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Principal Investigator: Adolfo Garcia-Sastre
Organization: JACKSON LABORATORY
Fiscal Year: 2024
Award: $2,465,186
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><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ATAC sequencing><ATAC-seq><ATACseq><Active Follow-up><Adjuvant><Adult><Adult Human><Aged 65 and Over><Aging><Antibodies><Antibody titer measurement><Antigen-Presenting Cells><Archives><Assay><Assay for Transposase-Accessible Chromatin using sequencing><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><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><COVID-19 vaccine><Cell Body><Cell Nucleus><Cells><Cellular Immune Function><Cellular Immunology><Cessation of life><Clinical assessments><Collaborations><Collection><Death><Dendritic Cells><Dose><Effectiveness><Epitope Mapping><FDA approved><Failure><Feces><Flu epidemic><Fluzone><Future><Genetic Diversity><Genetic Variation><Genome><Genomics><Goals><Grippe><Groups at risk><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><Inflammatory><Influenza><Influenza A Virus, H7N9 Subtype><Influenza HA><Influenza Hemagglutinin><Influenza Vaccines><Influenza Virus><Interferons><Length of Life><Leukocytes><Leukocytes Reticuloendothelial System><Long-term cohort><Longevity><Longitudinal cohort><Longterm cohort><MF59><Marrow leukocyte><Messenger RNA><Molecular><Nucleus><Older Population><Outcome Measure><Participant><Pathway interactions><Pattern><People at risk><Persons at risk><Phenotype><Populations at Risk><Production><QTL><Quantitative Trait Loci><RNA vaccine><RNA-based vaccine><Recording of previous events><Research Resources><Resources><Role><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Sampling><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><above age 65><accessory cell><active followup><adaptive immunity><adulthood><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated effects><age correlated><age dependent><age effect><age linked><age of 65 years onward><age related><age related effects><age specific><aged 65 and greater><aged 65+><aged ≥65><aging effect><analyzing longitudinal><anamnestic reaction><antibody titering><antibody-based immunity><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biologic><cohort><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cytokine><data integration><data resource><design><designing><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><global gene expression><global transcription profile><high risk group><high risk individual><high risk people><high risk population><histories><human old age (65+)><immune function><immune senescence><immunization strategy><immunogenic><immunological status><immunosenescence><impact of age><improved><influence of age><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><longitudinal analysis><mRNA><mRNA vaccine><mRNA-based vaccine><measurable outcome><microbiome><multiomics><multiple omics><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nasal swab><new approaches><next generation><novel approaches><novel strategies><novel strategy><old age><older adult><older adulthood><older groups><older individuals><older person><outcome measurement><over 65 years><pan influenza vaccine><pan influenza viral vaccine><pan influenza virus vaccine><panomics><pathway><predict responsiveness><predicting 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><responders/nonresponders><response><sample collection><scRNA-seq><seasonal flu><seasonal influenza><secondary immune response><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 COVID-19><vaccine against SARS-CoV-2><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 candidates against SARS-CoV-2><vaccine effectiveness><vaccine efficacy><vaccine for novel coronavirus><vaccine response><vaccine responsiveness><vaccine-induced response><vaccines preventing COVID><vaccines to prevent COVID><viral infection><virus infection><virus-induced disease><volunteer><white blood cell><white blood corpuscle><≥65 years>