Native-like Envelope Trimer Therapeutic Vaccination for Induction of Broadly Neutralizing Antibodies to Facilitate HIV Functional Cure

类天然包膜三聚体治疗性疫苗诱导广泛中和抗体促进 HIV 功能性治愈

• 批准号: 10602539
• 负责人: SHARON RIDDLER
• 金额: $ 208.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-14 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602539
• 关键词: Adjuvant; Adverse event; Affinity; Aluminum Hydroxide; Animal Model; Antibodies; Antibody Response; Antigen Presentation; Antigens; Antiviral Therapy; Apical; Autologous; Automobile Driving; B cell repertoire; B-Lymphocytes; Binding; Biological Assay; Blinded; Blocking Antibodies; Blood; Blood Cells; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Chronic; Clinical Research; Clinical Trials; DNA; Data; Development; Disease remission; Dose; Double-Blind Method; Engineering; Epitopes; Exhibits; Frequencies; Genetic Transcription; Glycoproteins; Goals; HIV; HIV Antibodies; HIV envelope protein; HIV immunization; HIV vaccine; HIV-1; Human; Immune response; Immunization; Immunoglobulin Somatic Hypermutation; Immunologics; Immunotherapeutic agent; Individual; Infection; Intervention; Knock-out; Macaca; Measures; Molecular Conformation; Monoclonal Antibodies; Mutation; NIH Vaccine Research Center; National Institute of Allergy and Infectious Disease; Participant; Pathway interactions; Persons; Phase; Phylogenetic Analysis; Placebo Control; Placebos; Plasma; Population; Prevention; Preventive vaccine; RNA; Randomized; Reporting; Research; Residual state; Safety; Sampling; Scientist; Serum; Specificity; Structure; Surface; T cell response; Testing; Thinking; Time; Vaccination; Vaccine Research; Vaccine Therapy; Vaccines; Viral; Viral Physiology; Viremia; Virion; Virus; aluminum sulfate; antiretroviral therapy; cohort; design; disulfide bond; follow-up; genome sequencing; immunogenic; immunogenicity; improved; in vivo; innovation; insight; neutralizing antibody; next generation sequencing; non-Native; novel; novel vaccines; passive antibodies; peripheral blood; response; secondary endpoint; therapy development; vaccine candidate; vaccine development

PROJECT SUMMARY Passively transferred broadly neutralizing antibodies (bnAbs) are being evaluated in clinical trials for HIV-1 treatment and prevention. The results of these studies in macaques and humans suggest that bnAbs have antiviral activity and possibly a “vaccinal” effect, i.e. induction of HIV-specific cellular immune responses. After several years of infection, approximately 5-15% of HIV-1 infected individuals develop some ability to cross- neutralize a broad range of heterologous viral strains, with only 1% of individuals developing potent bnAbs. It is possible that individuals with chronic HIV-1 infection have elicited precursors of HIV bnAbs, but that these responses have been stunted by viral escape or by affinity maturation away from highly conserved epitopes. If HIV bnAb precursors have indeed been elicited in these individuals as our preliminary data indicates, then such responses could be boosted by delivery of native-like HIV-1 envelope (Env) trimers. Development of therapies that may induce bnAb in vivo would be a valuable advance for both HIV-1 treatment and prevention. We conducted neutralization assays with curated virus panels that are particularly sensitive to VRC01-class precursor antibodies, V2 apex-precursors and PGT 121 precursor antibodies and demonstrated that the baseline frequencies of bnAb precursors was ~20% in a small cohort (N = 25) of chronically HIV 1-infected individuals receiving suppressive ART. We therefore propose to test if bnAbs can be induced by immunization with native- like Env trimer vaccination in chronic, ART-suppressed HIV-1 infection, including in individuals who have initiated the appropriate pathways of B-cell somatic hypermutation through natural infection. Native-like trimers mimic the structure of Env on the surface of the virus largely correctly and display multiple bnAb epitopes in a manner similar to how these epitopes appear on the virion-associated spike, and can induce autologous primary virus (Tier-2) responses in animal models .Accordingly, we will conduct a Phase 1, randomized, placebo controlled, exploratory dose-escalation study evaluating the safety and immunogenicity of a native-like trimer vaccine, VRC- HIVRGP096-00-VP (Trimer 4571), developed and provided to us by the NIH Vaccine Research Center, in HIV- 1 infected individuals on suppressive ART. We will assess vaccine induced changes in autologous and cross clade virus neutralization and trimer-specific antibody response. Additionally, we will perform detailed mechanistic studies to investigate the effect of bnAb precursor presence on bnAb B-cell lineage development, characterize epitope specificities and assess trimer-induced changes in the B cell repertoire. Using multiple, state-of-the-art assays, we will measure the effect of the immunogen on the size of the peripheral blood HIV-1 reservoir and potential sieving effect on the residual plasma viremia and cellular HIV Env RNA. Trimer induced virologic and immunological assessments will provide new insights into the conditions and the benefits of these neutralizing antibody responses toward achieving sustained HIV-1 remission without ART.

