Human monoclonal antibodies broadly neutralizing against influenza B virus.
Human monoclonal antibodies broadly neutralizing against influenza B virus.
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DOI：
10.1371/journal.ppat.1003150
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Ikuta K
中科院分区：
文献类型：
--
作者：
Yasugi M;Kubota-Koketsu R;Yamashita A;Kawashita N;Du A;Sasaki T;Nishimura M;Misaki R;Kuhara M;Boonsathorn N;Fujiyama K;Okuno Y;Nakaya T;Ikuta K
流感病毒能够通过快速的病毒遗传漂变和重组逃避宿主的免疫监视，因此，它仍然是一个持续的公共卫生威胁。产生广泛反应性抗体的疫苗的开发，以及使用具有全局反应性的人中和单克隆抗体（HuMAb）的治疗策略，最近已经引起了极大的兴趣。在此，使用来自接种疫苗的志愿者的外周淋巴细胞制备了三个产生抗流感B病毒的HuMAb的杂交瘤克隆，命名为5A 7、3A 2和10 C4，并研究了广泛的交叉反应性中和活性。在这些HuMAb中，3A 2和10 C4识别血凝素（HA）蛋白中受体结合位点附近的易突变的190-螺旋区域，仅与Yamagata谱系的流感B病毒反应。相比之下，HuMA B 5A 7广泛中和1985年至2006年分离的属于Yamagata和维多利亚谱系的流感B毒株。表位分析显示，5A 7识别HA 1 C端附近的316 G、318 C和321 W，这是B型流感病毒中高度保守的区域。事实上，即使在HuMAb 5A 7存在下将病毒传代10次后，也未诱导表位区域的氨基酸残基突变。此外，5A 7在小鼠中显示出显著的治疗功效，即使在感染后72小时施用时也是如此。这些结果表明5A 7是开发治疗剂的有希望的候选物，并为开发针对B流感病毒的通用疫苗提供了见解。流感病毒分为A、B和C型。甲型流感病毒进一步分为许多亚型，所有这些亚型都存在于动物中，表明有大流行的潜力。相比之下，B型流感病毒几乎只在人类中传播，由于没有证据表明与A型流感病毒发生重配，因此没有迹象表明存在大流行的可能性。因此，关于B型流感病毒的累积研究信息远少于A型流感病毒。然而，流感B病毒被分为两个系统谱系，其确实在人类中引起年度流行病，因此与流感A病毒一样是控制所必需的。最近，使用人单克隆抗体（HuMAbs）的通用疫苗和治疗策略的开发已经引起了极大的兴趣。本研究报告了一种HuMA B，可中和两种谱系的多种流感B病毒。该HuMAb识别血凝素的保守区域。此外，该HuMAb的治疗功效也通过体内动物实验证实。因此，本研究为开发针对B型流感病毒的广谱治疗剂和通用预防性疫苗提供了见解。
Influenza virus has the ability to evade host immune surveillance through rapid viral genetic drift and reassortment; therefore, it remains a continuous public health threat. The development of vaccines producing broadly reactive antibodies, as well as therapeutic strategies using human neutralizing monoclonal antibodies (HuMAbs) with global reactivity, has been gathering great interest recently. Here, three hybridoma clones producing HuMAbs against influenza B virus, designated 5A7, 3A2 and 10C4, were prepared using peripheral lymphocytes from vaccinated volunteers, and were investigated for broad cross-reactive neutralizing activity. Of these HuMAbs, 3A2 and 10C4, which recognize the readily mutable 190-helix region near the receptor binding site in the hemagglutinin (HA) protein, react only with the Yamagata lineage of influenza B virus. By contrast, HuMAb 5A7 broadly neutralizes influenza B strains that were isolated from 1985 to 2006, belonging to both Yamagata and Victoria lineages. Epitope mapping revealed that 5A7 recognizes 316G, 318C and 321W near the C terminal of HA1, a highly conserved region in influenza B virus. Indeed, no mutations in the amino acid residues of the epitope region were induced, even after the virus was passaged ten times in the presence of HuMAb 5A7. Moreover, 5A7 showed significant therapeutic efficacy in mice, even when it was administered 72 hours post-infection. These results indicate that 5A7 is a promising candidate for developing therapeutics, and provide insight for the development of a universal vaccine against influenza B virus. Influenza virus is classified into types A, B and C. Influenza A virus is further divided into many subtypes, all of which exist in animals, indicating pandemic potential. By contrast, influenza B virus circulates almost exclusively in humans and, as there is no evidence for reassortment with influenza A virus, there is no indication of pandemic potential. Hence, there is far less accumulated research information regarding influenza B virus than influenza A virus. Influenza B virus, which is classified into two phylogenetic lineages, does, however, cause annual epidemics in humans and is therefore as essential to control as influenza A virus. Recently, the development of a universal vaccine and therapeutic strategies using human monoclonal antibodies (HuMAbs) has been gathering great interest. The present study reports a HuMAb neutralizing a wide range of influenza B viruses of both lineages. This HuMAb recognizes the conserved region of hemagglutinin. Moreover, therapeutic efficacy of this HuMAb was also confirmed by in vivo animal experiments. Thus, this study provides insight for the development of broad-spectrum therapeutics and a universal prophylactic vaccine against influenza B virus.
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DOI：
10.1073/pnas.0804958105
发表时间：
2008-08-05
影响因子：
11.1
作者：
Jing, Xianghong;Ma, Chunlong;Lamb, Robert A.
通讯作者：
Lamb, Robert A.
影响因子：
5.5
作者：
Belshe, Robert B.
通讯作者：
Belshe, Robert B.
从接种疫苗的健康供体中，针对流感病毒的人类单克隆抗体广泛中和。
DOI：
10.1016/j.bbrc.2009.06.151
发表时间：
2009-09-11
影响因子：
3.1
作者：
Kubota-Koketsu R;Mizuta H;Oshita M;Ideno S;Yunoki M;Kuhara M;Yamamoto N;Okuno Y;Ikuta K
通讯作者：
Ikuta K
影响因子：
82.9
作者：
Jin, Aishun;Ozawa, Tatsuhiko;Muraguchi, Atsushi
通讯作者：
Muraguchi, Atsushi
影响因子：
5.4
作者：
Gulati, U;Hwang, CC;Air, GM
通讯作者：
Air, GM