Siew Wai Fong
Email Address
dbsfsw@nus.edu.sg
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Publication Efficient recall of SARS-CoV-2 variant-reactive B cells and T responses in the elderly upon heterologous mRNA vaccines as boosters(WILEY, 2022-11-16) Rouers, Angeline; Wong, Nathan; Goh, Yun Shan; Torres-Ruesta, Anthony; Tay, Matthew Zirui; Chang, Zi Wei; Fong, Siew-Wai; Neo, Vanessa; Kam, Isaac Kai Jie; Yeo, Nicholas Kim-Wah; Huang, Yuling; Loh, Chiew Yee; Hor, Pei Xiang; Wong, Joel Xu En; Tan, Yong Jie; Macary, Paul A; Qian, Xinlei; Wang Bei; Ngoh, Eve Zi Xian; Salleh, Siti Nazihah Mohd; Wang, Cheng-; Poh, Xuan Ying; Rao, Suma; Chia, Po Ying; Ong, Sean WX; Lee, Tau Hong; Lin, Ray JH; Lim, Clarissa; Teo, Jefanie; Ren, Ee Chee; Lye, David Chien; Young, Barnaby E; Ng, Lisa FP; Renia, Laurent; Assoc Prof Paul A MacAry; MEDICINE; ORTHOPAEDIC SURGERY; MICROBIOLOGY AND IMMUNOLOGY; BIOLOGICAL SCIENCES; BIOCHEMISTRYWaning antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of variants of concern highlight the need for booster vaccinations. This is particularly important for the elderly population, who are at a higher risk of developing severe coronavirus disease 2019 (COVID-19) disease. While studies have shown increased antibody responses following booster vaccination, understanding the changes in T and B cell compartments induced by a third vaccine dose remains limited. We analyzed the humoral and cellular responses in subjects who received either a homologous messenger RNA(mRNA) booster vaccine (BNT162b2 + BNT162b2 + BNT162b2; ‘‘BBB”) or a heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ‘‘BBM”) at Day 0 (prebooster), Day 7, and Day 28 (postbooster). Compared with BBB, elderly individuals (≥60 years old) who received the BBM vaccination regimen display higher levels of neutralizing antibodies against the Wuhan and Delta strains along with a higher boost in immunoglobulin G memory B cells, particularly against the Omicron variant. Circulating T helper type 1(Th1), Th2, Th17, and T follicular helper responses were also increased in elderly individuals given the BBM regimen. While mRNA vaccines increase antibody, T cell, and B cell responses against SARS-CoV-2 1 month after receiving the third dose booster, the efficacy of the booster vaccine strategies may vary depending on age group and regimen combination.Publication Fever patterns, cytokine profiles, and outcomes in COVID-19(Oxford University Press, 2020) Ng, D.H.L.; Choy, C.Y.; Chan, Y.-H.; Young, B.E.; Fong, S.-W.; Ng, L.F.P.; Renia, L.; Lye, D.C.; Chia, P.Y.; MEDICINE; BIOLOGICAL SCIENCES; BIOCHEMISTRYBackground. Prolonged fever is associated with adverse outcomes in dengue viral infection. Similar fever patterns are observed in COVID-19 with unclear significance. Methods. We conducted a hospital-based case.control study of patients admitted for COVID-19 with prolonged fever (fever >7 days) and saddleback fever (recurrence of fever, lasting <24 hours, after defervescence beyond day 7 of illness). Fever was defined as a temperature of ?38.0°C Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. Results. A total of 142 patients were included in the study; 12.7% (18/142) of cases had prolonged fever, and 9.9% (14/142) had saddleback fever. Those with prolonged fever had a median duration of fever (interquartile range [IQR]) of 10 (9.11) days for prolonged fever cases, while fever recurred at a median (IQR) of 10 (8.12) days for those with saddleback fever. Both prolonged (27.8% vs 0.9%; P < .01) and saddleback fever (14.3% vs 0.9%; P = .03) were associated with hypoxia compared with controls. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P = .05). Patients with prolonged fever had higher induced protein.10 and lower interleukin-1? levels compared with those with saddleback fever at the early acute phase of disease. Conclusions. