A non-inferiority trial to assess the safety and immunogenicity of yellow fever vaccine dose sparing strategies for campaign and programmatic use

黄热病是一种通过蚊子在人与人之间传播的病毒感染。在撒哈拉以南非洲和南美洲的44个国家中发现了这种病毒，最新的估计表明，它现在每年造成100多万人感染，其中仅在非洲就有18万例重症病例和7.8万人死亡。尽管有一种安全和高效的疫苗，这种疫苗只需注射一次即可终身预防疾病，但这些感染仍在继续发生。2016年，中非发生30年来最严重的黄热病疫情(疫情暴发)。由于国际旅行，中国也发生了病例，引发了人们对疾病在亚洲失控传播的担忧。黄热病的流行是在过去20年黄热病逐渐增多的背景下发生的，并促使世界卫生组织(WHO)在2016年底发布了新的《消除黄热病疫情的全球战略》。这份文件强调了黄热病构成的新的全球威胁，以及黄热病疫苗短缺在当前疾病死灰复燃中发挥的主要作用。在已将该疫苗纳入婴儿常规免疫计划的34个国家中，近一半的国家在2013至2015年间用完了疫苗，许多国家只获得了所需疫苗数量的50%。在最近的疫情中，当面对疫苗完全用完的可能性时，这些短缺变得更加严重，世卫组织决定建议在用于控制疫情的紧急疫苗接种活动中使用部分剂量的疫苗。通过这种方式，给每个人提供五分之一(0.1毫升)的正常剂量(0.5毫升)，这意味着可以接种疫苗的人数是正常剂量的五倍。没有研究表明部分剂量的黄热病疫苗对婴儿和儿童有多好，也没有研究表明在撒哈拉以南非洲地区测试了部分剂量的疫苗。这就是为什么这项研究很重要。我们想问9到12个月大的冈比亚婴儿的主要问题是：1.给婴儿注射部分剂量的黄热病疫苗，是否与给他们全量接种黄热病疫苗一样能保护他们免受黄热病感染？2.在皮下(皮下--黄热病疫苗的正常接种方式)或皮下(皮肤内)接种部分剂量黄热病疫苗时，对黄热病的保护量有何不同？3.部分剂量疫苗的安全性是否取决于疫苗是皮下接种还是皮下接种？研究结果将为世卫组织疫苗接种政策专家委员会提供重要信息。它将帮助他们决定是否可以建议在包括婴儿和儿童在内的未来紧急疫苗接种活动中推荐部分剂量而不是全剂量的黄热病疫苗。它还将帮助他们决定是否可以给婴儿部分剂量而不是全剂量，作为其常规计划疫苗接种的一部分，还是在预防运动中。希望这项研究的结果将有助于在未来阻止黄热病在撒哈拉以南非洲的流行。

Yellow fever is a viral infection which is transmitted from person to person by mosquitos. The virus is found in a total of 44 countries across sub-Saharan Africa and South America and most recent estimates suggest that it now causes more than one-million infections each year including 180 000 severe cases and 78 000 deaths in Africa alone. These infections continue to occur despite the availability of a safe and highly effective vaccine which confers lifelong protection against disease after only a single injection. In 2016, the worst epidemic (disease outbreak) of yellow fever in 30 years occurred in Central Africa. Cases due to international travel, also occurred in China sparking fears of uncontrolled disease spread in Asia. The epidemic occurred on the background of progressive increases in yellow fever disease over the past two decades and drove the publication of a new 'Global Strategy to Eliminate Yellow Fever Epidemics' by the World Health Organisation (WHO) in late 2016. This document highlighted the emerging global threat posed by the yellow fever and the major role played by shortages of the yellow fever vaccine in the current disease resurgence. Nearly half of the 34 countries which have introduced the vaccine into their routine immunization schedule for infants ran out of vaccine between 2013 and 2015 with many countries receiving only 50% of the number of doses of the vaccine they needed. These shortages got worse during the recent epidemic when, faced with the possibility of running out of vaccine completely, the WHO took the decision to recommend that 'fractional' doses of the vaccine should be used in the emergency vaccination campaigns being used to control the outbreak. In this way, one fifth (0.1mL) of the normal dose (0.5mL) is given to each person meaning that five times as many people can be vaccinated. There are no studies to see how good fractional doses of the yellow fever vaccine are in babies and children and no studies of have tested fractional doses of the vaccine in sub-Saharan Africa. This is why this study is important. The mains questions we want to ask in 9 to 12 month old Gambian infants are:1. Does giving a fractional dose of a yellow fever vaccine to an infant given them as much protection from yellow fever infection as giving them a full dose of the vaccine? 2. Is there a difference in the amount of protection from yellow fever generated when a fractional dose is given subcutaneously (under the skin - the normal way yellow fever vaccines are given) or intradermally (into the skin)3. Is there any difference in the safety of a fractional dose of the vaccine depending on whether it is given subcutaneously or intradermally? The results of the study will give the WHO expert committee on vaccination policy important information. It will help them to decide if fractional rather than full doses of the yellow fever vaccine can be recommended for future emergency vaccination campaigns including infants and children. It will also help them to decide if fractional rather than full doses can be given to infants as part of their routine scheduled vaccinations or in preventative campaigns. It is hoped that the results of the study will help to stop yellow fever epidemics across sub-Saharan Africa in the future.