Protection from lethal challenge in a neonatal mouse model by circulating recombinant form coxsackievirus A16 vaccine candidates

Jingliang Li,Jiaxin Yang,Xiao-Fang Yu,Wei Wei,Haoran Guo,Wenyan Zhang,Xin Liu,Junliang Chang

doi:10.1099/vir.0.063560-0

Jingliang Li, Jiaxin Yang + Show 6 more

Open Access

https://doi.org/10.1099/vir.0.063560-0

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Abstract

Circulating coxsackievirus A16 (CA16) is a major cause of hand, foot and mouth disease (HFMD) in South-east Asia. At present, there is no vaccine against CA16. Pathogenic animal models that are sensitive to diverse circulating CA16 viruses would be desirable for vaccine development and evaluation. In this study, we isolated and characterized several circulating CA16 viruses from recent HFMD patients. These CA16 viruses currently circulating in humans were highly pathogenic in a newly developed neonatal mouse model; we also observed and analysed the pathogenesis of representative circulating recombinant form CA16 viruses. An inactivated CA16 vaccine candidate, formulated with alum adjuvant and containing submicrogram quantities of viral proteins, protected neonatal mice born to immunized female mice from lethal-dose challenge with a series of CA16 viruses. Further analysis of humoral immunity showed that antibody elicited from both the immunized dams and their pups could neutralize various lethal viruses by a cytopathic effect in vitro. Moreover, viral titres and loads in the tissues of challenged pups in the vaccine group were far lower than those in the control group, and some were undetectable. This lethal-challenge model using pathogenic CA16 viruses and the vaccine candidates that mediated protection in this model could be useful tools for the future development and evaluation of CA16 vaccines.

Highlights

Coxsackievirus 16 (CA16) and enterovirus 71 (EV71) both belong to the Picornaviridae, a family of single-stranded positive-sense RNA viruses, and can cause hand, foot and mouth disease (HFMD) with various neurological symptoms (Hagiwara et al, 1978)
CA16CC024 was first evaluated for pathogenesis in newborn mice because viral infection with this strain has been associated with viral meningitis in HFMD patients
To determine whether our neonatal-lethal model in mice was sensitive to other circulating recombinant CA16related viruses, we examined the pathogenic effect of four unrelated coxsackievirus A16 (CA16) viruses isolated from HFMD patients

Summary

Introduction

Coxsackievirus 16 (CA16) and enterovirus 71 (EV71) both belong to the Picornaviridae, a family of single-stranded positive-sense RNA viruses, and can cause hand, foot and mouth disease (HFMD) with various neurological symptoms (Hagiwara et al, 1978). HFMD has become a serious public health problem in South-east Asia, with periodic large epidemics occurring in recent decades. Outbreaks of HFMD due to CA16 occurred in England in 1994 (Bendig & Fleming, 1996), Taiwan from 1999 to 2006 Accumulating evidence has demonstrated that CA16 infection causes severe neurological complications (Yen et al, 2009) and death (Wang et al, 2004; Wright et al, 1963). As an EV71 vaccine alone is not sufficient to prevent HFMD outbreaks, both EV71 and CA16 should be targeted for vaccine development so as to provide broad and effective protection against HFMD

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