Phase I HIV vaccine trial with DNAALVAC-HIV gp120 delta V1 vaccines

该项目将利用DNA/ALVAC-HIV疫苗平台诱导持久训练单核细胞记忆的能力，结合分支AE(A244毒株)V1缺失的HIV-gp160 Prime和新型V1缺失的HIV gp120/明矾蛋白Boost。从gp120包膜上删除V1将经过特殊设计，以将抗体干扰降至最低，并引发高水平的V2抗体，V2是RV144病毒风险的主要相关因素。氢氧化铝将被用作佐剂，因为它能够最大限度地诱导训练有素的免疫(通过诱导IL-1B的能力)和CD4+T细胞反应，这构成了RV144中艾滋病毒感染风险降低的次要关联。这项建议的总体目标是在GMP条件下设计和生产一种新型的HIV V1缺失的A244 gp160(A244 DeltaV1 Gp160)DNA疫苗和一种新型的HIV V1缺失的A244 gp120(A244 DeltaV1 Gp120)DNA疫苗，用于在I期人类HIV疫苗试验中进行测试。这些免疫原将首先在猕猴身上进行测试，以评估这种方法是否也能在人类中诱导持久的、非干扰的抗体、天生的单核细胞记忆和低炎症状态的适应性CD4+T细胞。对保护性单核细胞或NK记忆训练免疫的研究将被证明有助于对抗其他传染病和癌症。从无脊椎动物进化而来的训练有素的免疫是人类免疫系统的一个古老特征，由单核细胞的持久表观遗传重新编程定义，提供了抵御病原体的第一道防线。这不仅将导致新型艾滋病毒疫苗的生产和测试，而且还将导致对非人类灵长类动物(NHP)未知宿主保护性免疫反应的彻底研究，其免疫系统与人类相似。

The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2, the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1B) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. These immunogens will first be tested in macaques to assess whether this approach also induces long-lasting, non-interfering antibodies, innate monocyte memory, and adaptive CD4+ T-cells with a low inflammatory profile in humans. The investigation of protective monocyte, or NK memory trained immunity, will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates, trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes, providing the first line of defense against pathogens .This will lead not only to the production and testing of a novel HIV vaccine, but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans.