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

本申请的总体目标是确定新型三聚体的免疫原性和保护功效 使用恒河猴模型研究抗 HIV 的 gp120 免疫原。开发有效的疫苗 过去三十年来，抗击 HIV-1 一直是一个难以实现的目标。 RV144 疗效试验的结果 泰国首次提供人类证据，证明可以通过疫苗接种预防艾滋病毒感染 抗包膜 (Env) 抗体反应对这种保护有显着贡献。主要相关因素为 发现保护作用是对 gp120 可变环 V1V2 具有特异性的非中和抗体，这一发现 最近的非人类灵长类动物 (NHP) 试验支持了这一点，其中防止中和抗性猿猴 免疫缺陷病毒（SIV）感染也与抗 V1V2 抗体相关。因此，我们假设艾滋病毒 除了中和抗体反应外，疫苗还能产生强烈而广泛的抗 V1V2 反应， 将显着提高对多种 HIV-1 分离株的保护。为此，我们最近描述了 新型三聚体 gp120 免疫原 CycP-gp120 的设计、免疫原性和功效。这种免疫原是 基于循环排列的 gp120，其中在 V1 循环区域内生成从头 N 末端 天然 N 端和 C 端通过氨基酸连接链连接。为了诱导三聚体复合物， 人软骨基质蛋白 (hCMP) 卷曲螺旋三聚化结构域从头融合到 N 末端， 产生稳定的二硫键连接的三聚体 gp120。 cycP-gp120 免疫豚鼠 显示出强烈诱导针对中和抗性（第 2 级）HIV-1 分离株的中和抗体 多个进化枝。兔子和恒河猴的免疫显示诱导高水平的高亲和力 HIV-1 Env 特异性抗体具有显着的抗 gp70-V1V2 特异性反应，促进抗体的产生 从全球 HIV-1 分离株的多样化、多进化枝组中识别 V1V2 序列。最近的更多研究 恒河猴表明 MVA prime/CycP 加强方案可针对致病性 SHIV 提供保护 挑战。在本提案中，我们将进一步优化CycP免疫原设计和CycP佐剂 蛋白质增强，并测试 CycP 诱导的抗体反应的能力，以进一步增强对 HIV 的保护 在恒河猴中使用异源致病性 2 级 SHIV 攻击。

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.