TAK-021, an inactivated Enterovirus 71 vaccine candidate, provides cross-protection against heterologous sub-genogroups in human scavenger receptor B2 transgenic mice
TAK-021, an inactivated Enterovirus 71 vaccine candidate, provides cross-protection against heterologous sub-genogroups in human scavenger receptor B2 transgenic mice
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DOI：
10.1016/j.vaccine.2022.04.064
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发表时间：
2022-05-13
期刊：
影响因子：
5.5
通讯作者：
Dean，Hansi J.
中科院分区：
文献类型：
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作者：
Tamura，Kanami;Kohnoe，Mai;Dean，Hansi J.
背景肠道病毒 71 (EV71) 是手足口病爆发的主要原因，最常见于儿童，是亚太地区的一个公共卫生问题。武田正在开发 TAK-021，这是一种基于亚基因组 B2 毒株 MS87 的灭活 EV71 候选疫苗。在一项 I 期临床试验中，TAK-021 在健康成人中是安全的、耐受性良好且具有免疫原性，并引发针对异源 EV71 亚基因组病毒的交叉中和抗体。 TAK-021 为 AG129 小鼠提供了针对小鼠适应同源菌株的致命攻击的保护。然而，尚未确定TAK-021是否可以提供针对异源EV71亚基因组的交叉保护。方法我们在人类清道夫免疫后第42天（短期）检查TAK-021对抗EV71亚基因组B4、B5、C1、C2和C4以及第120天（长期）亚基因组B5和C4攻击的功效受体 B2 转基因 (hSCARB2-tg) 小鼠在第 0 天和第 28 天使用 TAK-021。使用同源疫苗病毒的空斑减少中和试验监测抗体滴度超过 120 天。结果TAK-021 在超过 90% 的小鼠中引发中和抗体 (nAb)，并且 nAb 持续到第 120 天。对照动物的挑战也导致体重减轻和死亡如各种器官中的病毒检测和大脑中的组织病理学病变。所有接受两剂 TAK-021 的小鼠均产生了 nAb，并在第 42 天给予的短期攻击中存活下来，而超过 80% 在第 120 天给予的长期攻击中存活下来。与未免疫对照小鼠相比，免疫小鼠的器官中检测到 EV71 的频率较低且水平较低。结论结果表明，TAK-021 可以为小鼠提供针对所测试的 EV71 亚基因组的保护。
BackgroundEnterovirus 71 (EV71) is a major cause of outbreaks of hand, foot and mouth disease, most frequently in children, and is a public health concern in the Asia-Pacific region. Takeda is developing TAK-021, an inactivated EV71 vaccine candidate based on sub-genogroup B2 strain MS87. In a phase I clinical trial, TAK-021 was safe, well tolerated, and immunogenic in healthy adults and elicited cross-neutralizing antibodies against heterologous EV71 sub-genogroup viruses. TAK-021 confers protection from lethal challenge with a mouse-adapted homologous strain in AG129 mice. However, it has not been determined whether TAK-021 can provide cross-protection against heterologous EV71 sub-genogroups.MethodsWe examined the efficacy of TAK-021 against challenge with EV71 sub-genogroups B4, B5, C1, C2, and C4 on day 42 (short-term) and sub-genogroups B5 and C4 on day 120 (long-term) after immunization of human scavenger receptor B2 transgenic (hSCARB2-tg) mice with TAK-021 on days 0 and 28. Antibody titers were monitored over 120 days using plaque reduction neutralization test of the homologous vaccine virus.ResultsTAK-021 elicited neutralizing antibody (nAb) in greater than 90% of the mice and nAb persisted through day 120. Challenge of control animals led to weight loss and death, as well as virus detection in various organs and histopathological lesions in the brain. All mice that received two doses of TAK-021 developed nAb and survived a short-term challenge given on day 42, while more than 80% survived a long-term challenge given on day 120. EV71 was detected less frequently and at lower levels in organs of immunized mice compared to non-immunized control mice.ConclusionsThe results show that TAK-021 can confer protection in mice against the EV71 sub-genogroups tested.