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: 10576980
• 负责人: Sasirekha Ramani
• 金额: $ 24.84万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576980
• 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; Controlled Clinical Trials; Country; Data; Data Analyses; Dehydration; 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; Licensing; Maintenance; Malnutrition; Maternal antibody; Microbe; Morbidity - disease rate; Mothers; Mucosal Immunity; Neonatal; Oligosaccharides; Oral; Outcome; Polysaccharides; Population; Probiotics; Public Health; Qualifying; Role; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Sampling; Sanitation; Southeastern Asia; Temperature; Testing; Vaccine Clinical Trial; Vaccines; Validation; Work; breast milk microbiome; burden of illness; candidate identification; 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; manufacture; microbial; microbial products; 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.

项目摘要 尽管引入了100多个国家 /地区的现场衰减的口服轮状病毒疫苗（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效率 在大多数低收入和中等收入国家（LMIC）中，高效率仅为90％，高效率为90％ 收入国家。这些差异并非特定于一种疫苗或一个国家。所有预先合格的ORV的人 在LMIC中显示出次优效率。这也不是疫苗覆盖或冷链要求的问题 由于即使在良好的临床试验中也观察到效率差。 ORV有几个优势 包括低成本，易于管理，产生粘膜免疫学的能力和产生牛群免疫学 通过疫苗脱落。因此，提高ORV效率的努力将对公共卫生产生重大影响。 我们的长期目标是制定基于证据的干预措施，以改善与 伯恩疾病高。关键步骤包括了解哪些因素将疫苗反应者与非非 - 人口中的响应者并确定可修改的因素，以使目标发展 干预措施。有了这个目标，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，（ii）产妇因素和 婴儿因素将比任何个体因素都更能预测疫苗反应的差异。理由 因为这一假设是我们最近的工作，证明了人乳寡糖之间相互作用的作用 （HMOS），牛奶微生物组和婴儿肠道微生物组促进新生儿RV感染。新数据也是如此 表明血糖表达中母体和婴儿遗传差异的考虑提供了更多 胃肠道感染和疫苗反应的全面图片比以前认识到的。坚强 初步数据，我们表明HMOS和牛奶微生物组可以直接调节体外感染 rotavac，一种不对称的新生儿轮状病毒菌株衍生的ORV，在印度国家免疫计划中使用。 像LMIC中的其他ORV一样，Rotavac也具有次优的效率，但具有非常成本效益，可以 如果提高了疫苗效率，则大大降低了与RV相关的伯恩。 HMO，共生细菌和 微生物产品有可能作为益生元和益生菌开发，因此很有吸引力 作为干预措施的未来发展的候选人。 在两个具体的目标中，我们提出：1）母乳生物活性成分的成分和功能活性 疫苗反应者和非反应者之间有所不同吗？ 2）结合产妇因素和 相协的婴儿因素比单独的任何因素更好地预测ORV反应？ 我们的短期目标是对母乳生物活性成分在ORV反应中的作用进行关键见解。 我们的长期目标是在未来的机械和功能研究中测试确定的候选人 开发可以与ORV共同管理的益生菌和益生元。