Bioactive Components in Breast Milk Impact Rotavirus Vaccine Response

项目摘要 尽管在100多个国家引入了口服轮状病毒减毒活疫苗（ORV），但轮状病毒（RV） 仍然是五岁以下儿童患急性肠胃炎的主要原因。这是因为ORV疗效 在大多数低收入和中等收入国家（LMICs）中，只有约50%的疗效，而在高收入国家中， 收入国家。这些差异并不特定于一种疫苗或一个国家;所有世卫组织预先鉴定的ORV 在LMIC中显示出次优功效。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较差的功效。ORV有几个优点 包括低成本、易于给药、产生粘膜免疫的能力和产生群体免疫 通过疫苗脱落。因此，提高ORV效力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循证干预措施，以改善ORV反应， 高疾病负担。关键步骤包括了解哪些因素区分疫苗应答者和非应答者。 在人群中的响应者，并确定可修改的因素，这将使有针对性的发展 干预措施。为此，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，以及（ii）母体因素和 婴儿因素将比任何个体因素更能预测疫苗应答的差异。的理由 我们最近的工作证明了人乳低聚糖之间的相互作用 （HMO）、乳汁微生物组和婴儿肠道微生物组在促进新生儿RV感染中的作用。新数据还 这表明，考虑到母亲和婴儿在聚糖表达方面遗传差异， 胃肠道感染和疫苗反应的全面情况比以前认识到的。在强 初步数据，我们表明HMO和牛奶微生物组可以直接调节体外感染性， 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也具有次优功效，但具有显著的成本效益， 如果疫苗效力得到改善，则可显著降低RV相关负担。健康维护组织、肠道细菌和 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。 作为未来发展的干预措施。 在两个具体的目标，我们问：1）是母乳生物活性成分的组成和功能活动 疫苗应答者和非应答者之间有什么不同？2)母亲的因素和 共变婴儿因素比任何单独因素更能预测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制和功能研究中测试确定的候选人， 开发可以与ORV共同施用的益生菌和益生元。

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.