项目概要 被动转移的广泛中和抗体 (bnAb) 正在 HIV-1 临床试验中进行评估 治疗和预防。这些对猕猴和人类的研究结果表明，bnAbs 抗病毒活性和可能的​​“疫苗”效应，即诱导艾滋病毒特异性细胞免疫反应。后 经过几年的感染，大约 5-15% 的 HIV-1 感染者发展出一定的交叉能力 中和多种异源病毒株，只有 1% 的个体产生有效的 bnAb。这是 慢性 HIV-1 感染者可能会引发 HIV bnAb 的前体，但这些 由于病毒逃逸或高度保守表位的亲和力成熟，反应受到阻碍。如果 正如我们的初步数据表明的那样，HIV bnAb 前体确实在这些个体中被引发，那么这样的 递送类似天然的 HIV-1 包膜 (Env) 三聚体可以增强反应。疗法的开发 可能在体内诱导bnAb对于HIV-1治疗和预防来说都是一个有价值的进步。我们 使用对 VRC01 类特别敏感的精选病毒组进行中和测定 前体抗体、V2 顶端前体和 PGT 121 前体抗体，并证明基线 在慢性 HIV 1 感染者的一个小队列 (N = 25) 中，bnAb 前体的频率约为 20% 接受抑制性ART。因此，我们建议测试 bnAb 是否可以通过天然- 例如，针对慢性、ART 抑制的 HIV-1 感染（包括已开始接受 ART 治疗的个体）进行 Env 三聚体疫苗接种 通过自然感染进行 B 细胞体细胞超突变的适当途径。类似天然的三聚体模仿 病毒表面的 Env 结构基本正确，并以某种方式显示多个 bnAb 表位 与这些表位在病毒粒子相关刺突上的出现方式相似，并且可以诱导自体原代病毒 动物模型中的（第 2 级）反应。因此，我们将进行第 1 阶段、随机、安慰剂对照、 探索性剂量递增研究，评估天然样三聚体疫苗 VRC- 的安全性和免疫原性 HIVRGP096-00-VP（三聚体 4571），由 NIH 疫苗研究中心开发并提供给我们，用于 HIV- 1 名接受抑制性 ART 的感染者。我们将评估疫苗引起的自体和交叉变化 分支病毒中和和三聚体特异性抗体反应。此外，我们还将进行详细的 机制研究调查 bnAb 前体的存在对 bnAb B 细胞谱系发育的影响， 表征表位特异性并评估 B 细胞库中三聚体诱导的变化。使用多个， 最先进的检测，我们将测量免疫原对外周血 HIV-1 大小的影响 储存库和对残留血浆病毒血症和细胞 HIV 包膜 RNA 的潜在筛分作用。三聚体诱导 病毒学和免疫学评估将为这些疾病的状况和益处提供新的见解 中和抗体反应，无需 ART 即可实现持续的 HIV-1 缓解。