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Emergence of dengue virus type 4 genotype IIA in Malaysia

AbuBakar S, Wong PF, Chan YF

J Gen Virol, 2002 Oct;83(Pt 10):2437-2442.
PMID: 12237425 DOI: 10.1099/0022-1317-83-10-2437

Phylogenetic analyses of the envelope (E) gene sequence of five recently isolated dengue virus type 4 (DENV-4) suggested the emergence of a distinct geographical and temporal DENV-4 subgenotype IIA in Malaysia. Four of the isolates had direct ancestral lineage with DENV-4 Indonesia 1973 and showed evidence of intra-serotypic recombination with the other recently isolated DENV-4, MY01-22713. The E gene of isolate MY01-22713 had strong evidence of an earlier recombination involving DENV-4 genotype II Indonesia 1976 and genotype I Malaysia 1969. These results suggest that intra-serotypic recombination amongst DENV-4 from independent ancestral lineages may have contributed to the emergence of DENV-4 subgenotype IIA in Malaysia.
Fulltext Outbreaks of enterovirus 71 infection

AbuBakar S, Chan YF, Lam SK

N Engl J Med, 2000 Feb 3;342(5):355-6.
PMID: 10660400 DOI: 10.1056/NEJM200002033420513
Immune responses against enterovirus A71 infection: Implications for vaccine success

Aw-Yong KL, NikNadia NMN, Tan CW, Sam IC, Chan YF

Rev Med Virol, 2019 09;29(5):e2073.
PMID: 31369184 DOI: 10.1002/rmv.2073

Enterovirus A71 (EV-A71) from the Picornaviridae family is an important emerging pathogen causing hand, foot, and mouth disease (HFMD) outbreaks worldwide. EV-A71 also caused fatal neurological complications in young children especially in Asia. On the basis of seroepidemiological studies from many Asian countries, EV-A71 infection is very common. Children of very young age are particularly vulnerable. Large-scale epidemics that occur every 3 to 4 years are associated with accumulation of an immunologically naive younger population. Capsid proteins especially VP1 with the presence of major B- and T-cell epitopes are the most antigenic proteins. The nonstructural proteins mainly contribute to T-cell epitopes that induce cross-reactive immune responses against other enteroviruses. Dominant epitopes and their neutralization magnitudes differ in mice, rabbits, and humans. Neutralizing antibody is sufficient for immune protection, but poorer cellular immunity may lead to severe neurological complications and deaths. Some chemokines/cytokines are consistently found in severely ill patients, for example, IL-6, IL-10, IL-17A, MCP-1, IL-8, MIG, IP-10, IFN-γ, and G-CSF. An increase in white cell counts is a risk factor for severe HFMD. Recent clinical trials on EV-A71 inactivated vaccine showed >90% efficacy and a robust neutralization response that was protective, indicating neutralizing antibody correlates for protection. No protection against other enteroviruses was observed. A comprehensive understanding of the immune responses to EV-A71 infection will benefit the development of diagnostic tools, potential therapeutics, and subunit vaccine candidates. Future development of a multivalent enterovirus vaccine will require knowledge of correlates of protection, understanding of cross-protection and memory T-cell responses among enteroviruses.
Fulltext Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

Aw-Yong KL, Sam IC, Koh MT, Chan YF

PLoS One, 2016;11(11):e0165659.
PMID: 27806091 DOI: 10.1371/journal.pone.0165659

Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD). Unlike other enteroviruses that cause HFMD, EV-A71 is more frequently associated with severe neurological complications and fatality. To date, no effective licensed antivirals are available to combat EV-A71 infection. Little is known about the immunogenicity of viral non-structural proteins in humans. Previous studies have mainly focused on characterization of epitopes of EV-A71 structural proteins by using immunized animal antisera. In this study, we have characterized human antibody responses against the structural and non-structural proteins of EV-A71. Each viral protein was cloned and expressed in either bacterial or mammalian systems, and tested with antisera by western blot. Results revealed that all structural proteins (VP1-4), and non-structural proteins 2A, 3C and 3D were targets of EV-A71 IgM, whereas EV-A71 IgG recognized all the structural and non-structural proteins. Sixty three synthetic peptides predicted to be immunogenic in silico were synthesized and used for the characterization of EV-A71 linear B-cell epitopes. In total, we identified 22 IgM and four IgG dominant epitopes. Synthetic peptide PEP27, corresponding to residues 142-156 of VP1, was identified as the EV-A71 IgM-specific immunodominant epitope. PEP23, mapped to VP1 41-55, was recognized as the EV-A71 IgG cross-reactive immunodominant epitope. The structural protein VP1 is the major immunodominant site targeted by anti-EV-A71 IgM and IgG antibodies, but epitopes against non-structural proteins were also detected. These data provide new understanding of the immune response to EV-A71 infection, which benefits the development of diagnostic tools, potential therapeutics and subunit vaccine candidates.
Fulltext Seroprevalence survey of Chikungunya virus in Bagan Panchor, Malaysia

Ayu SM, Lai LR, Chan YF, Hatim A, Hairi NN, Ayob A, et al.

