Significant research has gone into the development of a safe and effective vaccine for HIV-1. Although many strategies have been attempted; none has been successfully established. Even a partially effective vaccine could decrease the number of people who are infected with HIV, further reducing the number of people who can pass the virus on to others. By substantially reducing the number of new infections, we could eventually stop the pandemic. To date, the elicitation of broadly neutralizing antibodies (bNAbs) has proven extremely difficult to achieve which brought a lot of effort on the novel trimer design and modification. At the same time, it was found that induced HIV- specific CD8+ T cell responses could limit both the transmission and establishment of persistent viral reservoirs. All the evidence suggest that no individual factor will determine the ultimate success of a bNAb-inducing HIV-1 vaccine, which will likely require a combination of efficient precursor B cell priming, optimization of Env design and presentation, sustained heterologous Env boosting, a T cell-based strategy, and newly developed delivery systems or adjuvants. Adjuvants or delivery systems can stimulate different arms of the immune system and are vital components of subunit vaccines, especially in the case of poorly immunogenic envelope glycoprotein. Deliver systems can also be designed to address instability of mRNA-based vaccines. The goal of this program is therefore to overcome challenges with HIV-1 vaccination and deliver a safe and effective vaccine using a biocompatible, biodegradable, easily manufactured short carbon nanotube (CNTVac) platform. Env-trimer and mRNA encoding peptide will be antigens for delivery and will target generation of both humoral and cellular responses. A humanized mouse model and a non-human primate model will be used for immunogenicity and efficacy studies. As the novel non-viral gene transfer vector for HIV-1 vaccine delivery, we will establish methodology for potential GMP production and generate safety profiles under FDA requirements.
Public Health Relevance Statement: Project Narrative The elicitation of broadly neutralizing antibodies (bNAbs) against Tier 2 neutralization resistant HIV-1 viruses has proven extremely difficult to achieve by vaccination. Evidence to-date suggests that no individual factor will determine the ultimate success of an HIV-1 vaccine. The goal of this program is to overcome challenges with HIV-1 vaccination through the codelivery of an Env-trimer-modified and mRNA-modified carbon nanotube targeting both humoral and cellular immune responses.
Project Terms: Antibodies; Epitopes; Antigenic Determinants; Binding Determinants; Antigenic Variation; Antigen Variation; Antigenic Variability; Antigens; immunogen; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biotechnology; Biotech; Chemistry; Clinical Research; Clinical Study; Glycoproteins; Goals; HIV; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Human Immunodeficiency Viruses; LAV-HTLV-III; Lymphadenopathy-Associated Virus; Virus-HIV; HIV-1; HIV-I; HIV1; Human Immunodeficiency Virus Type 1; Human immunodeficiency virus 1; Immune system; allergic/immunologic body system; allergic/immunologic organ system; In Vitro; Infection; Macaca mulatta; M mulatta; M. mulatta; Rhesus Macaque; Rhesus Monkey; Masks; Methods; Methodology; Molecular Conformation; Molecular Configuration; Molecular Stereochemistry; conformation; conformational state; Persons; Peptides; Glycans; Polysaccharides; Production; Research; Retroviruses; Virus-Retrovirus; Retroviridae; mRNA; Messenger RNA; Safety; Synthetic Antigens; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Technology; Testing; Time; Translations; Universities; Vaccination; Vaccines; Virus; Work; Generations; HIV vaccine; HIV/AIDS Vaccines; human immunodeficiency virus vaccine; Injectable; Mediating; Yang; analytical method; base; Surface; Clinical; Phase; Physiological; Physiologic; Ensure; Individual; non-human primate; nonhuman primate; CD8 Cell; CD8 T cells; CD8 lymphocyte; CD8+ T cell; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; T8 Cells; T8 Lymphocytes; CD8-Positive T-Lymphocytes; Collaborations; Immunological response; host response; immune system response; immunoresponse; Immune response; programs; Intramuscular; System; neutralizing antibody; meetings; biocompatibility; biomaterial compatibility; success; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; Toxicities; Toxic effect; Structure; novel; gang; Modeling; response; immunogenic; Subunit Vaccines; Buckytubes; Carbon nano tubes; Carbon Nanotubes; Molecular Interaction; Binding; mRNA Instability; deliver vaccines; vaccine delivery; CD8; CD8B; CD8B1; LYT3; CD8B1 gene; Address; Absorption, Distribution, Metabolism, and Excretion Study; ADME Study; Affinity; Recombinants; in vivo; Validation; transmission process; Transmission; Process; Modification; Adjuvant; Radiolabeled; Development; developmental; pandemic disease; pandemic; preclinical study; pre-clinical study; cost; HIV-1 vaccine; HIV1 vaccine; immunogenicity; design; designing; gene transfer vector; manufacturing process; scale up; cost effective; mouse model; murine model; vaccine candidate; T cell response; arm; HIV resistance; HIV resistant; nanovaccine; nano vaccine; predicting response; prediction of response; predictive response; predictor of response; response prediction; Formulation; humanized mouse; humanized mice; Viral reservoir; Virus reservoir; vaccine discovery; discover vaccines; efficacy study; clinical translation; Injections; RNA vaccine; RNA-based vaccine; mRNA vaccine; mRNA-based vaccine; preservation; lipid nanoparticle; lipid based nanoparticle; mRNA delivery; vaccine formulation; vaccine platform
