A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine.

Chao Zhang,Lanlan Geng,Sitang Gong,Xueyang Zhang,Shuxia Wang,Qingwei Liu,Wenlong Dai,Zhong Huang,Pei Xiong

doi:10.3390/v10020058

Chao Zhang, Lanlan Geng + Show 7 more

Open Access

https://doi.org/10.3390/v10020058

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Abstract

In recent years, enterovirus D68 (EVD68) has been reported increasingly to be associated with severe respiratory tract infections and acute flaccid myelitis (AFM) in children all over the world. Yet, no effective vaccines or antiviral drugs are currently available for EVD68. Although several experimental animal models have been developed, immunogenicity and protective efficacy of inactivated EVD68 vaccines has not been fully evaluated. To promote the development of vaccines, we established an Institute of Cancer Research (ICR) suckling mouse model of EVD68 infection in this study. The results showed that ICR neonatal mice up to about nine days of age were susceptible to infection with EVD68 clinical strain US/MO/14-18947 by intraperitoneal injection. The infected mice exhibited progressive limb paralysis prior to death and the mortality of mice was age- and virus dose-dependent. Tissue viral load analysis showed that limb muscle and spinal cord were the major sites of viral replication. Moreover, histopathologic examination revealed the severe necrosis of the limb and juxtaspinal muscles, suggesting that US/MO/14-18947 has a strong tropism toward muscle tissues. Additionally, β-propiolactone-inactivated EVD68 vaccine showed high purity and quality and induced robust EVD68-specific neutralizing antibody responses in adult mice. Importantly, results from both antisera transfer and maternal immunization experiments clearly showed that inactivated EVD68 vaccine was able to protect against lethal viral infection in the mouse model. In short, these results demonstrate the successful establishment of the mouse model of EVD68 infection for evaluating candidate vaccines against EVD68 and also provide important information for the development of inactivated virus-based EVD68 vaccines.

Highlights

Human enterovirus D68 (EVD68) is an emerging pathogen for acute respiratory infections and it is linked to acute flaccid myelitis (AFM) [1]
Suckling mice are used in this study, because adult mice are not susceptible to EVD68 infection [20]
Mice infected with the Fermon strain showed no signs of disease and all survived; whereas US/MO/14-18947-infected mice exhibited limb paralysis and all died within 7 dpi. 62% of mice inoculated with US/KY/14-18953 developed clinical signs, including limb weakness and paralysis, and three of them eventually died with a final mortality rate of 23.1% (Figure 1A,B). These results indicate that US/MO/14-18947 is much more virulent for Institute of Cancer Research (ICR) mice than Fermon and US/KY/14-18953 strains

Summary

Introduction

Human enterovirus D68 (EVD68) is an emerging pathogen for acute respiratory infections and it is linked to acute flaccid myelitis (AFM) [1]. Since its first identification in the United States of America (USA) in 1962 [2], EVD68 was seldom reported around the world until the early 2000s [1,3]. EVD68 infections have notably increased in North America, Europe and Asia [1,3,4]. In 2014, the USA experienced a large outbreak of severe respiratory disease caused by EVD68, which led to 1153 laboratory-confirmed cases including 14 deaths by January 2015. EVD68 has been increasingly recognized as a significant respiratory pathogen in children Viruses 2018, 10, 58 studies have revealed that EVD68 continues circulating in various parts of the world after 2014 [5,6,7,8,9].

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