T Cell Transcriptional Signatures of Influenza A/H3N2 Antibody Response to High Dose Influenza and Adjuvanted Influenza Vaccine in Older Adults

Abstract

Older adults experience declining influenza vaccine-induced immunity and are at higher risk of influenza and its complications. For this reason, high dose (e.g., Fluzone) and adjuvanted (e.g., Fluad) vaccines are preferentially recommended for people age 65 years and older. However, T cell transcriptional activity shaping the humoral immune responses to Fluzone and Fluad vaccines in older adults is still poorly understood. We designed a study of 234 older adults (≥65 years old) who were randomly allocated to receive Fluzone or Fluad vaccine and provided blood samples at baseline and at Day 28 after immunization. We measured the humoral immune responses (hemagglutination inhibition/HAI antibody titer) to influenza A/H3N2 and performed mRNA-Seq transcriptional profiling in purified CD4+ T cells, in order to identify T cell signatures that might explain differences in humoral immune response by vaccine type. Given the large differences in formulation (higher antigen dose vs adjuvant), our hypothesis was that each vaccine elicited a distinct transcriptomic response after vaccination. Thus, the main focus of our study was to identify the differential gene expression influencing the antibody titer in the two vaccine groups. Our analyses identified three differentially expressed, functionally linked genes/proteins in CD4+ T cells: the calcium/calmodulin dependent serine/threonine kinase IV (CaMKIV); its regulator the TMEM38B/transmembrane protein 38B, involved in maintenance of intracellular Ca2+ release; and the transcriptional coactivator CBP/CREB binding protein, as regulators of transcriptional activity/function in CD4+ T cells that impact differences in immune response by vaccine type. Significantly enriched T cell-specific pathways/biological processes were also identified that point to the importance of genes/proteins involved in Th1/Th2 cell differentiation, IL-17 signaling, calcium signaling, Notch signaling, MAPK signaling, and regulation of TRP cation Ca2+ channels in humoral immunity after influenza vaccination. In summary, we identified the genes/proteins and pathways essential for cell activation and function in CD4+ T cells that are associated with differences in influenza vaccine-induced humoral immunity by vaccine type. These findings provide an additional mechanistic perspective for achieving protective immunity in older adults.

Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults

“…Demographic and clinical characteristics of the study cohort were briefly reported in our previous publication ( Haralambieva et al., 2022 ). Of 250 individuals enrolled for this study, 210 participants completed both blood sampling and questionnaires and were included in data analysis ( Figure 1 ; Table 1 ).…”

“…Some of the methods used in this study were similar or identical to the methods used in our previous publication ( Haralambieva et al., 2022 ). The sleep questionnaires used in this study are widely used and well validated ( Buysse et al., 1989 ; Johns, 1991 ; Chung et al., 2008 ).…”

“…Blood was sampled from each study participant at two time points: before (Day 0) influenza vaccination and 28 days thereafter (Day 28), as summarized in Figure 1 . Influenza A/H3N2-specific antibody titer was quantified by hemagglutination inhibition (HAI) assay and has been previously reported ( Haralambieva et al., 2022 ). The coefficient of variation (CV) of the HAI assay was 2.9% ( Haralambieva et al., 2022 ).…”

“…Influenza A/H3N2-specific antibody titer was quantified by hemagglutination inhibition (HAI) assay and has been previously reported ( Haralambieva et al., 2022 ). The coefficient of variation (CV) of the HAI assay was 2.9% ( Haralambieva et al., 2022 ). Full details of blood collection and HAI assay are described in Supplementary Material .…”

Early B cell transcriptomic markers of measles-specific humoral immunity following a 3rd dose of MMR vaccine

“…Next-generation mRNA sequencing was performed in purified B cells as previously described ( 12 ). B cells were first isolated from PBMCs via negative selection using the Miltenyi Biotec’s B cell isolation kit and MidiMACS™ Separator.…”