A deep longitudinal analysis of next generation influenza vaccines in older adults

PROJECT SUMMARY The WHO estimates that annual epidemics of influenza result in 3-5 million cases of severe illness and 300,000- 500,000 deaths. 90% of influenza-related deaths occur in older adults despite widespread vaccination programs with vaccines tailored for this high-risk group. The estimated effectiveness of the influenza vaccine in the U.S. for the 2018-2019 influenza season overall was 47%, but only 12-13% in older adults. There is therefore an urgent need to understand the mechanisms that are turned on/off in older adults that result in their limited response rate to the most commonly used influenza vaccine, Fluzone® High-Dose. There is also a need to understand whether and why next-generation influenza vaccines might be more efficacious. Immunosenescence is known to be associated with declines in optimal B cell and T cell adaptive immunity, however, our overall understanding of the mechanisms of immunosenescence is incomplete. The central goal of this proposal is to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through establishment of the 3FluAging cohort of healthy older adults who will be vaccinated with three different influenza vaccines three years in a row. We hypothesize that aging impacts specific regulatory mechanisms of humoral immunity to reduce vaccine effectiveness. In Aim 1, we will establish a cohort of 60 healthy older adults (≥65yrs) who will sequentially receive three different annual influenza vaccines, with serial blood and microbiome sample collection during three years of follow-up. Participants will undergo regular clinical assessments. In Aim 2, we will decipher the magnitude and immunodominance pattern of the humoral response to influenza virus in healthy older individuals upon vaccination. For each vaccine, we will characterize antibody titer and quality and will define responders and non-responders. In Aim 3, we will characterize the epigenome, transcriptome, cytokine production, and cell proportions of blood leukocytes in vaccinated healthy older participants. We will identify specific (epi)genomic and functional signatures, and their longevity, associated with vaccine response. We will also sequence all participants to uncover the role of genetic variation on influenza vaccine responses. In Aim 4, we will assess the function of T helper cells and antigen presenting cells, specifically dendritic cells, in influenza vaccine responders and non-responders. By identifying responders and non-responders for each vaccine and integrating these data with baseline immune status multi-omic signatures, we will determine which immune features can predict vaccine responsiveness. We expect to identify humoral immunity pathways that are altered in aging that can be used as the basis for designing novel approaches to boost efficacy of the most commonly used, as well as emerging, influenza vaccines.