Development of B Cell Responses and Markers of Immunity Following Oral Rotavirus Vaccination in Infants

婴儿口服轮状病毒疫苗接种后 B 细胞反应和免疫标志物的发展

• 批准号: 10256816
• 负责人: Benjamin Lee
• 金额: $ 20.01万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256816
• 关键词: Address; Affect; Africa South of the Sahara; Animal Model; Antibody Response; Asia; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Bangladesh; Blood Group Antigens; Cause of Death; Centers of Research Excellence; Child; Communicable Diseases; Computer Models; Country; Data; Dehydration; Development; Diarrhea; Disease; Enterovirus; Evaluation; Event; Failure; Flow Cytometry; Fluorochrome; Funding; Future; Generations; Genotype; Goals; Human; Immune; Immune response; Immunity; Immunobiology; Immunoglobulin G; Immunologic Memory; Immunophenotyping; Impairment; Income; Infant; Infection; Infectious Diseases Research; Ingestion; Intervention; Knowledge; Label; Lead; Low income; Lymphocyte; Marker Vaccines; Mediating; Memory B-Lymphocyte; Modeling; Oral; Outcome; Pathway interactions; Performance; Population; Population Research; Predisposition; Principal Investigator; Process; Research; Risk; Role; Rotavirus; Rotavirus Vaccines; Rotavirus disease; Serum; Serum zinc level result; Socioeconomic Factors; Surface; Surrogate Markers; T-Lymphocyte; Testing; Translational Research; Vaccination; Vaccines; Vermont; burden of illness; clinically relevant; co-infection; cofactor; cohort; design; diarrheal disease; efficacy trial; enteric virus infection; exhaustion; immunogenicity; improved; in silico; inflammatory disease of the intestine; insight; low income country; novel; novel vaccines; oral vaccine; particle; pathogen; peripheral blood; predictive modeling; prevent; prototype; response; response biomarker; tool; vaccination strategy; vaccine efficacy; vaccine response; vaccine trial

PROJECT SUMMARY Rotavirus (RV) remains the leading cause of death due to diarrheal disease in children worldwide, with a disproportionate burden of severe and fatal disease in low-income countries of sub-Saharan Africa and Asia. Oral RV vaccines such as Rotarix (GlaxoSmithKline) are highly efficacious in high-income countries, but for unclear reasons they significantly underperform in low-income countries, a significant obstacle to the reduction of diarrheal disease worldwide. Greater understanding of why oral vaccines fail in these settings is needed to improve vaccine performance and develop next-generation vaccines. The goal of this study is to refine approaches for assessing immunological responses to oral vaccines, using rotavirus (RV) as a prototype. Generation of pathogen-specific immunological memory is the fundamental goal of vaccination, but little is known about the ability of RV vaccines to do this. Since antibody responses have consistently been shown to be critical for RV immunity, assessment of B cell responses to RV vaccination is paramount, particularly the generation of RV-specific memory B cells. However, evaluations of RV-specific lymphocyte responses to currently licensed vaccines are completely lacking. The hypothesis is that under proper conditions (e.g. in high- income countries), circulating RV-specific B cell subsets reflecting immune memory can be identified following vaccination. Similarly, the project proposes that oral RV vaccine underperformance in low-income settings is due to a failure of the vaccine to generate memory B cell responses, and that this may be mediated in part by early B cell exhaustion due to the increased gut pathogen burden unique to these settings. To test these hypotheses, flow cytometry will be used to define the immunophenotype of circulating RV- specific B among infants in Burlington, VT, USA and Dhaka, Bangladesh following oral RV vaccination. These cohorts represent populations in which vaccine responses are excellent (VT) and diminished (Bangladesh). RV-specific subsets thus identified will be correlated with serum antibody responses and fecal vaccine shedding, surrogate markers of vaccine effect. Next, the project will evaluate the contribution of cofactors thought to impact RV vaccine performance on the development of RV-specific B cells. Finally, computational models of RV-specific vaccine responses will be developed, and the experimental results will be applied to iteratively test and refine these models to generate a predictive model of RV immunity. These results will lead to greater understanding of the development of immunity to RV and other enteric viral infections and identify key targets for intervention to improve oral vaccine performance around the world.

项目摘要 轮状病毒（RV）仍然是全球儿童腹泻病引起的主要死亡原因， 撒哈拉以南非洲和亚洲的低收入国家严重和致命疾病的负担不成比例。 口服RV疫苗（例如Rotarix（葛兰素史克林））在高收入国家中高效，但对于 他们在低收入国家的不明显理由显着表现不佳，这是减少的重大障碍 全球腹泻病。更了解为什么需要在这些情况下口服疫苗失败 改善疫苗性能并开发下一代疫苗。这项研究的目的是完善 使用轮状病毒（RV）作为原型，评估对口服疫苗的免疫反应的方法。 病原体特异性免疫记忆的产生是疫苗接种的基本目标，但几乎没有 关于RV疫苗执行此操作的能力已知。由于抗体反应一直被证明 对于RV免疫至关重要，评估B细胞对RV疫苗接种的反应至关重要，尤其是 RV特异性内存B细胞的产生。但是，对RV特异性淋巴细胞反应的评估 目前完全缺乏持牌疫苗。假设是在适当条件下（例如 收入国家），可以确定反映免疫记忆的RV特异性B细胞子集以下 疫苗接种。同样，该项目提出低收入设置中的口服RV疫苗的表现不佳 由于疫苗未能产生内存B细胞反应，并且可以部分介导 由于这些环境所特有的肠道病原体负担增加，早期的B细胞耗尽。 为了检验这些假设，流式细胞仪将用于定义循环RV-的免疫表型 口服RV疫苗接种后的伯灵顿，美国弗吉尼亚州伯灵顿和孟加拉国达卡的婴儿中的特定B。这些 队列代表疫苗反应非常出色（VT）和减少（孟加拉国）的人群。 因此，鉴定出RV特异性子集将与血清抗体反应和粪便疫苗相关 脱落，疫苗作用的替代标记。接下来，该项目将评估辅助因子的贡献 被认为会影响RV疫苗性能对RV特异性B细胞的发展。最后，计算 将开发RV特异性疫苗反应的模型，并将实验结果应用于 迭代测试并完善这些模型，以生成RV免疫的预测模型。 这些结果将导致对RV和其他肠道病毒的免疫发展的发展有更多的了解 感染并确定干预措施的关键目标，以改善全球口服疫苗的性能。