Impact of maternally derived antibodies and infant microbiota on the immunogenicity of rotavirus vaccines in African, Indian and European infants.

轮状病毒是导致严重儿童腹泻的最常见原因，每年导致全球近50万婴儿死亡。世界卫生组织建议所有婴儿接种轮状病毒疫苗，特别是在撒哈拉以南非洲和南亚腹泻病死亡率最高的国家，但目前的疫苗在腹泻死亡人数最多的国家效果最差。疫苗性能不佳的原因尚不清楚，但可能很复杂。轮状病毒疫苗依赖于口服减弱的轮状病毒，这些轮状病毒在婴儿的肠道中繁殖，以刺激免疫系统产生抗体，并保护儿童免受轮状病毒腹泻的影响。影响轮状病毒疫苗效果的因素可能包括a)母体抗体在子宫内或通过母乳传递给婴儿(被动获得性免疫)；b)婴儿的肠道细菌(微生物区系)，这对维持健康的肠道和促进自然感染或疫苗接种后的有效免疫反应非常重要；以及c)在一种病毒可能干扰另一种病毒的情况下一起接种两种口服疫苗。生活在贫穷国家的儿童还暴露于许多肠道感染，这会导致肠道炎症，并可能导致无法很好地对口服疫苗做出反应、营养不良以及身体和认知发育迟缓。该项目的主要目标是确定被动获得性免疫的作用、婴儿肠道细菌的组成以及同时接种两种口服疫苗对轮状病毒疫苗免疫反应的影响。这项研究将跟踪三个国家(马拉维、印度和英国)轮状病毒疫苗接种前后的婴儿，从出生到14到16周大。研究表明，马拉维和印度的婴儿对轮状病毒疫苗的反应很差，而英国的儿童会有更强的反应，从而防止轮状病毒腹泻，就像在其他高收入国家一样。我们将通过测量母亲血液和母乳中的抗体，比较母亲在怀孕期间和出生后从母亲身上转移给婴儿的抗体水平。我们将研究三组从出生到接种轮状病毒疫苗期间肠道微生物区系的组成。我们会将婴儿肠道内的微生物群与母亲肠道和母乳的微生物群组成联系起来，并考虑到营养和早期肠道感染等因素进行数据分析，这些因素因地点而异，以评估它们如何影响婴儿对轮状病毒疫苗接种的反应能力，并测量婴儿在接种轮状病毒疫苗后产生的轮状病毒抗体水平。我们还将在印度进行一项研究，比较在口服或注射两种不同途径接种脊髓灰质炎疫苗的同时接种轮状病毒疫苗的婴儿对轮状病毒疫苗的反应。这项研究很重要，因为作为根除脊髓灰质炎病毒计划的一部分，有一项引入可注射脊髓灰质炎疫苗的全球计划。这将有助于比较使用口服脊髓灰质炎疫苗的印度和马拉维，以及使用注射疫苗的印度和英国。我们还可以比较在同一人群中同时接种两种口服疫苗与口服轮状病毒疫苗和注射脊髓灰质炎疫苗的效果。这些研究将为新的分析和方案开发工具，以确保跨国比较不受研究和分析方式差异的影响。这些研究的结果将直接指导设计替代或补充战略，以改进这些疫苗和其他抗腹泻疫苗的性能，目的是通过提高发展中国家婴儿对腹泻的抵抗力来减少婴儿死亡。

Rotavirus is the commonest cause of severe childhood diarrhoea, leading to almost half a million infant deaths worldwide each year. Rotavirus vaccination is recommended by the World Health Organisation for all infants, especially in countries with the highest mortality due to diarrhoeal disease which are in sub-Saharan Africa and in southern Asia, but current vaccines are least effective in the countries where most deaths from diarrhoea occur. The reasons for the inferior vaccine performance are not well understood, but are likely to be complex. Rotavirus vaccines rely on the oral administration of weakened rotaviruses which multiply in the gut of the baby to stimulate the immune system to produce antibodies and protect the child from developing rotavirus diarrhoea. Factors that affect how well rotavirus vaccines perform may include a) maternal antibodies passed to the baby in the womb or via breast milk (passively-acquired immunity); b) the baby's gut bacteria (microbiota), which is important for maintaining a healthy gut and promoting effective immune responses following natural infection or vaccination and c) giving two oral vaccines together where one virus may interfere with the other. Children living in poor countries are also exposed to many gut infections, which lead to gut inflammation and which may contribute to the inability to respond well to oral vaccines, development of malnutrition and physical and cognitive growth delays. The key goals of this project are to determine the roles of passively-acquired immunity, the composition of the baby's gut bacteria and the effect of giving two oral vaccines together on immune responses to rotavirus vaccine. The study will follow babies before and after rotavirus vaccination in three countries (Malawi, India and the UK), from birth to 14 to 16 weeks of age. Studies have shown that babies in Malawi and India have poor responses to rotavirus vaccination, whereas children in the UK will have stronger responses leading to protection from rotavirus diarrhoea, as in other high-income countries. We will compare the levels of antibodies transferred from the mothers to the babies during pregnancy and after birth, by measuring the antibodies in the mothers' blood and in their breast-milk. We will study the composition of the gut microbiota from birth to the time of rotavirus vaccination in each of the three groups. We will relate the microbiota composition in the gut of child to that of the mother's gut and breast-milk, and analyse the data taking into account factors such as nutrition and early gut infections, which differ by location, in order to assess how they impact the infant's ability to respond to rotavirus vaccination, and measure the levels of rotavirus antibody generated by the babies after vaccination. We will also carry out a study in India that compares the response to rotavirus vaccine in babies who are given polio vaccines at the same time as the oral rotavirus vaccine by two different routes, orally or by injection. This study is important because there is a global plan to introduce the injectable polio vaccine as part of the plan to eradicate poliovirus. This will help provide a comparison between India and Malawi which uses the oral polio vaccine, and India and the UK which uses the injectable vaccine. We can also compare the effect of giving two oral vaccines together compared with the oral rotavirus vaccine given with the injectable polio vaccine in the same population. These studies will develop the tools for new assays and protocols to ensure that the cross-country comparisons are not affected by differences in the way the studies and the analyses were conducted. The results of these studies will directly inform the design of alternative or complementary strategies to improve the performance of these and other anti-diarrhoea vaccines, with an aim to reduce infant deaths by improving resistance to diarrhoea in infants living in developing countries.