Enhancing protective antibody responses for a GM-CSF adjuvanted HIV vaccine

增强 GM-CSF 佐剂 HIV 疫苗的保护性抗体反应

• 批准号: 8603508
• 负责人: Sue Fen Kwa
• 金额: $ 27.67万
• 依托单位: GEOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603508
• 关键词: AIDS/HIV problem; Adjuvant; Antibodies; Antibody Formation; Avidity; Binding; CD4 Positive T Lymphocytes; Cells; Cessation of life; Clinical; Clinical Trials; DNA; DNA Vaccines; Data; Developing Countries; Development; Epitopes; Exposure to; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; Health; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immunodominant Epitopes; Individual; Infection; Kinetics; Length; Macaca; Measures; Modified Vaccinia Virus Ankara; Mosses; Mucous Membrane; Persons; Phase; Positioning Attribute; Poxviridae; Prevention; Process; Proteins; Ramp; Recombinants; Regimen; Relative (related person); Risk; Role; SIV; Safety; Specificity; Stress; T-Lymphocyte; Testing; Time; United States; Ursidae Family; Vaccinated; Vaccine Design; Vaccines; Virus; Virus-like particle; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cGMP production; commercialization; cost; cytokine; experience; global health; glycosylation; gp160; immunogenicity; improved; neutralizing antibody; plasmid DNA; preclinical study; programs; prototype; public health relevance; rectal; research clinical testing; response; simian human immunodeficiency virus; success; vaccine efficacy; vector

DESCRIPTION (provided by applicant): HIV/AIDS remains a major health problem and there is a need for effective and durable HIV vaccines. Establishing potent and durable antibodies (Ab) that have neutralizing and non-neutralizing mechanisms can contribute to the prevention of mucosal HIV infection. Findings from the recent RV144 trial have highlighted a significant role for protective non-neutralizing Ab mechanisms. It was also observed in the RV144 trial, that vaccine efficacy diminished as Ab responses waned thus underlining the importance of developing HIV vaccines that are also durable. Therefore our main goal is to improve the magnitude while maintaining the durability and quality of the Ab responses elicited by the GeoVax HIV vaccines that are currently undergoing Phase 1/2a clinical testing. GeoVax HIV vaccines are designed using plasmid DNA and Modified Vaccinia Ankara (MVA) vectors to express proteins that form non-infectious virus like-particles (VLP) displaying trimeric gp160 envelope (DNA vaccines) or trimeric gp150 envelope (MVAVLP). To augment vaccine potency, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is co-expressed as an adjuvant with VLPs by the DNA prime (DNAGM). Our SIV prototype vaccine with GM-CSF enhanced the avidity, binding titers of anti-envelope (Env) Ab and protected 71% of vaccinated macaques against 12 repeat rectal exposures to SIVsmE660, whereas a matched vaccine without co-expressed GM-CSF provided only 25% protection. While this adjuvanted vaccine represents a significant step toward achieving a protective HIV vaccine, data from our clinical trials indicate that much lower levels of Env-specific Ab are elicited by our HIV vaccines in humans than our SIV prototype vaccines in macaques. The RV144 Thai trial showed moderate protection against infection by combining a protein with a poxvirus boost. Thus, we are working to identify conditions that will achieve higher titer of protective Env Ab responses in humans. Here, we are proposing to 1) add a soluble oligomeric gp140 Env to our current MVA boost regimen or 2) substitute our current MVA boost with an MVA that secretes soluble gp140, to enhance the magnitude and maintain the durability and quality, of Ab elicited by our DNAGM/MVA vaccine. Our collaborators are Drs Xiaoying Shen, David Montefiori, Bernard Moss, Linda Wyatt and Hanne Elyard who are experts in the field of HIV vaccines, humoral immunity, MVA recombinants. Our goal is to achieve at least a 10-fold enhancement of anti-Env binding Ab titers in Phase I. With success, we plan to submit a Phase II proposal testing protection against SHIV with the best vaccine regimen. The data gained from this study will be of great importance in providing the initial safety and efficacy data needed for an IND submission and the work to be carried out in clinical trials. With our experience in clinical trials and MVA manufacture, we are well positioned with the capability to move these vaccine components into clinical testing, apply for IND approval and ramp into commercialization. We highly stress the importance of eliciting higher titers and durable protective Ab responses for HIV vaccines and that enhancing our DNAGM/MVAVLP vaccine is a critical step forward to achieving an effective HIV vaccine.

描述（由申请人提供）：艾滋病毒/艾滋病仍然是一个主要的健康问题，需要有效和持久的艾滋病毒疫苗。建立具有中和和非中和机制的有效和持久的抗体（Ab）有助于预防粘膜HIV感染。最近RV 144试验的结果强调了保护性非中和抗体机制的重要作用。在RV 144试验中还观察到，随着抗体应答减弱，疫苗效力降低，因此强调了开发也是持久的HIV疫苗的重要性。因此，我们的主要目标是提高幅度，同时保持目前正在进行1/2a期临床试验的GeoVax HIV疫苗引起的抗体反应的持久性和质量。GeoVax HIV疫苗使用质粒DNA和修饰的安卡拉牛痘（MVA）载体设计，以表达形成展示三聚gp 160包膜（DNA疫苗）或三聚gp 150包膜（MVAVLP）的非感染性病毒样颗粒（VLP）的蛋白质。为了增强疫苗效力，粒细胞-巨噬细胞集落刺激因子（GM-CSF）作为佐剂与VLP通过DNA引物（DNAGM）共表达。我们的具有GM-CSF的SIV原型疫苗增强了抗包膜（Env）Ab的亲合力和结合滴度，并保护71%的接种疫苗的猕猴免于12次重复直肠暴露于SIVsmE 660，而没有共表达的GM-CSF的匹配疫苗仅提供25%的保护。虽然这种含佐剂的疫苗代表了实现保护性HIV疫苗的重要一步，但来自我们临床试验的数据表明，我们的HIV疫苗在人类中引起的Env特异性Ab水平远低于我们的SIV原型疫苗在猕猴中的水平。RV 144泰国试验显示，通过将蛋白质与痘病毒加强相结合，可适度保护免受感染。因此，我们正在努力确定将在人体中实现更高滴度的保护性Env Ab应答的条件。在这里，我们建议1）将可溶性寡聚gp 140 Env添加到我们当前的MVA加强方案中，或者2）用分泌可溶性gp 140的MVA替代我们当前的MVA加强，以增强由我们的DNAGM/MVA疫苗引发的Ab的量级并保持其持久性和质量。我们的合作者是沈晓颖博士、大卫蒙蒂菲奥里博士、伯纳德莫斯博士、琳达怀亚特博士和汉娜埃利亚德博士，他们是艾滋病毒疫苗、体液免疫、MVA重组体领域的专家。我们的目标是在I期中实现抗Env结合Ab滴度的至少10倍增强。成功后，我们计划提交第二阶段提案，测试最佳疫苗方案对SHIV的保护作用。本研究获得的数据对于提供IND提交所需的初始安全性和有效性数据以及临床试验中开展的工作非常重要。凭借我们在临床试验和MVA生产方面的经验，我们有能力将这些疫苗成分转移到临床试验中，申请IND批准并进入商业化。我们高度强调了引发更高滴度和持久保护性抗体应答对于HIV疫苗的重要性，并且增强我们的DNAGM/MVAVLP疫苗是实现有效HIV疫苗的关键一步。