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

联合乙型肝炎和 HIV-1 包膜疫苗接种，通过对不相关抗原的关联识别来增强 T 细胞的帮助

• 批准号: 9764517
• 负责人: Justin Joseph Pollara
• 金额: $ 34.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764517
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adolescence; Adolescent; Affinity; Animals; Antibodies; Antibody Response; Antigens; Award; B-Lymphocytes; CD4 Positive T Lymphocytes; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Clinical Trials; Communicable Diseases; Conjugate Vaccines; Development; Epidemic; Foundations; Generations; Goals; HIV; HIV Antibodies; HIV Antigens; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; Haemophilus influenzae; Helper-Inducer T-Lymphocyte; Hepatitis B; Hepatitis B Surface Antigens; Human; Immune; Immune response; Immunization; Immunization Schedule; Immunize; Immunologist; Infant; Infection; Knowledge; Lead; Life; Link; Macaca; Macaca mulatta; Mature B-Lymphocyte; Memory; Mentors; Mentorship; Mission; Modeling; National Institute of Allergy and Infectious Disease; National Institute of Child Health and Human Development; Neonatal; Outcome; Population; Positioning Attribute; Preventive Intervention; Preventive vaccine; Proteins; Public Health; Recombinants; Regimen; Research; Research Personnel; Schedule; Stimulus; Streptococcus pneumoniae; Subunit Vaccines; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Training; Underserved Population; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Vulnerable Populations; base; career; career development; env Gene Products; experience; immunogenic; immunogenicity; immunological intervention; improved; infancy; interest; lymph nodes; neutralizing antibody; nonhuman primate; novel; novel vaccines; peripheral blood; preadolescence; preclinical study; prevent; programs; prophylactic; protein B; recruit; response; sexual debut; skills; vaccine candidate

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.

项目摘要 迫切需要一种有效的艾滋病毒疫苗，以防止新的感染，并结束艾滋病毒的传播。 全球艾滋病流行。迄今为止进行的研究尚未确定一种安全、高度 有效和持久的预防性HIV疫苗。增加CD 4 + T细胞帮助T滤泡 辅助（TFH）细胞是一种潜在的策略，用于改善由 候选艾滋病毒疫苗。TFH细胞对于长寿命亲和力成熟的B的发育是必需的 细胞，最近已被确定为免疫反应的关键组成部分， 这些抗体具有中和多种HIV分离株的能力。然而，目前存在一个差距， 增加疫苗诱导的TFH反应的最佳方法的知识。解决 这一限制，申请人将获得领导发展所需的技能和经验， 在非人灵长类动物的临床前研究中， (NHP)人类临床试验。专业知识将由经验丰富的导师提供 团队，并与额外的教学和实践培训。申请人的职业目标是领导一个 研究计划致力于开发用于预防和治疗的免疫干预措施 治疗婴儿、儿童和青少年的传染病。的总体目标 一项建议是开发一种HIV包膜（Env）疫苗方案， 通过招募儿童免疫接种引起的记忆TFH细胞来帮助， 对HIV Env.新型B型肝炎表面抗原（HBsAg）和HIV Env缀合物 疫苗将用于增强B型肝炎免疫恒河猴中TFH对HIV Env的应答 猕猴假设是，能够招募HIV-Env特异性和 非HIV-Env-特异性TFH细胞为Env-特异性B细胞提供帮助将改善 HIV-Env抗体应答的数量和质量。疫苗接种方案将于 新生猕猴作为人类婴儿期的替代品， 时间表，允许完成方案和诱导成熟抗体， 青春期，在初次性行为之前。拟议的研究将证明概念的证明 结合疫苗可以利用来自儿童疫苗的预先存在的记忆T细胞帮助， 加强对HIV-Env疫苗的反应，从而提高疫苗接种的规模、质量和 Env特异性抗体的成熟。此外，该奖项将提供必要的培训， 对确定有效和可实施的预防措施感兴趣的早期职业研究者 疫苗用于脆弱和服务不足的儿科人群。