Conserved Element DNA Vaccine

保守元件DNA疫苗

• 批准号: 10926003
• 负责人: BARBARA K FELBER
• 金额: $ 68.16万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926003
• 关键词: 2019-nCoV; AIDS clinical trial group; Achievement; Address; Adjuvant; Antibody Response; Antigens; COVID-19; Chronic; Clinic; Clinical Trials; Collaborations; Combination immunotherapy; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; DNA delivery; Data; Data Analyses; Development; Disease remission; Electroporation; Elements; Epitopes; Exclusion; Exhibits; Formulation; Genes; Goals; HIV; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Highly Active Antiretroviral Therapy; Homologous Gene; Human; Immune checkpoint inhibitor; Immune response; Immunization; Immunologics; Immunotherapeutic agent; Immunotherapy; Individual; Infection; Interleukin-12; Length; Macaca; Mediating; Memory; Messenger RNA; Methodology; Methods; Modality; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nucleic Acid Vaccines; Pathway interactions; Persons; Phase; Preventive vaccine; Process; Proteins; Proteome; Publications; RNA vaccine; Regimen; Research; SIV; Secondary Immunization; T cell response; T-Lymphocyte; Testing; Translating; Translations; Vaccination; Vaccines; Variant; Viral; Viral reservoir; Virus; Virus Diseases; clinical development; cohort; combinatorial; cytokine; expression vector; frontier; human disease; immunogenic; in vivo; insight; lipid nanoparticle; novel; novel strategies; novel vaccines; preclinical trial; prevent; response; therapeutic vaccine; tool; treatment strategy; vaccin protein; vaccine development; vaccine evaluation; vaccine platform; vaccine strategy; vaccine trial

An ideal HIV vaccine should provide protection against all HIV-1 variants. Thus, an important aspect of HIV vaccine development is the selection of immunogens, which has to take into consideration the diversity of the different HIV clades and the identification of the critical epitopes able to induce relevant immune responses, avoiding potential immunodominant "decoy" epitopes. Considering the diversity of the different HIV clades, we are focusing on highly conserved regions of HIV to induce immune responses to nearly invariable proteome segments, essential for the function of the virus, while excluding responses to variable and potentially immunodominant "decoy" epitopes (Kulkarni, PLoS One 9: e86254, 2014; Kulkarni, PLoS One 9: e111085, 2014; Hu, Hum. Vaccin. Immunother. 14: 2163, 2018). In proof-of-concept studies in mice and macaques, we demonstrated that immunization with Gag CE DNA elicits robust cellular and humoral immune responses including robust cytotoxic T cell responses targeting subdominant epitopes against CE, which cannot be achieved by vaccination with the full-length p55gag DNA and induces Priming with CE DNA and boosting with CE+gag DNA maximizes both magnitude and breadth (Kulkarni, PLoS One 9: e86254. 2014; Kulkarni, PLoS One 9: e111085, 2014; Hu, J. Immunol. 197: 3999, 2016). This DNA vaccine regimen induces potent memory responses that can be rapidly recalled 2 years later by CE DNA booster vaccinations (Hu, Hum. Gene Ther. 29: 1029-1043, 2018). Thus, we identified a novel and effective strategy to maximize responses against Gag and provide a novel strategy to shift the immunodominance hierarchy and to induce robust immune responses to subdominant epitopes, effectively targeting the Achilles' heel of the virus. We are currently expanding this concept to SARS-Co-V2. We further developed an SIV homolog of the CE and demonstrated that priming with CE DNA followed by CE+gag DNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth (Hu, J. Immunol. 197: 3999, 2016). These data mirror our findings from the HIV p24CE vaccine and provide us with a tool to explore the functional applications of the Gag CE DNA vaccine in the macaque model. SIV Gag CE-specific T cells are able to reduce viral infection (Hu, Hum. Vaccin. Immunother. 14: 2163-2177, 2018) and application of this CE DNA vaccine is expanded to our on-going therapeutic vaccine trials in the macaque model. We have translated the HIV CE DNA vaccine concept to the clinic in the HIV Vaccine Trial Network (HVTN)/DAIDS/NIAID-supported clinical trial (HVTN 119; NCT03181789) with the aim to test whether our p24CE DNA vaccine concept elicits superior breath and magnitude of Gag responses compared to the optimized immunogen comprising the complete p55Gag protein. This vaccine includes Profectus' GENEVAX IL-12 DNA as molecular adjuvant and in vivo electroporation as DNA delivery method, two vaccine components our research had shown to be of importance to induce potent T cell responses in macaques. HVTN 119 combines several of milestones (DNA expression vectors, adjuvants, and delivery) we have achieved over many years in vaccine development. This trial is now closed, and we are finalizing data analysis for publication. In another on-going study, we have translated the Gag CE DNA vaccine in a phase I/IIb trial (ACTG A5369; NCT03560258) supported by the AIDS Clinical Trial Group, to be tested in HIV-infected persons under HAART. This trial is now closed, and we are finalizing data analysis for publication. Together, HVTN119 and A5369 allowed us to explore the translation of our data from mice and macaques to humans and initial data analysis supports our achievement of this goal. Both trails have demonstrated that the p24CE DNA vaccine is safe and immunogenic in humans. We achieved our goal to translate results from pre-clinical trials to humans and found that iclusion fo the CE immunogen contributesd significantly to direct to immune response to these highly conserved regions. These two trials offer further another unique opportunity to directly compare the same vaccines in two different cohorts, naive and HIV-infected on ART, using the same methodology, and will provide novel insight in the development in immune responses comparing the two cohorts. In addition, the CE DNA vaccine regimen is being tested in a third trial NCT04357821 supported by amfAR and UCSF as part of a combinatorial therapy to induce an HIV remission. Importantly, this trial showed that the majority of individuals who received combination immunotherapy exhibited evidence of virologic control post-ART, indicating that the treatment mediated immunological and virological control. We are in the process of dissecting thiese machanisms. These data are in support of our goal is to develop and test immunotherapeutic methods that can lead to virus reservoir reduction or elimination. We have further expanded the CE vaccine regimen in collaboration with CureVac, Inc. as an mRNA/lipid nanoparticle (LNP) formulation in the macaque model (Valentin, Frontiers Immunol, 2022). The mRNA/LNP formulation induced robust, durable antibody responses but lower adaptive T-cell responses, a feature also shared with the current COVID-19 mRNA vaccine. On the other hand, the mRNA/LNP vaccine was able to strongly boost pre-existing cellular response suggesting that it could be useful in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases. Our studies have provided useful information about different nucleic acid vaccine platforms and guide further clinical development.

