Selective priming of HA-specific CD4 T cells in influenza heterosubtypic immunity

流感异亚型免疫中 HA 特异性 CD4 T 细胞的选择性启动

• 批准号: 8567751
• 负责人: Jennifer L. Nayak
• 金额: $ 16.91万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567751
• 关键词: Address; Affect; Antibodies; Antibody Formation; Area; Avian Proteins; Award; B-Lymphocytes; Biometry; Bird Flu vaccine; Birds; CD4 Positive T Lymphocytes; Cells; Cellular biology; Cessation of life; Childhood; Collaborations; Communicable Diseases; Cross-Priming; Data; Development; Dose; Epitopes; Exposure to; Faculty; Frequencies; Goals; Hemagglutinin; Hospitalization; Human; Immunity; Immunization; Immunoglobulin Class Switching; Immunology; Inactivated Vaccines; Individual; Infection; Infection prevention; Influenza; Influenza vaccination; Institution; Kinetics; Knowledge; Laboratories; Lead; Memory; Mentors; Mentorship; Mexico; Modeling; Morbidity - disease rate; Mus; Population; Process; Proteins; Public Health; Recombinants; Regimen; Research; Research Personnel; Risk; Role; Sampling; Specificity; Students; T cell response; T-Cell Immunologic Specificity; Techniques; Testing; Time; United States; Universities; Vaccination; Vaccine Production; Vaccines; Viral; Viral Proteins; Virus; Work; arm; base; design; experience; improved; influenza virus vaccine; innovation; memory CD4 T lymphocyte; mortality; mouse model; neutralizing antibody; novel; pandemic disease; pandemic influenza; public health relevance; research study; respiratory virus; response; seasonal influenza; secondary infection; skills; vaccination strategy; vaccine efficacy

DESCRIPTION (provided by applicant): This is a K08 award application for Dr. Jennifer Nayak, a Pediatric Infectious Diseases subspecialist at the University of Rochester. Dr. Nayak is a young investigator establishing herself in the field of influenza immunology. The period of support offered by this K08 award will provide Dr. Nayak with the time and mentorship needed to acquire the knowledge, technical skills, and critical thought processes necessary in a successful independent researcher. During this time period, she will become adept at utilizing biostatistics to more effectively design experiments and analyze results, expand her skills in a broad range of experimental techniques, gain experience mentoring junior fellows and students engaged in similar areas of research, and increase her collaborations with faculty both within and outside of the University of Rochester. To achieve these goals, Dr. Nayak's primary mentor will be Dr. Andrea Sant, an established researcher with expertise in CD4 T cell biology and the CD4 T cell response to influenza. The proposed research addresses the fact that current pandemic influenza vaccination strategies are inadequate because the inability to predict the next pandemic strain and the time required for vaccine production lead to inadequate global protection in the face of a spreading pandemic. The objective is to understand how CD4 T cell specificity affects B cell and antibody responses on secondary infection or vaccination with a novel influenza strain, with the long-term goal of enhancing the potential of an individual to respond to novel influenza strains through optimal vaccination strategies that increase neutralizing antibody production. Based on preliminary data demonstrating decreased HA-specific CD4 T cells and antibody following a heterosubtypic influenza infection with a virus containing both novel and conserved epitopes, the central hypothesis that prior selective expansion of HA-specific CD4 T cells will result in more robust neutralizing antibody production in the setting of heterosubtypic infection or pandemic vaccination was developed. This hypothesis will be tested by 1) determining if selective expansion of HA-specific CD4 T cells facilitates B cell reactivity to novel epitopes and enhances HA-specific antibody production on heterosubtypic infection; and 2) evaluating if initial vaccination with a recombinant avian protein in the setting of prior immunity to seasonal influenza enhances HA-specific CD4 T cell and antibody responses on boosting with an inactivated avian vaccine. The proposed research will fill a critical gap in the understanding of the role of HA-specific CD4 T cells in both heterosubtypic infection and vaccination, potentially providing the first step towards a viable pre pandemic vaccination strategy that selectively arms the CD4 T cell compartment. This innovative approach to pandemic vaccination could promote accelerated neutralizing antibody production following natural infection or immunization with a novel influenza strain, enhancing individual pandemic protection, improving post-pandemic vaccine efficacy, and ultimately mitigating the impact of the next influenza pandemic.

描述（由申请人提供）：这是罗切斯特大学儿科传染病专家 Jennifer Nayak 博士的 K08 奖项申请。 Nayak 博士是一位年轻的研究者，在流感免疫学领域崭露头角。 K08 奖项提供的支持期将为 Nayak 博士提供获得成功的独立研究人员所需的知识、技术技能和批判性思维过程所需的时间和指导。在此期间，她将善于利用生物统计学更有效地设计实验和分析结果，扩展各种实验技术的技能，获得指导从事类似研究领域的初级研究员和学生的经验，并加强合作与罗切斯特大学内外的教师一起。为了实现这些目标，Nayak 博士的主要导师将是 Andrea Sant 博士，他是一位在 CD4 T 细胞生物学和 CD4 T 细胞对流感反应方面拥有专业知识的资深研究员。拟议的研究解决了当前大流行性流感疫苗接种策略不足的事实，因为无法预测下一次大流行毒株和疫苗生产所需的时间导致面对大流行病蔓延时全球保护不足。目的是了解 CD4 T 细胞特异性如何影响 B 细胞和抗体对继发感染或新型流感毒株疫苗接种的反应，长期目标是通过最佳疫苗接种策略增强个体对新型流感毒株做出反应的潜力增加中和抗体的产生。初步数据表明，在含有新型和保守表位的病毒感染异亚型流感后，HA 特异性 CD4 T 细胞和抗体减少，中心假设是，事先选择性扩增 HA 特异性 CD4 T 细胞将产生更强大的中和抗体开发了异亚型感染或大流行疫苗接种环境下的生产。这一假设将通过以下方式进行检验：1) 确定 HA 特异性 CD4 T 细胞的选择性扩增是否促进 B 细胞对新表位的反应性，并增强异亚型感染时 HA 特异性抗体的产生； 2) 评估是否使用重组禽类蛋白进行初始疫苗接种 在先前对季节性流感产生免疫力的情况下，使用灭活禽疫苗加强HA特异性CD4 T细胞和抗体反应。拟议的研究将填补了解 HA 特异性 CD4 T 细胞在异亚型感染和疫苗接种中的作用的关键空白，有可能为可行的预治疗迈出第一步。 选择性武装 CD4 T 细胞区室的大流行疫苗接种策略。这种大流行疫苗接种的创新方法可以促进自然感染或新型流感毒株免疫后加速中和抗体的产生，增强个人大流行保护，提高大流行后疫苗的功效，并最终减轻下一次流感大流行的影响。