Enterovirus 71 infection and vaccines

Abstract

Hand, foot and mouth disease (HFMD) is a highly contagious viral infection affecting young children during the spring to fall seasons. Recently, serious outbreaks of HFMD were reported frequently in the Asia-Pacific region, including China and Korea. The symptoms of HFMD are usually mild, comprising fever, loss of appetite, and a rash with blisters, which do not need specific treatment. However, there are uncommon neurological or cardiac complications such as meningitis and acute flaccid paralysis that can be fatal. HFMD is most commonly caused by infection with coxsackievirus A16, and secondly by enterovirus 71 (EV71). Many other strains of coxsackievirus and enterovirus can also cause HFMD. Importantly, HFMD caused by EV71 tends to be associated with fatal complications. Therefore, there is an urgent need to protect against EV71 infection. Development of vaccines against EV71 would be the most effective approach to prevent EV71 outbreaks. Here, we summarize EV71 infection and development of vaccines, focusing on current scientific and clinical progress.

Keywords: Animal models; Enterovirus 71; Hand; VP1; Vaccine; foot and mouth disease.

Fig. 1. Enterovirus 71 (EV71) genotypes identified from outbreaks. The genotypes and sub-genotypes of EV71 strains identified from outbreaks since 1997 in each country of the Asia-Pacific region and from Europe (EU) are summarized. EU combines data from Austria, Germany, the Netherlands, and the United Kingdom. The data for 2012-2014 may be incomplete since recent statistics were not published in some cases.

Fig. 2. Structure of the enterovirus 71 (EV71) virion. (A) EV71 is a non-enveloped and icosahedral particle with a diameter of 20-30 nm. The EV71 capsid consists of 60 copies of four different structural proteins (VP1-VP4). These four structural proteins assemble to form a protomer. Five protomers are assembled to form a pentamer, and 12 pentamers plus the viral genome form a virion. (B) The RNA genome of EV71 is approximately 7.4 kb, with an untranslated region (UTR) at the 5' and 3' ends of the genome. The 5'UTR contains an internal ribosomal entry site (IRES) for cap-independent translation. The 5'UTR is bound covalently to VPg (also known as viral protein 3B), and the 3'UTR includes a poly-A tail. The RNA is translated to a polyprotein that is sequentially cleaved by the viral 2A protease (2A^pro), 3CD protease, and 3C protease (3C^pro). Viral protein 3D has an RNA-dependent-RNA polymerase activity.

Fig. 3. Viral receptors for enterovirus 71 (EV71) on host cells. EV71 can bind human scavenger receptor B2 (hSCARB2), P-selectin glycoprotein ligand (PSGL-1), heparin sulfate, annexin A2, and sialylated glycans. EV71 enters host cells via receptor binding and becomes enclosed within an endosome having low internal pH. Following conformational deformation of the capsid, uncoated viral RNA is released into the cytoplasm, and protein translation and viral replication are initiated.