Differential Induction of Interferon Stimulated Genes by Cell-based Versus Egg-based Quadrivalent Influenza Vaccines in Children During the 2018-19 Season.

Cell-based quadrivalent inactivated influenza vaccine has been shown to have higher vaccine effectiveness than traditional egg-based quadrivalent inactivated influenza vaccine. This is observed despite similar levels of serum hemagglutinin antibodies induced by each vaccine. Here, we examine peripheral immune activation following egg-based or cell-based influenza vaccination in a clinical trial in children. Peripheral blood mononuclear cells were isolated and RNA sequenced from 81 study participants (41 Fluzone, egg-based and 40 Flucelvax, cell based) pre- and 7 days post- vaccination. Seroconversion was assessed by hemagglutinin inhibition assay. Differential gene expression was determined and pathway analysis was conducted. Cell-based influenza vaccine induced greater interferon stimulated and innate immune gene activation compared with egg-based influenza vaccine. Participants who seroconverted had increased interferon signaling activation versus those who did not seroconvert. These data suggest that cell-based influenza vaccine stimulates immune activation differently from egg-based influenza vaccine, shedding light on reported differences in vaccine effectiveness.

Differential gene expression in peripheral blood mononuclear cells from children immunized with inactivated influenza vaccine.

The human immune response to inactivated influenza vaccine is dynamic and impacted by age and preexisting immunity. Our goal was to identify postvaccination transcriptomic changes in peripheral blood mononuclear cells from children. Blood samples were obtained before and at 3 or 7 days postvaccination with 2016-2017 quadrivalent inactivated influenza vaccine and RNA sequencing was performed. There were 1,466 differentially expressed genes (DEGs) for the Day 0-Day 3 group and 513 DEGs for the Day 0-Day 7 group. Thirty-three genes were common between the two groups. The majority of the transcriptomic changes at Day 3 represented innate inflammation and apoptosis pathways. Day 7 DEGs were characterized by activation of cellular processes, including the regulation of cytoskeleton, junctions, and metabolism, and increased expression of immunoglobulin genes. DEGs at Day 3 were compared between older and younger children revealing increased inflammatory gene expression in the older group. Vaccine history in the year prior to the study was characterized by robust DEGs at Day 3 with decreased phagosome and dendritic cell maturation in those who had been vaccinated in the previous year. PBMC responses to inactivated influenza vaccination in children differed significantly by the timing of sampling, patient age, and vaccine history. These data provide insight into the expected molecular pathways to be temporally altered by influenza vaccination in children.

IL-22-binding protein exacerbates influenza, bacterial super-infection.

Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary pathogens of interest. IL-22 promotes S. aureus and S. pneumoniae host defense in the lung through epithelial integrity and induction of antimicrobial peptides and is inhibited by the soluble decoy receptor IL-22-binding protein (IL-22BP). Little is known about the effect of the IL-22/IL-22BP regulatory pathway on lung infection, and it has not been studied in the setting of super-infection. We exposed wild-type and IL-22BP-/- mice to influenza A/PR/8/34 for 6 days prior to infection with S. aureus (USA300) S. pneumoniae. Super-infected IL-22BP-/- mice had decreased bacterial burden and improved survival compared to controls. IL-22BP-/- mice exhibited decreased inflammation, increased lipocalin 2 expression, and deletion of IL-22BP was associated with preserved epithelial barrier function with evidence of improved tight junction stability. Human bronchial epithelial cells treated with IL-22Fc showed evidence of improved tight junctions compared to untreated cells. This study revealed that IL-22BP-/- mice are protected during influenza, bacterial super-infection, suggesting that IL-22BP has a pro-inflammatory role and impairs epithelial barrier function likely through interaction with IL-22.