Protective efficacy of formaldehyde-inactivated whole-virus vaccine and antivirals in a murine model of coxsackievirus A10 infection.

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Protective efficacy of formaldehyde-inactivated whole-virus vaccine and antivirals in a murine model of coxsackievirus A10 infection.

J Virol. 2017 Apr 19;:

Authors: Zhang Z, Dong Z, Li J, Carr MJ, Zhuang D, Wang J, Zhang Y, Ding S, Tong Y, Li D, Shi W

Abstract
Coxsackievirus A10 (CVA10) is one of the major pathogens associated with hand, foot and mouth disease (HFMD). CVA10 infection can cause herpangina and viral pneumonia, which can be complicated by severe neurological sequelae. Morbidity and mortality of CVA10-associated HFMD has been increasing in recent years, particularly in the pan-Pacific region. There are limited studies however on the pathogenesis and immunology of CVA10-associated HFMD infections, and few antiviral drugs or vaccines have been reported. In the present study, a cell-adapted CVA10 strain was employed to inoculate intramuscularly five-day-old ICR mice, which developed significant clinical signs including: reduced mobility, lower weight gain and quadriplegia, with significant pathology in the brain, hind limb skeletal muscles and lungs of infected mice in the moribund state. The severity of illness was associated with abnormally high expression of the proinflammatory cytokine IL-6. Antiviral assays demonstrated that ribavirin and gamma interferon administration could significantly inhibit CVA10 replication both in vitro and in vivo In addition, formaldehyde-inactivated CVA10 whole-virus vaccines induced immune responses in adult mice and maternal neutralizing antibodies could be transmitted to neonatal mice providing protection against CVA10 clinical strains. Furthermore, high titer antisera were effective against CVA10 and could relieve early clinical symptoms and improve the survival rates of CVA10-challenged neonatal mice. In summary, we present a novel murine model to study CVA10 pathology which will be extremely useful to develop effective antivirals and vaccines to diminish the burden of HFMD-associated disease.IMPORTANCE Hand, foot and mouth disease cases in infancy, arising from coxsackievirus A10 (CVA10) infections, are typically benign, resolving without any significant adverse events. Severe disease and fatalities can however occur in some children, necessitating the development of vaccines and antiviral therapies. The present study has established a newborn mouse model of CVA10 which, importantly, recapitulates many aspects of human disease, with respect to the neuropathology and skeletal muscle pathology. We found that high levels of the proinflammatory cytokine interleukin 6 correlated with disease severity and that ribavirin and gamma interferon could decrease viral titers in vitro and in vivo Whole-virus vaccines produced immune responses in adult mice and immunized mothers conferred protection to neonates against challenge from CVA10 clinical strains. Passive immunization with high titer antisera could also improve survival rates in newborn animals.

PMID: 28424287 [PubMed - as supplied by publisher]

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