Human B cell responses to a live attenuated cholera vaccine

人类 B 细胞对霍乱减毒活疫苗的反应

基本信息

批准号：
10186688
负责人：
Jens Peter Wrammert
金额：
$ 39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186688
关键词：
Acute Acute Diarrhea Address Adult Affinity Africa Agglutination Animal Model Antibodies Antibody Response Antigenic Specificity Antigens Area Attenuated Attenuated Vaccines B-Cell Activation B-Lymphocytes Benchmarking Biological Assay Biology Blood Cell Compartmentation Cell Survival Cells Cessation of life Characteristics Child Cholera Cholera Vaccine Clinic Collaborations Country Cryoelectron Microscopy Developing Countries Development Diagnostic Diarrhea Differentiation Antigens Disease Dose Epidemic FDA approved Future General Hospitals Generations HIV Haiti Heterogeneity Homing Human Humoral Immunities Image Immune Immune response Immunity Immunization Programs Immunogenetics Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Isotypes Immunoglobulin M Immunologics Individual Infection International Intestinal Mucosa Lead Longevity Maintenance Massachusetts Mediating Memory Memory B-Lymphocyte Microscopy Monoclonal Antibodies Mucosal Immunity Mucous Membrane Negative Staining Patients Phenotype Plasma Cells Plasmablast Population Process Property Rotavirus Route Sampling Sanitation Serotyping Specificity Therapeutic Therapeutic Uses Travel Vaccination Vaccine Design Vaccines Vibrio cholerae Vibrio cholerae infection Virulent Water Whole Cell Vaccine Work acute infection cell motility child protection diarrheal disease dimer experience experimental study human disease human monoclonal antibodies human pathogen insight longitudinal human study medical schools migration novel novel vaccines pathogen peripheral blood prevent protective efficacy receptor response single cell analysis vaccine development vaccine-induced antibodies

项目摘要

PROJECT SUMMARY Vibrio cholerae causes an acute diarrheal disease that is estimated to lead to 3 to 5 million cases of cholera and causes over 100,000 deaths annually. The increasing burden of cholera, the inability to achieve benchmarks for sanitation and safe water, and the emergence of more virulent strains of V. cholerae suggest that more aggressive approaches to preventing cholera, including vaccination programs, are needed. However, currently available killed whole cell vaccines generate immunity that rapidly wanes and provides only partial protection; especially in young children. In contrast, natural infection with V. cholerae induces 90-100 % protection against re-infection that lasts for up to 10 years in adults and children. It remains unknown why current vaccines are markedly less effective than natural infection. Understanding mucosal immunity and mechanisms regulating homing of immune cells to mucosal tissues in humans is of key importance, not only for V. cholerae infection, but for many other pathogens with a mucosal route of infection. A novel live attenuated cholera vaccine (Vaxchora) was recently approved in the US for use in travelers. This vaccine has showed excellent protection in human challenge studies. However, little is known about the long-term duration of protection, what determines the longevity of cholera specific memory B cells and mucosal plasmacells, or what governs plasmacell migration to, and survival within, the intestinal mucosa. In the current proposal, we seek to identify key differences in the early B cell responses after vaccination with the live attenuated vaccine, that may predict long-term humoral immunity. We propose to draw upon existing collaborations between the Emory Vaccine Center, the Emory Hope Clinic and the Massachusetts General Hospital/Harvard Medical School (MGH/HMS) to address this question in humans. Specifically, we will study both early and long term B cell responses in peripheral blood and in intestinal mucosae samples, using both global and single cell approaches. These studies will provide unprecedented insight into heterogeneity of the acute plasmablasts responses to cholera, their origin and activation process, affinity maturation and class switching, mucosal homing potential, ability to provide long-lived immunity after infection is resolved, and the antigenic specificity of the BCR, at a single cell level. Finally, imaging experiments will provide mechanistic insight into the mode of action of anti-cholera antibodies. These studies will generate a large number of monoclonal antibodies against cholera that might have both diagnostic and therapeutic uses. Findings herein may also instruct future vaccine development for this important human pathogen.

项目概要霍乱弧菌引起一种急性腹泻病，估计会导致 3 至 500 万例霍乱病例霍乱，每年造成超过 10 万人死亡。霍乱负担日益加重，无法实现卫生和安全用水的基准以及毒性更强的霍乱弧菌菌株的出现表明需要采取更积极的方法来预防霍乱，包括疫苗接种计划。然而，目前可用的灭活全细胞疫苗产生的免疫力会迅速减弱，并且只能提供部分保护；尤其是幼儿。相比之下，自然感染霍乱弧菌可导致 90-100% 防止成人和儿童再次感染的效果可持续长达 10 年。原因尚不清楚目前的疫苗明显不如自然感染有效。了解粘膜免疫和调节人类免疫细胞归巢到粘膜组织的机制至关重要，不仅适用于霍乱弧菌感染，也适用于许多其他具有粘膜感染途径的病原体。一种新型霍乱减毒活疫苗（Vaxchora）最近在美国获得批准用于旅行者。该疫苗在人类攻击研究中显示出出色的保护作用。然而，鲜为人知关于保护的长期持续时间，是什么决定了霍乱特异性记忆B细胞的寿命和粘膜浆细胞，或者控制浆细胞迁移到肠粘膜并在肠粘膜内存活的因素。在当前的提案中，我们试图确定接种疫苗后早期 B 细胞反应的关键差异减毒活疫苗，可以预测长期的体液免疫。我们建议利用现有的埃默里疫苗中心、埃默里希望诊所和马萨诸塞州总医院之间的合作医院/哈佛大学医学院 (MGH/HMS) 致力于解决人类的这一问题。具体来说，我们将研究外周血和肠粘膜样本中的早期和长期 B 细胞反应，使用全局和单细胞方法。这些研究将为我们提供前所未有的关于异质性的见解。急性浆母细胞对霍乱的反应，其起源和激活过程，亲和力成熟和类别转换、粘膜归巢潜力、感染解决后提供长期免疫力的能力，以及 BCR 在单细胞水平上的抗原特异性。最后，成像实验将提供机制深入了解抗霍乱抗体的作用方式。这些研究将产生大量可能具有诊断和治疗用途的抗霍乱单克隆抗体。本文的调查结果也可能指导未来针对这种重要人类病原体的疫苗开发。