PDF(Pubmed)
Abstract：
The leading cause of gastroenteritis in children under the age of five is rotavirus infection, accounting for 37% of diarrhoeal deaths in infants and young children globally. Oral rotavirus vaccines have been widely incorporated into national immunisation programs, but whilst these vaccines have excellent efficacy in high-income countries, they protect less than 50% of vaccinated individuals in low- and middle-income countries. In order to facilitate the development of improved vaccine strategies, a greater understanding of the immune response to existing vaccines is urgently needed. However, the use of mouse models to study immune responses to human rotavirus strains is currently limited as rotaviruses are highly species-specific and replication of human rotaviruses is minimal in mice. To enable characterisation of immune responses to human rotavirus in mice, we have generated chimeric viruses that combat the issue of rotavirus host range restriction. Using reverse genetics, the rotavirus outer capsid proteins (VP4 and VP7) from either human or murine rotavirus strains were encoded in a murine rotavirus backbone. Neonatal mice were infected with chimeric viruses and monitored daily for development of diarrhoea. Stool samples were collected to quantify viral shedding, and antibody responses were comprehensively evaluated. We demonstrated that chimeric rotaviruses were able to efficiently replicate in mice. Moreover, the chimeric rotavirus containing human rotavirus outer capsid proteins elicited a robust antibody response to human rotavirus antigens, whilst the control chimeric murine rotavirus did not. This chimeric human rotavirus therefore provides a new strategy for studying human-rotavirus-specific immunity to the outer capsid, and could be used to investigate factors causing variability in rotavirus vaccine efficacy. This small animal platform therefore has the potential to test the efficacy of new vaccines and antibody-based therapeutics.
摘要：
五岁以下儿童肠胃炎的主要原因是轮状病毒感染,占全球婴儿和幼儿腹泻死亡的37%。口服轮状病毒疫苗已被广泛纳入国家免疫计划，但是尽管这些疫苗在高收入国家有很好的疗效，它们保护低收入和中等收入国家不到50%的接种疫苗的个人。为了促进改进疫苗策略的发展，迫切需要更好地了解对现有疫苗的免疫反应。然而,目前，使用小鼠模型研究对人类轮状病毒株的免疫反应是有限的，因为轮状病毒具有高度的物种特异性，人类轮状病毒在小鼠中的复制很少。为了能够表征小鼠对人类轮状病毒的免疫反应，我们已经产生了嵌合病毒来对抗轮状病毒宿主范围限制的问题.利用反向遗传学，来自人或鼠轮状病毒毒株的轮状病毒外衣壳蛋白(VP4和VP7)在鼠轮状病毒骨架中编码.用嵌合病毒感染新生小鼠并每天监测腹泻的发展。收集粪便样本以量化病毒脱落，和抗体反应进行了全面评估。我们证明了嵌合轮状病毒能够在小鼠中有效复制。此外，含有人类轮状病毒外衣壳蛋白的嵌合轮状病毒引发了对人类轮状病毒抗原的强烈抗体反应，而对照嵌合鼠轮状病毒则没有。因此，这种嵌合人类轮状病毒为研究人类轮状病毒对外部衣壳的特异性免疫提供了一种新策略，并可用于研究导致轮状病毒疫苗效力变异性的因素。因此，这种小型动物平台具有测试新疫苗和基于抗体的疗法的功效的潜力。
