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Fulltext Development of Novel Vaccines against Enterovirus-71

Yee PT, Poh CL

Viruses, 2015 Dec 30;8(1).
PMID: 26729152 DOI: 10.3390/v8010001

The hand, foot and mouth disease is caused by a group of Enteroviruses such as Enterovirus 71 (EV-A71) and Coxsackievirus CV-A5, CV-A8, and CV-A16. Mild symptoms of EV-A71 infection in children range from high fever, vomiting, rashes and ulcers in mouth but can produce more severe symptoms such as brainstem and cerebellar encephalitis, leading up to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents against EV-A71 to prevent further fatalities. Research groups have developed experimental inactivated vaccines, recombinant Viral Protein 1 (VP1) vaccine and virus-like particles (VLPs). The inactivated EV-A71 vaccine is considered the safest viral vaccine, as there will be no reversion to the infectious wild type strain. The recombinant VP1 vaccine is a cost-effective immunogen, while VLPs contain an arrangement of epitopes that can elicit neutralizing antibodies against the virus. As each type of vaccine has its advantages and disadvantages, increased studies are required in the development of such vaccines, whereby high efficacy, long-lasting immunity, minimal risk to those vaccinated, safe and easy production, low cost, dispensing the need for refrigeration and convenient delivery are the major goals in their design.
Development of Novel miRNA-based Vaccines and Antivirals against Enterovirus 71

Yee PT, Poh CL

Curr Pharm Des, 2016;22(44):6694-6700.
PMID: 27510488 DOI: 10.2174/1381612822666160720165613

The Hand, Foot and Mouth Disease (HFMD) is caused by Enterovirus 71 (EV-A71) and Coxsackieviruses. Common HFMD symptoms are high fever (≥ 39°C), rashes, and ulcers but complications due to virulent EV-A71 may arise leading to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents. Recent studies have reported the emergence of novel antiviral agents and vaccines that utilize microRNAs (miRNAs). They belong to a class of small (19-24 nt) non coding RNA molecules. As miRNAs play a major role in the host regulatory system, there is a huge opportunity for interplay between host miRNAs and EV-A71 expressions. A total of 42 out of 64 miRNAs were up-regulated in EV-A71-infected cells. There was consistent up-regulation of miR-1246 gene expression that targeted the DLG3 gene which contributes to neurological pathogenesis. In contrast, miR-30a that targets calcium channels for membrane transportation was down-regulated. This leads to repression of EV-A71 replication. The impact of host miRNAs on immune activation, shutdown of host protein synthesis, apoptosis, signal transduction and viral replication are discussed. miRNAs have been used in the construction of live attenuated vaccines (LAV) such as the poliovirus LAV that has miRNA binding sites for let-7a or miR-124a. The miRNAbearing vaccine will not replicate in neuronal cells carrying the corresponding miRNA but could still replicate in the gastrointestinal tract and hence remains to act as immunogens. As such, miRNAs are attractive candidates to be developed as vaccines and antivirals.
Identification of molecular determinants of cell culture growth characteristics of Enterovirus 71

Yee PT, Tan KO, Othman I, Poh CL

Virol J, 2016 11 28;13(1):194.
PMID: 27894305

BACKGROUND: Hand, foot and mouth disease is caused by Enterovirus 71 (EV-A71) and Coxsackieviruses. EV-A71 infection is associated with high fever, rashes and ulcers but more severe symptoms such as cardiopulmonary failure and death have been reported. The lack of vaccines highlighted the urgency of developing preventive agents against EV-A71. The molecular determinants of virulent phenotypes of EV-A71 is unclear. It remains to be investigated if specific molecular determinants would affect the cell culture growth characteristics of the EV-A71 fatal strain in Rhabdomyosarcoma (RD) cells.
RESULTS: In this study, several genetically modified sub-genotype B4 EV-A71 mutants were constructed by site-directed mutations at positions 158, 475, 486, 487 and 5262 or through partial deletion of the 5'-NTR region (∆ 11 bp from nt 475 to 486) to generate a deletion mutant (PD). EV-A71 mutants 475 and PD caused minimal cytopathic effects, produced lowest viral RNA copy number, viral particles as well as minimal amount of viral protein (VP1) in RD cells when compared to mutants 158, 486, 487 and 5262.
CONCLUSIONS: The molecular determinants of virulent phenotypes of EV-A71 sub-genotype B4 strain 41 (5865/Sin/000009) were found to differ from the C158 molecular determinant reported for the fatal EV-A71 sub-genotype B1 strain (clinical isolate 237). The site-directed mutations (SDM) introduced at various sites of the cDNA affected growth of the various mutants when compared to the wild type. Lowest viral RNA copy number, minimal number of plaques formed, higher infectious doses required for 50% lethality of RD cells and much reduced VP1 of the EV-A71 sub-genotype B4 strain 41 genome was attained in mutants carrying SDM at position 475 and through partial deletion of 11 bp at the 5'-NTR region.

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