Project 1 - Development of mRNA Immunogens for Protective Antibody Induction

项目 1 - 开发用于诱导保护性抗体的 mRNA 免疫原

• 批准号: 10355428
• 负责人: Barton F. Haynes
• 金额: $ 219.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-11 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355428
• 关键词: ALVAC; Adjuvant; Affinity; Antibodies; Antibody Response; Antibody titer measurement; Antigens; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cells; Complement; Complex; Data; Development; Elements; Epitopes; Grant; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Vaccine Trials Network; HIV vaccine; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Human; Immune; Immunize; Immunoglobulin Class Switching; Infectious Agent; Inflammatory; Interferon Type I; Intramuscular; Knock-in Mouse; MF59; Macaca; Macaca mulatta; Maintenance; Mediating; Memory B-Lymphocyte; Messenger RNA; Mosaicism; Mus; Natural Killer Cells; Nucleosides; Phase; Phase I Clinical Trials; Plasma; Production; Proteins; RNA vaccination; RNA vaccine; Risk; Safety; Structure of germinal center of lymph node; T cell response; Testing; Translations; Vaccine Design; Vaccines; Wild Type Mouse; Zika Virus; aluminum sulfate; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; comparative; cost; cytokine; design; efficacy trial; expectation; follow-up; immune RNA; improved; innovation; lipid nanoparticle; neutralizing antibody; nonhuman primate; novel vaccines; response; sensor; simian human immunodeficiency virus; therapeutic protein; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine platform; vaccine trial

Vaccine trials in non-human primates challenged with R5, tier 2 SHIVs have shown protection in the presence of high levels of non-neutralizing antibodies (NNAbs), and one of the 5 Phase IIb HIV-1 vaccine efficacy trials using alum (ALVAC/AIDSVAX in RV144) showed an estimated vaccine efficacy of 31%, with a correlate of decreased transmission risk of V2 and other FcR-mediated anti-HIV antibodies. NNAbs are polyfunctional antibodies capable of mediating a number of FcR-mediated or complement-mediated functions such as ADCC, antibody dependent cellular phagocytosis (ADCP) or NK cytokine production. A new efficacy trial is ongoing to follow-up on RV144, called HVTN702, using ALVAC-C, a bivalent clade C gp120 boost, and the adjuvant MF59. We have demonstrated that a multivalent wildtype (WT) Env ALVAC/protein vaccine protected macaques by ~55% from robust (12 intrarectal challenges) challenge with R5, tier 2 SHIV. In this study, the immune correlates of protection were NNAbs that mediated infected cell antibody binding, ADCC, ADCP of challenge SHIV and MIP1β expression by NK cells. The overall hypothesis of project 1 is that the efficacy of RV144 and the current HVTN 702 efficacy trial will be improved upon by use of mRNAs encoding trivalent ADCC mosaic Envs that are specifically designed to overcome NNAb epitope diversity. This will be accomplished by the following Specific Aims: Specific Aim 1. Design and produce multivalent nucleoside-modified mRNAs encoding either polyvalent WT or ADCC mosaic Env gp120s. Specific Aim 2. Determine the induction of NNAbs induced by trivalent ADCC mosaic vs. WT Envs in bnAb VH + VL UCA knock-in (KI) mice that express the RV144-derived V2 ADCC-mediating antibody, CH58. Specific Aim 3. Test ALVAC-C/trivalent ADCC Env gp120s in rhesus macaques (RMs) for ability to protect against an R5, tier 2 transmitted/founder SHIV for use in a phase I clinical trial in year 5.

在受R5挑战的非人类素数中的疫苗试验，第2层SHIV在 高水平的非中和抗体的存在（NNABS）和5期IIB HIV-1疫苗之一 使用明矾（RV144中的ALVAC/AIDSVAX）进行的效率试验显示，估计的疫苗效率为31％，A V2和其他FCR介导的抗HIV抗体的传播风险降低的相关。 NNAB是 能够介导许多FCR介导或补体介导的功能的多功能抗体 例如ADCC，抗体依赖性细胞吞噬作用（ADCP）或NK细胞因子的产生。一种新的效率 使用ALVAC-C，二价进化枝C GP120 Boost和 调整MF59。我们已经证明了多价野生型（WT）ENV ALVAC/蛋白质疫苗 R5，第2层SHIV受到鲁棒（12个直肠内挑战）挑战的保护猕猴约55％。在这个 研究，保护元是NNABS，介导了感染的细胞抗体结合，ADCC， NK细胞的挑战SHIV和MIP1β表达的ADCP。项目1的总体假设是 RV144和当前HVTN 702效​​率试验的效率将通过使用mRNA编码来提高 三价ADCC马赛克Envs专门设计用于克服NNAB表位多样性。这将是 以以下特定目的完成： 特定目标1。设计和生成编码的多价核苷修饰的mRNA 多价WT或ADCC Mosaic Env GP120S。 具体目的2。确定由三价ADCC马赛克与WT ENV诱导的NNAB的诱导 BNAB VH + VL UCA敲入（KI）小鼠，表达RV144衍生的V2 ADCC抗体， CH58。 特定目标3。测试恒河猕猴（RMS）的ALVAC-C/Triverent ADCC Env GP120s的能力 预防R5，第2级传输/创始人SHIV在5年级的I期临床试验中使用。