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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2019, Vol. 39 Issue (3): 97-104    DOI: 10.13523/j.cb.20190312
综述     
登革病毒3'UTRΔ30系列疫苗的研究进展
许嘉越,李紫倩,张革()
中山大学药学院 广州 510006
Advanced in Research Dengue Virus 3'UTRΔ30 Series Vaccines
Jia-yue XU,Zi-qian LI,Ge ZHANG()
School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China
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摘要：

登革病毒引发的登革热等疾病每年在全球范围内造成了相当大的经济、医疗、社会负担,严重威胁到人类生命健康。在目前研究的各种登革病毒疫苗中,采用反向遗传技术制得的3'UTRΔ30系列减毒活疫苗由于其免疫原性好,效价高,成本低等特点,在临床试验中展现出良好保护作用,研究推进快。能对四种血清型登革病毒都产生均衡免疫保护的3'UTRΔ30四联疫苗已处于III期临床试验阶段,效力强,不良反应少,待随访期结束后有望上市,是当今最有前景的登革减毒灭活疫苗之一。为更深入了解3'UTRΔ30系列疫苗,现主要从起源、制备方法、临床研究等方面进行介绍。
关键词： 登革病毒;  3'UTRΔ30疫苗;  制备方法;  临床研究    
Abstract:

Diseases such as dengue fever caused by denugue virus lead to considerable economic, medical and social burdens every year, which seriously threaten the health of human life. Among the various dengue virus vaccines currently under study, the 3'UTRΔ30 series of live attenuated vaccines prepared by reverse genetics have shown good protection in clinical trials because of their good immunogenicity, high titer and low cost. As a consequence, research on this kind of vaccine advances fast. The 3'UTRΔ30 quadruple vaccine, one of the most promising dengue attenuated inactivated vaccines today, which can produce balanced immune protection against the four serotypes of dengue virus, is in phase III clinical trials, showing strong efficacy and few adverse reactions. It is expected to be on the market after the end of the follow-up period. In order to gain a deeper understanding of the 3'UTRΔ30 series vaccines, the origin, preparation methods and clinical research are mainly focused on.
Key words: Dengue    virus    3'UTRΔ30    vaccine    Preparation    Clinical    research
收稿日期: 2018-09-20 出版日期: 2019-04-12
ZTFLH:  R186  
通讯作者: 张革     E-mail: zhangge@mail.sysu.edu.cn
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许嘉越,李紫倩,张革. 登革病毒3'UTRΔ30系列疫苗的研究进展[J]. 中国生物工程杂志, 2019, 39(3): 97-104.

Jia-yue XU,Zi-qian LI,Ge ZHANG. Advanced in Research Dengue Virus 3'UTRΔ30 Series Vaccines. China Biotechnology, 2019, 39(3): 97-104.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20190312    或    https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I3/97

图1  DENV的基因结构[1]
图2  rDENV4Δ30与rDENV1Δ30的部分结构[9]
试验疫苗 时间 试验分期 试验地点 试验对象 接种方式&剂量 参考文献
rDENV4Δ30 1996 临床前 美国
NIAID		 恒河猴 单次免疫;s.c.1); 剂量(1×105 PFU) [11]
2001 临床I期 美国
CIR		 健康志愿者20人 单次免疫;s.c.;剂量(1×105 PFU/0.5ml) [12][14]
2005 临床II期 美国
NIAID		 健康志愿者5人 单次免疫;s.c.;剂量递减(1×103 PFU,1×102 PFU,10 PFU) [13]
rDENV4Δ30-200,201 2008 临床I期 美国
NIAID		 健康志愿者20人 单次免疫;s.c.;剂量(1×105 PFU/0.5ml) [15]
rDENV4Δ30-4995 2009 临床I期 美国
NIAID		 健康志愿者20人 单次免疫;s.c.;剂量(1×105 PFU/0.5ml) [16]
rDENV1Δ30 2003 临床前 美国
NIAID		 恒河猴 单次免疫;s.c.;剂量(1×105 PFU/0.5ml) [17]
2006 临床I期 美国
NIAID		 健康志愿者28人 单次免疫;s.c.;剂量(1×103 PFU/0.5ml) [18]
rDENV2/4Δ30 2003 临床前 美国
NIAID		 小鼠,恒河猴等 单次免疫;s.c.;剂量(小鼠1×104 PFU,猴1×105 PFU) [19]
2006 临床I期 美国
NIAID		 健康志愿者20人 单次免疫;s.c.;剂量(1×103 PFU/0.5ml) [21]
rDENV3/4Δ30 2004 临床前 美国
NIAID		 小鼠,恒河猴等 单次免疫;s.c.;剂量(小鼠1×104 PFU,猴1×105 PFU) [20]
rDENV3Δ30/31 2011 临床I期 美国
NIAID		 健康志愿者20人 单次免疫;s.c.;剂量(1×103 PFU) [22]
rDENV3-3'D4Δ30 2011 临床I期 美国
NIAID		 健康志愿者20人 单次免疫;s.c.;剂量(1×103 PFU) [22]
TV001TV004 2013 临床I期 美国
NIAID		 每种疫苗健康志愿者28人,共112人 单次免疫;s.c.;剂量(1×103 PFU/0.5ml) [23]
TV003、TV005 2015 临床I期 美国
NIAID		 健康志愿者共168人 6个月后加强免疫;s.c.;剂量(1×103 PFU) [24]
TV003 2016 临床I期 美国
NIAID		 健康志愿者48人 12个月后加强免疫;s.c.;剂量(1×103 PFU) [25]
2016 临床II期 美国
NIAID		 健康志愿者48人 单次免疫;s.c.;剂量(1×103 PFU) [26]
2016 - 临床II期 泰国,
孟加拉国		 单剂量 [25],[28]
2016年
2月 -		 临床III期 巴西 单剂量,五年随访 [25], [27],
[28]
表1  登革病毒疫苗3'UTRΔ30的研究现状
图3  rDENV2/4△30的制备过程[19]
疫苗类型 每种成分剂量
(以Log10PFU计)		 用于指定血清型的单价疫苗成分
DENV-1 DENV-2 DENV-3 DENV-4
TV001 3,3,3,3 rDENV1Δ30 rDENV2/4Δ30 rDENV3-3'D4Δ30 rDENV4Δ30
TV002 3,3,3,3 rDENV1Δ30 rDENV2/4Δ30 rDENV3-3'D4Δ30 rDENV4Δ30-200,201
TV003 3,3,3,3 rDENV1Δ30 rDENV2/4Δ30 rDENV3Δ30/31 rDENV4Δ30
TV004 3,3,3,3 rDENV1Δ30 rDENV2/4Δ30 rDENV3Δ30/31 rDENV4Δ30-200,201
TV005 3,4,3,3 rDENV1Δ30 rDENV2/4Δ30 rDENV3Δ30/31 rDENV4Δ30
表2  3'UTRΔ30四联疫苗TV001TV004的配伍组成
CYD-TDVTM TV003
结构 缺少DENV的全部非结构蛋白NS蛋白 包含 DENV 全部 NS 蛋白
免疫次数 受试者需在第0、6、12个月接受3次免疫[31] 一次免疫
免疫保护效果 未能够对四型 DENV 提供均衡的保护[32,33];持久性短 均衡的免疫保护效果,效力持续时间长
人群差异性 人群差异性显著
①对9岁以上保护率明显高于9岁以下[34,35]
②对从未感染过DENV或体内DENV抗体阴性的接种者的整体保护效率偏低		 暂时未观察到明显人群差异性现象
表3  TV003与CYD-TDVTM的比较
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