Novel chimeric Env vaccines to elicit broadly neutralizing antibodies against HIV

新型嵌合 Env 疫苗可引发针对 HIV 的广泛中和抗体

• 批准号: 7554753
• 负责人: LING YE
• 金额: $ 34.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-25 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554753
• 关键词: AIDS Vaccines; Adjuvant; Affect; Amino Acid Sequence; Amino Acids; Animal Model; Antibodies; Antibody Formation; Biological Assay; Cavia; Cell surface; Cells; Chemical Vaccines; Chimeric Proteins; Clinical Trials; Communities; DNA; DNA Vaccines; DNA Viruses; Development; Drug Formulations; Effectiveness; Epitopes; Evaluation; Exhibits; Foundations; Future; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV vaccine; HIV-1; Hemagglutinin; Human; Immune response; Immune system; Immunization; Insecta; Mammalian Cell; Mediating; Membrane Lipids; Modeling; Modification; Molecular Conformation; Monoclonal Antibodies; Mus; Oryctolagus cuniculus; Peptide Sequence Determination; Property; Proteins; Public Health; Research; Role; Structure; Surface; System; Testing; Treatment Protocols; Vaccine Design; Vaccines; Viral; Virus Diseases; Virus-like particle; base; covalent bond; design; env Glycoproteins; human monoclonal antibodies; immunogenicity; improved; influenzavirus; insight; neutralizing antibody; nonhuman primate; novel; novel vaccines; success; vaccine development

DESCRIPTION (provided by applicant): This project focuses on the development of a novel vaccine strategy, HA/gp41 chimeric protein-based vaccines, for eliciting broadly neutralizing antibody responses against HIV infection. Two properties of the HIV Env underscore the difficulty in inducing broadly neutralizing antibodies, the high variability of its protein sequence even among isolates of the same clade and the steric hindrance exerted by the large, hypervariable, and heavily glycosylated gp120 subunit on conserved neutralizing epitopes. The gp41 subunit is less variable than gp120, and has been shown to contain conserved neutralizing epitopes such as those recognized by the human monoclonal antibodies 2F5, 4E10, and Z13. However, neutralizing antibodies against such conserved neutralizing epitopes in gp41 have been difficult to raise. We have in our recent studies constructed and characterized a chimeric protein HA/gp41 that it is expressed on the cell surface and exhibits enhanced reactivity to the monoclonal antibodies 2F5 and 4E10 compared to the HIV Env. Moreover, evaluation of immunogenicity in mice showed that a DNA vaccine expressing the HA/gp41 chimeric protein effectively induced gp41-specific antibody responses. Further evaluation of immunogenicity in guinea pigs showed that HA/gp41 DNA or virus-like particle (VLP) vaccines induced significant levels of gp41-specific antibody responses and these antibodies exhibit neutralizing activity against HIV Env-mediated virus infection. These observations indicate that the conserved neutralizing epitopes in the HIV gp41 can be more efficiently presented to the immune system in the setting of HA/gp41 chimeric proteins by eliminating the steric hindrance conferred by the large gp120 subunit. Furthermore, induction of HIV neutralizing antibodies suggests that the neutralizing epitopes in gp41 are presented in a proper conformation in HA/gp41 chimeric proteins. Built on these promising results, we will further develop the HA/gp41 vaccines and investigate ways to enhance their ability to induce broadly neutralizing antibodies against HIV infection. We plan to achieve our goals from two aspects. First, we will investigate whether induction of neutralizing antibodies can be augmented by an adjuvant or modifications to improve immunogenicity of the HA/gp41 vaccines (Specific Aim 1). Second, we will explore alternative approaches to modify the HA/gp41 chimeric protein and evaluate the effectiveness of these approaches for enhancing induction of neutralizing antibodies against conserved epitopes in gp41 (Specific Aim 2). Through these studies, we will gain insight to the obstacles that hinder the induction of broadly neutralizing antibodies and develop a systemic approach to tackle these difficulties for obtaining a potent HIV vaccine that induces strong broadly neutralizing antibody responses. PUBLIC HEALTH RELEVANCE: While progress has been made in the development of vaccines that elicit strong cellular immune responses, efforts to develop AIDS vaccines that induce HIV neutralizing antibody responses have met with little success, especially for the induction of cross-reactive neutralizing antibodies, which is of particular importance for an effective AIDS vaccine. The focus of this study is to further develop a novel vaccine design strategy that provide a more effctive presentation of the conserved neutralizing epitopes in gp41, with the goal to obtain a potent HIV vaccine that can induce strong and broadly HIV neutralizing antibodies

描述（由申请人提供）：该项目重点开发一种新的疫苗策略，即基于 HA/gp41 嵌合蛋白的疫苗，用于引发针对 HIV 感染的广泛中和抗体反应。 HIV Env 的两个特性强调了诱导广泛中和抗体的难度，其蛋白质序列的高度变异性（即使在同一进化枝的分离株中）以及由大的、高度可变的和高度糖基化的 gp120 亚基对保守中和表位产生的空间位阻。 gp41 亚基的变异性低于 gp120，并且已被证明含有保守的中和表位，例如人单克隆抗体 2F5、4E10 和 Z13 识别的表位。然而，针对 gp41 中此类保守中和表位的中和抗体很难产生。我们在最近的研究中构建并表征了嵌合蛋白 HA/gp41，它在细胞表面表达，并且与 HIV Env 相比，对单克隆抗体 2F5 和 4E10 表现出增强的反应性。此外，对小鼠免疫原性的评估表明，表达HA/gp41嵌合蛋白的DNA疫苗可有效诱导gp41特异性抗体应答。对豚鼠免疫原性的进一步评估表明，HA/gp41 DNA 或病毒样颗粒 (VLP) 疫苗诱导显着水平的 gp41 特异性抗体反应，并且这些抗体表现出针对 HIV Env 介导的病毒感染的中和活性。这些观察结果表明，在HA/gp41嵌合蛋白的情况下，通过消除大gp120亚基赋予的空间位阻，HIV gp41中保守的中和表位可以更有效地呈递给免疫系统。此外，HIV中和抗体的诱导表明gp41中的中和表位在HA/gp41嵌合蛋白中以正确的构象存在。基于这些有希望的结果，我们将进一步开发 HA/gp41 疫苗，并研究增强其诱导针对 HIV 感染的广泛中和抗体的能力的方法。我们计划从两个方面来实现我们的目标。首先，我们将研究是否可以通过佐剂或修饰来增强中和抗体的诱导，以提高 HA/gp41 疫苗的免疫原性（具体目标 1）。其次，我们将探索修饰 HA/gp41 嵌合蛋白的替代方法，并评估这些方法增强诱导针对 gp41 保守表位的中和抗体的有效性（具体目标 2）。通过这些研究，我们将深入了解阻碍广泛中和抗体诱导的障碍，并开发一种系统方法来解决这些困难，以获得诱导强广泛中和抗体反应的有效艾滋病毒疫苗。公共健康相关性：虽然在开发引发强烈细胞免疫反应的疫苗方面取得了进展，但开发诱导 HIV 中和抗体反应的艾滋病疫苗的努力却收效甚微，特别是在诱导交叉反应性中和抗体方面。对于有效的艾滋病疫苗尤为重要。本研究的重点是进一步开发一种新的疫苗设计策略，更有效地呈现 gp41 中保守的中和表位，目标是获得一种有效的 HIV 疫苗，能够诱导强效且广泛的 HIV 中和抗体