The goal of this U19 application is to further advance the DNA prime/protein boost approach to focus on the development of broadly reactive antibody responses. This proposal is developed based on our recent phase 1 study result that, for the first time, a candidate AIDS vaccine induced both cell-mediated immunity and neutralizing antibody responses against selected primary HIV-1 isolates in the same human clinical trial. It was also the first time that DNA immunization was effective in priming high level antibody responses in human volunteers. The current proposal represents a key progress that we are able to use a highly reproducible vaccination technology platform to conduct incremental improvements on the components of actual vaccine formulations. By using the current IPCAVD program, we propose to conduct advanced vaccine optimization studies in order to address two key issues: 1) to conduct a rational selection of Env antigens in order to improve the breadth of neutralizing antibody responses, and 2) to optimize the selection of adjuvants to reduce any potential high reactogenicity in those volunteers who received the one protein boost after the high dose DNA prime in our previous clinical trial. Specifically, the following aims are proposed: Objective 1: To assemble and manage a highly productive research and development team. Objective 2: To develop the next generation polyvalent Env formulation by including Env antigens that were selected based on a well controlled rational screening system. Objective 3: To improve the safety profile by testing different adjuvants and using alternative DNA vaccine delivery method to reduce any potential reactogenicity. Objective 4: To conduct GMP manufacturing of DNA and protein vaccine components, definitive toxicology studies, and regulatory reviews of the next generation polyvalent HIV vaccine formulation. Objective 5: To plan for a Phase 1 safety and immunogenicity clinical trial and transfer GMP products to be tested in humans to NIH's HIV Vaccine Trial Network (HVTN).
Developing a further improved candidate AIDS vaccine to control HIV virus transmission in the world. An early version of this vaccine design showed promising results in its first human study. PROJECT 1 Project Title: Optimizing the Immunogenicity of Next Generation Polyvalent HIV Vaccine Formulations Project Leader: Shan Lu, MD, PhD PROJECT 1 DESCRIPTION (provided by applicant): Project 1 will focus on the optimization of the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime/protein boost technology platform. Our first HIV vaccine formulation, DP6-001, was developed several years ago for a proof-of-concept trial to demonstrate the immunogenicity of the DNA prime/protein boost approach in human volunteers. The primary Env antigens isolated from HIV infected patients in mid-1990s were selected randomly based on their genetic clades. Rapid progress in the HIV vaccine field now provides us with a much larger selection of primary Env antigens, especially those Env proteins from clades less studied in the past and those Env proteins with more detailed information about the patients from whom the viruses were isolated. In addition, the recently developed pseudotyped neutralization assay and newly established target HIV-1 primary virus panel (""""""""the Tiers System"""""""") provides a measurable standard to guide our selection of more relevant primary Env antigens for the development of HIV vaccines focusing on the induction of neutralizing antibody responses. By taking advantage of the above progress, we have identified a group of primary Env antigens that were able to elicit much broader neutralizing antibodies than those included in our previous formulation DP6-001. In the current Project 1 of this IPCAVD program, the following studies will be conducted:
Aim 1 To finalize the selection of next generation polyvalent Env formulation to further improve the quality of neutralizing antibody activities.
Aim 2 To select an immunogenic adjuvant to be used as part of the protein boost for the next generation polyvalent Env formulation.
Aim 3 To test the immunogenicity of next generation polyvalent Env formulation when the DNA priming is delivered by the electroporation method.
Aim 4 To examine the epitope profiles in immune sera elicited by DNA prime-protein boost approach and identify the epitope specificities of antibodies responsible for the neutralizing activities.
To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform.
|Li, Xiaoyan; Grant, Oliver C; Ito, Keigo et al. (2017) Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting. Biochemistry 56:957-970|
|Marty-Roix, Robyn; Vladimer, Gregory I; Pouliot, Kimberly et al. (2016) Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants. J Biol Chem 291:1123-36|
|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|
|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|
|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|
|Pouliot, Kimberly; Buglione-Corbett, Rachel; Marty-Roix, Robyn et al. (2014) Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine. Vaccine 32:5049-56|
|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|
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