We will carry out deep sequencing of rearranged immunoglobulin (Ig) and T cell receptor (TCR) genes from lymphocytes in human subjects responding to several distinct viral (H1N1 influenza, varicella zoster, and measles/mumps/rubella) and bacterial (meningococcal) vaccines, as well as natural infections with HI N1 influenza and varicella zoster. Our initial analysis will examine rearranged Ig and TCR repertoire in total peripheral blood lymphocyte populations. Subsequent analysis will define repertoire in subsets of B cells and T-cells selected on the basis of their immunophenotype or antigen binding activity. These data will provide a fine-detailed view of the number, size, and receptor sequence features of expanded B and T cell clones arising during these human immune responses, and will be correlated with a variety of parallel serological and cellular functional immune assays from the Stanford Human Immune Monitoring Research (SHIMR) Center to enable detection ofthe characteristics of effective vaccination and the immune response to natural infection. The effects of patient age and genetic background on immune responses will also be assessed in a subset of experiments. Our intertwined goals for the five-year period of this grant are: 1. Characterize immune receptor populations in adults before and following immunization with influenza H1N1 vaccine and following natural infection by H1N1. 2. Characterize immune receptor populations in adults before and following immunization with a conjugated bacterial polysaccharide vaccine (Menactra). 3. Characterize immune receptor populations following vaccination against Varicella Zoster (in older adults) and measles virus (in children). 4. Develop new quantitative analytical tools for high throughput immunome data and use these tools to characterize the clinical relevance of commonalities and differences in immune spectra amongst immunized individuals. 5. Interface immune repertoire data with additional immunophenotyping data including HLA type, antibody binding affinity and specificity, target killing, cytokine production, signaling response spectra, and cellular surface marker distribution.

Public Health Relevance

We will apply new DNA sequencing methods to study the unique receptors expressed by populations of B and T cells in the immune system following protective vaccination against viral and bacterial diseases, and during active infections. Better understanding of which B cells and T cells respond to vaccination and infection, and which are most helpful for fighting disease, will aid the design and testing of new vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090019-05
Application #
8705366
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Bongen, Erika; Vallania, Francesco; Utz, Paul J et al. (2018) KLRD1-expressing natural killer cells predict influenza susceptibility. Genome Med 10:45
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
Nair, Nitya; Feng, Ningguo; Blum, Lisa K et al. (2017) VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans. Sci Transl Med 9:
Brodin, Petter; Davis, Mark M (2017) Human immune system variation. Nat Rev Immunol 17:21-29
Haddon, D James; Wand, Hannah E; Jarrell, Justin A et al. (2017) Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment. J Rheumatol 44:631-638
Furman, David; Chang, Junlei; Lartigue, Lydia et al. (2017) Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 23:174-184
HIPC-CHI Signatures Project Team; HIPC-I Consortium (2017) Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses. Sci Immunol 2:
O'Gorman, W E; Kong, D S; Balboni, I M et al. (2017) Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients. J Autoimmun :
Blazkova, Jana; Gupta, Sarthak; Liu, Yudong et al. (2017) Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy. J Immunol 198:2479-2488
Toby, Inimary T; Levin, Mikhail K; Salinas, Edward A et al. (2016) VDJML: a file format with tools for capturing the results of inferring immune receptor rearrangements. BMC Bioinformatics 17:333

Showing the most recent 10 out of 121 publications