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

• 批准号: 10434686
• 负责人: Jens Peter Wrammert
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434686
• 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; Persons; Phenotype; Plasma Cells; Plasmablast; Population; Process; Property; Rotavirus; Route; Sampling; Sanitation; Serotyping; Specificity; Therapeutic; Therapeutic Uses; Travel; Vaccination; Vaccine Design; Vaccinee; 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

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.

项目摘要 弧菌霍乱引起急性腹泻病，估计导致3至500万例 霍乱和每年造成100,000多人死亡。霍乱的负担增加，无法实现 用于卫生和安全水的基准，以及霍乱的V. 需要采用更积极的方法来预防霍乱，包括疫苗接种计划。 但是，目前可用的全细胞疫苗会产生免疫力，迅速减弱，仅提供 部分保护；特别是在幼儿。相反，霍乱弧菌的自然感染诱导90-100％ 防止重新感染可持续长达10年的成人和儿童。仍然不知道为什么 当前的疫苗明显不如自然感染有效。了解粘膜免疫和 调节免疫细胞向人类粘膜组织归巢的机制至关重要，不仅是 对于霍乱谷，但对于许多其他具有粘膜感染途径的病原体。 最近在美国批准了一种新颖的现场减毒霍乱疫苗（Vaxchora） 旅行者。这种疫苗在人类挑战研究中显示出极好的保护。但是，鲜为人知 关于长期保护的持续时间，决定了霍乱特定记忆B细胞的寿命 和粘膜纤溶酶，或粘膜迁移到肠粘膜内的纤溶酶迁移和生存的内容。 在当前的提案中，我们试图确定疫苗接种后早期B细胞反应的关键差异 活疫苗可预测长期的体液免疫。我们建议利用现有 Emory疫苗中心，Emory Hope诊所和马萨诸塞州将军之间的合作 医院/哈佛医学院（MGH/HMS）在人类中解决了这个问题。具体来说，我们将学习 外周血和肠粘膜样品中的早期和长期B细胞反应都使用两者 全局和单细胞方法。这些研究将提供对异质性的前所未有的见解 急性浆质对霍乱的反应，其起源和激活过程，亲和力成熟和类别 切换，粘膜归巢潜力，解决感染后提供长寿命的免疫力的能力，并 BCR的抗原特异性，在单个细胞水平上。最后，成像实验将提供机械 深入了解抗凝胶抗体的作用方式。这些研究将产生大量 对霍乱的单克隆抗体可能具有诊断性和治疗用途。这里的发现 还可以指导这种重要人类病原体的未来疫苗开发。

项目成果

Impact of Immunoglobulin Isotype and Epitope on the Functional Properties of Vibrio cholerae O-Specific Polysaccharide-Specific Monoclonal Antibodies.

• DOI: 10.1128/mbio.03679-20
• 发表时间: 2021-04-20
• 期刊: mBio
• 影响因子: 6.4
• 作者: Kauffman RC;Adekunle O;Yu H;Cho A;Nyhoff LE;Kelly M;Harris JB;Bhuiyan TR;Qadri F;Calderwood SB;Charles RC;Ryan ET;Kong J;Wrammert J
• 通讯作者: Wrammert J