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，需要有效且持久的艾滋病毒疫苗。建立具有中和和非中和机制的有效且持久的抗体 (Ab) 有助于预防粘膜 HIV 感染。最近 RV144 试验的结果强调了保护性非中和抗体机制的重要作用。 RV144 试验还观察到，随着抗体反应减弱，疫苗功效也会减弱，因此强调了开发持久的 HIV 疫苗的重要性。因此，我们的主要目标是提高目前正在进行 1/2a 期临床测试的 GeoVax HIV 疫苗引起的抗体反应的强度，同时保持其持久性和质量。 GeoVax HIV 疫苗采用质粒 DNA 和改良安卡拉牛痘 (MVA) 载体设计，以表达蛋白质，形成非传染性病毒样颗粒 (VLP)，展示三聚体 gp160 包膜（DNA 疫苗）或三聚体 gp150 包膜 (MVAVLP)。为了增强疫苗效力，粒细胞巨噬细胞集落刺激因子 (GM-CSF) 通过 DNA 引发 (DNAGM) 作为佐剂与 VLP 共表达。我们的含有 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% 的接种猕猴免受 12 次重复直肠暴露于 SIVsmE660 的影响，而不含共表达 GM-CSF 的匹配疫苗仅提供25% 的保护。虽然这种佐剂疫苗代表了实现保护性 HIV 疫苗的重要一步，但我们的临床试验数据表明，我们的 HIV 疫苗在人类中引发的 Env 特异性抗体水平比我们在猕猴中的 SIV 原型疫苗低得多。 RV144 泰国试验显示，通过将蛋白质与痘病毒增强剂相结合，可提供适度的感染保护作用。因此，我们正在努力寻找能够在人类中实现更高滴度的保护性 Env Ab 反应的条件。在这里，我们建议 1) 在我们当前的 MVA 加强方案中添加可溶性寡聚 gp140 Env 或 2) 用分泌可溶性 gp140 的 MVA 替代我们当前的 MVA 加强方案，以增强 Ab 引发的幅度并保持其持久性和质量通过我们的 DNAGM/MVA 疫苗。我们的合作者是Xiaoying Shen博士、David Montefiori博士、Bernard Moss博士、Linda Wyatt博士和Hanne Elyard博士，他们是HIV疫苗、体液免疫、MVA重组领域的专家。我们的目标是在第一阶段将抗 Env 结合抗体滴度提高至少 10 倍。如果成功，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。从这项研究中获得的数据对于提供 IND 提交和临床试验工作所需的初始安全性和有效性数据非常重要。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投入临床测试、申请 IND 批准并进入商业化。我们高度强调 HIV 疫苗引发更高滴度和持久保护性抗体反应的重要性，并且增强我们的 DNAGM/MVAVLP 疫苗是实现有效 HIV 疫苗的关键一步。