MVA Prime/Novel Trimeric Cyclically Permuted Envelope Protein Boost Vaccines for HIV

MVA Prime/新型三聚体循环排列包膜蛋白增强 HIV 疫苗

• 批准号: 10449340
• 负责人: Rama Rao Amara
• 金额: $ 78.54万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449340
• 关键词: AIDS/HIV problem; Adjuvant; Affinity; Agonist; Amino Acids; Animal Model; Animals; Antibodies; Antibody Formation; Antibody Response; Antigens; Autologous; Avidity; Binding; Cavia; Cells; Complex; Development; Enterotoxins; Epitopes; Failure; Formulation; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Human; Humoral Immunities; Immune; Immunization; Infection prevention; Laboratories; Link; Macaca; Macaca mulatta; Modality; Modeling; Modified Vaccinia Virus Ankara; Molecular; Molecular Conformation; Mosaicism; Mucous Membrane; Mutation; Oryctolagus cuniculus; Pathogenicity; Periodicity; Proteins; Regimen; Resistance; SIV; Secondary Immunization; Specificity; TLR7 gene; TNFSF5 gene; Testing; Thailand; Time; Vaccination; Vaccines; Virus; Virus Diseases; aluminum sulfate; base; cartilage matrix protein; cross reactivity; design; disulfide bond; efficacy trial; env Gene Products; immunogenicity; improved; mutant; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel vaccines; prevent; protective efficacy; response; scaffold; simian human immunodeficiency virus; vaccine efficacy; vaccine strategy; AIDS/HIV problem; Adjuvant; Affinity; Agonist; Amino Acids; Animal Model; Animals; Antibodies; Antibody Formation; Antibody Response; Antigens; Autologous; Avidity; Binding; Cavia; Cells; Complex; Development; Enterotoxins; Epitopes; Failure; Formulation; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Human; Humoral Immunities; Immune; Immunization; Infection prevention; Laboratories; Link; Macaca; Macaca mulatta; Modality; Modeling; Modified Vaccinia Virus Ankara; Molecular; Molecular Conformation; Mosaicism; Mucous Membrane; Mutation; Oryctolagus cuniculus; Pathogenicity; Periodicity; Proteins; Regimen; Resistance; SIV; Secondary Immunization; Specificity; TLR7 gene; TNFSF5 gene; Testing; Thailand; Time; Vaccination; Vaccines; Virus; Virus Diseases; aluminum sulfate; base; cartilage matrix protein; cross reactivity; design; disulfide bond; efficacy trial; env Gene Products; immunogenicity; improved; mutant; nanoparticle; neutralizing antibody; nonhuman primate; novel; novel vaccines; prevent; protective efficacy; response; scaffold; simian human immunodeficiency virus; vaccine efficacy; vaccine strategy

The overall goal of this application is to determine the immunogenicity and protective efficacy of novel trimeric gp120 immunogens against HIV using the rhesus macaque model. Development of an effective vaccine against HIV-1 has been an elusive goal for the past three decades. The results from the RV144 efficacy trial in Thailand provided a first proof in humans that HIV infection can be prevented by vaccination and demonstrated that anti-envelope (Env) antibody response contributes significantly for this protection. The major correlate of protection was found to be non-neutralizing antibodies specific for the variable loops V1V2 of gp120, a finding supported by recent non-human primate (NHP) trials in which protection from neutralization resistant simian immunodeficiency virus (SIV) infection also correlated with anti-V1V2 antibodies. Thus, we hypothesize HIV vaccines that generate a strong and broad anti-V1V2 response, in addition to neutralizing antibody response, will significantly improve protection against diverse HIV-1 isolates. Towards this, we recently described the design, immunogenicity and efficacy of a novel trimeric gp120 immunogen, CycP-gp120. This immunogen is based on a cyclically permuted gp120 in which a de novo N-terminus is generated within the V1 loop region with the native N- and C- termini joined via an amino acid linker chain. To induce a trimeric complex, the human cartilage matrix protein (hCMP) coiled-coil trimerization domain was fused to the de novo N-termini, resulting in a stabilized, disulfide bond linked trimeric gp120. Immunization of guinea pigs with cycP-gp120 showed strong induction of neutralizing antibodies against neutralization resistant (tier-2) HIV-1 isolates from multiple clades. Immunization of rabbits and rhesus macaques showed induction of high levels of high avidity HIV-1 Env specific antibodies with a remarkable anti-gp70-V1V2 specific response, promoting antibodies recognizing V1V2 sequences from a diverse, multi-clade panel of global HIV-1 isolates. More recent studies in rhesus macaque showed that MVA prime/CycP boost regimen confers protection against pathogenic SHIV challenges. In this proposal we will further optimize the CycP immunogen design and the adjuvant for CycP protein boost, and test the ability of CycP-induced antibody response to further enhance protection against HIV using a heterologous pathogenic tier 2 SHIV challenge in rhesus macaques.

该应用的总体目标是确定新型三聚体的免疫原性和保护功效 使用恒河猕猴模型对HIV的GP120免疫原子。开发有效的疫苗 在过去的三十年中，对抗HIV-1一直是一个难以捉摸的目标。 RV144疗效试验的结果 泰国提供了人类的第一个证据，表明可以通过疫苗预防艾滋病毒感染并证明 该抗Envelope（ENV）抗体反应对此保护产生了重大贡献。主要关联 发现保护是针对GP120的可变环V1V2特异性的非中和抗体 在最近的非人类灵长类动物（NHP）试验中支持的，其中保护免受中和抗性猿猴的保护 免疫缺陷病毒（SIV）感染也与抗V1V2抗体有关。因此，我们假设艾滋病毒 除了中和抗体反应外，还会产生强大而广泛的抗V1V2反应的疫苗 将显着改善针对不同HIV-1分离株的保护。在此方面，我们最近描述了 新型三聚体GP120免疫原的设计，免疫原性和功效，CYCP-GP120。这种免疫原是 基于循环排列的GP120，其中从N-末端产生了V1回路区域 与天然N-和C-末端通过氨基酸接头链加入。为了诱导三聚体复合物， 人体软骨基质蛋白（HCMP）盘绕螺旋的三聚化结构域被融合到从头N-末端， 导致稳定的二硫键连接的三聚体GP120。用CYCP-GP120对豚鼠进行免疫接种 表现出对中和抗体抗体抗体（TIER-2）HIV-1分离物的强烈诱导 多个进化枝。兔子和恒河猕猴的免疫表现出高水平的诱导 具有显着抗GP70-V1V2特异性响应的HIV-1 ENV特异性抗体，促进抗体 识别来自全局HIV-1分离株的多种多样，多层层小组的V1V2序列。最新的研究 恒河猕猴表明，MVA Prime/CYCP提升方案赋予了针对致病性SHIV的保护 挑战。在此提案中，我们将进一步优化CYCP免疫原和CYCP的佐剂 蛋白质提升，并测试CYCP诱导的抗体反应进一步增强对HIV的保护的能力 使用恒河猕猴中的异源致病层SHIV挑战。