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.

项目总结