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Principal Investigator: DAVID B. WEINER
Organization: WISTAR INSTITUTE
Fiscal Year: 2024
Award: $4,420,687
Funding agency: National Institute of Allergy and Infectious Diseases
Overall Summary
A protective vaccine for HIV is arguably the most important prevention strategy to end the global HIV pandemic.
The RV144 trial demonstrated a correlation between protection and envelope (Env) specific serum IgG
antibodies. However, there was a notable lack of HIV-specific neutralizing antibodies (nAbs) and T cell
responses. The DNA platform has several advantages, it is (1) simple to design, (2) can co-deliver molecular
adjuvants, (3) can deliver complex structural antigens, and (4) is safe and well tolerated, even after numerous
boosts. In our previous IPCAVD program we developed DNA-launched nanoparticle (DLNP) vaccines targeting
Env which induced potent and neutralizing immunity in vivo. We have also developed DNA-launched native-like
trimer (DL-NLT) immunogens including the clinically relevant BG505 MD39 trimer (Xu et al. Nat. Comm 2022).
Protein nanoparticles are difficult to manufacture and poorly stimulate CD8+ T cells. We reported that in vivo
assembled nanoparticles drive extremely rapid and strong B and T cell immunity. Functional antibody responses
require help from germinal center (GC) follicular helper T cells (TFH). In previous clinical trials with HIV antigens,
we observed increased B and T cell responses in the presence of plasmid-encoded IL-12 (pIL-12). Work from
members of this team has demonstrated that co-delivery of adenosine deaminase (ADA-1) and plasmid-encoded
IL-21 (pIL-21) can enhance antibody induction in mice in a GC-dependent fashion. Here, we combine the DLNP
and DL-NLT platforms to generate DNLPs bearing stabilized NLTs focusing immune responses on apex and
CD4bs B cell lineage-targeting Envs (DNLP-ACE). We will characterize humoral and cellular immunity to these
constructs in the presence of molecular IL-12 with and without additional GC-targeting adjuvants, in mouse and
non-human primate vaccination studies. The overarching hypothesis of this project is that DLNP-ACE
immunogen technology combined with the co-delivery of genetic adjuvants is a novel approach for the
development of HIV-1 vaccines that promotes robust, durable, broad, and neutralizing antibody
responses, and supports effector T cell function in vivo A key innovation of this project will be to integrate
the selected DNLP-ACE HIV vaccine constructs in a dual expressing plasmid construct with next generation
noninvasive intradermal skin electroporation (EP) devices which promote functional CTL and humoral immune
responses. The clinical development plan for this IPCAVD is directed by a leading HIV vaccine development
organization, Inovio Pharmaceuticals (INO), which has expertise in development of synthetic DNA vaccines and
in vivo electroporation delivery. Inovio will oversee clinical grade production of 2 plasmid constructs at a state-
of-the-art cGMP plasmid manufacturing facility. Inovio’s processes have passed rigorous international regulatory
reviews and have been used in dozens of human clinical trials in the U.S., Europe and Asia, including multiple
Phase II and in Phase III studies.
Terms: <7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adenosine Aminohydrolase><Adjuvant><Adoptive Transfer><Advanced Development><Agreement><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Repertoire><Antibody Response><Antigenic Determinants><Antigens><Apical><Asia><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Binding Sites><Blood Serum><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Function><Cell Lineage><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell-Mediated Immunity><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Clinic><Clinical><Clinical Protocols><Clinical Research><Clinical Study><Clinical Trials><Collaborations><Combining Site><Complex><Cyclic GMP><DNA><DNA Vaccines><DNA delivery><Deoxyribonucleic Acid><Development><Development Plans><Devices><Edodekin Alfa><Electroporation><Epitopes><Europe><Genetic><Germ Lines><Germinal Center><Goals><Guanosine Cyclic Monophosphate><HIV><HIV Antigens><HIV Vaccine Trials Network><HIV vaccine><HIV-1><HIV-Associated Antigens><HIV-I><HIV/AIDS Vaccines><HIV1><HTLV-III Antigens><HTLV-III-LAV Antigens><HVTN><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antigens><Human immunodeficiency virus 1><Humoral Immunities><IL-12><IL12><IL21><IgG><Immune><Immune response><Immunes><Immunity><Immunoglobulin G><Immunological response><Inducer Cells><Inducer T-Lymphocytes><Infection><Interleukin-12><International><Investigation><KI mice><Knock-in Mouse><LAV Antigens><LAV-HTLV-III><Lymphadenopathy-Associated Antigens><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><NKSF><Naked DNA Vaccines><Natural Killer Cell Stimulatory Factor><Needles><Nucleic Acids><Other Genetics><Peripheral><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phase III study><Phenotype><Plasmids><Preventative strategy><Prevention strategy><Preventive strategy><Primates><Primates Mammals><Process><Production><Proteins><Reactive Site><Recombinant DNA Vaccines><Reporting><Rhesus Macaque><Rhesus Monkey><SHIV><Serum><Skin><Structure><Structure of germinal center of lymph node><Subcellular Process><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Technology><Teff cell><Translations><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Design><Vaccines><Virus-HIV><Work><adenosine deaminase><antibody-based immunity><cGMP><cGMP production><candidate selection><clinical development><clinical relevance><clinical translation><clinically relevant><clinically translatable><cytokine><deliver DNA><deliver vaccines><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><effector T cell><electroporative delivery><experience><gene electrotransfer><global health><host response><human immunodeficiency virus vaccine><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><in vivo><innovate><innovation><innovative><interleukin-21><knockin mice><lead candidate><manufacture><manufacturing facility><manufacturing plants><member><model of animal><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><new approaches><new vaccines><next generation><next generation vaccines><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><novel vaccines><pandemic><pandemic disease><pharmaceutical><phase 3 study><pre-clinical><preclinical><production plants><programs><promoter><promotor><response><simian HIV><simian human immunodeficiency virus><synthetic DNA><synthetic construct><thymus derived lymphocyte><tool><translation><vaccination study><vaccination trial><vaccine acquired immunity><vaccine associated immunity><vaccine delivery><vaccine development><vaccine study><vaccine trial><vaccine-induced immunity><vaccine-induced protection>