Am J Trop Med Hyg, 2010 Dec;83(6):1245-8.
PMID: 21118929 DOI: 10.4269/ajtmh.2010.10-0279

In 2006, an outbreak of Chikungunya virus (CHIKV) of the Asian genotype affected over 200 people in Bagan Panchor village in Malaysia. One year later, a post-outbreak survey was performed to determine attack rate, asymptomatic rate, and post-infection sequelae. Findings were compared with recent CHIKV outbreaks of the Central/East African genotype. A total of 180 residents were interviewed for acute symptoms and post-infection physical quality of life and depressive symptoms. Sera from 72 residents were tested for CHIKV neutralizing antibodies. The estimated attack rate was 55.6%, and 17.5% of infected residents were asymptomatic. Arthralgia was reported up to 3 months after infection, but there were no reports of long-term functional dependence or depression. Symptomatic and seropositive residents were significantly more likely to live in the area with the most dense housing and commercial activities. CHIKV had a high attack rate and considerable clinical impact during the Bagan Panchor outbreak.
Fulltext SARS-CoV-2 genomic surveillance in Malaysia: displacement of B.1.617.2 with AY lineages as the dominant Delta variants and the introduction of Omicron during the fourth epidemic wave

Azami NAM, Perera D, Thayan R, AbuBakar S, Sam IC, Salleh MZ, et al.

Int J Infect Dis, 2022 Dec;125:216-226.
PMID: 36336246 DOI: 10.1016/j.ijid.2022.10.044

OBJECTIVES: This study reported SARS-CoV-2 whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program.
METHODS: COVID-19 samples that tested positive by reverse transcription polymerase chain reaction and with cycle threshold values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data database.
RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern, including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time, was displaced by AY.59 and AY.79 lineages in Peninsular (west) Malaysia, and the AY.23 lineage in east Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron variant of concern) in the country.
CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between west and east Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.
Stability of enteroviruses on toys commonly found in kindergarten

Baharin SNAN, Tan SL, Sam IC, Chan YF

Trop Biomed, 2023 Dec 01;40(4):478-485.
PMID: 38308836 DOI: 10.47665/tb.40.4.014

Hand, foot, and mouth disease (HFMD) is a contagious childhood disease caused by enteroviruses including enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6) and CV-A16 transmitted via direct and indirect contact. Different types of toy surfaces can affect the stability of viruses. Understanding the stability of enteroviruses on toys provides insightful data for effective disinfection in kindergartens or homes. Porous (ethylene-vinyl acetate mat foam, paper, pinewood, polyester fabric, and squishy polyurethane foam) and non-porous (acrylonitrile butadiene styrene plastic and stainless-steel coin) surfaces were inoculated with EV-A71 at 4, 24, and 35°C, and coxsackieviruses at 24°C. Infectious enteroviruses were recovered and titred in median tissue culture infectious dose assay (TCID50). Atomic force microscopy (AFM) images were taken from surfaces to examine association of surface roughness with virus stability. Overall, infectious enteroviruses were persistent on all non-porous and porous surfaces. Virus persistence was longest at 4°C followed by 24°C and 35°C. EV-A71 half-lives ranged between 6.4-12.8 hours at 4°C, 2.4-6.7 hours at 24°C, and 0.13-2.7 hours at 35°C. At lower virus titres exposed to 24°C, half-lives of enteroviruses ranged from 0.1-1.4 hours. Surface roughness values from AFM suggested smooth surfaces of non-porous surfaces were associated with better virus stability. Temperature, enterovirus concentration, and type of surface affected persistence and stability of enteroviruses. Our findings suggest both porous and non-porous surfaces in kindergartens allow enterovirus persistence and should be frequently disinfected to curb HFMD outbreaks in kindergartens.
Fulltext Isolation and Identification of Inter-Species Enterovirus Recombinant Genomes

Bentley K, Tee HK, Pearson A, Lowry K, Waugh S, Jones S, et al.

