Abstract
The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of human influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. In this study we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days postvaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced Ab responses were distinct in young and older adults; for example, increased expression of killer cell lectin-like receptor B1 (KLRB1; CD161) 28 days postvaccination positively and negatively predicted vaccine-induced Ab responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults.
Highlights
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We developed maximum residual after baseline adjustment (maxRBA), which corrects for the dependence on baseline titers for each strain by modeling titer fold changes as an exponential function of prevaccination titers and selecting the maximum residual across strains (Fig. 1A)
The models of response in older adults were significantly enriched for several blood transcriptional modules (BTM) of monocyte signatures as well as TLR and inflammatory signaling (M16), which positively predicted vaccine response; together with previous studies linking age-associated impairments in TLR function to influenza vaccine Ab response [44, 45], these findings provide additional support for the crucial role of innate immune function in vaccination (Supplemental Table VIII)
Summary
To identify correlates and predictors of vaccine response, we selected a subset of individuals (20–40 subjects per season) from young and older adult cohorts who had strong or weak Ab responses according to HAI titers and performed longitudinal transcriptional profiling prevaccination (baseline) and 4 (2010 cohort) or 2 (all other cohorts), 7, and 28 d postvaccination (Table I; Materials and Methods). To further assess shared patterns in vaccine-induced changes across five seasons, we performed a PC analysis (PCA) on gene expression fold changes postvaccination for all DEGs. The first two components together explained 38% of the variation in young adults’ and 46% of the variation in older adults’ transcriptional changes postvaccination (Fig. 2B, Supplemental Fig. 4B).
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