Evaluation of safety and immunogenicity of a genetically modified rabies virus for use as an oral vaccine in several non-target species

doi:10.1016/j.jia.2024.07.031

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Xijun Wang^1*#, Hong Huo^1*, Lei Shuai¹, Jinying Ge¹, Liyan Peng¹, Jinming Wang¹, Shuang Xiao¹, Weiye Chen¹, Zhiyuan Wen¹, Jinliang Wang¹, Zhigao Bu^{1, 2#}

¹ State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin150069, China

² Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China

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摘要

全球每年死于狂犬病（Rabies）的人数高达50,000，是一个严重的公共卫生问题。据统计，99%以上的人间狂犬病死亡病例因病犬或带毒犬咬伤所致。对于人间狂犬病的控制，最有效的措施是通过疫苗接种从源头上控制犬狂犬病。目前我国批准的狂犬病疫苗均为灭活疫苗，对犬安全、有效，但需要经肌肉注射途径免疫接种。散养犬和流浪犬抓捕困难，因此对其免疫难度较大。口服免疫是一种有效的替代或补充方法，可以显著提高犬（特别是散养犬和流浪犬）的群体免疫率，因此迫切需要安全、有效的狂犬病口服疫苗。在之前的研究中，作者利用反向遗传技术，将狂犬病病毒(Rabies virus, RABV)ERA弱毒疫苗株G蛋白第333位精氨酸（Arginine,Arg, R)突变为谷氨酸（Glutamic acid, Glu, E），拯救获得了重组狂犬病病毒rERAG_333E。研究结果表明，与亲本毒株ERA相比，重组病毒rERAG_333E对小鼠的致病力显著下降，对成年小鼠和狗安全，且口服免疫接种犬能够诱导显著而持久的保护性免疫反应。本研究进一步评价了重组病毒rERAG_333E对乳鼠、恒河猴、狐狸、貉、仔猪、山羊和绵羊等与犬密切接触的非靶动物的安全性和免疫原性。乳鼠试验结果显示，用重组病毒rERAG_333E脑内接种后，10日龄及以上乳鼠未出现任何狂犬病相关症状和死亡现象，表明G_333E突变显著降低了亲本毒株ERA的致病力。动物试验结果显示，用10倍剂量的重组病毒rERAG_333E口服接种后，恒河猴、狐狸、貉、仔猪、山羊和绵羊等非靶动物均未出现任何疾病相关症状；用狂犬病灭活疫苗Rabvac 3加强免疫后，这些试验动物仍未出现任何疾病相关症状和“早死”现象，表明重组病毒rERAG_333E对恒河猴、狐狸、貉、仔猪、山羊和绵羊安全。同时，用重组病毒rERAG_333E口服免疫恒河猴、狐狸、貉和仔猪，能够诱导显著的RABV中和抗体反应。研究结果表明，重组病毒rERAG_333E是一种有希望的、安全的狂犬病口服候选疫苗。

Abstract

Oral immunization is an alternative or supplementary approach that can significantly improve dog vaccination coverage, especially for free-roaming dogs. Safe and effective oral rabies vaccines for dogs are still being sought. In our previous studies, we generated a genetically modified rabies virus (RABV) ERA strain, rERAG_333E, containing a mutation from arginine (Arg, R) to glutamic acid (Glu, E) at residue 333 of the G protein (G_333E). Our previous results demonstrated that rERAG_333E was safe for adult mice and dogs, and oral vaccination with rERAG_333E induced a strong and long-lasting protective immune response in dogs. Here, we further investigated the safety and immunogenicity of rERAG_333E in non-target species, including suckling mice, rhesus monkeys, foxes, raccoon dogs, piglets, goats, and sheep. Suckling mice studies demonstrated that the G_333E mutation significantly reduced the virulence of the ERA strain. All of the suckling mice aged 10 days and above survived and showed no apparent signs of disease after intracerebral inoculation with rERAG_333E. Animal studies demonstrated that rERAG_333E was safe in rhesus monkeys, foxes, raccoon dogs, piglets, goats, and sheep. None of those animals inoculated orally with 10 times the intended field dose of rERAG_333E showed abnormal clinical signs before and after the booster immunization with Rabvac 3, an inactivated rabies vaccine. Meanwhile, oral inoculation with rERAG_333E induced strong neutralizing antibody (NA) responses to RABV in rhesus monkeys, foxes, raccoon dogs, and piglets. These results demonstrated that rERAG_333E has the potential to serve as a safe oral rabies vaccine for dogs.

Keywords: Rabies Genetically modified rabies virus Oral vaccine

Online: 22 July 2024

Fund:

This work was supported by the Natural Science Foundation of Heilongjiang Province of China (YQ2022C040).

About author: Xijun Wang, E-mail: wangxijun@caas.cn; Hong Huo, E-mail: huohong617@163.com; #Correspondence Zhigao Bu, E-mail: buzhigao@caas.cn; Wang Xi-jun, E-mail: wangxijun@caas.cn * These authors contributed equally to this work.

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Xijun Wang, Hong Huo, Lei Shuai, Jinying Ge, Liyan Peng, Jinming Wang, Shuang Xiao, Weiye Chen, Zhiyuan Wen, Jinliang Wang, Zhigao Bu. 2024. Evaluation of safety and immunogenicity of a genetically modified rabies virus for use as an oral vaccine in several non-target species. Journal of Integrative Agriculture, Doi:10.1016/j.jia.2024.07.031

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