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Patients with saddleback fever appeared to have good outcomes regardless of the fever. © 2020 The Author(s).Publication Decreased memory B cell frequencies in COVID-19 delta variant vaccine breakthrough infection(WILEY, 2022-01-21) Tay, Matthew Zirui; Rouers, Angeline; Fong, Siew-Wai; Goh, Yun Shan; Chan, Yi-Hao; Chang, Zi Wei; Xu, Weili; Tan, Chee Wah; Chia, Wan Ni; Torres-Ruesta, Anthony; Amrun, Siti Naqiah; Huang, Yuling; Hor, Pei Xiang; Loh, Chiew Yee; Yeo, Nicholas Kim-Wah; Wang, Bei; Ngoh, Eve Zi Xian; Salleh, Siti Nazihah Mohd; Chavatte, Jean-Marc; Lim, Alicia Jieling; Maurer-Stroh, Sebastian; Wang, Lin-Fa; Lin, Raymond Valentine Tzer Pin; Wang, Cheng-I; Tan, Seow-Yen; Young, Barnaby Edward; Leo, Yee-Sin; Lye, David C; Renia, Laurent; Ng, Lisa FP; Assoc Prof Tzer Pin Raymond Valentine Lin; MEDICINE; ORTHOPAEDIC SURGERY; MICROBIOLOGY AND IMMUNOLOGY; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOL; PATHOLOGYThe SARS-CoV-2 Delta (B.1.617.2) variant is capable of infecting vaccinated persons. An open question remains as to whether deficiencies in specific vaccine-elicited immune responses result in susceptibility to vaccine breakthrough infection. We investigated 55 vaccine breakthrough infection cases (mostly Delta) in Singapore, comparing them against 86 vaccinated close contacts who did not contract infection. Vaccine breakthrough cases showed lower memory B cell frequencies against SARS-CoV-2 receptor-binding domain (RBD). Compared to plasma antibodies, antibodies secreted by memory B cells retained a higher fraction of neutralizing properties against the Delta variant. Inflammatory cytokines including IL-1β and TNF were lower in vaccine breakthrough infections than primary infection of similar disease severity, underscoring the usefulness of vaccination in preventing inflammation. This report highlights the importance of memory B cells against vaccine breakthrough and suggests that lower memory B cell levels may be a correlate of risk for Delta vaccine breakthrough infection.Publication Systemic and coronary levels of CRP, MPO, sCD40L and PlGF in patients with coronary artery disease(2015) Fong, S.W; Few, L.L; See Too, W.C; Khoo, B.Y; Nik Ibrahim, N.N.I; Yahaya, S.A; Yusof, Z; Mohd Ali, R; Abdul Rahman, A.R; Yvonne-Tee, G.B; BIOLOGICAL SCIENCESBackground: Biomarkers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome. This study aimed to investigate the differences in level of several biomarkers, i.e. C-reactive protein, myeloperoxidase, soluble CD40 ligand and placental growth factor, between acute coronary syndrome and chronic stable angina patients. The relationship between these biomarkers in the coronary circulation and systemic circulation was also investigated. Methods: A total of 79 patients were recruited in this study. The coronary blood was sampled from occluded coronary artery, while the peripheral venous blood was withdrawn from antecubital fossa. The serum concentrations of C-reactive protein, soluble CD40 ligand and placental growth factor and plasma concentration of myeloperoxidase were measured using ELISA method. Results: The systemic level of the markers measured in the peripheral venous blood was significantly increased in acute coronary syndrome compared to chronic stable angina patients. The concentrations of the C-reactive protein, myeloperoxidase and soluble CD40 ligand taken from peripheral vein were closely similar to the concentration found in coronary blood of ACS patients. The level of placental growth factor was significantly higher in coronary circulation than its systemic level. Conclusion: The concentration of these C-reactive protein, myeloperoxidase, soluble CD40 ligand and placental growth factor were significantly increased in acute coronary syndrome patients. The concentration of the markers measured in the systemic circulation directly reflected those in the local coronary circulation. Thus, these markers have potential to become a useful tool in predicting plaque vulnerability in the future. © 2015 Fong et al.Publication Linear B-cell epitopes in the spike and nucleocapsid proteins as markers of SARS-CoV-2 exposure and disease severity(Elsevier B.V., 2020) Amrun, S.N.; Lee, C.Y.-P.; Lee, B.; Fong, S.-W.; Young, B.E.; Chee, R.S.-L.; Yeo, N.K.-W.; Torres-Ruesta, A.; Carissimo, G.; Poh, C.M.; Chang, Z.W.; Tay, M.Z.; Chan, Y.-H.; Chen, M.I.-C.; Low, J.G.-H.; Tambyah, P.A.; Kalimuddin, S.; Pada, S.; Tan, S.-Y.; Sun, L.J.; Leo, Y.