理想的 HIV 疫苗应针对所有 HIV-1 变种提供保护。因此，HIV疫苗开发的一个重要方面是免疫原的选择，这必须考虑到不同HIV进化枝的多样性以及能够诱导相关免疫反应的关键表位的鉴定，避免潜在的免疫显性“诱饵”表位。考虑到不同 HIV 分支的多样性，我们将重点放在 HIV 的高度保守区域，以诱导对几乎不变的蛋白质组片段的免疫反应，这对于病毒的功能至关重要，同时排除对可变的和潜在的免疫显性“诱饵”表位的反应（Kulkarni ，公共图书馆一号 9：e86254，2014；库尔卡尼，公共图书馆一号 9：e111085，2014；胡，嗯，疫苗。 14：2163，2018）。在小鼠和猕猴的概念验证研究中，我们证明用 Gag CE DNA 进行免疫可引发强大的细胞和体液免疫反应，包括针对 CE 亚优势表位的强大细胞毒性 T 细胞反应，而这是通过接种全长 DNA 无法实现的。 p55gag DNA 并诱导使用 CE DNA 引发和使用 CE+gag DNA 加强，可最大限度地提高幅度和广度（Kulkarni，PLoS One 9：e86254. 2014；库尔卡尼，公共图书馆一号 9：e111085，2014；胡，免疫学杂志 197：3999，2016。这种 DNA 疫苗方案可诱导有效的记忆反应，两年后可通过 CE DNA 加强疫苗接种快速回忆起来（Hu, Hum. Gene Ther. 29: 1029-1043, 2018）。因此，我们确定了一种新颖有效的策略，可以最大限度地提高针对 Gag 的反应，并提供一种新策略来改变免疫优势层次并诱导对次优势表位的强大免疫反应，从而有效地针对病毒的致命弱点。我们目前正在将这一概念扩展到 SARS-Co-V2。我们进一步开发了 CE 的 SIV 同系物，并证明用 CE DNA 引发，然后进行 CE+gag DNA 加强疫苗接种可显着增加细胞毒性 T 细胞对亚优势高度保守的 Gag 表位的反应，并最大化反应宽度（Hu，J.Immunol.197：3999） ，2016）。这些数据反映了我们在 HIV p24CE 疫苗中的发现，并为我们提供了探索 Gag CE DNA 疫苗在猕猴模型中功能应用的工具。 SIV Gag CE 特异性 T 细胞能够减少病毒感染（Hu, Hum. Vaccin.Immunother. 14: 2163-2177, 2018），并且这种 CE DNA 疫苗的应用已扩展到我们正在进行的猕猴治疗性疫苗试验中模型。我们已将 HIV CE DNA 疫苗概念转化为 HIV 疫苗试验网络 (HVTN)/DAIDS/NIAID 支持的临床试验（HVTN 119；NCT03181789）中的临床，目的是测试我们的 p24CE DNA 疫苗概念是否能引起卓越的呼吸和免疫效果。与包含完整 p55Gag 蛋白的优化免疫原相比，Gag 反应的幅度。该疫苗包括作为分子佐剂的 Profectus GENEVAX IL-12 DNA 和作为 DNA 递送方法的体内电穿孔，我们的研究表明这两种疫苗成分对于在猕猴中诱导有效的 T 细胞反应非常重要。 HVTN 119 结合了我们多年来在疫苗开发中取得的几个里程碑（DNA 表达载体、佐剂和递送）。该试验现已结束，我们正在完成数据分析以供发布。在另一项正在进行的研究中，我们在艾滋病临床试验组支持的 I/IIb 期试验（ACTG A5369；NCT03560258）中转化了 Gag CE DNA 疫苗，以在 HAART 下对 HIV 感染者进行测试。该试验现已结束，我们正在完成数据分析以供发布。 HVTN119 和 A5369 一起使我们能够探索将小鼠和猕猴的数据转化为人类，并且初步数据分析支持我们实现这一目标。两项试验均证明 p24CE DNA 疫苗对人类是安全的且具有免疫原性。我们实现了将临床前试验结果转化为人类的目标，并发现 CE 免疫原的包含显着有助于直接对这些高度保守区域的免疫反应。这两项试验提供了另一个独特的机会，可以使用相同的方法直接比较两个不同队列（首次接受 ART 的人和感染 HIV 的 ART）中的相同疫苗，并将为比较这两个队列的免疫反应的发展提供新的见解。此外，CE DNA 疫苗方案正在 amfAR 和 UCSF 支持的第三次试验 NCT04357821 中进行测试，作为诱导 HIV 缓解的组合疗法的一部分。重要的是，这项试验表明，大多数接受联合免疫治疗的个体在 ART 后表现出病毒学控制的证据，表明治疗介导了免疫学和病毒学控制。我们正在剖析这些机制。这些数据支持我们的目标，即开发和测试可以减少或消除病毒库的免疫治疗方法。我们与 CureVac, Inc. 合作，进一步扩展了 CE 疫苗方案，作为猕猴模型中的 mRNA/脂质纳米颗粒 (LNP) 制剂（Valentin，Frontiers Immunol，2022）。 mRNA/LNP 配方诱导了强大、持久的抗体反应，但适应性 T 细胞反应较低，这一特征也与当前的 COVID-19 mRNA 疫苗相同。另一方面，mRNA/LNP 疫苗能够强烈增强预先存在的细胞反应，这表明它可用于异源初免/加强模式以及针对 HIV 感染或其他慢性人类疾病的免疫治疗干预。我们的研究提供了有关不同核酸疫苗平台的有用信息，并指导进一步的临床开发。

