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）仍然是全世界儿童腹泻病导致死亡的主要原因， 撒哈拉以南非洲和亚洲低收入国家严重和致命疾病的负担不成比例。 口服RV疫苗如Rotarix（葛兰素史克）在高收入国家非常有效，但对于 原因不明，它们在低收入国家的表现明显不佳，这是减少的一个重大障碍 世界范围内的疟疾病。需要更好地了解口服疫苗在这些环境中失败的原因， 提高疫苗性能和开发下一代疫苗。这项研究的目的是提炼 以轮状病毒（RV）为原型，评估口服疫苗免疫应答的方法。 病原体特异性免疫记忆的产生是疫苗接种的基本目标，但很少有免疫记忆的产生。 我们知道RV疫苗的这种能力。由于抗体反应一直被证明是 对于RV免疫至关重要，评估B细胞对RV疫苗接种的应答至关重要，特别是 RV特异性记忆B细胞的产生。然而，RV特异性淋巴细胞对 目前完全没有获得许可的疫苗。假设是在适当的条件下（例如，在高 收入国家），反映免疫记忆的循环RV特异性B细胞亚群可以如下鉴定： 预防针同样，该项目提出，口服RV疫苗在低收入环境中表现不佳， 由于疫苗不能产生记忆B细胞应答，这可能部分由 早期B细胞耗竭，这是由于这些环境特有的肠道病原体负荷增加所致。 为了检验这些假设，将使用流式细胞术来确定循环RV的免疫表型。 美国佛蒙特州伯灵顿和孟加拉国达卡口服RV疫苗后婴儿中的特异性B。这些 队列代表疫苗应答极佳（VT）和应答减弱（孟加拉国）的人群。 如此鉴定的RV特异性亚群将与血清抗体应答和粪便疫苗相关。 脱落，疫苗效果的替代标志物。接下来，该项目将评估辅因子的贡献 被认为影响RV疫苗对RV特异性B细胞发育的性能。最后，计算 将开发RV特异性疫苗反应模型，并将实验结果应用于 迭代地测试和改进这些模型以生成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有更深入的了解。 感染和确定干预的关键目标，以改善世界各地的口服疫苗的性能。