VLP-Based Antibody-Inducing Vaccines for HIV-1

基于 VLP 的 HIV-1 抗体诱导疫苗

• 批准号: 7845275
• 负责人: Robert G. Whalen
• 金额: $ 29.98万
• 依托单位: ALTRAVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845275
• 关键词: AIDS/HIV problem; Address; Animals; Antibodies; Antibody Formation; Antigens; Autologous; Binding; Capsid; Cellular Membrane; Cessation of life; Clinical; Clinical Trials; Complex; Dissociation; Epidemic; Epitopes; Failure; Genetic; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Hepatitis B Virus; Immunization; In Vitro; Infection; Infection prevention; Length; Life; Ligands; Measures; Membrane; Nature; Oryctolagus cuniculus; Patients; Phase; Physiological; Primates; Process; Production; Property; Public Health; Recombinants; Relative (related person); Research; Research Proposals; Small Business Innovation Research Grant; Structure; Surface; Surface Antigens; T-Lymphocyte; Vaccines; Viral; Viral Envelope Proteins; Virus; Virus-like particle; Vision; Work; base; design; env Gene Products; gag Gene Products; gp160; immunogenic; immunogenicity; improved; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; particle; polypeptide; prevent; public health relevance; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): The HIV-1 epidemic has resulted in ~2.7 million new infections in 2007 for a total of ~33 million people living with HIV/AIDS. Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with monomeric recombinant forms of viral envelope (Env) proteins. However, it is clear that the HIV-1 Env contains epitopes that can induce neutralizing antibodies and that such antibodies can protect primates from infection. The HIV-1 Env is a transmembrane glycoprotein. Both the external subunit (gp120) and the membrane- proximal external region of Env (located within the gp41 subunit) contain epitopes that are the target of broadly neutralizing monoclonal antibodies (mAbs) isolated from infected patients. Considerable effort has been devoted to creating soluble forms of the Env trimer. The improvements in immunogenicity of these molecules relative to monomeric gp120 are limited at best. Another approach to creating improved Env-based immunogens is to produce virus-like particles (VLP). VLPs are multivalent and often very immunogenic. The full-length HIV-1 Env protein can be presented on the surface of VLPs composed of Gag protein and cellular membrane components. These VLP structures have the potential to represent true mimics of the Env trimer spike. Several challenges must be overcome to create HIV-1 vaccines based on VLPs. They must be produced at high levels. The number of Env molecules on each VLP must be maximized. Processing of the gp160 Env polypeptide must take place, without dissociation of the gp120 subunit, to create a functional form of the Env trimer. It might also be necessary to minimize the immunogenicity of the variable sequences. In preliminary studies on the creation of VLPs carrying HIV-1 Env proteins, we have begun to address the challenges outlined above. The preliminary results are encouraging and provide a basis for more detailed work on preparing VLP-based immunogens as candidates for HIV-1 vaccines. The objective is to create VLPs that carry the Env protein in a form that most resembles the current vision of the functional Env trimer of the virus. The Specific Aims of this Phase I SBIR proposal are as follows: (1) prepare optimized Env constructs for VLP production; (2) prepare VLP constructs with different Env sequences; and (3) evaluate the ability of various VLPs to induce neutralizing antibodies in rabbits If the VLP-based Env immunogens prove to be superior to soluble gp120 or gp140 constructs in their ability to induce neutralizing antibodies, then additional studies will form the basis of a Phase II SBIR proposal. PUBLIC HEALTH RELEVANCE: The HIV/AIDS epidemic has resulted in 2 million deaths and 2.7 million new infections in 2007, for a total of nearly 33 million people living with HIV/AIDS. Development of a vaccine is considered to be an essential component of the public health measures needed to slow the epidemic. This research proposal is designed to create a vaccine that can induce antibodies capable of preventing infection by the HIV virus.

描述（由申请人提供）：2007 年，HIV-1 流行已导致约 270 万新感染者，总计约 3300 万艾滋病毒/艾滋病感染者。临床试验表明，使用单体重组形式的病毒包膜 (Env) 蛋白进行免疫无法预防 HIV-1 感染。然而，很明显，HIV-1 包膜含有可以诱导中和抗体的表位，并且此类抗体可以保护灵长类动物免受感染。 HIV-1 Env 是一种跨膜糖蛋白。 Env 的外部亚基 (gp120) 和近膜外部区域（位于 gp41 亚基内）均含有表位，这些表位是从感染患者中分离出的广泛中和单克隆抗体 (mAb) 的目标。为了创造可溶形式的 Env 三聚体，人们付出了相当大的努力。这些分子相对于单体 gp120 的免疫原性的改善充其量是有限的。 创造改进的基于 Env 的免疫原的另一种方法是生产病毒样颗粒 (VLP)。 VLP 是多价的并且通常具有很强的免疫原性。全长HIV-1 Env蛋白可呈递于由Gag蛋白和细胞膜成分组成的VLP表面。这些 VLP 结构有可能代表 Env 三聚体尖峰的真正模拟物。 开发基于 VLP 的 HIV-1 疫苗必须克服多项挑战。它们必须以高水平生产。每个 VLP 上的 Env 分子数量必须最大化。 gp160 Env 多肽的加工必须在 gp120 亚基不解离的情况下进行，以产生 Env 三聚体的功能形式。可能还需要尽量减少可变序列的免疫原性。 在关于创建携带 HIV-1 包膜蛋白的 VLP 的初步研究中，我们已经开始解决上述挑战。初步结果令人鼓舞，并为制备基于 VLP 的免疫原作为 HIV-1 疫苗候选物的更详细工作奠定了基础。目标是创建携带 Env 蛋白的 VLP，其形式最类似于当前病毒功能性 Env 三聚体的外观。 第一阶段 SBIR 提案的具体目标如下：（1）为 VLP 生产准备优化的 Env 构建体； (2) 制备具有不同Env序列的VLP构建体； (3)评估各种VLP在兔体内诱导中和抗体的能力 如果基于 VLP 的 Env 免疫原被证明在诱导中和抗体的能力方面优于可溶性 gp120 或 gp140 构建体，那么额外的研究将构成 II 期 SBIR 提案的基础。 公共卫生相关性：2007 年，艾滋病毒/艾滋病流行已导致 200 万人死亡和 270 万人新感染，总共有近 3,300 万名艾滋病毒/艾滋病感染者。疫苗的开发被认为是减缓流行病所需的公共卫生措施的重要组成部分。该研究计划旨在研制一种疫苗，能够诱导产生能够预防艾滋病毒感染的抗体。