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

基本信息

批准号：
8076718
负责人：
LING YE
金额：
$ 34.18万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-25 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8076718
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 Health 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 Regimen Research Role Structure Surface System Testing Vaccine Design Vaccines Viral Virus Diseases Virus-like particle base design env Glycoproteins human monoclonal antibodies immunogenicity improved influenzavirus insight meetings neutralizing antibody nonhuman primate novel novel vaccines success vaccine development

项目摘要

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）：该项目的重点是开发新型疫苗策略，HA/GP41基于嵌合蛋白的疫苗，用于引起针对HIV感染的广泛中和抗体反应。 HIV ENV的两种特性强调了诱导广泛中和抗体的难度，即使在同一进化枝的分离株中，其蛋白质序列的高变异性以及大型，高变量和大糖基化的GP120亚基在保守的中性中性化的异位植物上施加的大型，高变量和大量糖基化的GP120亚基。 GP41亚基的变化不如GP120，并且已显示包含保守的中和表位，例如人类单克隆抗体2f5、4E10和Z13识别的表位。但是，对这种保守的中和gp41中和中和抗体的中和抗体很难升高。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，与HIV Env相比，对单克隆抗体2F5和4E10的反应性增强。此外，对小鼠免疫原性的评估表明，表达HA/GP41嵌合蛋白的DNA疫苗有效诱导了GP41特异性抗体反应。对豚鼠的免疫原性的进一步评估表明，HA/GP41 DNA或病毒样颗粒（VLP）疫苗诱导了显着水平的GP41特异性抗体反应，这些抗体表现出对HIV环境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，可以通过消除大型GP120亚基赋予的空间阻力，在HA/GP41嵌合蛋白的情况下，可以更有效地将HIV GP41中的中和表位呈现给免疫系统。此外，诱导HIV中和抗体表明GP41中的中和表位以适当的构象表现在HA/GP41嵌合蛋白中。基于这些有希望的结果，我们将进一步开发HA/GP41疫苗，并研究增强其诱导抗HIV感染抗体的能力的方法。我们计划从两个方面实现我们的目标。首先，我们将研究是否可以通过辅助抗体或修饰来增强中和抗体的诱导，以改善HA/GP41疫苗的免疫原性（特定AIM 1）。其次，我们将探索修改HA/GP41嵌合蛋白的替代方法，并评估这些方法在GP41中增强对保守表位的中和抗体诱导的有效性（特定的目标2）。通过这些研究，我们将深入了解阻碍诱导广泛中和抗体的障碍，并开发出一种系统性的方法来应对这些困难，以获得有效的HIV疫苗，从而诱导强烈的广泛中和抗体反应。公共卫生相关性：尽管在引起强烈细胞免疫反应的疫苗开发中取得了进展，但开发诱导HIV中和抗体反应的艾滋病疫苗的努力几乎取得了成功，尤其是在诱导交叉反应性中和中和抗体方面，这对于有效辅助疫苗至关重要。这项研究的重点是进一步制定一种新型的疫苗设计策略，该策略为GP41中保守的中和表位提供了更高的表现，其目标是获得有效的HIV疫苗，该疫苗可以诱导强大的HIV中和抗体，