Efficacy of an HSV-1 Neuro-Attenuated Vaccine in Mice Is Reduced by Preventing Viral DNA Replication.
Efficacy of an HSV-1 Neuro-Attenuated Vaccine in Mice Is Reduced by Preventing Viral DNA Replication.
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DOI：
10.3390/v14050869
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发表时间：
2022-04-22
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我们先前分离到一个HSV-1突变体Kos-NA，它在UL39中包含两个非同义突变。其中一个突变导致ICP6中的R950H氨基酸替换，使Kos-NA严重神经衰弱，并显著缩短HSV-1潜伏期。在角膜攻击前给小鼠接种Kos-NA疫苗，即使在很低的免疫剂量下，也能显著保护小鼠免受HSV-1介导的眼部疾病的侵袭，这表明它作为疫苗支架的实用性。由于Kos-NA在单个基因中包含神经衰减突变，我们试图通过删除UL29基因的一部分来提高其安全性，UL29基因的蛋白质产物ICP8是病毒DNA复制所必需的。虽然Kos-NA减少了HSV-1挑战病毒在角膜上皮细胞中的复制，并保护小鼠免受挑战病毒引起的眼缘炎和角膜炎，但Kos-NA/8-和ICP8-病毒的效果明显较差，除非在较高剂量下。我们的结果表明，即使与野生型HSV-1相比水平显著降低，复制能力也可能是有效疫苗的一个重要特征。应寻求在不影响效力的情况下提高减毒病毒作为疫苗的安全性的方法。
We previously isolated an HSV-1 mutant, KOS-NA, that contains two non-synonymous mutations in UL39. One of the mutations, resulting in an R950H amino acid substitution in ICP6, renders KOS-NA severely neuro-attenuated and significantly reduces HSV-1 latency. Vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated eye diseases even at a very low immunizing dose, indicating its utility as a vaccine scaffold. Because KOS-NA contains a neuro-attenuating mutation in a single gene, we sought to improve its safety by deleting a portion of the UL29 gene whose protein product, ICP8, is essential for viral DNA replication. Whereas KOS-NA reduced replication of HSV-1 challenge virus in the corneal epithelium and protected mice against blepharitis and keratitis induced by the challenge virus, KOS-NA/8- and an ICP8- virus were significantly less efficacious except at higher doses. Our results suggest that the capacity to replicate, even at significantly reduced levels compared with wild-type HSV-1, may be an important feature of an effective vaccine. Means to improve safety of attenuated viruses as vaccines without compromising efficacy should be sought.
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