Vaccine induced T-cell protection against SIV infection

疫苗诱导 T 细胞针对 SIV 感染提供保护

• 批准号: 8664801
• 负责人: Boris Dominik Juelg
• 金额: $ 18.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-23 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664801
• 关键词: Academia; Acquired Immunodeficiency Syndrome; Address; Adenoviruses; Affect; Anatomy; Animal Model; Animals; Antibodies; Antigens; Antiviral Agents; Area; B-Lymphocytes; Basic Science; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cellular Immunology; Characteristics; Clinical Investigator Award; Clinical Research; Collaborations; Communicable Diseases; Communities; Cytomegalovirus; Cytoprotection; Data; Development; Disease; Dissection; Doctor of Medicine; Doctor of Philosophy; Exhibits; Fellowship; Funding; Future; Gagging; General Hospitals; Generations; Germany; Goals; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Heterogeneity; Home environment; Homing; Hospitals; Human; Immune; Immune response; Immunity; Immunization; Immunology; Infection; Infection Control; Infection prevention; Institutes; Lead; Letters; Link; Macaca; Macaca mulatta; Massachusetts; Mediating; Medicine; Mentors; Monkeys; Mucous Membrane; Nanotechnology; Pathogenesis; Patient Care; Phenotype; Physicians; Plasma; Population; Postdoctoral Fellow; Predisposition; Property; Proteins; Publications; Recombinants; Research; Research Infrastructure; Research Personnel; SIV; Sampling; Scientist; Signal Transduction; Site; Solid; Specificity; T cell response; T memory cell; T-Lymphocyte; Technology; Training; Translating; Translational Research; Universities; Vaccinated; Vaccine Design; Vaccines; Viral; Viral Physiology; Viremia; Virus Diseases; Walkers; Woman; Work; career; comparative; control trial; env Gene Products; experience; gag Gene Products; insight; instructor; interest; knowledge base; medical schools; mucosal site; neutralizing antibody; novel; novel strategies; patient oriented research; peripheral blood; pol Gene Products; poxvirus vectors; prevent; prophylactic; public health relevance; response; skills; trend; vaccine candidate; vaccine development; vaccinology; vector; vector-based vaccine; vector-induced

DESCRIPTION (provided by applicant): The candidate is dedicated to a career that combines basic research and patient care with a particular focus on translational science in the area of HIV disease, pathogenesis and vaccine development. He is an M.D.-Ph.D. graduate from the University of Kiel, Germany and did his postdoctoral research fellowship on correlates of protective CD4+ and CD8+ T cells in natural HIV infection at the Ragon Institute of MGH, MIT and Harvard (formerly known as Partners AIDS Research Center). He is currently a clinical and research fellow in Infectious Disease at Massachusetts General Hospital/Brigham and Women's Hospital and an Instructor in Medicine at Harvard Medical School. The candidate's previous path has helped him to define and sharpen his scientific career moving the focus of his research interest from pure HIV pathogenesis to translational aspects, in particular vaccine directed questions. He is particularly interested in investigating correlates of vaccine-elicited T cell responses associated with protection and would like to apply some of the novel nano-technologies; he had developed during his post-doctoral fellowship, to further dissect antiviral T cell characteristics. The candidate's previous work has been very productive and has enabled him to gain a strong knowledge base in human T cell immunology and a solid skill set in immunological research technologies. Mentored training under the K08 mechanism would allow him to translate his previously acquired immunological skills to develop sufficient scientific expertise, publications and collaborations in the field of HIV vaccinology and would permit his continued development as a physician scientist. The candidate's longer-term goal is to establish himself within academia as an independently funded investigator engaged in patient oriented research on HIV vaccine development. He is fortunate to have two mentors, Drs. Dan Barouch and Bruce Walker, who have extensive experience in the field of vaccine development and cellular immunology and who both have successfully mentored K-awardees before. Furthermore the candidate will be placed at the Ragon Institute, which offers superb research infrastructure, a rich scientific community and is highly suited for the candidate's successful conduction of his project. In addition, a committee of distinguished scientists will oversee his progress toward independence. The development of a prophylactic HIV vaccine has been extremely difficult and although neutralizing antibodies are induced in some instances in natural HIV infection, it is likely that only the combined activity of T and B cell responses can prevent infection. T cells are most likely not only necessary to help the generation of effective B cell responses but also to rapidly contain and clear an initially localized mucosal infection, thereby preventing viral spread, and to modulate viremia should infection occur. Two recent studies in rhesus macaques have shown that both reduced susceptibility to infection and post-infection viral control (and potential clearance) can be achieved following the induction of T cell immunity. In both studies the presence of robust SIV-specific T cell responses was linked to a 60-80% reduction in SIV acquisition or control. Yet little is known about the functional characteristics of these vaccine-induced protective T cell responses and whether they are able to home to the sites of infection, where they may provide the greatest level of protection. Understanding the precise functional correlate of the antiviral immune response(s) elicited by these 2 vaccines offers a unique opportunity to develop new approaches at specifically amplifying such immunological activity for future HIV vaccine design. Moreover, comprehensive comparative dissection of the T cell response induced in these 2 animal models may help define the specific properties of the T cell response associated with protection from or after infection. In this proposal, the candidate will investigate the hypothesis that protection in vaccinated rhesus monkeys is mediated by specific functional and anatomic subsets of vaccine-elicited CD4+ and CD8+ T lymphocyte responses, related to unique functional antiviral profiles. The following specific aims will be addressed: 1) Define the antiviral signature(s) of rAd and CMV-vector induced CD4+ and CD8+ T cells associated with protection in rhesus monkeys; 2) Determine antiviral properties of mucosal rAd-induced CD4+ and CD8+ T cells in rhesus macaques and investigate mechanism(s) leading to mucosal T cell homing and persistence. These studies will provide critical insights into the specific cellular immune responses that may provide an additional key barrier to infection/disease should vaccine-induced antibodies fail to provide sterilizing protection from infection and will help guide future efficacious vaccine development.

