The goal of this revised R01 application is to further optimize the DNA prime and protein boost approach for the development of improved polyvalent HIV vaccine formulations that can generate broad neutralizing antibodies against targeted HIV-1 viruses. This application is based on our recent results that the DNA prime plus protein boost immunization approach was effective in eliciting neutralizing antibody responses against certain primary HIV isolates across multiple clades from both preclinical animal and early phase human clinical studies. This was achieved when the Env antigens from primary HIV-1 isolates were used in this prime/boost vaccination approach. It is believed that DNA priming contributes to the quality of the final antibody responses while the protein boost leads to a quick production of high level antibody responses. Because DNA immunization has been traditionally used for cell mediated immune responses rather than antibody responses, this unexpected finding will bring novel applications to DNA immunization in eliciting neutralizing antibodies against HIV-1. Therefore our approach has exciting potential in human HIV vaccine development.
Aim 1. To further expand the breadth of neutralizing antibodies against additional primary viral isolates especially those resistant to our pilot polyvalent formulations.
Aim 2. To develop the next generation DNA prime and protein boost HIV vaccines by using optimized forms of Env antigen designs and optimized immunization schedules.
Aim 3. To study the immunological mechanism and the antibody affinity maturation process that may contribute to the efficacy of DNA prime plus protein boost strategy so that more effective polyvalent DNA plus protein vaccines can be developed. The current application combines two important technologies in HIV vaccine development: the DNA prime plus protein boost vaccination approach which has been shown promise in generating neutralizing antibodies against primary HIV-1 isolates and the high throughput neutralization assays with standardized primary viral panels. This will allows us to effectively screen a large number of unique primary Env antigens to formulate the effective polyvalent HIV vaccines for the next phase of clinical testing. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065250-02
Application #
7261244
Study Section
Special Emphasis Panel (ZRG1-AARR-A (02))
Program Officer
Miller, Nancy R
Project Start
2006-07-15
Project End
2010-06-30
Budget Start
2007-07-31
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$405,707
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
Pan, Ruimin; Chen, Yuxin; Vaine, Michael et al. (2015) Structural analysis of a novel rabbit monoclonal antibody R53 targeting an epitope in HIV-1 gp120 C4 region critical for receptor and co-receptor binding. Emerg Microbes Infect 4:e44
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
Chen, Yuxin; Vaine, Michael; Wallace, Aaron et al. (2013) A novel rabbit monoclonal antibody platform to dissect the diverse repertoire of antibody epitopes for HIV-1 Env immunogen design. J Virol 87:10232-43
Wang, Shixia; Lu, Shan (2013) DNA immunization. Curr Protoc Microbiol 31:18.3.1-18.3.24
Pan, Ruimin; Sampson, Jared M; Chen, Yuxin et al. (2013) Rabbit anti-HIV-1 monoclonal antibodies raised by immunization can mimic the antigen-binding modes of antibodies derived from HIV-1-infected humans. J Virol 87:10221-31
Buglione-Corbett, Rachel; Pouliot, Kimberly; Marty-Roix, Robyn et al. (2013) Serum cytokine profiles associated with specific adjuvants used in a DNA prime-protein boost vaccination strategy. PLoS One 8:e74820
Wang, Zheng; Zhang, Mingshun; Wang, Yan et al. (2011) A versatile vector for the production of pseudotyped viruses expressing gp120 antigens from different clades of primary HIV-1 isolates. J Virol Methods 171:183-9
Zolla-Pazner, Susan; Kong, X-P; Jiang, Xunqing et al. (2011) Cross-clade HIV-1 neutralizing antibodies induced with V3-scaffold protein immunogens following priming with gp120 DNA. J Virol 85:9887-98
Vaine, Michael; Duenas-Decamp, Maria; Peters, Paul et al. (2011) Two closely related Env antigens from the same patient elicited different spectra of neutralizing antibodies against heterologous HIV-1 isolates. J Virol 85:4927-36

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