Bioactive Components in Breast Milk Impact Rotavirus Vaccine Response

项目总结 尽管100多个国家推出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的疗效 在大多数低收入和中等收入国家(LMIC)，与高收入国家近90%的有效率相比，LMIC仅为50%左右 收入国家。这些差异并不是一种疫苗或一个国家所特有的；所有世卫组织预审的ORV 在LMIC中显示出次优效果。这也不是疫苗覆盖率或冷链要求的问题。 因为即使在良好控制的临床试验中也观察到了较差的疗效。ORV有几个优点 包括低成本、易管理、产生粘膜免疫和产生群体免疫的能力 通过疫苗脱皮。因此，改善口服避孕药疗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，以改善在以下情况下的ORV反应 疾病负担高。关键步骤包括了解哪些因素将疫苗应答者与非应答者区分开来 人口中的响应者，并确定可修改的因素，以实现有针对性的发展 干预措施。基于这一目标，我们将重点放在母乳中的生物活性成分上。我们假设：(I)生物活性 母乳中的成分是ORV反应的关键调节因素，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反应的差异。其基本原理是 因为这一假说是我们最近的工作，证明了母乳低聚糖之间的相互作用 (HMOS)、乳汁微生物组和婴儿肠道微生物组促进新生儿轮状病毒感染。新数据还 说明考虑母婴遗传差异在多糖表达上提供了更多 胃肠道感染和疫苗反应的全面图景比以前认识的要好。在斯特朗 初步数据表明，HMOS和乳汁微生物群可直接调节牛乳杆菌的体外感染力。 Rotavac，一种无症状的新生儿轮状病毒株衍生ORV，用于印度的国家免疫计划。 与LMIC中的其他ORV一样，Rotavac的疗效也不佳，但具有显著的成本效益，可以 如果疫苗效力得到改善，将大大减少与轮状病毒相关的负担。HMOS、共生菌和 微生物产品具有作为益生菌和益生菌开发的潜力，因此具有吸引力。 作为未来发展的干预措施的候选人。 在两个具体目标中，我们问：1)母乳中生物活性成分的组成和功能活性 疫苗应答者和无应答者之间的区别？2)母体因素和 共同变化的婴儿因素比任何单独的因素更好地预测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确定的候选者，目的是 开发可与口服避孕药联合使用的益生菌和益生菌。

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.