项目成果

Nuclear export factor RBM15 facilitates the access of DBP5 to mRNA.

核输出因子 RBM15 促进 DBP5 接近 mRNA。

• 发表时间: 2009-11
• 影响因子: 14.9
• 作者: Zolotukhin, Andrei S;Uranishi, Hiroaki;Lindtner, Susan;Bear, Jenifer;Pavlakis, George N;Felber, Barbara K
• 通讯作者: Felber, Barbara K

Secretion and biological activity of short signal peptide IL-15 is chaperoned by IL-15 receptor alpha in vivo.

短信号肽IL-15的分泌和生物活性在体内由IL-15受体α陪伴。

• 发表时间: 2009-09-01
• 作者: Bergamaschi, Cristina;Jalah, Rashmi;Kulkarni, Viraj;Rosati, Margherita;Zhang, Gen;Alicea, Candido;Zolotukhin, Andrei S;Felber, Barbara K;Pavlakis, George N
• 通讯作者: Pavlakis, George N

The RNA transport element RTE is essential for IAP LTR-retrotransposon mobility.

RNA 转运元件 RTE 对于 IAP LTR 逆转录转座子的移动性至关重要。

• 发表时间: 2008-07-20
• 影响因子: 3.7
• 作者: Zolotukhin, Andrei S;Schneider, Ralf;Uranishi, Hiroaki;Bear, Jenifer;Tretyakova, Irina;Michalowski, Daniel;Smulevitch, Sergey;O'Keeffe, Sean;Pavlakis, George N;Felber, Barbara K
• 通讯作者: Felber, Barbara K

Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity.

在生产过程中，IL-15 与其受体 α 的细胞内相互作用导致相互稳定并增加生物活性。

• 发表时间: 2008-02-15
• 作者: Bergamaschi, Cristina;Rosati, Margherita;Jalah, Rashmi;Valentin, Antonio;Kulkarni, Viraj;Alicea, Candido;Zhang, Gen;Patel, Vainav;Felber, Barbara K;Pavlakis, George N
• 通讯作者: Pavlakis, George N

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion.

在没有淋巴细胞清除的情况下，异二聚体 IL15 治疗可增强过继转移的肿瘤特异性 T 细胞的肿瘤浸润、持久性和效应器功能。

• 发表时间: 2017-06-01
• 作者: Ng, Sinnie Sin Man;Nagy, Bethany A;Jensen, Shawn M;Hu, Xintao;Alicea, Candido;Fox, Bernard A;Felber, Barbara K;Bergamaschi, Cristina;Pavlakis, George N
• 通讯作者: Pavlakis, George N