Viruses, 2021 11 29;13(12).
PMID: 34960659 DOI: 10.3390/v13122390

Positive-strand RNA virus evolution is partly attributed to the process of recombination. Although common between closely genetically related viruses, such as within species of the Enterovirus genus of the Picornaviridae family, inter-species recombination is rarely observed in nature. Recent studies have shown recombination is a ubiquitous process, resulting in a wide range of recombinant genomes and progeny viruses. While not all recombinant genomes yield infectious progeny virus, their existence and continued evolution during replication have critical implications for the evolution of the virus population. In this study, we utilised an in vitro recombination assay to demonstrate inter-species recombination events between viruses from four enterovirus species, A-D. We show that inter-species recombinant genomes are generated in vitro with polymerase template-switching events occurring within the virus polyprotein coding region. However, these genomes did not yield infectious progeny virus. Analysis and attempted recovery of a constructed recombinant cDNA revealed a restriction in positive-strand but not negative-strand RNA synthesis, indicating a significant block in replication. This study demonstrates the propensity for inter-species recombination at the genome level but suggests that significant sequence plasticity would be required in order to overcome blocks in the virus life cycle and allow for the production of infectious viruses.
Fulltext The use of the amplification refractory mutation system (arms) in the detection of rare beta-thalassemia mutations in the Malays and Chinese in Malaysia

Chan YF, Tan KL, Wong YC, Wee YC, Yap SF, Tan JAMA

Southeast Asian J. Trop. Med. Public Health, 2001 Dec;32(4):872-9.
PMID: 12041567

Molecular characterization and prenatal diagnosis for beta-thalassemia can be carried out using the Amplification Refractory Mutation System (ARMS). The ARMS is a rapid and direct molecular technique in which beta-thalassemia mutations are visualized immediately after DNA amplification by gel electrophoresis. In the University of Malaya Medical Center, molecular characterization and prenatal diagnosis for beta-thalassemia is carried out using ARMS for about 96% of the Chinese and 84.6% of the Malay patients. The remaining 4% and 15.4% of the uncharacterized mutations in the Chinese and Malay patients respectively are detected using DNA sequencing. DNA sequencing is an accurate technique but it is more time-consuming and expensive compared with the ARMS. The ARMS for the rare Chinese beta-mutations at position -29 (A-->G) and the ATG-->AGG base substitution at the initiator codon for translation in the beta-gene was developed. In the Malays, ARMS was optimized for the beta-mutations at codon 8/9 (+G), Cap (+1) (A-->C) and the AATAAA-->AATAGA base substitution in the polyadenylation region of the beta-gene. The ARMS protocols were developed by optimization of the parameters for DNA amplification to ensure sensitivity, specificity and reproducibility. ARMS primers (sequences and concentration), magnesium chloride concentration, Taq DNA polymerase and PCR cycling parameters were optimized for the specific amplification of each rare beta-thalassemia mutation. The newly-developed ARMS for the 5 rare beta-thalassemia mutations in the Chinese and Malays in Malaysia will allow for more rapid and cost-effective molecular characterization and prenatal diagnosis for beta-thalassemia in Malaysia.
Cellular proteome alterations in response to enterovirus 71 and coxsackievirus A16 infections in neuronal and intestinal cell lines

Chan SY, Sam IC, Lai JK, Chan YF

J Proteomics, 2015 Jul 1;125:121-30.
PMID: 26003530 DOI: 10.1016/j.jprot.2015.05.016

Hand, foot and mouth disease is mainly caused by enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16), but EV-A71 is also associated with severe neurological complications. Host factors may contribute to the different clinical outcomes of EV-A71 and CV-A16 infections. A neurovirulent EV-A71 strain (EV-A71/UH1) from a fatal case, a non-neurovirulent EV-A71 strain (EV-A71/Sha66) and a CV-A16 strain (CV-A16/22159) from cases of uncomplicated HFMD were used. Replication of the viruses in SK-N-MC (neuronal) and HT-29 (intestinal) cell lines correlated with the severity of clinical disease associated with each virus. EV-A71/UH1 showed the greatest replication in neuronal cells. In HT-29 cells, both EV-A71 strains replicated well, but CV-A16/22159 showed no effective replication. The proteomes of mock and infected SK-N-MC and HT-29 cell lines were compared by 2D-SDS-PAGE. The differentially expressed proteins were identified by MALDI-TOF/TOF analysis. There were 46 and 44 differentially expressed proteins identified from SK-N-MC and HT-29 cells, respectively, categorized under apoptosis, stress, cytoskeletal, energy metabolism proteins and others. Western blot validation showed that EV-A71/UH1 and CV-A16 also differentially induced proteins involved in viral RNA translation and host cell stress responses in neuronal and intestinal cell lines.
Diverse human rhinoviruses A and C from children with respiratory infections in Kuala Lumpur, Malaysia

Chan YF, Jafar FL, Nathan AM, de Bruyne JA, Hassan A, Nor'e SS, et al.

