A randomised controlled trial to evaluate the effect of maternal or neonatal pneumococcal conjugate vaccination on pneumococcal carriage in early life

在过去十年中，全世界儿童在五岁以下死亡(五岁以下儿童死亡率)的人数大幅减少。尽管如此，我们远远没有达到千年发展目标4，该目标要求在1990年至2015年期间将五岁以下儿童的死亡率降低三分之二。总体而言，70%的五岁以下儿童死亡率(2010年为540万例死亡)发生在一岁以下儿童中，40%发生在婴儿出生后的第一个月。近一半的死亡发生在撒哈拉以南非洲，包括冈比亚在内的西非国家的死亡率是世界上最高的。因此，在这种情况下，降低婴幼儿早期死亡率的新干预措施具有巨大的拯救生命的潜力。肺炎链球菌(或肺炎球菌)是全球儿童死亡的主要原因。最近的估计表明，这种细菌导致了大约11%的五岁以下儿童死亡，其中一半以上发生在非洲。在这种情况下，婴儿很快就会被鼻背上的细菌“殖民”。例如，在冈比亚，超过80%的婴儿在两个月大时将携带这种细菌。携带是疾病的直接和必要的先兆。最近的一项系统回顾证实，肺炎球菌是撒哈拉以南非洲三个月以下婴儿感染--包括败血症和脑膜炎--的主要原因，反映了这些高携带率。与肺炎相关的死亡率负担在同一组中同样极高。目前可用的肺炎球菌结合疫苗(PCV)是世界卫生组织推荐的，按6、10和14周三剂的时间表接种。因此，婴儿直到16到18周大时才能对肺炎球菌产生保护，或者如果疫苗延迟接种，婴儿就不会受到肺炎球菌的保护，到那时，与肺炎球菌相关的死亡已经出现了很大的负担。因此，这项试验的目的是探索PCV给药的替代方案，以在这一关键的易感窗口预防肺炎球菌病。两个干预组将与对照组进行比较，在对照组中，婴儿将按照标准的三剂表接受PCV。在孕产妇干预臂中，孕妇将在怀孕第三个月时获得一剂PCV。这旨在提高母亲的肺炎球菌抗体水平，期望这些抗体将通过胎盘和母乳传染给婴儿，从而保护婴儿免受出生的伤害。在新生儿干预组，将在新生儿出生的第一天接种一剂疫苗，目的是尽早在新生儿中产生保护性免疫反应。将比较两个干预组和控制组的婴儿鼻后部肺炎球菌携带率。鉴于携带者与疾病之间的联系，携带者的获得率正在成为肺炎球菌疫苗试验中疾病的既定“替代品”，大大降低了所需试验的规模和复杂性。还将测量抗体水平和肺炎球菌免疫的其他措施，并收集重要的安全数据。鉴于孕妇和新生儿接种疫苗的敏感性，试验还将审查这些干预措施的可接受性，目的是查明执行方面的任何障碍。世界卫生组织已经建议接种PCV疫苗，并通过GAVI联盟提供的资金向符合条件的国家提供疫苗。因此，受这一试验结果影响的政策变化可以在没有重大障碍的情况下迅速实施。考虑到婴儿期的疾病负担，如果得到证实，这项试验在挽救早期生命方面的影响可能很快就会显著。

The last decade has witnessed significant reductions in the number of children dying before they reach their fifth birthday (under-five mortality) across the world. Despite this, we fall far short of Millennium Development Goal 4 which called for a two-third reduction in under-five mortality between 1990 and 2015. Overall, 70 percent of under-five mortality (5.4 million deaths, 2010) occurs in those under the age of one and forty percent occurs in the first month of life. Nearly half of all deaths occur in sub-Saharan Africa, with countries in West Africa, including The Gambia, having the highest mortality rates anywhere in the world. Consequently, new interventions to reduce mortality in early infancy in this setting have tremendous potential for life-saving impact. Streptococcus pneumoniae (or pneumococcus) is a leading cause of childhood mortality worldwide. Recent estimates suggest the bacteria are responsible for around 11 percent of deaths in children under five, with over half of these deaths occurring in Africa. Infants in this setting become rapidly 'colonised' with bacteria in the back of the nose. For example, in The Gambia, over 80 percent of infants will be carrying the bacteria by two months of age. Carriage is an immediate and necessary precursor to disease. Reflecting these high carriage rates, a recent systematic review confirmed that pneumococcus is the leading cause of life-threatening infections, both sepsis and meningitis, in infants up to three months of age in sub-Saharan Africa. The burden of pneumonia related mortality is similarly extremely high in the same group.The currently available pneumococcal-conjugate vaccines (PCV) are recommended by the WHO according to a three dose six, 10 and 14 week schedule. As a result, infants are not protected against pneumococcus until 16 to 18 weeks of age, or later if the vaccines are delayed, by which point a significant burden of pneumococcal related mortality has already occurred. Therefore, the objective of this trial is to explore alternative schedules for PCV administration to prevent pneumococcal disease in this critical window of susceptibility. Two intervention arms will be compared to a control arm in which infants will receive PCV according to a standard three dose schedule. In the maternal intervention arm, expectant mothers will be given a dose of PCV in the third trimester of pregnancy. This aims to boost the mother's pneumococcal antibody levels with the expectation that these will be transferred to the infant across the placenta and in breast milk, thus protecting the infant from birth. In the neonatal intervention arm, a dose of the vaccine will be administered to newborns on the first day of life with the aim of generating a protective immune response in the newborn as early as possible. The rate at which the infants acquire pneumococcal carriage in the back of the nose will be compared between the two intervention arms and the control arm. Given the link between carriage and disease, the rate of carriage acquisition is becoming an established 'surrogate' for disease in pneumococcal vaccine trials, substantially reducing the size and complexity of the trials required. Antibody levels and other measures of pneumococcal immunity will also be measured and important safety data will be collected throughout. Given the sensitivity of vaccination in both expectant mothers and newborns the trial will also examine the acceptability of these interventions with the aim of identifying any barriers to implementation. The WHO already recommends PCV vaccination and the vaccines are provided to eligible countries through funding provided by the GAVI Alliance. Consequently, a policy change influenced by the results of this trial could be rapidly implemented without major barriers. Given the burden of disease in infancy, if proven, the impact of the trial in terms of lives saved in early life could be rapidly significant.