Nielsen Sebastian, Fisker Ane B, da Silva Isaquel, Byberg Stine, Biering-Sørensen Sofie, Balé Carlitos, Barbosa Amarildo, Bjerregaard-Andersen Morten, Hansen Nadja Skadkær, Do Vu An, Bæk Ole, Rasmussen Stine Møller, Damkjær Lone, Hvidt Sophus, Baltzersen Olga, Rodrigues Amabelia, Martins Cesario, Jensen Kristoffer J, Whittle Hilton C, Smits Gaby, van der Klis Fiona, Aaby Peter, Benn Christine S
Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau.
Bandim Health Project, OPEN, Odense Patient data Explorative Network, Institute of Clinical Research, and Danish Institute of Advanced Science, Odense University Hospital/ University of Southern Denmark, Denmark.
EClinicalMedicine. 2022 May 27;49:101467. doi: 10.1016/j.eclinm.2022.101467. eCollection 2022 Jul.
Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%.
Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355.
Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n=4,397; n=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n=90; n=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n=21; n=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n=10/2,801; n=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n=27/1,602; n=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: n=51/3,132; n=31/1,028].
The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further.
ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.
在之前的一项试验中，4月龄和9月龄时接种两剂麻疹疫苗（MV）与世界卫生组织9月龄接种MV的策略相比，降低了儿童全因死亡率。我们旨在检验两个假设：1）两剂次接种策略可使4至60月龄儿童死亡率降低30%；2）在有和没有母体麻疹抗体（MatAb）的情况下，4月龄时尽早接种MV可使儿童死亡率降低35%。
在几内亚比绍进行的一项单中心、开放标签、基于社区的随机对照试验，按性别以2:1的比例进行区组随机分组，分为两剂次（4 + 9月龄）与一剂次（9月龄）MV策略。健康儿童在第3剂含白喉 - 破伤风 - 百日咳疫苗接种4周后符合纳入标准。随机分组前采集血样以测定MatAb水平。主要结局为全因死亡率。风险比（HR）来自符合方案人群的Cox回归分析。我们检验了与国家口服脊髓灰质炎疫苗（C - OPV）接种运动的相互作用。试验注册号：NCT01486355。
2011年8月至2015年4月17日期间，共纳入6636名儿童，6598名（n = 4397；n = 2201）纳入主要结局分析，4至60月龄时的HR（两剂次/一剂次）为1.38（95%CI：0.92 - 2.06）[死亡人数：n = 90；n = 33]。在9月龄MV接种前，HR（一剂次/未接种）为0.94（0.45 - 1.96）[死亡人数：n = 21；n = 11]。未接受C - OPV的儿童中，HR（两剂次/一剂次）为0.81（0.29 - 2.22）[死亡人数/儿童数：n = 10/2801；n = 6/1365]，而在入组前后接受C - OPV的儿童中，HR为4.73（1.44 - 15.6）（交互作用p值 = 0.027）[死亡人数/儿童数：n = 27/1602；n = 3/837]。在4月龄时接受早期MV的两剂次组中，有MatAb时接种疫苗的儿童死亡率比没有MatAb时低50%（20 - 68%）[死亡人数/儿童数：n = 51/3132；n = 31/1028]。
主要结果与之前的研究结果相反，但尽管基于少量事件，这可能是由于频繁的OPV接种运动降低了死亡率，但显然与早期MV产生了负面相互作用。MV在有MatAb时的有益非特异性效应应进一步研究。
欧洲研究委员会、丹麦国家研究基金会、丹麦发展研究理事会、外交部、诺和诺德基金会、欧盟和伦德贝克基金会。
