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: 10377564
• 负责人: SHARON RIDDLER
• 金额: $ 169.51万
• 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/10377564
• 关键词: Adjuvant; Adverse event; Affinity; Aluminum Hydroxide; Animal Model; Antibodies; Antibody Response; Antigen Presentation; Antigens; Antiviral Therapy; 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; Follow-Up Studies; Frequencies; Genetic Transcription; Glycoproteins; Goals; HIV; HIV Antibodies; 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; Viremia; Virion; Virus; antiretroviral therapy; base; cohort; design; disulfide bond; 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.

项目摘要 在临床试验中评估了被动转移的广泛中和抗体（BNAB）的HIV-1 治疗和预防。这些研究的结果在猕猴和人类中都表明BNAB具有 抗病毒活性和可能的​​“疫苗”作用，即HIV特异性细胞免疫复杂的诱导。后 几年的感染，大约5-15％的HIV-1感染个体具有某种交叉的能力 中和广泛的异源病毒菌株，只有1％的个体发展了潜在的BNAB。这是 患有慢性HIV-1感染的个体可能引起了HIV BNAB的前体，但是这些 病毒逃生或亲和力成熟远离高度组成的表位，反应已经阻碍了反应。如果 如我们的初步数据所表明的那样 可以通过输送类似天然的HIV-1信封（ENV）三聚体来提高响应。疗法的发展 对于HIV-1治疗和预防，这可能引起体内BNAB是有价值的进步。我们 用策划的病毒面板进行了神经化测定，对VRC01级特别敏感 前体抗体，V2 Apex-前体和PGT 121前体抗体，并证明了基线 在慢性HIV 1感染的个体的小队列（n = 25）中，BNAB前体的频率约为20％ 接受抑制艺术。因此，我们建议测试是否可以通过天然的免疫来诱导BNAB- 像ENV触发疫苗接种在慢性抑制的HIV-1感染中一样，包括发起的个体 通过自然感染的B细胞体细胞超成熟的适当途径。类似于本地的三聚体模仿 Env在病毒表面的结构很大程度上正确，并以某种方式显示多个BNAB表位 类似于这些表位在病毒相关的尖峰上的出现方式，并且可以诱导自体病毒 （第2层）在动物模型中的反应。相当地，我们将进行1期，随机，安慰剂控制， 探索性剂量提升研究评估了天然触发疫苗的安全性和免疫原性，VRC- HIVRGP096-00-VP（Trimer 4571），由HIV-的NIH疫苗研究中心开发并提供给我们 1个受抑制艺术的感染者。我们将评估疫苗引起的自体和交叉变化 进化枝病毒神经化和三聚体特异性抗体反应。此外，我们将执行详细 机械研究以研究BNAB前体存在对BNAB B细胞谱系发展的影响， 表征表位规格并评估三聚体诱导的B细胞库的变化。使用多个 最先进的测定法，我们将测量免疫原对外周血HIV-1大小的影响 储层和潜在的筛分对残余血浆病毒血症和细胞HIV ENV RNA的效果。三聚体诱导 病毒学和免疫学评估将为这些条件及其益处提供新的见解 中和抗体反应在没有艺术的情况下实现持续的HIV-1缓解。