Combined Hepatitis B and HIV-1 envelope vaccination to augment T cell help via linked recognition of unrelated antigens

项目总结 迫切需要一种有效的艾滋病毒疫苗来预防新的感染和结束 全球艾滋病流行。到目前为止进行的研究还没有发现一种安全、高度 有效、持久的预防性艾滋病毒疫苗。T滤泡对提高CD4+T细胞的作用 辅助性(TFH)细胞是一种潜在的提高抗体应答的策略 候选艾滋病毒疫苗。TFH细胞对长寿亲和成熟B细胞的发育至关重要 细胞，最近被确定为免疫反应的关键组成部分， 具有中和不同艾滋病毒分离株能力的抗体。然而，目前存在一个差距。 关于增加疫苗诱导的TFH反应的最佳方法的知识。致信地址 在这一限制下，申请者将获得领导发展所需的技能和经验 在非人类灵长类动物的临床前研究中发现具有可靠路径的新疫苗策略 (NHP)进行人体临床试验。专业知识将由经验丰富的导师提供 团队，并接受额外的教学和实践培训。申请者的职业目标是领导一个 致力于开发预防和免疫干预措施的研究计划 婴儿、儿童和青少年传染病的治疗。《公约》的总体目标 建议开发一种能够最大限度地提高T细胞的HIV包膜(Env)疫苗方案 帮助招募儿童免疫诱导的记忆TFH细胞 特定于HIV环境。新型乙肝表面抗原(HBs)与HIV-env结合物 疫苗将用于增强乙肝免疫恒河猴对HIV env的TFH应答 猕猴。假设一种疫苗方案能够招募HIV-Env特异性和 非HIV-Env特异性TFH细胞为环境特异性B细胞提供帮助将改善 HIV-Env抗体反应的数量和质量。疫苗方案将于#年启动。 新生猕猴作为人类婴儿期的代用品，将成为儿童免疫的典范 时间表，允许完成方案和诱导成熟抗体预先 青春期，在首次性行为之前。拟议的研究将证明概念的证明。 结合疫苗可以利用儿童疫苗中先前存在的记忆T细胞帮助 增强对HIV-Env疫苗的反应，从而产生更高的疫苗数量、质量和 Env特异性抗体的成熟。此外，该奖项还将为 对确定有效和可实施的预防措施感兴趣的早期职业调查员 用于脆弱和服务不足的儿科人群的疫苗。

PROJECT SUMMARY There is a critical need for an effective HIV vaccine to prevent new infections and to end the global AIDS epidemic. Studies conducted to date have not yet identified a safe, highly efficacious, and durable prophylactic HIV vaccine. Increasing CD4+ T cell help from T follicular helper (TFH) cells is one potential strategy for improving the antibody response elicited by candidate HIV vaccines. TFH cells are essential for development of long-lived affinity-matured B cells and have recently been identified as a key component of immune responses that generate antibodies with the ability to neutralize diverse HIV isolates. However, there is presently a gap in knowledge on the best approaches to increase vaccine-induced TFH responses. To address this limitation, the applicant will gain the skills and experience required to lead the development of novel vaccine strategies with tenable paths from preclinical studies in non-human primates (NHP) to human clinical trials. Expertise will be provided by a highly experienced mentorship team, and with additional didactic and practical training. The applicant’s career goal is to lead a research program dedicated to the development of immune interventions for prevention and cure of infectious diseases in infants, children, and adolescents. The overall objective of the proposal is to develop an HIV envelope (Env) vaccine regimen that is able to maximize T cell help by recruiting memory TFH cells elicited by childhood immunizations in addition to those specific for HIV Env. Novel Hepatitis B surface antigen (HBsAg) and HIV Env conjugate vaccines will be used to augment the TFH response to HIV Env in Hepatitis B immune rhesus macaques. The hypothesis is that a vaccine regimen able to recruit both HIV-Env-specific and non-HIV-Env-specific TFH cells for providing help to Env-specific B cells will improve the quantity and quality of the HIV-Env antibody response. The vaccine regimen will be initiated in neonatal macaques as a surrogate of human infancy, and will model a childhood immunization schedule that allows for completion of the regimen and induction of mature antibodies pre- adolescence, prior to sexual debut. The proposed study will demonstrate the proof of concept that conjugate vaccines can leverage pre-existing memory T cell help from childhood vaccines to augment the response to an HIV-Env vaccine, resulting in higher magnitude, quality, and maturation of Env-specific antibodies. In addition, this award will provide essential training to an early career investigator interested in identifying effective and implementable prophylactic vaccines for use in vulnerable and underserved pediatric populations.