The goal of this program to produce an enhanced E/P delivered gene adjuvanted DNA vaccine (E-DNA) and combine this with a highly novel polyvalent A, B, C, A/E recombinant protein boost (PPB) as a vaccine platform. The EP focus of this application is to utilize novel surface delivery. By this combination we hypothesize that we will generate an improved spectrum of T and B anti HIV immune responses compared to current HIV vaccine modalities. This project builds on a major innovations and accomplishments by the members of this team that have led to this proposal. The team has worked together productively for multiple years. Furthermore they have an outstanding track record of productivity working with the HVTN. The inclusion of CHAVI investigators as part of the preclinical development immune analysis is a major strength of the program. There are 3 highly interrelated, translational focused, exceptionally novel projects which build on a strong track record of accomplishment together that comprise this program. They are supported by a highly respected and critical protein core as well as seasoned administrative core.
There remains a pressing need for an effective HIV vaccine and no current vaccine technology induces strong CTL as well as humoral anti HIV immunity, viral vector approaches suffer from serological issues. The goal of this program to produce an enhanced E/P delivered gene adjuvanted DNA vaccine (E-DNA) and combine this with a highly novel polyvalent A, B, C, A/E recombinant protein boost (PPB) as a vaccine platform. The EP focus of this application is to utilize novel surface delivery thus facilitating vaccine deployment By this combination we hypothesize that we will generate an improved spectrum of T and B anti HIV immune responses compared to current HIV vaccine modalities that would represent a major advance for HIV vaccine development. Project-001: Cellular Responses Project Leader (PL): David B. Weiner DESCRIPTION (as provided by applicant): An effective HIV vaccine remains an elusive goal. The possible limited success of the RV144 vaccine trial supports that it is possible to provide protection from HIV acquisition through immunization. However, the vaccine-induced responses elicited by the RV144 ALVAC vCP1521-AIDSVAX B/E strategy were modest and of limited durability. The immune responses induced in a preferred vaccine should be superior to those observed in RV-144 (low T cells, limted antibodies, partially effective) as well as STEP and HVTN 505 (limited antibody responses, non effective T cell responses). A vaccine platform that avoids induction of anti-vector immunity is of growing importance in light of possible enhancement issues. Currently, there is no such HIV vaccine available, and few groups have the combination of technologies proven in the clinic to produce such a platform. This innovative program makes major advances in new DNA adaptive EP + gene adjuvant vaccine technology which in the clinic generates T cell immunity equivalent or superior to live viral vector vaccines (30, 2). We will build on this recent clinical success by novel genetic adjuvants focused on improved antibody induction as well as next generation adaptive EP focusing on skin delivery. We concentrate on increasing the breadth of coverage induced by these designed DNA vaccine by exploring the potential of a multivalent DNA prime followed by a multivalent protein boost. Furthermore, we plan to develop this collection of technologies in a simplified vaccine scheme that has distinct clinical advantages for global testing. There are three aims that comprise this program.
|Schultheis, Katherine; Smith, Trevor R F; Kiosses, William B et al. (2018) Delineating the Cellular Mechanisms Associated with Skin Electroporation. Hum Gene Ther Methods 29:177-188|
|Xu, Ziyang; Wise, Megan C; Choi, Hyeree et al. (2018) Synthetic DNA delivery by electroporation promotes robust in vivo sulfation of broadly neutralizing anti-HIV immunoadhesin eCD4-Ig. EBioMedicine 35:97-105|
|Wang, Shixia; Chou, Te-Hui; Hackett, Anthony et al. (2017) Screening of primary gp120 immunogens to formulate the next generation polyvalent DNA prime-protein boost HIV-1 vaccines. Hum Vaccin Immunother 13:2996-3009|
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|Tebas, Pablo; Roberts, Christine C; Muthumani, Kar et al. (2017) Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report. N Engl J Med :|
|Smith, Trevor R F; Schultheis, Katherine; Broderick, Kate E (2017) Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods. Hum Vaccin Immunother 13:2626-2629|
|Smith, Trevor R F; Schultheis, Katherine; Morrow, Matthew P et al. (2017) Development of an intradermal DNA vaccine delivery strategy to achieve single-dose immunity against respiratory syncytial virus. Vaccine 35:2840-2847|
|Ake, Julie A; Schuetz, Alexandra; Pegu, Poonam et al. (2017) Safety and Immunogenicity of PENNVAX-G DNA Prime Administered by Biojector 2000 or CELLECTRA Electroporation Device With Modified Vaccinia Ankara-CMDR Boost. J Infect Dis 216:1080-1090|
|Griffiths, Kristin L; Villarreal, Daniel O; Weiner, David B et al. (2016) A novel multivalent tuberculosis vaccine confers protection in a mouse model of tuberculosis. Hum Vaccin Immunother 12:2649-2653|
|Kutzler, M A; Wise, M C; Hutnick, N A et al. (2016) Chemokine-adjuvanted electroporated DNA vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge. Mucosal Immunol 9:13-23|
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