Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.
Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.
复制标题
DOI：
10.1016/s1473-3099(16)30054-8
复制
发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Levine MM
中科院分区：
文献类型：
--
作者：
Tapia MD;Sow SO;Tamboura B;Tégueté I;Pasetti MF;Kodio M;Onwuchekwa U;Tennant SM;Blackwelder WC;Coulibaly F;Traoré A;Keita AM;Haidara FC;Diallo F;Doumbia M;Sanogo D;DeMatt E;Schluterman NH;Buchwald A;Kotloff KL;Chen WH;Orenstein EW;Orenstein LAV;Villanueva J;Bresee J;Treanor J;Levine MM
尽管婴儿时期患严重流感的风险很高，但不建议6个月以下的婴儿接种疫苗。我们的目标是评估三价灭活流感疫苗母体免疫的安全性、免疫原性和有效性，以保护婴儿免受实验室确认的第一次流感的侵袭。我们在马里巴马科的六个转诊中心和社区卫生中心进行了这项前瞻性、主动对照、观察者盲目的随机第四阶段试验。妊娠晚期(≥28周)的孕妇被随机分配(1：1)，通过计算机生成的特定于中心的列表，具有交替的区块大小为6或12，接种三价灭活流感疫苗或四价脑膜炎双球菌疫苗。接种疫苗的研究人员没有对治疗分配隐瞒，但对临床医生、实验室人员和参与者隐瞒了分配。每周对婴儿进行探访，直到6个月大，以检测流感样疾病；通过RT-PCR诊断出实验室确认的流感。我们评估了两个主要目标：在产前任何时候接种疫苗的妇女(意向治疗人群)所生婴儿对实验室确认的流感的疫苗效力，以及在产前至少14天免疫的妇女所生婴儿(按方案人群)的疫苗效力。主要结果是在6个月大时出现第一例实验室确认的流感病例。这项试验在ClinicalTrials.gov注册，编号NCT01430689。我们从2011年9月12日到2014年1月28日进行了这项试验。在2011年9月12日至2013年4月18日期间，我们随机分配4193名妇女接种三价灭活流感疫苗(n=2108)或四价脑膜炎双球菌疫苗(n=2085)。有4105名活产；三价灭活流感疫苗组2064名婴儿中的1797名(87%)和四价脑膜炎双球菌疫苗组2041名婴儿中的1793名(88%)获得了6个月的随访。我们在2789名(68%)婴儿中记录了5279次流感样疾病发作，其中131次(2%)是实验室确认的流感发作。129例(98%)实验室确诊的流感病例为首发病例(四价脑膜炎双球菌疫苗组77例，三价灭活流感疫苗组52例)。在意向治疗人群中，婴儿疫苗的总有效率为33.1%(95%可信区间为3.753·9)，在按方案治疗的人群中，疫苗有效率为37.3%(7.657.8)。疫苗效力在前4个月保持强劲(67.9%[95%CI 35·1~85.03]和70.2%[35·7~87.6%])，第5个月下降(分别为57.3%[30·6~74.4%]和60.7%[33.87.77.5%])。妇女和婴儿的不良事件发生率在不同组中相似。注射部位的疼痛在接受四价脑膜炎双球菌疫苗的女性中比接受三价灭活流感疫苗的女性更常见(n=253比n=132；p<；0·0001)，尽管354[92%]反应轻微。报告的产科和非产科严重不良事件中，四价脑膜炎双球菌疫苗组有60名妇女(3%)，三价灭活流感疫苗组有61名妇女(3%)。三价灭活流感疫苗组婴儿中推定的新生儿感染比四价脑膜炎双球菌疫苗组更常见(n=60比n=37；p=0.02)。没有与接种疫苗有关的严重不良事件。马里是一个资源贫乏、婴儿死亡率很高的国家，为孕妇接种三价灭活流感疫苗在技术和后勤上是可行的，并在4个月内保护婴儿免受实验室确认的流感的影响。有了足够的资金来采购疫苗，实施将与获得产前护理和接种破伤风类毒素孕妇的免疫覆盖范围相平行。比尔和梅琳达·盖茨基金会。
Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza. We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689. We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p<0·0001), although 354 [92%] reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination. Vaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid. Bill & Melinda Gates Foundation.