-S.; Lye, D.C.; Renia, L.; Ng, L.F.P.; MEDICINE; DEAN'S OFFICE (SSH SCH OF PUBLIC HEALTH); SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOLOGICAL SCIENCES; BIOCHEMISTRYBackground: Given the unceasing worldwide surge in COVID-19 cases, there is an imperative need to develop highly specific and sensitive serology assays to define exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Methods: Pooled plasma samples from PCR positive COVID-19 patients were used to identify linear B-cell epitopes from a SARS-CoV-2 peptide library of spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins by peptide-based ELISA. Hit epitopes were further validated with 79 COVID-19 patients with different disease severity status, 13 seasonal human CoV, 20 recovered SARS patients and 22 healthy donors. Findings: Four immunodominant epitopes, S14P5, S20P2, S21P2 and N4P5, were identified on the S and N viral proteins. IgG responses to all identified epitopes displayed a strong detection profile, with N4P5 achieving the highest level of specificity (100%) and sensitivity (>96%) against SARS-CoV-2. Furthermore, the magnitude of IgG responses to S14P5, S21P2 and N4P5 were strongly associated with disease severity. Interpretation: IgG responses to the peptide epitopes can serve as useful indicators for the degree of immunopathology in COVID-19 patients, and function as higly specific and sensitive sero-immunosurveillance tools for recent or past SARS-CoV-2 infections. The flexibility of these epitopes to be used alone or in combination will allow for the development of improved point-of-care-tests (POCTs). Funding: Biomedical Research Council (BMRC), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from Agency of Science, Technology and Research (A*STAR), and National Medical Research Council (NMRC) COVID-19 Research fund (COVID19RF-001) and CCGSFPOR20002. ATR is supported by the Singapore International Graduate Award (SINGA), A*STAR. © 2020 The AuthorsPublication Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals(FRONTIERS MEDIA SA, 2022-11-14) Goh, Yun Shan; Rouers, Angeline; Fong, Siew-Wai; Zhuo, Nicole Ziyi; Hor, Pei Xiang; Loh, Chiew Yee; Huang, Yuling; Neo, Vanessa Kexin; Kam, Isaac Kai Jie; Wang, Bei; Ngoh, Eve Zi Xian; Salleh, Siti Nazihah Mohd; Lee, Raphael Tze Chuen; Pada, Surinder; Sun, Louisa Jin; Ong, Desmond Luan Seng; Somani, Jyoti; Lee, Eng Sing; Maurer-Stroh, Sebastian; Wang, Cheng-I; Leo, Yee-Sin; Ren, Ee Chee; Lye, David C; Young, Barnaby Edward; Ng, Lisa FP; Renia, Laurent; Dr Somani Jyoti; MEDICINE; MICROBIOLOGY AND IMMUNOLOGY; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOLOGICAL SCIENCES; BIOCHEMISTRYThe emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.Publication Systematic analysis of disease-specific immunological signatures in patients with febrile illness from Saudi Arabia(John Wiley and Sons Inc, 2020) Kam, Y.-W.; Ahmed, M.Y.; Amrun, S.N.; Lee, B.; Refaie, T.; Elgizouli, K.; Fong, S.-W.; Renia, L.; Ng, L.F.P.; BIOLOGICAL SCIENCES; BIOCHEMISTRYObjectives: Little is known about the prevalence of febrile illness in the Arabian region as clinical, laboratory and immunological profiling remains largely uncharacterised. Methods: A total of 2018 febrile patients from Jazan, Saudi Arabia, were recruited between 2014 and 2017. Patients were screened for dengue and chikungunya virus, Plasmodium, Brucella, Neisseria meningitidis, group A streptococcus and Leptospira. Clinical history and biochemical parameters from blood tests were collected. Patient sera of selected disease-confirmed infections were quantified for immune mediators by multiplex microbead-based immunoassays. Results: Approximately 20% of febrile patients were tested positive for one of the pathogens, and they presented overlapping clinical and laboratory parameters. Nonetheless, eight disease-specific immune mediators were identified as potential biomarkers for dengue (MIP-1?, MCP-1), malaria (TNF-?), streptococcal and meningococcal (eotaxin, GRO-?, RANTES, SDF-1? and PIGF-1) infections, with high specificity and sensitivity profiles. Notably, based on the conditional inference model, six of these mediators (MIP-1?, TNF-?, GRO-?, RANTES, SDF-1? and PIGF-1) were revealed to be 68.4% accurate in diagnosing different febrile infections, including those of unknown diseases. Conclusions: This study is the first extensive characterisation of the clinical analysis and immune biomarkers of several clinically important febrile infections in Saudi Arabia. Importantly, an immune signature with robust accuracy, specificity and sensitivity in differentiating several febrile infections was identified, providing useful insights into patient disease management in the Arabian Peninsula. © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian New Zealand Society for Immunology, Inc.Publication Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals(Frontiers Media S.A., 2021-11-19) Lim, Jackwee; Puan, Kia Joo; Wang, Liang Wei; Teng, Karen Wei Weng; Loh, Chiew Yee; Tan, Kim Peng; Carissimo, Guillaume; Chan, Yi-Hao; Poh, Chek Meng; Lee, Cheryl Yi-Pin; Fong, Siew-Wai; Yeo, Nicholas Kim-Wah; Chee, Rhonda Sin-Ling; Amrun, Siti Naqiah; Chang, Zi Wei; Tay, Matthew Zirui; Torres-Ruesta, Anthony; Leo Fernandez, Norman; How, Wilson; Andiappan, Anand Kumar; Lee, Wendy; Duan, Kaibo; Tan, Seow-Yen; Yan, Gabriel; Kalimuddin, Shirin; Lye, David Chien; Leo, Yee-Sin; Ong, Sean W. X.; Young, Barnaby E.; Renia, Laurent; Ng, Lisa F. P.; Lee, Bernett; Rötzschke, Olaf; DEAN'S OFFICE (DENTISTRY); MEDICINE; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOLOGICAL SCIENCES; BIOCHEMISTRYSevere SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and V?2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of “long COVID-19”, and defines key cells and cytokines that delineate true and quasi-convalescent states. Copyright © 2021 Lim, Puan, Wang, Teng, Loh, Tan, Carissimo, Chan, Poh, Lee, Fong, Yeo, Chee, Amrun, Chang, Tay, Torres-Ruesta, Leo Fernandez, How, Andiappan, Lee, Duan, Tan, Yan, Kalimuddin, Lye, Leo, Ong, Young, Renia, Ng, Lee and Rötzschke.Publication Viperin controls chikungunya virus-specific pathogenic T cell IFN? Th1 stimulation in mice(Rockefeller University Press, 2019) Carissimo, G.; Teo, T.-H.; Chan, Y.-H.; Lee, C.Y.-P.; Lee, B.; Torres-Ruesta, A.; Tan, J.J.L.; Chua, T.-K.; Fong, S.-W.; Lum, F.-M.; Ng, L.F.P.; MEDICINE; BIOLOGICAL SCIENCES; BIOCHEMISTRYChikungunya virus (CHIKV) has been a worldwide threat since its reemergence in La Reunion Island in 2004. Expression of the interferon-stimulated protein Viperin correlates with viral load burden in patients, and studies in mice have demonstrated its role to limit disease severity against CHIKV infection. Using Viperin2/2 mice, we aimed to understand the contribution of Viperin to the T-cell immune response against CHIKV. CD4 T-cell depletion in Viperin2/2 mice showed that increased late acute joint inflammation (5-8 d postinfection) was exclusively mediated by T cells. Specifically, CHIKV-infected Viperin2/2 mice showed an increased INF? Th1 profile of CD4 T cells, enhanced INF? stimulation by APCs, an increased INF? secretion profile in the joint microenvironment, and increased numbers of inflammatory monocytes in virus-infected joints compared with WT mice. Bone marrow grafting experiments showed that Viperin expression in both hematopoietic and non-hematopoietic cells is instrumental in reducing disease severity associated with a CD4 T-cell response. © 2019 Carissimo et al.Publication Resistance of SARS-CoV-2 variants to neutralization by convalescent plasma from early COVID-19 outbreak in Singapore(Nature Research, 2021-10-25) Wang, Bei; Goh, Yun Shan; Prince, Tessa; Ngoh, Eve Zi Xian; Salleh, Siti Nazihah Mohd; Hor, Pei Xiang; Loh, Chiew Yee; Fong, Siew Wai; Hartley, Catherine; Tan, Seow-Yen; Young, Barnaby Edward; Leo, Yee-Sin; Lye, David C.; Maurer-Stroh, Sebastian; Ng, Lisa F. P.; Hiscox, Julian A.; Renia, Laurent; Wang, Cheng-, I; MEDICINE; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH; BIOLOGICAL SCIENCES; BIOCHEMISTRYThe rapid spreading of SARS-CoV-2 variants B.1.1.7 originated from the United Kingdom and B.1.351 from South Africa has contributed to the second wave of COVID-19 cases in the respective countries and also around the world. In this study, we employed advanced biochemical and virological methodologies to evaluate the impact of Spike mutations of these strains on the degree of protection afforded by humoral immune responses following natural infection of the ancestral SARS-CoV-2 strain during the early stages of the outbreak. We found that antibody-mediated neutralization activity was partially reduced for B.1.1.7 variant and significantly attenuated for the B.1.351 strain. We also found that mutations outside the receptor-binding domain (RBD) can strongly influence antibody binding and neutralization, cautioning the use of solely RBD mutations in evaluating vaccine efficacy. These findings highlight an urgent need to develop new SARS-CoV-2 vaccines that are not based exclusively on the ancestral SARS-CoV-2 Spike gene sequence. © 2021, The Author(s).