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.
|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|
|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|
|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|
|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|
|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|
|Marty-Roix, Robyn; Lien, Egil (2013) (De-) oiling inflammasomes. Immunity 38:1088-90|
|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|
|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|
|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; Wang, Shixia; Hackett, Anthony et al. (2010) Antibody responses elicited through homologous or heterologous prime-boost DNA and protein vaccinations differ in functional activity and avidity. Vaccine 28:2999-3007|
Showing the most recent 10 out of 11 publications