Investigating the Protective Efficacy of SIV/HIV T and B cell Immunity Induced by RNA Replicons

研究 RNA 复制子诱导的 SIV/HIV T 和 B 细胞免疫的保护功效

基本信息

批准号：
10673223
负责人：
Gaurav Das Gaiha
金额：
$ 92.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673223
关键词：
Address Algorithmic Analysis Algorithms Alleles Animals Antibodies Antibody Response Antigens B-Lymphocytes Biological Assay CD4 Lymphocyte Count CD8-Positive T-Lymphocytes Cells Clinical Complement Computational Technique Data Development Dose Epitopes Evaluation Frequencies Generations Goals HIV HIV Infections HIV envelope protein HIV vaccine Health Priorities Humoral Immunities Immunity Immunization Immunize Immunologics Individual Laboratories Macaca Macaca mulatta Modality Modeling Mutation Pathway Analysis Phase Phenotype Preventive vaccine Proteome RNA RNA amplification Replicon SIV Structure T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Vaccinated Vaccination Vaccines Viral Viral Load result Virus Diseases Virus Replication Work efficacy study global health immunogenic immunogenicity innovation neutralizing antibody nonhuman primate novel vaccines prevent prophylactic protective efficacy protein structure replicon vaccine resistance mutation seroconversion simian human immunodeficiency virus vaccine delivery vaccine development vaccine efficacy vaccine platform vaccine response

项目摘要

ABSTRACT The development of a prophylactic vaccine for HIV would benefit from the generation of immunogens and vaccine delivery modalities that can induce a combination of highly functional CD8+ T cell responses towards mutation constrained epitopes and broadly neutralizing antibody responses to the HIV envelope trimer. Thus, in this proposal, we plan to leverage three components towards this goal: an approach known as structure-based network analysis that was used to identify a set of protective epitopes preferentially targeted by CD8+ T cell responses in spontaneous HIV controllers, 2) an envelope trimer that is capable of eliciting heterologous neutralizing antibody responses and 3) and an innovative vaccine delivery platform of self-amplifying RNA replicons that can elicit both robust CD8+ T cell and humoral immunity. Having applied structure-based network analysis to SIV protein structures, we have already identified a set of mutation constrained (‘highly networked’) SIV epitopes restricted by an array of Mamu class I alleles. In addition, we have also produced compelling data demonstrating the ability of RNA replicons to induce CD8+ T cell responses to highly networked SIV epitopes and strong trimer-specific antibody responses in rhesus macaques. What remains to be determined is whether functional CD8+ T cell responses towards highly networked SIV epitopes have a protective benefit against heterologous challenge, either individually or in tandem with antibodies. Thus, in Aim 1 of this proposal we will assess the protective efficacy of a RNA replicon vaccine immunogen comprised of highly networked SIV epitopes in a group of 20 rhesus macaques. These immunized macaques will be divided equally between those receiving mock immunization or highly networked SIV epitope immunization (10 per group). Following immunization, vaccine-induced CD8+ T cell responses directed against highly networked SIV epitopes will be assessed and vaccinated animals would then be subjected to repeated low dose SHIV.BG505 challenge. These SHIV challenged macaques will have viral load, CD4 count and CD8+ T cell phenotype assessments every 2 weeks during the challenge period and for 20 weeks following the challenge period as well. Go/No-Go criteria regarding T cell immunogenicity and the effects of vaccination on SHIV viral loads will be established and evaluated at the end of year 2. In Aim 2, we will assess the immunogenicity and efficacy of a combined RNA replicon-based vaccination with a highly networked SIV epitope immunogen and HIV Env trimer immunogen. These immunized macaques will be divided equally between those receiving mock immunization, HIV Env trimer + mock immunization and a combination of both HIV Env Trimer and highly networked SIV epitope immunogens (10 per group). These studies will help determine whether vaccine-induced CD8+ T cell responses directed towards highly networked epitopes can provide a protective benefit either individually or in combination with antibody- based vaccination. Additionally, this work will provide critical support of the self-amplifying RNA replicon vaccine delivery platforms towards the development of an effective, prophylactic HIV vaccine.

抽象的 HIV预防性疫苗的开发将受益于免疫原和疫苗的产生可以诱导高功能性 CD8+ T 细胞对突变反应的组合的递送方式因此，在这种情况下，限制性表位和广泛中和包膜抗体对 HIV 三聚体的反应。根据提案，我们计划利用三个组成部分来实现这一目标：一种称为基于结构的方法用于识别 CD8+ T 细胞优先靶向的一组保护性表位的网络分析自发 HIV 控制者的反应，2) 能够引发异源性的包膜三聚体中和抗体反应，3) 以及自放大 RNA 的创新疫苗递送平台应用基于结构的网络，可以引发强大的 CD8+ T 细胞和体液免疫。通过对 SIV 蛋白质结构的分析，我们已经确定了一组突变受限（“高度网络化”）受一系列 Mamu I 类等位基因限制的 SIV 表位此外，我们还产生了令人信服的数据。证明 RNA 复制子诱导 CD8+ T 细胞对高度网络化的 SIV 表位做出反应的能力恒河猴中是否存在强烈的三聚体特异性抗体反应尚待确定。功能性 CD8+ T 细胞对高度网络化的 SIV 表位的反应具有保护作用因此，在本提案的目标 1 中，我们将单独或与抗体一起进行异源攻击。评估由高度网络化的 SIV 表位组成的 RNA 复制子疫苗免疫原的保护功效一组 20 只恒河猴，这些经过免疫的猕猴将被平均分配给接受接种的猕猴。模拟免疫或高度网络化的 SIV 表位免疫（每组 10 次）。将评估针对高度网络化的 SIV 表位的疫苗诱导的 CD8+ T 细胞反应，并然后，接种疫苗的动物将接受重复的低剂量 SHIV.BG505 攻击。受到挑战的猕猴将每两周进行一次病毒载量、CD4 计数和 CD8+ T 细胞表型评估挑战期期间以及挑战期后 20 周内，关于通过/不通过标准的规定。 T 细胞免疫原性以及疫苗接种对 SHIV 病毒载量的影响将在 2 年年底。在目标 2 中，我们将评估基于组合 RNA 复制子的免疫原性和功效使用高度网络化的 SIV 表位免疫原和 HIV Env 三聚体免疫原进行疫苗接种。猕猴将平均分配给接受模拟免疫、HIV 包膜三聚体 + 模拟免疫的猕猴免疫以及 HIV 包膜三聚体和高度网络化的 SIV 表位免疫原的组合（每 10 个）这些研究将有助于确定疫苗诱导的 CD8+ T 细胞反应是否针对。高度网络化的表位可以单独或与抗体组合提供保护作用此外，这项工作将为自扩增RNA复制子疫苗提供关键支持。开发有效的预防性艾滋病毒疫苗的交付平台。