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Principal Investigator: Adolfo Garcia-Sastre
Organization: JACKSON LABORATORY
Fiscal Year: 2022
Award: $1,622,607
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019-nCoV vaccine><21+ years old><ATAC-seq><ATACseq><Active Follow-up><Adjuvant><Adult><Adult Human><Age><Aging><Antibodies><Antibody titer measurement><Antigen-Presenting Cells><Archives><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biologic Assays><Biological><Biological Assay><Blood><Blood Reticuloendothelial System><Blood leukocyte><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CITE sequencing><CITE-seq><CITEseq><COVID-19 vaccine><COVID19 vaccine><Cell Body><Cell Nucleus><Cells><Cellular Immune Function><Cellular Immunology><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Cessation of life><Clinical assessments><Collaborations><Collection><Data><Death><Dendritic Cells><Dose><Effectiveness><Elderly><Epitope Mapping><FDA approved><Failure><Feces><Flu epidemic><Fluzone><Future><Genetic Diversity><Genetic Variation><Genome><Genomics><Goals><Grippe><H7N9><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemagglutination><History><Humoral Immunities><IFN><Immune><Immune memory><Immunes><Immunization Programs><Immunologic Memory><Immunological Memory><Individual><Inducer Cells><Inducer T-Lymphocytes><Influenza><Influenza A Virus, H7N9 Subtype><Influenza HA><Influenza Hemagglutinin><Influenza Vaccines><Influenza Virus><Interferons><Lead><Length of Life><Leukocytes><Leukocytes Reticuloendothelial System><Long-term cohort><Longevity><Longitudinal cohort><Longterm cohort><MF59><Marrow leukocyte><Messenger RNA><Molecular><Nucleus><Outcome Measure><Participant><Pathway interactions><Pattern><Pb element><Phenotype><Production><QTL><Quantitative Trait Loci><RNA vaccine><RNA-based vaccine><Recording of previous events><Research Resources><Resources><Risk><Role><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Sampling><Seasons><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Specificity><Structure><Systems Biology><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Technology><Time><Vaccinated><Vaccination><Vaccination Programs><Vaccines><Veiled Cells><Viral Diseases><Virus Diseases><White Blood Cells><White Cell><accessory cell><active followup><adaptive immunity><adulthood><advanced age><age dependent><age related><ages><anamnestic reaction><antibody titering><antibody-based immunity><base><biologic><cellular indexing of transcriptomes and epitopes by single cell sequencing><cohort><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cytokine><data resource><design><designing><elders><epigenome><epigenomics><flu HA><flu hemagglutinin><flu serotype><flu strain><flu subtype><flu vaccine><flu viral strain><flu virus strain><flu virus vaccine><follow up><follow-up><followed up><followup><geriatric><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><high risk group><high risk population><immune function><immunization strategy><immunogenic><immunological status><immunosenescence><improved><influenza epidemic><influenza serotype><influenza strain><influenza subtype><influenza viral HA><influenza viral hemagglutinin><influenza viral strain><influenza virus HA><influenza virus hemagglutinin><influenza virus strain><influenza virus vaccine><influenzavirus><late life><later life><life span><lifespan><longitudinal analysis><mRNA><mRNA vaccine><mRNA-based vaccine><microbiome><multiomics><multiple omics><nasal swab><new approaches><next generation><novel approaches><novel strategies><novel strategy><older adult><older person><pathway><predicting response><prediction of response><predictive response><predictor of response><primary outcome><programs><recruit><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><response><response prediction><sample collection><scRNA-seq><seasonal flu><seasonal influenza><secondary immune response><senior citizen><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><specimen collection><stool><synergism><thymus derived lymphocyte><transcriptome><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine against flu><universal vaccine against influenza><vaccination strategy><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against flu><vaccine against influenza><vaccine effectiveness><vaccine efficacy><vaccine for novel coronavirus><vaccine response><vaccine responsiveness><vaccine-induced response><viral infection><virus infection><virus-induced disease><volunteer><white blood cell><white blood corpuscle>