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与艾滋病毒疾病，发病机理和疫苗发育领域的转化科学相结合的职业。他是医学博士学位。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 Institute在天然HIV感染中的保护性CD4+和CD8+ T细胞的相关性进行了博士后研究奖学金（以前称为合作伙伴AIDS研究中心）。他目前是马萨诸塞州综合医院/杨百翰和妇女医院的传染病临床和研究研究员，也是哈佛医学院医学教练。候选人以前的道路帮助他定义并培养了他的科学生涯 翻译方面，尤其是疫苗指示问题。他特别有兴趣研究与保护相关的疫苗引起的T细胞反应的相关性，并希望应用一些新型的纳米技术。他在博士后研究金期间发展了，以进一步剖析抗病毒T细胞特征。候选人以前的工作非常有生产力，使他能够在人类T细胞免疫学方面获得强大的知识基础，并在免疫研究技术方面具有扎实的技能。根据K08机制进行的指导培训将使他能够翻译他以前获得的免疫技能，以发展足够的科学专业知识，出版物和合作 艾滋病毒疫苗学领域，将允许他作为医师科学家的持续发展。候选人的长期目标是在学术界建立自己，成为一名独立资助的研究人员，从事以患者为导向的HIV疫苗开发研究。他很幸运有两位导师，博士。丹·巴鲁奇（Dan Barouch）和布鲁斯·沃克（Bruce Walker），他们在疫苗开发和细胞免疫学领域拥有丰富的经验，并且以前曾成功指导过K-Awardees。此外，候选人将被安置在Ragon Institute，该研究所提供了一流的研究基础设施，这是一个丰富的科学界，非常适合候选人成功地传导其项目。此外，杰出科学家委员会将监督他在独立方面的进步。预防性HIV疫苗的发展非常困难，尽管在天然HIV感染的某些情况下诱导了中和抗体，但很可能只有T和B细胞反应的合并活性才能阻止感染。 T细胞很可能不仅需要帮助生成有效的B细胞反应，还需要快速包含并清除最初局部的粘膜感染，从而防止病毒传播，并 调节病毒血症应感染。恒河猕猴最近的两项研究表明，在诱导T细胞免疫力后，可以实现降低感染的易感性和感染后病毒控制（以及潜在的清除）。在这两项研究中，强大的SIV特异性T细胞反应的存在与SIV采集或对照的减少60-80％有关。然而，对于这些疫苗诱导的保护性T细胞反应的功能特性以及它们是否能够回家感染部位，在那里它们可能提供最大的保护水平，对它们的功能特征知之甚少。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，以特别扩大这种免疫活性，以用于未来的HIV疫苗设计。而且，全面的比较解剖 在这两个动物模型中诱导的T细胞反应可能有助于定义与感染或感染后的保护相关的T细胞反应的特定特性。在该提案中，候选人将研究以下假设：疫苗接种的恒河猴的保护是由疫苗吸收的CD4+和CD8+ T淋巴细胞反应的特定功能和解剖亚集介导的，该功能与独特的功能性抗病毒谱有关。将解决以下具体目的：1）定义与恒河猴保护中的RAD和CMV-VECTOR诱导的CD4+和CD8+ T细胞的抗病毒特征； 2）确定恒河猕猴中粘膜rad诱导的CD4+和CD8+ T细胞的抗病毒特性，并研究机制，导致粘膜T细胞归巢和持久性。这些研究将为特定的细胞免疫反应提供关键的见解，如果疫苗诱导的抗体无法提供免受感染的保护，可能会为感染/疾病提供额外的关键障碍，并有助于指导未来的有效疫苗开发。