeb) – Using a combination of blood gene expression and immune cell profiling, an international team led by investigators in the UK has identified age-related differences in individuals' responses to an adjuvanted flu vaccine.

As they reported online today in Nature Immunology, the researchers did array-based gene expression testing, white blood cell analysis, and more on blood samples from nearly 200 healthy individuals who received an adjuvanted vaccine against swine flu.

They uncovered subtle differences in early immune response amongst individuals older than 35, as well as a B cell-related expression signature present even before vaccination that was associated with adverse events.

Such findings may set the stage for understanding human immune variation and vaccine response in a manner that eventually makes it possible to predict vaccine response more reliably, according to the study's senior author Adrian Hayday, an immunobiology researcher affiliated with King's College London and the Francis Crick Institute, and his co-authors.

Past studies have suggested that the unperturbed human immune system is relatively stable from one day to the next, the team noted, making it possible to track the immune events that mark response to vaccination and other immune-centered treatments. In particular, the researchers set out to uncover signatures associated with typical vaccination response as well as immune differences associated with poor vaccine response and/or adverse events.

"Transient adverse events … can undermine herd immunity by provoking diminished vaccination compliance and even halting vaccine trials," the team wrote. "Additionally, there have been highly public concerns that vaccines may exacerbate preexisting pathologies."

As part of a longitudinal "human immune response dynamics" (HIRD) study, the researchers collected blood samples one week before vaccination, immediately before vaccination, and four more times after vaccination in 178 volunteers enrolled from spring 2010 to August 2011.

The individuals each had blood and urine analyses done prior to vaccination as part of a standard health exam and none had known histories of immunodeficiency, cancer, autoimmune disorders, or inflammatory disease.

Each of the participants received the same dose of a UK vaccine called Pandemrix, which was developed to combat the strain of H1N1 swine flu that caused the 2009 outbreak and contains an adjuvant compound to boost immune response to the vaccination.

The team did array-based gene expression profiling on peripheral blood samples collected from 46 of the volunteers at two pre-vaccination and two post-vaccination time points each. The researchers also tested the same blood samples by flow cytometry and Luminex analysis to assess the representation of various white blood cell populations.

Within the first 24 hours after vaccination, the researchers detected dramatic gene expression shifts compared with expression patterns in blood samples taken a week before vaccination or earlier in the day of vaccination.

These expression changes appeared to be in the same direction as changes in the proportion of various white blood cells. From the extent of the expression shifts, however, the team suspected that vaccination not only altered the proportion of white blood cells, but also transcription by individual cells.

Along with an overall upregulation in transcripts coding for interferons and other immune effectors, the researchers uncovered slight gene expression differences in samples taken a day after vaccination from participants older than 35.

In the roughly 80 percent of participants showing a vaccine response — marked by at least a four-fold rise in antibodies against influenza — the team found differences in both antigen activity and gene expression compared with non-responders, though no one signature of non-response stood out. 

On the other hand, the researchers did see a shared expression signature, including higher-than-usual expression of B cell-related genes, in samples taken before and after vaccination from individuals who experienced adverse events such as drowsiness, fatigue, or flu-like symptoms.