Influenza remains a continual threat to health of many Americans, resulting in 9.2-35.6 million illnesses, 140,000-710,000 hospitalizations, and 12,000-56,000 deaths annually since 2010 (CDC), as well as the ever-present likelihood of a devastating pandemic that could kill millions. Recent work has also suggested that a universal flu vaccine may be possible, although there is considerable uncertainty about how to achieve this. This renewal application seeks to leverage some of the important methodologies and data that we have developed in this past granting period to understand at a much deeper level what constitutes broad and effective B and T cell responses against influenza so as to better inform next generation vaccine efforts. Specifically, we have developed a unique tonsil organoid system that we can expose to a flu vaccine and produce high affinity antibodies several days to a week later. This gives us an ability to manipulate and test vaccine constructs and adjuvants in a fully human system in order to find the best way to trigger broadly neutralizing antibodies. In addition, we have developed powerful new T and B cell repertoire analysis methods that will allow us to productively analyze large flu- specific TCR and Ig data sets to identify which specificities or other correlates contribute the most to protection or amelioration of diseases in challenge studies. We also plan to further analyze influenza vaccine responses in pregnant women, the elderly and twins, to test various hypotheses that we have developed in our previous work in the CCHI. Lastly we will take advantage of recent advances by the Nolan lab in imaging tissue sections with large numbers of different antibodies to analyze the cellular organization the tonsil organoids with time during a flu vaccine response and after different interventions.

Public Health Relevance

Influenza morbidity and mortality cause a significant global health burden due to the lack of a universal vaccine. The goal of the Stanford CCHI is to provide missing immunologic data through novel organoid systems derived from tonsils and lymph nodes, lymphocyte repertoire analysis, and 2D/3D cellular neighborhoods and spatial interactions. We will utilize these approaches to determine important characteristics of broadly-neutralizing antibodies, delivery systems and adjuvants, and prior immunity and ?imprinting? of influenza exposures which will contribute to the development of a universal influenza vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI057229-16
Application #
9674968
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Jiang, Chao
Project Start
2003-09-30
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Sweeney, Timothy E; Azad, Tej D; Donato, Michele et al. (2018) Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters. Crit Care Med 46:915-925
Lin, Dongxia; Maecker, Holden T (2018) Mass Cytometry Assays for Antigen-Specific T Cells Using CyTOF. Methods Mol Biol 1678:37-47
Goltsev, Yury; Samusik, Nikolay; Kennedy-Darling, Julia et al. (2018) Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging. Cell 174:968-981.e15
Gee, Marvin H; Sibener, Leah V; Birnbaum, Michael E et al. (2018) Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. Proc Natl Acad Sci U S A 115:E7369-E7378
Cheung, Peggie; Vallania, Francesco; Warsinske, Hayley C et al. (2018) Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell 173:1385-1397.e14
Mamedov, Murad R; Scholzen, Anja; Nair, Ramesh V et al. (2018) A Macrophage Colony-Stimulating-Factor-Producing ?? T Cell Subset Prevents Malarial Parasitemic Recurrence. Immunity 48:350-363.e7
Kooreman, Nigel G; Kim, Youngkyun; de Almeida, Patricia E et al. (2018) Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo. Cell Stem Cell 22:501-513.e7
Haynes, Winston A; Tomczak, Aurelie; Khatri, Purvesh (2018) Gene annotation bias impedes biomedical research. Sci Rep 8:1362
Sweeney, Timothy E; Thomas, Neal J; Howrylak, Judie A et al. (2018) Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome. Crit Care Med 46:244-251
Kronstad, Lisa M; Seiler, Christof; Vergara, Rosemary et al. (2018) Differential Induction of IFN-? and Modulation of CD112 and CD54 Expression Govern the Magnitude of NK Cell IFN-? Response to Influenza A Viruses. J Immunol 201:2117-2131

Showing the most recent 10 out of 249 publications