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，需要有效耐用的艾滋病毒疫苗。建立具有中和和非中和机制的有效耐用抗体（AB）可以有助于预防粘膜HIV感染。最近的RV144试验的发现突出了保护性非中和AB机制的重要作用。在RV144试验中也观察到，随着AB反应减弱，疫苗功效降低，从而强调了开发也持久的HIV疫苗的重要性。因此，我们的主要目标是提高幅度，同时保持当前正在进行1/2A临床测试的Geovax HIV疫苗引起的AB反应的耐用性和质量。 Geovax HIV疫苗是使用质粒DNA和修饰的Ankara（MVA）载体设计的，以表达形成非感染性病毒类似颗粒（VLP）的蛋白质，显示三聚体GP160外壳疫苗（DNA疫苗）或内置GP150 gp150 envelope（Mvavlp）。为了增加疫苗效力，粒细胞 - 巨噬细胞刺激因子（GM-CSF）被DNA Prime（DNAGM）共表达，作为VLPS佐剂。我们使用GM-CSF的SIV原型疫苗增强了抗Envelope（Env）AB的粘合滴度，并保护了71％的接种疫苗猕猴，以12次反复直肠暴露于SIVSME660，而仅提供25％的GM-CSF的匹配疫苗，而GM-CSF仅提供25％的保护。尽管这种辅助疫苗代表了获得保护性HIV疫苗的重要一步，但我们临床试验的数据表明，与猕猴中的SIV原型疫苗相比，我们的HIV疫苗在人类中引起了ENV特异性AB的水平要低得多。 RV144泰国试验通过将蛋白质与痘病毒增强作用结合起来显示了对感染的中等保护。因此，我们正在努力确定将获得人类保护性环境反应的较高效率的条件。在这里，我们提议为1）在我们当前的MVA增强方案中添加可溶性低聚GP140 ENV或2）用我们当前的MVA增压代替我们当前的MVA增压，该MVA可分泌可溶性GP140，以增强我们的dnagm/mva vaccine sab ab的耐用性和质量。我们的合作者是Xiaoying Shen博士，David Montefiori，Bernard Moss，Linda Wyatt和Hanne Elyard，他们是HIV疫苗，体液免疫，MVA重组的专家。我们的目标是在第一阶段中至少实现抗ENV结合AB滴度的10倍增强，并成功地提出了II期提案测试保护保护SHIV，并使用最佳的疫苗方案提交SHIV。从这项研究中获得的数据将在提供IND提交所需的初始安全性和功效数据以及在临床试验中进行的工作非常重要。凭借我们在临床试验和MVA制造方面的经验，我们可以将这些疫苗成分转移到临床测试中，并申请IND批准，并逐步进行商业化。我们高度强调了引起更高滴度和对HIV疫苗的持久保护AB反应的重要性，并且增强我们的DNAGM/MVAVLP疫苗是实现有效的HIV疫苗的重要一步。