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Seasonal Influenza Vaccination Leads to Immune Cell Epigenomic Changes

NEW YORK – Influenza vaccination may trigger epigenomic changes that last months and bolster defenses against other viruses as well, a new analysis has found.

Previously, vaccination with the live, attenuated BCG vaccine for tuberculosis had been found to lead to epigenetic changes in monocytes, but it was unclear how widespread the epigenetic changes following vaccination may be.

Using single-cell analytical approaches, a Stanford University-led team of researchers examined whether such epigenomic changes also occurred following vaccination for the seasonal flu or for the pandemic H5N1 flu. As they reported Friday in the journal Cell, the researchers uncovered epigenetic changes in monocytes after both types of flu vaccinations, though noted that the H5N1 flu vaccine, which includes the AS03 adjuvant, led to additional changes and provided increased resistance to the unrelated Zika and dengue viruses.

"These findings have implications for the design of future vaccines consisting of epigenetic adjuvants that provide broad, non-specific protection by manipulating the epigenomic landscape," senior author Bali Pulendran, a professor of pathology at Stanford, and his colleagues wrote in their paper.

Based on epigenetic landscape profiling using cytometry by time-of-flight, the researchers examined the epigenomic landscape of 21 healthy people before and after they received the trivalent inactivated seasonal influenza vaccine. The acetylation, methylation, and phosphorylation states of numerous histone marks changed in different cells following vaccination. For instance, there was an increase in histone methylation in CD34+ cells 30 days after vaccination, as compared to baseline, but a decrease in that same time frame of acetylation marks in myeloid cells.

This epigenetic remodeling within myeloid cells lasted up to about six months. This persistence suggested to the researchers that the hematopoietic progenitor cell compartment in the bone marrow was likely changed as most immune cells have a lifespan of less than seven days. These epigenetic changes further led to differences in cytokine production.

Using ATAC-seq of FACS-sorted cells, the researchers homed in on certain regions of the genome where chromatin accessibility was altered following vaccination. These regions include immune-related genes like ones encoding cytokines, chemokines, and their receptors. In addition, these differentially accessible regions were enriched for transcription factors belonging to the AP-1 family like c-Jun and c-Fos. AP-1 is a key regulator of differentiation, inflammation, and polarization in myeloid cells and has recently been proposed to be a central epigenomic regulator. In their study, the researchers found AP-1 accessibility to be strongly reduced 30 days after vaccination in classic monocytes and myeloid dendritic cells.

The researchers also inoculated a separate cohort of healthy individuals with an H5N1 influenza vaccine containing the AS03 adjuvant, which similarly led to epigenetic and chromatin accessibility changes. But this vaccination additionally influenced chromatin accessibility at antiviral response loci. When the researchers exposed blood cells from these vaccinated individuals to the Zika virus or the virus that causes dengue fever, they found enhanced resistance to those viruses, even though they do not resemble influenza.

This suggested to the researchers that a more broad, epigenetic-based antiviral response might be provoked by the AS03 adjuvant and could inform future vaccine production, both of seasonal flu and other vaccines.

"In conclusion, our results demonstrate that vaccination with AS03-adjuvanted pandemic influenza vaccine induces persistent epigenomic changes in myeloid cells, leading to an antiviral state and protection against heterologous viruses," the researchers wrote. "These findings have implications for the design of future vaccines consisting of epigenetic adjuvants that provide broad, non-specific protection by manipulating the epigenomic landscape."