Bioactive Components in Breast Milk Impact Rotavirus Vaccine Response

母乳中的生物活性成分影响轮状病毒疫苗反应

• 批准号: 10354154
• 负责人: Sasirekha Ramani
• 金额: $ 19.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354154
• 关键词: 5 year old; Acute; Africa South of the Sahara; Age; Attenuated; Binding Proteins; Biological Assay; Blood Group Antigens; Breast Feeding; Capsid Proteins; Cessation of life; Child; Child Health; Childhood; Cold Chains; Communicable Diseases; Complex; Conflict (Psychology); Controlled Clinical Trials; Country; Data; Data Analyses; Development; Effectiveness; Enteral; Evidence based intervention; Foundations; Functional disorder; Future; Gastroenteritis; Generations; Genetic; Goals; Herd Immunity; Human Milk; Hygiene; Immune response; Immunization Programs; Immunoglobulin A; In Vitro; Income; India; Individual; Infant; Intervention; Intervention Studies; Laboratory Study; Maintenance; Malnutrition; Maternal antibody; Microbe; Morbidity - disease rate; Mothers; Mucosal Immunity; Neonatal; Oligosaccharides; Oral; Outcome; Polysaccharides; Population; Probiotics; Public Health; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sampling; Sanitation; Southeastern Asia; Temperature; Testing; Vaccine Clinical Trial; Vaccines; Validation; Work; base; breast milk microbiome; burden of illness; cohort; commensal bacteria; compare effectiveness; cost; cost effective; diarrheal disease; enteric infection; evidence base; gastrointestinal; gastrointestinal infection; gut microbiome; immunogenicity; improved; infant gut microbiome; insight; low and middle-income countries; microbial; microbiome; microbiome composition; milk microbiome; mortality; oral vaccine; pathogen; prebiotics; recruit; responders and non-responders; success; sugar; vaccine efficacy; vaccine response

PROJECT SUMMARY Despite the introduction of live attenuated oral rotavirus vaccines (ORVs) in over 100 countries, rotavirus (RV) remains the leading cause of acute gastroenteritis in children under the age of 5. This is because ORV efficacy in most low- and middle-income countries (LMICs) is only about 50% compared to nearly 90% efficacy in high- income countries. These differences are not specific to one vaccine or one country; all WHO pre-qualified ORVs show sub-optimal efficacy in LMICs. This is also not an issue of vaccine coverage or cold chain requirements since poor efficacy was observed even within well controlled clinical trials. ORVs have several advantages including low costs, ease of administration, ability to generate mucosal immunity and generation of herd immunity through vaccine shedding. Efforts to improve ORV efficacy will therefore have substantial public health impact. Our long-term goal is to develop evidence-based interventions to improve ORV response in settings with high disease burden. Critical steps include understanding what factors distinguish vaccine responders from non- responders within a population and identifying modifiable factors that will enable the development of targeted interventions. With this objective, we focus on bioactive components in breastmilk. We hypothesize: (i) Bioactive components in breast milk are key modulators of ORV response, and (ii) A combination of maternal factors and infant factors will be more predictive of differences in vaccine response than any individual factor. The rationale for this hypothesis is our recent work demonstrating a role for interactions between human milk oligosaccharides (HMOs), the milk microbiome and infant gut microbiome in promoting neonatal RV infections. New data also indicate that consideration of maternal and infant genetic differences in glycan expression provides a more comprehensive picture of gastrointestinal infections and vaccine responses than previously recognized. In strong preliminary data, we show that HMOs and the milk microbiome can directly modulate the in vitro infectivity of Rotavac, an asymptomatic neonatal rotavirus strain-derived ORV used in India’s national immunization program. Like other ORVs in LMICs, Rotavac also has sub-optimal efficacy but is remarkably cost effective and can substantially reduce RV-associated burden if vaccine efficacy is improved. HMOs, commensal bacteria and microbial products have the potential to be developed as prebiotics and probiotics and thus are attractive candidates for future development as interventions. In two specific aims we ask: 1) Is the composition and functional activity of breast milk bioactive components different between vaccine responders and non-responders? 2) Does the combination of maternal factors and covarying infant factors better predict ORV response than any factor individually? Our short-term goal is to gain critical insight into the role of breast milk bioactive components in ORV response. Our long-term goal is to test identified candidates in future mechanistic and functional studies aimed at developing probiotics and prebiotics that can be co-administered with ORVs.

项目概要 尽管 100 多个国家引入了口服减毒活轮状病毒疫苗 (ORV)，但轮状病毒 (RV) 仍然是 5 岁以下儿童急性胃肠炎的主要原因。这是因为 ORV 的功效 大多数低收入和中等收入国家 (LMIC) 的有效率仅为 50% 左右，而高收入国家的有效率接近 90% 收入国家。这些差异并不特定于一种疫苗或一个国家；所有经过 WHO 预审的 ORV 在中低收入国家 (LMIC) 中显示出次优疗效。这也不是疫苗覆盖率或冷链要求的问题 因为即使在良好对照的临床试验中也观察到疗效不佳。 ORV 有几个优点 包括低成本、易于管理、产生粘膜免疫和产生群体免疫的能力 通过疫苗脱落。因此，提高 ORV 功效的努力将对公共卫生产生重大影响。 我们的长期目标是开发基于证据的干预措施，以改善有以下情况的 ORV 反应： 疾病负担高。关键步骤包括了解哪些因素区分疫苗反应者和非疫苗反应者 人群中的响应者并确定可改变的因素，从而能够制定有针对性的 干预措施。为了实现这一目标，我们专注于母乳中的生物活性成分。我们假设：（i）生物活性 母乳中的成分是 ORV 反应的关键调节剂，并且 (ii) 母体因素和 婴儿因素比任何个体因素更能预测疫苗反应的差异。理由 对于这一假设，我们最近的工作证明了母乳寡糖之间相互作用的作用 （HMO）、乳汁微生物组和婴儿肠道微生物组促进新生儿 RV 感染。新数据也 表明考虑母体和婴儿在聚糖表达方面的遗传差异提供了更多 胃肠道感染和疫苗反应的全面情况比以前认识的要全面。强中 初步数据显示，HMO 和乳汁微生物组可以直接调节细菌的体外感染性 Rotavac，一种无症状新生儿轮状病毒株衍生的 ORV，用于印度国家免疫计划。 与中低收入国家的其他 ORV 一样，Rotavac 的疗效也不是最佳，但具有显着的成本效益，并且可以 如果疫苗功效得到改善，将大大减少与 RV 相关的负担。 HMO、共生细菌和 微生物产品具有开发为益生元和益生菌的潜力，因此具有吸引力 作为干预措施的未来发展的候选者。 我们提出两个具体目标：1) 母乳生物活性成分的组成和功能活性 疫苗反应者和非反应者之间有什么不同？ 2) 是否与母体因素相结合 共变婴儿因素比任何单独因素都能更好地预测 ORV 反应？ 我们的短期目标是深入了解母乳生物活性成分在 ORV 反应中的作用。 我们的长期目标是在未来的机械和功能研究中测试已确定的候选人，旨在 开发可与 ORV 共同施用的益生菌和益生元。