Supramolecular pediatric HIV vaccine design

摘要 针对艾滋病毒的儿科疫苗将产生重大的临床影响，因为超过15万名婴儿 全球每年都有艾滋病毒感染者，尽管有抗逆转录病毒药物可用来预防母婴传播 儿童变速箱。此外，一种儿科艾滋病毒疫苗，在婴儿时期提供保护，并提供持久的保护 首次性行为前的免疫将大大减少青少年艾滋病毒感染。发展中的儿童艾滋病病毒 疫苗将需要克服特定的免疫学挑战，由于早期生命免疫的局限性 系统包括1)提供T细胞帮助的能力降低，这导致较差的体细胞超突变 抗体和抗体亲和力不足，以及2)需要几种疫苗加强以实现持久 豁免权。矛盾的是，最近的研究表明，儿童可以发展中和广度 比成人更早，这表明早期生命的免疫系统可能更容易被诱导 这种通过接种疫苗的高度可取的反应。引发广泛中和的领先战略 抗体反应是用天然活的HIV包膜三聚体免疫。然而，尽管在稳定方面取得了进展， 在过去十年中生产了类似本地的HIV-1包膜三聚体，典型的疫苗接种策略包括 HIV-1包膜SOSIP三聚体产品在提高广泛和有效病毒的能力方面一直令人失望- 中和活性。可能需要新的疫苗平台来提高包膜的免疫原性 SOSIP三聚体疫苗。在这项合作中，我们将开发一种创新的纳米纤维儿科艾滋病毒疫苗 由支架CH505 SOSIP环境三聚体和自组装的合成T细胞表位(PADRE)组成 变成超分子纳米纤维。我们推测PADRE-纳米纤维偶联HIV-1CH505 SOSIP 三聚体疫苗(P-Q11 CH505三聚体)将增强二级病毒中和的强度和效力 在小动物和婴儿非人灵长类(NHP)模型中的反应，并将保护 婴儿NHP挑战模型中的同源SHIV挑战。我们的具体目标是：1)开发和评估 纳米纤维偶联CH505 SOSIP三聚体亚单位疫苗的抗原性；2)确定免疫原性 P-Q11 CH505三聚体疫苗对新生兔和幼年恒河猴免疫效果的比较 Ch505 SOSIP环境三聚体单独(通过/不进行终点)；以及3)确定P-Q11 CH505三聚体的能力 在婴儿出生后晚期非人灵长类动物模型中预防低剂量口服SIV攻击的疫苗 通过母乳喂养传播。这一新的儿科艾滋病毒疫苗策略可以克服 婴儿接种疫苗，同时利用早期生命免疫的免疫学和实际好处 用来激发保护性免疫。

Abstract A pediatric vaccine against HIV would have a significant clinical impact, because more than 150,000 infants are infected with HIV every year globally, despite the availability of antiretroviral drugs to prevent mother-to- child transmission. In addition, a pediatric HIV vaccine that offers protection in infancy and durable protective immunity prior to sexual debut would significantly reduce adolescent HIV infections. Developing a pediatric HIV vaccine will require to overcome specific immunological challenges dues of limitations of the early life immune system including 1) a reduced ability to provide T-cell help, which results in poor somatic hypermutation of antibodies and inadequate antibody affinity, and 2) the need for several vaccine boosts to achieve durable immunity. Paradoxically, recent studies have demonstrated that children can develop neutralization breadth earlier than adults, suggesting that the early life immune system could be more amendable for the elicitation of this highly desirable response through vaccination. A leading strategy for elicitation of broad neutralizing antibody response is to immunize with native live HIV envelope trimers. Yet, despite advances in stabilization and production of native-like HIV-1 envelope trimers over the last decade, typical vaccination strategies with HIV-1 Envelope SOSIP trimer products have been disappointing in their ability to raise broad and potent virus- neutralizing activity. Novel vaccine platforms may be needed to improve the immunogenicity of Envelope SOSIP trimer vaccines. In this collaboration, we will develop an innovative nanofiber pediatric HIV vaccine comprised of a scaffolded CH505 SOSIP Env trimer and a synthetic T-Cell epitope (PADRE) self-assembled into supramolecular nanofibers. We hypothesize that the PADRE- nanofiber conjugated HIV-1 CH505 SOSIP trimer vaccine (P-Q11 CH505 trimer) will enhance the magnitude and potency of tier 2 virus neutralization responses in small animal and infant non-human primate (NHP) models, and will be protective against homologous SHIV challenge in an infant NHP challenge model. Our specific aims are: 1) Develop and assess the antigenicity the nanofiber-conjugated CH505 SOSIP trimer subunit vaccine; 2) Define the immunogenicity of the P-Q11 CH505 trimer vaccine in neonatal rabbits and infant rhesus macaques in comparison to that of CH505 SOSIP Env trimer alone (Go/No-Go endpoint); and 3) Determine the ability of the P-Q11 CH505 trimer vaccine to protect against low dose oral SHIV challenge in an infant nonhuman primate model of late postnatal transmission via breastfeeding. This novel pediatric HIV vaccine strategy could overcome the challenges of infant vaccination, while taking advantage of the immunologic and practical benefits of early life immunization for elicitation of protective immunity.