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效果。 用恒河猴模型研究抗HIV的gp120免疫原。一种有效疫苗的研制 在过去的三十年里，对抗艾滋病毒-1一直是一个难以实现的目标。年RV144疗效试验的结果 泰国提供了第一个人类感染艾滋病毒可以通过接种疫苗预防的证据，并展示了 这种抗包膜(Env)抗体反应对这种保护作用有很大贡献。的主要关联性 研究发现，gp120可变环V1V2的非中和抗体具有保护作用 得到了最近的非人灵长类(NHP)试验的支持，在这些试验中，抵抗中和的猿猴 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 产生强烈和广泛的抗V1V2反应的疫苗，除了中和抗体反应外， 将显著提高对不同HIV-1毒株的保护。为此，我们最近描述了 新型三聚体gp120免疫原CycP-gp120的设计、免疫原性和有效性。这种免疫原是 基于循环置换的GP120，其中在V1环区内产生从头N末端 与天然的N-末端和C-末端通过氨基酸连接链连接。为了诱导三聚体复合体， 将人软骨基质蛋白(HCMP)卷曲-螺旋三聚结构域融合到新的N-末端， 从而得到稳定的二硫键连接的三聚物gp120。CycP-gp120免疫豚鼠的实验研究 显示出强烈的中和抗体诱导抗中和抗性(Tier-2)HIV-1分离株从 多个分支。兔和恒河猴的免疫表现出高水平的高亲和力 HIV-1 env特异性抗体具有显著的抗gp70-V1V2特异性反应，促进抗体的产生 从不同的、多分支的全球HIV-1分离株中识别V1V2序列。最近的研究在 恒河猴表明，MVA Prime/CycP Boost方案对致病性新城疫具有保护作用 挑战。在这项建议中，我们将进一步优化CycP免疫原设计和CycP佐剂 蛋白质增强，并检测CycP诱导的抗体应答能力，进一步增强对HIV的保护 在恒河猴中使用异源致病的第2层SIV挑战。

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.