描述（由申请人提供）：候选人致力于将基础研究和患者护理相结合的职业，特别关注艾滋病毒疾病、发病机制和疫苗开发领域的转化科学。他是医学博士-博士。毕业于德国基尔大学，并在 MGH、麻省理工学院和哈佛大学的 Ragon 研究所（前身为 Partners AIDS 研究中心）进行博士后研究，研究保护性 CD4+ 和 CD8+ T 细胞在自然 HIV 感染中的相关性。他目前是马萨诸塞州总医院/布莱根妇女医院传染病的临床和研究员，以及哈佛医学院的医学讲师。该候选人之前的道路帮助他定义和加强了他的科学生涯，将他的研究兴趣重点从纯粹的艾滋病毒发病机制转移到 翻译方面，特别是针对疫苗的问题。他对研究疫苗引发的 T 细胞反应与保护的相关性特别感兴趣，并希望应用一些新颖的纳米技术；他在博士后研究期间开发了一种方法，进一步剖析抗病毒 T 细胞的特性。该候选人之前的工作非常富有成效，使他获得了人类 T 细胞免疫学方面的深厚知识基础和免疫学研究技术方面的扎实技能。 K08机制下的指导培训将使他能够将之前获得的免疫学技能转化为在以下领域发展足够的科学专业知识、出版物和合作： HIV 疫苗学领域的研究将使他能够继续发展成为一名医学科学家。候选人的长期目标是在学术界成为一名独立资助的研究人员，从事以患者为导向的艾滋病毒疫苗开发研究。他很幸运有两位导师，博士。 Dan Barouch 和 Bruce Walker 在疫苗开发和细胞免疫学领域拥有丰富的经验，并且之前都曾成功指导过 K 奖获得者。此外，候选人将被安置在拉贡研究所，该研究所提供一流的研究基础设施、丰富的科学界，非常适合候选人成功开展其项目。此外，一个由杰出科学家组成的委员会将监督他走向独立的进展。预防性 HIV 疫苗的开发极其困难，尽管在自然 HIV 感染的某些情况下会诱导中和抗体，但很可能只有 T 细胞和 B 细胞反应的联合活性才能预防感染。 T 细胞很可能不仅有助于产生有效的 B 细胞反应，而且还有助于快速遏制和清除最初的局部粘膜感染，从而防止病毒传播，并 如果发生感染，则调节病毒血症。最近两项针对恒河猴的研究表明，在诱导 T 细胞免疫后，可以实现降低感染易感性和感染后病毒控制（和潜在清除）。在这两项研究中，强大的 SIV 特异性 T 细胞反应的存在与 SIV 获得或控制减少 60-80% 相关。然而，人们对这些疫苗诱导的保护性 T 细胞反应的功能特征以及它们是否能够回到感染部位并提供最大程度的保护知之甚少。了解这两种疫苗引起的抗病毒免疫反应的精确功能相关性为开发新方法提供了独特的机会，以专门增强未来艾滋病毒疫苗设计的这种免疫活性。此外，综合比较剖析 在这两种动物模型中诱导的 T 细胞反应可能有助于确定与感染或感染后保护相关的 T 细胞反应的具体特性。在本提案中，候选人将研究这样的假设：接种疫苗的恒河猴的保护作用是由疫苗引起的 CD4+ 和 CD8+ T 淋巴细胞反应的特定功能和解剖子集介导的，与独特的功能性抗病毒特征相关。将解决以下具体目标： 1) 定义与恒河猴保护相关的 rAd 和 CMV 载体诱导的 CD4+ 和 CD8+ T 细胞的抗病毒特征； 2) 确定恒河猴粘膜 rAd 诱导的 CD4+ 和 CD8+ T 细胞的抗病毒特性，并研究导致粘膜 T 细胞归巢和持久存在的机制。这些研究将为特定细胞免疫反应提供重要见解，如果疫苗诱导的抗体无法提供针对感染的灭菌保护，这些反应可能会为感染/疾病提供额外的关键屏障，并将有助于指导未来有效的疫苗开发。