Abstract

The B Cell Biology Scientific Research Support Component (SRSC) will assist in the generation of novel vaccines that target broad neutralizing antibodies (BnAbs) or other protective B-cell precursors by B lineage immunogen design. The novel vaccines generated by the CHAVI-ID B Cell Focus will be designed to activate the unmutated ancestors (UA) of highly mutated BnAb B cells isolated by flow cytometry. As a parallel strategy, this B Cell Biology SRSC will first isolate human B-cell precursors, and drives their maturation in vitro. BnAb precursors will then be identified and allowed to proliferate, mature and undergo Ig class-switching (CSR) in vitro. In this manner, the B Cell Biology SRSC will complement the work of the B Lineage Immunogen Design teams by identifying and selecting BnAb precursors -unmutated ancestors B cells - that are comparable to, and possibly better than, those inferred from BnAb clonal lineages. This support component will identify, isolate, characterize, and activate de novo B cells capable of generating BnAb responses, allowing the direct study of BnAb UA and intermediate antibody (IA) B cells.
Specific Aims Aim 1. Culture Env-specific immature B cells from human bone marrow in vitro and drive them to express AID and undergo Ig class-switch recombination in vitro to characterize BnAb maturation pathways.
Aim 2. Culture Env-specific immature B cells from humanized Velocimmune? mice in vitro and drive antigen-specific B cells to compete and mature by AID expression and Ig CSR to characterize BnAb maturation pathways.
Aim 3. Immunize immunoglobulin humanized mice with candidate Env vaccines to determine their immunogenicity by characterizing serum antibody responses and hybridoma lines.

Public Health Relevance

This support component will grow human and immunoglobulin humanized mouse B cells in test tubes and these will be used to identify candidate HlV-1 vaccine antigens. This approach will allow novel molecular vaccine designs to be tested inexpensively, rapidly, and ethically.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI100645-02
Application #
8508874
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$854,462
Indirect Cost
$310,219

  Institution

Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Brown, Eric P; Weiner, Joshua A; Lin, Shu et al. (2018) Optimization and qualification of an Fc Array assay for assessments of antibodies against HIV-1/SIV. J Immunol Methods 455:24-33
Finney, Joel; Yeh, Chen-Hao; Kelsoe, Garnett et al. (2018) Germinal center responses to complex antigens. Immunol Rev 284:42-50
Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S et al. (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215:1571-1588
Eudailey, Joshua A; Dennis, Maria L; Parker, Morgan E et al. (2018) Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques. mSphere 3:
Kelsoe, Garnett; Haynes, Barton F (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling. Cold Spring Harb Perspect Biol 10:
Wagh, Kshitij; Kreider, Edward F; Li, Yingying et al. (2018) Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth. Cell Rep 25:893-908.e7
Fu, Qingshan; Shaik, Md Munan; Cai, Yongfei et al. (2018) Structure of the membrane proximal external region of HIV-1 envelope glycoprotein. Proc Natl Acad Sci U S A 115:E8892-E8899
Fera, Daniela; Lee, Matthew S; Wiehe, Kevin et al. (2018) HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. Nat Commun 9:1111
McMichael, Andrew J (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? Could a CD8+ T-Cell Vaccine Prevent Persistent HIV Infection? Cold Spring Harb Perspect Biol 10:
Williams, Wilton B; Han, Qifeng; Haynes, Barton F (2018) Cross-reactivity of HIV vaccine responses and the microbiome. Curr Opin HIV AIDS 13:9-14

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