Indeed, several cohort studies confirmed that there is an association between EV-D68 and AFM.
Coinciding with this outbreak, 120 acute flaccid myelitis (AFM) cases were reported in the USA, suggesting that this AFM cluster was likely associated with EV-D68 infection. In particular, a nationwide outbreak of EV-D68 associated with severe respiratory illness occurred in the USA in 2014, resulting in a total of 1153 confirmed cases including at least 14 deaths, and it is the largest and most widespread one of EV-D68 outbreaks ever recorded in the world ( ). However, in the past 10 years, the incidence of EV-D68 infections has remarkably increased all over the world. ĮV-D68 was first identified in the United States of America (USA) in 1962, and was once considered to be a rare cause of respiratory disease, with only 26 cases reported between 19 in the USA. Recent studies have identified neuron-specific intercellular adhesion molecule-5 (ICAM-5/telencephalin) and sialic acid as two cellular receptors for EV-D68. A crystal structure of EV-D68 virus shows that the EV-D68 viral capsid is made of 60 copies of each of VP1, VP2, VP3, and VP4 subunit proteins and it possesses structural features typical for enteroviruses, such as three-fold propeller-like protrusions, star-shaped five-fold plateaus, narrow depressions (canyons) surrounding each plateau, and hydrophobic pockets inside VP1 and directly beneath the canyon floor. After viral RNA encapsidation, VP0 may be further cleaved into VP2 and VP4 via an autocatalytic mechanism. Subsequently, P1 precursor is cleaved by viral protease 3CD to yield three capsid subunit proteins (VP0, VP1, and VP3), all of which co-assemble to form viral capsid shells. This polyprotein can be processed to produce three precursor proteins, P1, P2, and P3. Like other enteroviruses, the genome of EV-D68 is a positive-sense single-stranded RNA of ~7.4 kb and contains a single open reading frame (ORF) that encodes a large polyprotein. Collectively, these results demonstrate the proof-of-concept for VLP-based broadly effective EV-D68 vaccines.Įnterovirus D68 (EV-D68) is a virus belonging to the Enterovirus genus of the Picornaviridae family. The first challenge experiment showed that neonatal mice born to the VLP-immunized dams were fully protected from lethal EV-D68 infection, whereas in the second experiment, passive transfer of anti-VLP sera was found to confer complete protection in the recipient mice.
The in vivo protective efficacy of the EV-D68 VLP candidate vaccine was assessed in two challenge experiments. Mice immunized with these VLPs produced serum antibodies capable of specifically neutralizing EV-D68 infections in vitro.
We found that co-expression of the P1 precursor and 3CD protease of EV-D68 in Pichia pastoris yeast resulted in the generation of EV-D68 VLPs, which were composed of processed VP0, VP1, and VP3 capsid proteins and were visualized as ~30 nm spherical particles. In the present study, we investigated the possibility of developing a virus-like particle (VLP)-based EV-D68 vaccine. However, no vaccine is currently available to prevent EV-D68 infection. Enterovirus D68 (EV-D68) has been increasingly associated with severe respiratory illness and neurological complications in children worldwide.
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