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Globally Appropriate Genome Reduced Killed Whole Bacterial HIV Vaccines

全球适用的基因组减少灭活全细菌 HIV 疫苗

基本信息

批准号：
10672822
负责人：
Steven L. Zeichner
金额：
$ 56.53万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-13 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672822
关键词：
2019-nCoV Adjuvant Animal Model Antibodies Antibody Binding Sites Antibody Formation Antigens Bacteria Bacterial Vaccines Binding Binding Sites Biological Assay Biomedical Engineering Biomedical Research Cells Cellular Immunity Chimeric Proteins Clinical Cold Chains Combined Vaccines Consensus Coronavirus Cryopreservation DNA DNA biosynthesis Data Development Disease Dose Engineering Enzyme-Linked Immunosorbent Assay Epidemic Escherichia coli Escherichia coli Vaccines Exhibits Family suidae Funding Future Genome Goals HIV HIV Antigens HIV vaccine HIV-1 HIV-1 vaccine Hand Human Immune response Immunize Inactivated Vaccines Industrialization International Knowledge Letters Manufacturer Medical Membrane Modeling Monitor Monoclonal Antibodies Mus Peptide Vaccines Peptides Phase Plasmids Positioning Attribute Preventive vaccine Production Proteins Recombinants Recording of previous events Research Route Safety Structure Study models Surface System T cell response Technology Transfer Testing Training Translating Vaccinated Vaccination Vaccine Antigen Vaccine Production Vaccines Viral Antigens Viral Envelope Proteins Viral Fusion Proteins Virus Virus Diseases Whole Cell Vaccine Work antigen-specific T cells cell mediated immune response clinical efficacy cost design early phase clinical trial forgiveness high reward high risk immunogenicity improved in vivo evaluation innovation manufacturing capabilities meetings monomer mouse model neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel novel strategies novel vaccines porcine epidemic diarrhea virus prophylactic response safety assessment skills success synthetic biology vaccine candidate vaccine development vaccine immunogenicity vaccine platform vaccine response

项目摘要

A broad consensus regarding HIV vaccine development calls for engineering antigens that elicit production of antibodies like the known Broadly Neutralizing (BN) Monoclonal Antibodies (MAbs). Two Env BN MAb binding sites, the Membrane Proximal External Region (MPER) and Fusion Peptide (FP), are attractive targets because they are linear peptides. We developed a new, low cost, globally appropriate vaccine platform: Killed Whole Cell (KWC) Genome-Reduced E. coli (grEc), with vaccine antigens expressed on bacterial surfaces using Gram- autotransporters. Using synthetic biology, testable vaccine candidates can be made in ~3 wks for ~$50 each. Vaccines made with the platform will cost ~$1/dose, can be produced in existing factories globally, and have forgiving cold chain requirements. We made coronavirus FP vaccines using the KWC grEc platform and showed clinical efficacy in an animal model. We propose to make KWC grEc HIV vaccines targeting MPER and FP. Our preliminary data show that we can express HIV MPER and FP Ags with this approach and elicit HIV neutralizing sera in mice using an MPER-derived Ag. We hypothesize that the KWC grEc platform, targeting MPER and FP, will yield safe, effective, low cost, globally appropriate HIV vaccines. In PHASE 1, Aim 1, we will synthesize DNAs encoding MPER and FP Ags, employing bioengineering strategies to enhance Ag exposure and antigenicity. We will clone these DNAs into our expression plasmid and transform into grEc to make KWC candidate vaccines. Using highly neutralizing and relatively non-neutralizing MAbs, we will test candidate vaccines, selecting those that show the best difference in binding neutralizing vs. less neutralizing MAbs for in vivo testing. In Aim 2, we will vaccinate mice to assess vaccine immunogenicity, comparing the different candidate vaccines, alone and in combination, to identify the best vaccines and dose/route/adjuvant using ELISAs, ELIspot assays, and PhenoSense neutralization assays against a representative panel of viruses. Decision Gate to progress to Phase 2: Production of a single or combination vaccine that elicits sera in vaccinated mice yielding an IC50 >100 in the PhenoSense neutralization assay for ≥75% of mice immunized, for ≥75% of HIV-1 Env reference strains, while sera from control immunized mice (mice immunized with bacteria not expressing viral antigen) show no neutralization above baseline control. In PHASE 2 we will, in Aim 3, conduct a non-human primate (NHP) model study to assess the safety, immunogenicity, and ability to elicit a neutralizing Ab response by the vaccines. We expect that our vaccines will induce specific HIV Ag-binding Abs, HIV antigen-specific T cell responses, and BN neutralizing Ab responses in NHP, implying that the vaccine will be safe and effective in humans. KWC vaccines have a long history, are inexpensive to make, and can be produced globally in existing facilities, we anticipate that our work can be quickly translated into safe and effective, inexpensive, globally appropriate, prophylactic HIV vaccines.

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