Project summary
Seasonal influenza (“flu”) remains a serious public health threat with the highest burden of severe disease
and complications affecting older adults, particularly those over age 75. In addition to vaccine itself, responses
to vaccination and vaccine effectiveness in older adults are likely influenced by comorbidity (e.g., frailty),
immune senescent remodeling (i.e., immunosenescence and inflammaging), repeated annual vaccination,
intra-seasonal immune waning, and virus strain variations both in vaccine formula and in circulation.
Since 2014, we have established a study cohort in community-dwelling older adults >75. The cohort has
accumulated 815 person-seasons with comprehensive demographic, clinical, functional and laboratory data, as
well as banked pre- and post-vaccination serum, plasma, and peripheral blood mononuclear cell (PBMC)
samples. We also identified 15 breakthrough flu infection cases with banked post-infection serum, plasma and
PBMC samples. Importantly, 20 subjects participated in all 7 seasons, 36 in 6 seasons, 31 in 5 seasons, 16 in
4 seasons, and 165 in 3 seasons or less. Here, we propose to leverage this unique cohort and employ cutting
edge immunologic research tools to develop state-of-the-art “immune signatures” reflecting both general
immune status (distribution and function of immune cell subsets through high-dimensional flow analysis and
RNA-Seq; cytokine profiling) and influenza-specific immunity (breadth and depth of flu-specific T cell repertoire;
distribution/function of homotypic/heterotypic anti-flu T cells through flow analysis and scRNA-Seq; deep
serological profiling of strain-specific and cross-reactive flu antibodies). Our objective is to characterize
immune signatures and their intra- and inter-seasonal changes over time as determinants of vaccine
responses and risk of breakthrough infection in older adults >75. Our specific aims are: 1) Characterize
seasonal baseline (pre-existing) immune signatures as determinants of vaccine response and how
they change over time. We will not only determine inter-season longitudinal trajectory, but also identify
specific baseline immune signatures predict responses to vaccination; 2) Characterize seasonal immune
signature responses to vaccination as determinants of risk of breakthrough infection and how they
change over time. We will evaluate and compare differences and similarities of immune signature responses
elicited by vaccination vs natural infection to explore immune mechanisms of vulnerability; and 3) Characterize
intra-seasonal waning of immune signature responses to vaccination and its change across seasons
through monthly blood sampling until the end of each flu season across multiple seasons.
Upon completion, the proposed studies will advance our understanding of immune signatures as key
immunologic mechanisms for vaccine responses and risk of breakthrough infection in a typical geriatric
population. Ultimately, these studies will help define correlates of protection and develop more effective
immunization strategies including a universal vaccine for this highly vulnerable subset of older adults.