The isolation of antibodies directly from immune donors offers the advantage of fully exploiting the strength of the human antibody response to vaccination or infection. By following the developmental fate of antigenspecific B cell populations through analysis of their antibodies we can generate a direct survey of B cell function. In this competitive renewal of our Technology Development Project (TOP) on Human Monoclonal Antibodies we combine two uniquely powerful new technologies recently developed that for the first time allow the efficient analysis of human B cell specificity en mass. One approach pioneered by Dr. Lanzavecchia, provides an analysis of the entire history of B cell specificities by efficiently producing mAbs from the long-term memory B cell compartment. The second technology from the Wilson and Ahmed laboratories scrutinizes current, ongoing plasmablast specificities and generates large numbers of antigenspecific antibodies in a short time that are predominantly specific to the antigens. We will use these tools to address fundamental questions about the human B cell response to yellow fever virus (YFV) and dengue virus. By combining these powerful platforms of generating human mAbs (plasmablasts and memory B cells) we should be able to comprehensively analyze the human B cell response to these viruses and to probe the relationship between memory B cells and antibody secreting plasma cells. Because the antibodies produced are fully human they can yield valuable diagnostics and allow for safer Pharmaceuticals than chimeric or humanized antibodies. Thus, in addition to addressing these fundamental questions, our proposed studies should also result in the development of a large panel of human mAbs against YFV and dengue - two flaviviruses that are of important public health concern and are high priority biodefense pathogens.
Three specific aims are proposed: 1) Characterize the primary human B cell response to YFV-17D leading to the generation of ASCs and long-term memory B cells;2) Analyze the dynamics, variable gene repertoire, and the specificity of ASC and memory cells induced by booster vaccination with YFV-17D. 3) Characterize the human B cell response to acute dengue virus infection of Children.

Public Health Relevance

The yellow fever and dengue viruses are emerging infectious diseases that are of important public health concern and are high priority biodefense pathogens. In addition to addressing a number of fundamental questions concerning the human immune response induced by these viruses, our proposed studies should also result in a large panel of human antibodies that may be used therapeutically for these viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057266-10
Application #
8468623
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$549,448
Indirect Cost
$113,782
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hohensinner, Philipp J; Goronzy, Jörg J; Weyand, Cornelia M (2014) Targets of immune regeneration in rheumatoid arthritis. Mayo Clin Proc 89:563-75
Suthar, Mehul S; Pulendran, Bali (2014) Systems analysis of West Nile virus infection. Curr Opin Virol 6:70-5
Pulendran, Bali (2014) Systems vaccinology: probing humanity's diverse immune systems with vaccines. Proc Natl Acad Sci U S A 111:12300-6
Janssens, Sophie; Pulendran, Bali; Lambrecht, Bart N (2014) Emerging functions of the unfolded protein response in immunity. Nat Immunol 15:910-9
Kwissa, Marcin; Nakaya, Helder I; Onlamoon, Nattawat et al. (2014) Dengue virus infection induces expansion of a CD14(+)CD16(+) monocyte population that stimulates plasmablast differentiation. Cell Host Microbe 16:115-27
Weyand, Cornelia M; Yang, Zhen; Goronzy, Jorg J (2014) T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol 26:93-100
Yang, Rendong; Bai, Yun; Qin, Zhaohui et al. (2014) EgoNet: identification of human disease ego-network modules. BMC Genomics 15:314
Burke, Rachel M; Smith, Emily R; Dahl, Rebecca Moritz et al. (2014) The economic burden of pediatric gastroenteritis to Bolivian families: a cross-sectional study of correlates of catastrophic cost and overall cost burden. BMC Public Health 14:642
Chiu, Christopher; McCausland, Megan; Sidney, John et al. (2014) Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV. PLoS Pathog 10:e1004008
Jagger, Ann; Shimojima, Yasuhiro; Goronzy, Jorg J et al. (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60:130-7

Showing the most recent 10 out of 127 publications