J Infect, 2012 Jun;64(6):633-6.
PMID: 22425558 DOI: 10.1016/j.jinf.2012.03.011
Phylogenetic designation of enterovirus 71 genotypes and subgenotypes using complete genome sequences

Chan YF, Sam IC, AbuBakar S

Infect Genet Evol, 2010 Apr;10(3):404-12.
PMID: 19465162 DOI: 10.1016/j.meegid.2009.05.010

Human enterovirus 71 (EV-71) is genotyped for molecular epidemiological investigation mainly using the two structural genes, VP1 and VP4. Based on these, EV-71 is divided into three genotypes, A, B and C, and within the genotypes B and C, there are further subgenotypes, B1-B5 and C1-C5. Classification using these genes is useful but gives incomplete phylogenetic information. In the present study, the phylogenetic relationships amongst all the known EV-71 and human enterovirus A (HEV-A) isolates with complete genome sequences were examined. A different tree topology involving EV-71 isolates of subgenotypes, C4 and B5 was obtained in comparison to that drawn using VP1. The nucleotide sequence divergence of the C4 isolates was 18.11% (17-20%) when compared to other isolates of subgenotype C. However, this positions the C4 isolates within the cut-off divergence value of 17-22% used to designate the virus genotypes. Hence, it is proposed here that C4 should be designated as a new genotype D. In addition, the subgenotype B5 isolates had an average nucleotide divergence of only 6.14% (4-8%) when compared to other subgenotype B4 isolates. This places the B5 isolates within the subgenotype B4. It is proposed here that the B5 isolates to be redesignated as B4. With the newly proposed genotype D and inclusion of subgenotype B5 within B4, the average nucleotide divergence between genotypes was 18.99% (17-22%). Inter- and intra-subgenotype average divergences were 12.02% (10-14%) and 3.92% (1-10%), respectively. A phylogenetic tree built using the full genome sequences is robust as it takes into consideration changes in the sequences of both the structural and non-structural genes. Similar nucleotide similarities, however, were obtained if only VP1 and 3D RNA polymerase genes were used. Furthermore, addition of 3D RNA polymerase sequences will also show recombination events. Hence, in the absence of full genome sequences, it is proposed here that a combination of VP1 and 3D RNA polymerase gene sequences be used for initial genotyping of EV-71 isolates.
Enterovirus 71 infection induces apoptosis in Vero cells

Chan YF, Abubakar S

Malays J Pathol, 2003 Jun;25(1):29-35.
PMID: 16196375

The effects of Enterovirus 71 (HEV71) infection on African green monkey kidney cells (Vero) were investigated. It was found that the infected cells showed progressive cellular morphological changes characteristic in apoptotic cells within 10 hours post-infection. The number of apoptotic cells correlated significantly with the number of HEV71 antigen positive cells when cells were labeled using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and stained for HEV71 antigen. Approximately 11, 26, 45 and 50% of the infected cells were apoptotic at 12, 24, 48 and 72 hours post-infection, respectively. Internucleosomal DNA fragmentation, characteristic in the late stage of apoptosis was noted beginning on day 2 post-infection. The DNA fragmentation, however, was absent in cells treated with the heat- and ultraviolet light-inactivated virus inocula. These results demonstrate the capacity of HEV71 to induce apoptosis in the infected cells. The induction, however, requires high level of HEV71 infectivity and the presence of live virus particles, suggesting the need for the presence of specific viral proteins for apoptosis to occur.
Human enterovirus 71 subgenotype B3 lacks coxsackievirus A16-like neurovirulence in mice infection

Chan YF, AbuBakar S

Virol J, 2005;2:74.
PMID: 16122396

At least three different EV-71 subgenotypes were identified from an outbreak in Malaysia in 1998. The subgenotypes C2 and B4 were associated with the severe and fatal infections, whereas the B3 virus was associated with mild to subclinical infections. The B3 virus genome sequences had >= 85% similarity at the 3' end to CV-A16. This offers opportunities to examine if there are characteristic similarities and differences in virulence between CV-A16, EV-71 B3 and EV-71 B4 and to determine if the presence of the CV-A16-liked genes in EV-71 B3 would also confer the virus with a CV-A16-liked neurovirulence in mice model infection.
Fulltext Virucidal activity of Virkon S on human enterovirus

