Venezuelan Equine Encephalitis Virus V3526 Vaccine RNA-Dependent RNA Polymerase Mutants Increase Vaccine Safety Through Restricted Tissue Tropism in a Murine Model.
Venezuelan Equine Encephalitis Virus V3526 Vaccine RNA-Dependent RNA Polymerase Mutants Increase Vaccine Safety Through Restricted Tissue Tropism in a Murine Model.
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DOI：
10.15212/zoonoses-2021-0016
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发表时间：
2022-01-01
期刊：
影响因子：
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通讯作者：
Rossi, Shannan L
中科院分区：
文献类型：
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作者：
Haines, Clint A;Campos, Rafael K;Rossi, Shannan L
背景：委内瑞拉马脑炎病毒（VEEV）是美洲的一种地方性虫媒病毒。目前还没有批准的疫苗或抗病毒药物。TC-83和V3526是最具特征的VEEV候选疫苗。这两种疫苗都是减毒活疫苗，与安全问题有关，尽管V3526的安全性较低。先前改进TC-83疫苗的尝试侧重于通过添加改变RNA依赖性RNA聚合酶（RdRp）错误掺入率的突变来进一步减毒疫苗。方法：本研究通过克隆V3526的3X和4X菌株，评估疫苗对成年雌性CD-1小鼠的攻击效果，检测中和抗体滴度，研究疫苗的组织倾向性，并测试突变菌株的稳定性，来检测这些RdRp突变对V3526的影响。结果：我们的研究结果表明，与野生型V3526相比，V3526 RdRp突变体在脾脏和肾脏的组织趋向性降低，同时保持疫苗效力。Illumina测序显示RdRp突变可以恢复到野生型V3526。结论：观察到的基因型逆转可能是有限的关注，因为野生型V3526仍然是一种能够提供保护的有效疫苗。我们的结果表明，V3526 RdRp突变体可能是一种比原始V3526更安全的疫苗设计。
Background: Venezuelan equine encephalitis virus (VEEV) is an arbovirus endemic to the Americas. There are no approved vaccines or antivirals. TC-83 and V3526 are the best-characterized vaccine candidates for VEEV. Both are live-attenuated vaccines and have been associated with safety concerns, albeit less so for V3526. A previous attempt to improve the TC-83 vaccine focused on further attenuating the vaccine by adding mutations that altered the error incorporation rate of the RNA-dependent RNA polymerase (RdRp).Methods: The research presented here examines the impact of these RdRp mutations in V3526 by cloning the 3X and 4X strains, assessing vaccine efficacy against challenge in adult female CD-1 mice, examining neutralizing antibody titers, investigating vaccine tissue tropism, and testing the stability of the mutant strains.Results: Our results show that the V3526 RdRp mutants exhibited reduced tissue tropism in the spleen and kidney compared to wild-type V3526, while maintaining vaccine efficacy. Illumina sequencing showed that the RdRp mutations could revert to wild-type V3526.Conclusions: The observed genotypic reversion is likely of limited concern because wild-type V3526 is still an effective vaccine capable of providing protection. Our results indicate that the V3526 RdRp mutants may be a safer vaccine design than the original V3526.