Developing a structure-specific HIV vaccine using chimeric virus-like particles

使用嵌合病毒样颗粒开发结构特异性 HIV 疫苗

• 批准号: 8465707
• 负责人: Anette Schneemann
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465707
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Antibody Formation; Antigens; Bacteriophages; Binding; Biological Assay; Capsid; Cessation of life; Cloning; Electron Microscopy; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Epitopes; Goals; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV vaccine; HIV-1; Heterophile Antigens; Housing; Human; Immune response; Immune system; Individual; Infection; Infection prevention; Insect Viruses; Lead; Membrane; Monoclonal Antibodies; Oryctolagus cuniculus; Particulate; Patients; Peptides; Production; Property; Proteins; Reporting; Serum; Solutions; Specificity; Structure; Surface; Tertiary Protein Structure; Testing; Vaccinated; Vaccines; Viral Load result; Virion; Virus; Virus-like particle; base; design; expectation; human subject; immunogenicity; in vitro Assay; in vivo; inhibitor/antagonist; meetings; neutralizing antibody; novel strategies; particle; prevent; public health relevance; research study; success; vaccine development

DESCRIPTION (provided by applicant): There are approximately 2.6 million new infections of human immunodeficiency virus type 1 (HIV-1) and 1.8 million AIDS-related deaths reported annually. Anti-HIV inhibitors are available that can control viral loads, but they are not widely available worldwide and do not eliminate or prevent infection. Thus, an effective vaccine is needed to prevent the continuing spread of HIV. A protective antibody response is generated in about 30% of infected individuals. These potent broadly neutralizing antibodies (bNAb) have been found to target a small number of conserved epitopes on the HIV envelope spike, which is composed of trimeric heterodimers of gp120 and gp41. Presenting these epitopes as heterologous antigens to the immune system provides the best opportunity to re-elicit bNAb's that can protect against HIV infection. Attempts to re-elicit neutralizing antibodies against the gp120 and gp41 epitopes has focused on presenting them as peptides, engineered trimers, and unstructured or structured insertions in heterologous monomeric proteins or virus-like particles. These studies have met with limited success indicating that the structural environment of the cognate epitopes needs to be more faithfully reproduced using control over a wider selection of properties, including the ability to orient and expose key residues and structural features for antibody recognition. We propose a novel strategy for presenting the gp41 epitopes of monoclonal antibodies 4E10 and 10E8 on chimeric virus-like particles (VLPs) engineered to present specific structures on their surfaces. The epitopes will be precisely grafted onto well characterized and highly exposed surface regions of the insect virus Flock House virus (FHV) and bacteriophage PP7 capsids, both proven platforms for displaying biologically active foreign epitopes and protein domains as polyvalent particulate arrays that induce potent antibody responses. The particles will then be used to vaccinate rabbits and the resulting sera characterized by ELISA, in-solution virus capture and neutralization assays. The immunized rabbits are expected to generate neutralizing antibodies whose specificity will be determined in competition experiments. The proposed approach using structure-specific display on VLPs, if successful, could lead to a significant advance in HIV vaccine development.

描述（由申请人提供）：每年报告大约有 260 万例新感染 1 型人类免疫缺陷病毒 (HIV-1) 和 180 万例与艾滋病相关的死亡。抗艾滋病毒抑制剂可以控制病毒载量，但它们并未在全球范围内广泛使用，并且不能消除或预防感染。因此，需要一种有效的疫苗来防止艾滋病毒的持续传播。大约 30% 的感染者会产生保护性抗体反应。这些有效的广泛中和抗体 (bNAb) 被发现可靶向 HIV 包膜刺突上的少量保守表位，该包膜刺突由 gp120 和 gp41 的三聚异二聚体组成。将这些表位作为异源抗原呈递给免疫系统，为重新引发可预防 HIV 感染的 bNAb 提供了最佳机会。重新引发针对 gp120 和 gp41 表位的中和抗体的尝试集中于将它们呈现为肽、工程三聚体以及异源单体蛋白或病毒样颗粒中的非结构化或结构化插入。这些研究取得了有限的成功，表明同源表位的结构环境需要通过控制更广泛的特性来更忠实地再现，包括定向和暴露关键残基和结构特征以进行抗体识别的能力。我们提出了一种新的策略，将单克隆抗体 4E10 和 10E8 的 gp41 表位呈现在嵌合病毒样颗粒 (VLP) 上，这些颗粒被设计为在其表面呈现特定结构。这些表位将被精确地移植到昆虫病毒 Flock House 病毒 (FHV) 和噬菌体 PP7 衣壳的特征明确且高度暴露的表面区域，这两个平台都经过验证，可将生物活性外来表位和蛋白质结构域展示为多价颗粒阵列，从而诱导有效的抗体反应。然后，这些颗粒将用于对兔子进行疫苗接种，并通过 ELISA、溶液内病毒捕获和中和测定对所得血清进行表征。免疫兔子预计会产生中和抗体，其特异性将在竞争实验中确定。所提出的在 VLP 上进行结构特异性展示的方法如果成功，可能会导致 HIV 疫苗开发的重大进展。