Chan YF, Abu Bakar S

Med J Malaysia, 2005 Jun;60(2):246-8.
PMID: 16114171

The efficacy of Virkon S, a commercial disinfectant as a virucidal spray against human enterovirus 71 (HEV71), the causative agent of the fatal form of hand, foot and mouth disease was examined. At least one log10 reduction of HEV71 titer was achieved when one spray of Virkon (1% or 2%) with ten minutes of contact time was applied. The infectivity was completely lost when four sprays of 1% or 2% Virkon were applied, suggesting that at least four sprays of 1% Virkon to the surface bound HEV71 was necessary to completely inactivate the virus. These findings suggest that Virkon S at the proper concentration is suitable to be used as an effective and easy to use disinfectant against HEV71.
Metastatic tumours of the jaws

Chan YF

Med J Malaya, 1972 Sep;27(1):48-51.
PMID: 4264825
Fulltext Comparative genetic analysis of VP4, VP1 and 3D gene regions of enterovirus 71 and coxsackievirus A16 circulating in Malaysia between 1997-2008

Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina W MZ, et al.

Trop Biomed, 2012 Sep;29(3):451-66.
PMID: 23018509 MyJurnal

Three genomic regions, VP4 capsid, VP1 capsid and 3D RNA polymerase of human enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) were sequenced to understand the evolution of these viruses in Malaysia. A total of 42 EV-71 and 36 CV-A16 isolates from 1997- 2008 were sequenced. Despite the presence of many EV-71 subgenotypes worldwide, only subgenotypes B3, B4, B5, C1 and C2 were present in Malaysia. Importation of other subgenotypes such as C3, C4/D and C5 from other countries was infrequent. For CV-A16, the earlier subgenotype B1 was replaced by subgenotypes B2a and the recent B2c. Subgenotype B2a was present throughout the study while B2c only emerged in 2005. No genetic signatures could be attributed to viral virulence suggesting that host factors have a major role in determining the outcome of infection. Only three EV-71 B3 isolates showed non-consistent phylogeny in the 3D RNA polymerase region which indicated occurrence of recombination in EV-71. High genetic diversity was observed in the Malaysian EV-71 but Malaysian CV-A16 showed low genetic diversity in the three genomic regions sequenced. EV-71 showed strong purifying selection, but that occurred to a lesser extent in CV-A16.
Hyperosmolar non-ketotic diabetic coma following leptospirosis--a case report

Chan YF

Med J Malaya, 1972 Mar;26(3):211-4.
PMID: 5031019
Some medical conditions in relation to dentistry

Chan YF

Dent J Malaysia Singapore, 1972 May;12(1):35-8.
PMID: 4507355
Seroepidemiology of enterovirus D68 infection in Kuala Lumpur, Malaysia between 2013-2015

Chan YF, Sam IC, Nayan E, Tan XH, Yogarajah T

J Med Virol, 2021 Oct 07.
PMID: 34617599 DOI: 10.1002/jmv.27381

Enterovirus D68 (EV-D68) is an emerging respiratory pathogen since the 2014 outbreak in USA. A low level of virus circulation has been reported in Kuala Lumpur, Malaysia in the past. However, the extent of the infection in Malaysia is not known. In the present study, we determine the seroepidemiology of EV-D68 in Kuala Lumpur, Malaysia before and after the USA outbreak in Aug 2014. A luciferase-based seroneutralization test was developed using a clone-derived prototype Fermon strain carrying a nanoluciferase marker. We screened the neutralization capacity of 450 serum samples from children and adults (1-89 years old) collected between 2013 to 2015. EV-D68 seropositivity increased with age, with children aged 1-3 showing significantly lower seroprevalence compared to adults. Multivariate analysis showed that older age groups 13-49 years (odds ratio [OR] 4.78 [95% CI 2.69-8.49], p<0.0001) and >50 years (OR 3.83 [95% CI 2.19-6.68], p<0.0001) were more likely to be EV-D68 seropositive than children <13 years. Sampling post-Sept 2014 compared to pre-Sept 2014 also predicted seropositivity (OR 1.66 [95% CI 1.04-2.65]). Presence of neutralizing antibodies against EV-D68 in the study population suggests that EV-D68 was circulating prior to 2014. A higher seropositivity post-Sept 2014 suggests that Malaysia also experienced an upsurge in EV-D68 infections after the USA outbreaks in Aug 2014. A low seropositivity rate observed in children, especially those aged 1-3 years old, suggests that they are at risk and should be prioritized for future vaccination. This article is protected by copyright. All rights reserved.

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