Supramolecular pediatric HIV vaccine design

超分子儿科艾滋病疫苗设计

• 批准号: 10341039
• 负责人: Joel H Collier
• 金额: $ 76.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341039
• 关键词: Acute; Address; Adherence; Adolescent; Adult; Affinity; Animals; Anti-Retroviral Agents; Antibodies; Antibody Affinity; Antibody Response; B-Lymphocytes; Breast Feeding; Child; Childhood; Clinical; Collaborations; Development; Dose; Drug resistance; Engineering; Epitopes; Goals; Grant; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Immune system; Immunity; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Immunologics; Infant; Infection; Intervention; Life; Macaca mulatta; Modeling; Molecular; Mothers; Neonatal; Oral; Oryctolagus cuniculus; Peptides; Pharmaceutical Preparations; Pregnancy; Preventive measure; Production; Regimen; Residual state; Risk; Subunit Vaccines; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Toxic effect; Vaccinated; Vaccination; Vaccine Design; Vaccines; Vertical Disease Transmission; Virus; base; engineering design; falls; fetal; immunogenicity; improved; infancy; infant infection; innovation; manufacturability; nanofiber; neonatal immune system; neutralizing antibody; nonhuman primate; novel; novel vaccines; pediatric human immunodeficiency virus; postnatal; preservation; prevent; resistant strain; response; scaffold; sexual debut; simian human immunodeficiency virus; transmission process; vaccination strategy

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.

抽象的 针对 HIV 的儿科疫苗将产生重大的临床影响，因为超过 150,000 名婴儿 尽管有抗逆转录病毒药物可以预防母婴传播，但全球每年仍有艾滋病毒感染者 儿童传播。此外，还有一种儿童艾滋病毒疫苗，可以在婴儿期提供保护，并提供持久的保护作用。 首次性行为之前的免疫力将显着减少青少年艾滋病毒感染。开发儿童艾滋病毒 疫苗需要克服由于生命早期免疫的局限性而导致的特定免疫挑战 系统包括 1) 提供 T 细胞帮助的能力降低，从而导致不良的体细胞超突变 抗体和抗体亲和力不足，以及 2) 需要多次疫苗加强才能实现持久 免疫。矛盾的是，最近的研究表明，儿童可以发展中和广度 比成年人更早，这表明生命早期的免疫系统可能更容易引发 通过疫苗接种获得这种非常理想的反应。引发广泛中和的领先策略 抗体反应是用天然活 HIV 包膜三聚体进行免疫。然而，尽管稳定方面取得了进展 以及过去十年中类似天然 HIV-1 包膜三聚体的产生，典型的疫苗接种策略 HIV-1 包膜 SOSIP 三聚体产品在产生广泛而有效的病毒的能力方面令人失望 - 中和活性。可能需要新型疫苗平台来提高 Envelope 的免疫原性 SOSIP 三聚体疫苗。在这次合作中，我们将开发一种创新的纳米纤维儿童艾滋病毒疫苗 由支架式 CH505 SOSIP Env 三聚体和自组装的合成 T 细胞表位 (PADRE) 组成 成超分子纳米纤维。我们假设 PADRE-纳米纤维缀合 HIV-1 CH505 SOSIP 三聚体疫苗（P-Q11 CH505 三聚体）将增强 2 级病毒中和的程度和效力 小动物和婴儿非人类灵长类动物 (NHP) 模型中的反应，并且将具有保护作用 婴儿 NHP 攻击模型中的同源 SHIV 攻击。我们的具体目标是： 1) 开发和评估 纳米纤维缀合的CH505 SOSIP三聚体亚单位疫苗的抗原性； 2) 定义免疫原性 P-Q11 CH505 三聚体疫苗在新生兔和幼年恒河猴中的效果与 单独 CH505 SOSIP Env 三聚体（Go/No-Go 端点）； 3) 确定 P-Q11 CH505 三聚体的能力 疫苗可在产后晚期的婴儿非人灵长类动物模型中预防低剂量口服 SHIV 攻击 通过母乳喂养传播。这种新颖的儿科艾滋病毒疫苗策略可以克服以下挑战： 婴儿疫苗接种，同时利用生命早期免疫的免疫学和实际益处 用于激发保护性免疫力。