Abstract

This revised application is in response to the Program Announcement PA-09-119, Phased Innovation Award Program for AIDS Vaccine Research (R21/R33). This application proposes to produce neutralizing human monoclonal antibody (mAb) from human volunteers who received a polyvalent DNA prime-protein boost HIV vaccine in a Phase I clinical trial and their sera have demonstrated positive neutralizing activities against primary HIV-1 from clades A to E. If successful, this will be the first time that neutralizing human mAbs can be produced from HIV vaccinees. Detailed analyses of these mAbs will provide valuable information on their specificity, strength, and breadth of neutralizing activities. Similar to several available mAbs generated from HIV-1 infected patients, successful production of human mAb from HIV-1 vaccinees will provide useful information for the further optimization of Env-based HIV-1 vaccines.
Specific Aims for R21 phase (Years 1~2):
Specific Aim 1 : To produce human hybridoma using PBMCs isolated from human vaccinees and to screen and identify Env-specific monoclonal antibodies including those with neutralizing activities.
Specific Aim 2 : To generate mAbs from single Env-specific B cells using a high throughput in vitro Ig expression strategy Specific Aims for R33 phase (Years 3-5):
Specific Aim 3 To examine the strength and breadth of neutralizing mAbs and identify other protective functions of non-neutralizing mAbs produced from our proposed studies.
Specific Aim 4 : To analyze the epitope specificity of neutralizing mAbs produced in this proposal.
Specific Aim 5 : To expand the production of Env-specific mAbs from additional vaccinees including PBMCs collected at different time points in the immunization schedule.

Public Health Relevance

We propose to use existing blood cells collected from human volunteers who received a novel HIV vaccine in an already completed clinical trial to generate a unique type of cells that can continuously produce highly specific antibodies - research tools that can guide the design of next generation of HIV vaccines.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI087191-05
Application #
8680117
Study Section
HIV/AIDS Vaccines Study Study Section (VACC)
Program Officer
Li, Yen
Project Start
2010-06-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Chan, Kun-Wei; Pan, Ruimin; Costa, Matthew et al. (2018) Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection. J Virol 92:
Farfán-Arribas, Diego J; Liu, Shuying; Wang, Shixia et al. (2017) The dynamics of immunoglobulin V-gene usage and clonotype expansion in mice after prime and boost immunizations as analyzed by NGS. Hum Vaccin Immunother 13:2987-2995
Costa, Matthew R; Pollara, Justin; Edwards, Regina Whitney et al. (2016) Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001. J Virol 90:10362-10378
Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2016) A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines. J Immunol 196:310-6
Zhang, Lu; Wang, Wei; Wang, Shixia (2015) Effect of vaccine administration modality on immunogenicity and efficacy. Expert Rev Vaccines 14:1509-23
Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2015) Identification of Aim2 as a sensor for DNA vaccines. J Immunol 194:630-6
Buglione-Corbett, Rachel; Pouliot, Kimberly; Marty-Roix, Robyn et al. (2014) Reduced MyD88 dependency of ISCOMATRIX™ adjuvant in a DNA prime-protein boost HIV vaccine. Hum Vaccin Immunother 10:1078-90
Hollister, Kristin; Chen, Yuxin; Wang, Shixia et al. (2014) The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination. Hum Vaccin Immunother 10:
Hollister, Kristin; Chen, Yuxin; Wang, Shixia et al. (2014) The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination. Hum Vaccin Immunother 10:1985-92
Wallace, Aaron; West, Kim; Rothman, Alan L et al. (2013) Post-translational intracellular trafficking determines the type of immune response elicited by DNA vaccines expressing Gag antigen of Human Immunodeficiency Virus Type 1 (HIV-1). Hum Vaccin Immunother 9:2095-102

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