小柯机器人

瑞士武田制药国际公司的Vianney Tricou课题组研究了四价登革热疫苗对2-17岁儿童的安全性和免疫原性。该项研究成果发表在2020年3月17日出版的《柳叶刀》杂志上。

对于全年龄人群，无论其血清状况如何，有效的四价登革热疫苗临床上仍供不应求。研究组评估了居住在登革热流行国家的儿童在48个月内接种3种不同剂量方案的四价登革热疫苗（TAK-003）的免疫原性和安全性。

2014年12月5日至2015年2月13日，研究组在多米尼加共和国、巴拿马和菲律宾的三个地点进行了一项大型、临床2期、双盲、安慰剂对照试验。共招募了1800名2-17岁的儿童，将其随机分组，其中201名在第1天和第91天接种两剂TAK-003，398名接受1剂，1002名接种1剂，一年后再加强1剂，199名接受安慰剂。

共有1479名（82%）参与者完成了为期48个月的研究。在第48个月，与安慰剂组相比，所有TAK-003组的抗体滴度仍然升高，且与基线血清状况无关。

血清分型DENV1的参与者中，两剂组的几何平均滴度为378，一剂组为421，一剂加1年加强剂组为719，安慰剂组为100；DENV2分别为1052、1319、1200和208；DENV3分别为183、201、288和71；DENV4则分别为152、164、219和46。四价血清阳性率则分别为89%、86%、97%和60%。

TAK-003组中共有37名（2%）确诊登革热，安慰剂组有13名（7%），相对风险比为0.35。未发生疫苗相关严重不良事件或严重登革热病。

总之，TAK-003引发了所有四种血清型的抗体反应，无论基线血清状况如何，这种反应均持续至疫苗接种后48个月，且未发生严重安全风险。该结果为正在进行的3期临床试验提供了支持。

附：英文原文

Title: Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2–17 years: a randomised, placebo-controlled, phase 2 trial

Author: Vianney Tricou, Xavier Sáez-Llorens, Delia Yu, Luis Rivera, José Jimeno, Ana Cecilia Villarreal, Epiphany Dato, Onix Saldaa de Suman, Nathali Montenegro, Rodrigo DeAntonio, Sonia Mazara, Maria Vargas, Debbie Mendoza, Martina Rauscher, Manja Brose, Inge Lefevre, Suely Tuboi, Astrid Borkowski, Derek Wallace

Issue&Volume: 2020-03-17

Abstract: BackgroundAn unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries.MethodsWe did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2–17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066.FindingsBetween Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226–632) in two-dose, 421 (285–622) in one-dose, 719 (538–960) in one-dose plus 1-year booster, and 100 (50–201) in placebo recipients against DENV 1; 1052 (732–1511), 1319 (970–1794), 1200 (927–1553), and 208 (99–437) against DENV 2; 183 (113–298), 201 (135–298), 288 (211–392), and 71 (37–139) against DENV 3; and 152 (97–239), 164 (114–236), 219 (165–290), and 46 (26–82) against DENV 4; and tetravalent seropositivity rate was 89% (79–96), 86% (80–92), 97% (93–99), and 60% (47–72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19–0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported.InterpretationTAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study.

DOI: 10.1016/S0140-6736(20)30556-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30556-0/fulltext

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