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

• 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
• 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

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.

摘要 免疫原和疫苗的产生将有利于HIV预防性疫苗的开发 可以诱导针对突变的高功能性CD 8 + T细胞应答的组合的递送方式 限制性表位和对HIV包膜三聚体的广泛中和抗体应答。所以针对本 根据这一建议，我们计划利用三个组成部分实现这一目标：一种称为基于结构的方法 网络分析用于鉴定一组CD 8 + T细胞优先靶向的保护性表位 2）能够引发异源HIV抗体的包膜三聚体， 中和抗体反应和3）和自扩增RNA的创新疫苗递送平台 这些复制子可以引发稳健的CD 8 + T细胞和体液免疫。应用基于结构的网络 通过对SIV蛋白结构的分析，我们已经确定了一组突变约束（“高度网络化”） 由Mamu I类等位基因阵列限制的SIV表位。此外，我们还提供了令人信服的数据， 证明了RNA复制子诱导CD 8 + T细胞对高度网络化的SIV表位的应答的能力 和强烈的三聚体特异性抗体应答。尚待确定的是， 针对高度网络化的SIV表位的功能性CD 8 + T细胞应答具有保护性益处， 异源攻击，单独地或与抗体串联。因此，在本提案的目标1中，我们将 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效力 在一组20只恒河猴中。这些免疫的猕猴将被平均分配给那些接受 模拟免疫或高度网络化的SIV表位免疫（每组10个）。免疫后， 将评估针对高度网络化的SIV表位的疫苗诱导的CD 8 + T细胞应答， 接种疫苗的动物然后将经受重复的低剂量SHIV.BG505攻击。这些SIV 受攻击的猕猴将每2周进行一次病毒载量、CD 4计数和CD 8 + T细胞表型评估 在攻毒期间以及攻毒期后20周。关于以下方面的通过/不通过标准 T细胞免疫原性和疫苗接种对SHIV病毒载量的影响将在 年底2。在目标2中，我们将评估基于RNA复制子的组合的免疫原性和功效。 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。这些免疫 猕猴将在接受模拟免疫、HIV Env三聚体+模拟免疫 免疫以及HIV Env三聚体和高度网络化SIV表位免疫原两者的组合（10个/ 组）。这些研究将有助于确定疫苗诱导的CD 8 + T细胞应答是否针对 高度网络化的表位可以单独或与抗体组合提供保护性益处。 基于疫苗。此外，这项工作将为自扩增RNA复制子疫苗提供关键支持 我们正在努力开发一种有效的、预防性的艾滋病毒疫苗。