Dr Kok Kin-hang
Associate Professor 
Department of Microbiology

I am a molecular virologist researching host-virus interaction and host antiviral responses, including “interferon signaling”. In 2011, I identified a host antiviral protein, PACT, that can recognize the viral defective interfering RNAs and optimally induce the production of type-I interferon, an indispensable primary antiviral response in early infection.[1] [2]

After joining the Department of Microbiology in 2014, I continued to characterise this novel antiviral mechanism and the viral interferon antagonists encoded by the influenza A virus, Herpes Simplex virus, Measles virus, and MERS-CoV (reference 3-7).[3] [4] [5] [6] [7] I believed that understanding the weaknesses and strengths of viruses and the defence mechanism of our body system is the crucial starting point to designing new strategies against viral infections. 

In 2018, inspired by the leader of the department, Professor Yuen Kwok-yung, I started investigating the defective interfering genomes found in H7N9-infected patients. Using the third-generation sequencing technology, a set of highly expressed avian influenza defective interfering genes were identified.[8] This work is the foundation of the newly designed intradermal influenza vaccine prototype that used these defective genomes (US provisional patent: 63/300,864). Right before the start of the COVID-19 pandemic, I was studying MERS-CoV - host interaction by CRISPR-Cas9 genome-wide editing approach and generating recombinant MERS-CoV using a bac recombineering technique. 

All these projects were postponed because of the new coronavirus outbreak at the end of December 2019. As a great leader, Professor Yuen coordinated the department's basic scientists and clinicians to prepare and tackle this potentially significant pandemic. Under his supervision, I completed the sequence analysis of the new coronavirus SARS-CoV-2 and characterised its genome in January 2020.[9] [10] Professor Yuen is not just a chair professor but is also much more like a CEO of a company or parent of a big family. He coordinated senior department members and highlighted and prioritised the critical tasks during the first phase of the pandemic so that everyone could maximise their contribution to understanding this new disease. 

I continued to study viral interferon antagonists. One of the differences between SARS-CoV-1 and SARS-CoV-2 is the presence of the viral orf8. Further characterisation of this unique SARS-CoV-2 protein revealed its early high-level expression in the serum of patients. This discovery led to the development of an accurate diagnosis of COVID-19 by this new immunogenic secreted orf8 protein.[11] [12]

I had been studying MERS-CoV-host interaction before the pandemic. Several small-molecule drugs had been preliminarily tested to suppress MERS-CoV infection. These drugs are host targeting, implying that they also work for SARS-CoV-2. One of the small-molecule drugs, targeting the class III phosphoinositide 3-kinase, potently suppresses the SARS-CoV-2 infection in ex-vivo human lung tissue.[13] In addition to searching for possible host-targeting small-molecule drugs, my team continued to investigate the property of this new virus, reporting the potent interferon antagonistic activity of the SARS-CoV-2 nsp13, nsp14, nsp15, and orf6. This indicated that the new coronavirus is afraid of human interferon signalling, similar to the SARS-CoV-1 and MERS-CoV.[14] [15]

“If the virus is so afraid of the interferon, can we utilise this to design a better vaccine?,” I asked myself when the mRNA vaccine entered the market. The hosts infected with SARS-CoV-1, MERS-CoV and SARS-CoV-2 have a characteristic called “delayed Type-I interferon signalling”. I proposed the hypothesis that putting the interferon gene (which the virus hates most) into the viral genome would restore the proper interferon signalling, resulting in a better immune response and broad protection. 










 




This idea could only be tested in our department because we have a well-established BSL3 laboratory, animal models, and colleagues with different expertise. After one and half years of effort, this next-generation COVID-19 vaccine was made and shown to have broader protection and better T-cell response in animals with just one single nasal spray (US provisional patent 63/382,009). I hope that this interferon vaccine and nasal protein vaccine boosters will benefit human health in coming years.[16] [17][18]

The Department of Microbiology is a lovely big family, and every member shared a common goal in the past three years: to fight against this emerging disease. During the early part of the pandemic, most of the laboratories on Sassoon Road were shut down or partially closed. By contrast, the lights from the microbiology laboratories were always on – weekdays and weekends. We should honour the hard work of every staff and student, junior or senior.


[1] Kok KH, Lui PY, Ng MHJ, Siu KL, Au SWN, Jin DY. (2011) The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host Microbe 9:299-309.  
[2] Kok KH, Jin DY. (2013) Balance of power in host-virus arms races. Cell Host Microbe 14:5-6.  
[3] Kew C, Lui PY, Chan CP, Au WN, Mohr I, Jin DY, Kok KH. (2013) Suppression of PACT-induced type I interferon production by herpes simplex virus type 1 Us11 protein. J Virol 87:13141-13149.
[4] Ho TH, Kew C, Lui PY, Chan CP, Satoh T, Akira S, Jin DY, Kok KH. (2015) PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine. Journal of Virology. 90:1557-68.  
[5] Yuen CK, Chan CP, Fung SY, Wang PH, Wong WM, Tang HM, Yuen KS, Chan CP, Jin DY, Kok KH. (2016) Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation. Journal of Virology. 90:3902-12.  
[6] Lui PY, Wong LR, Ho TH, Au SWN, Chan CP, Kok* KH, Jin DY. (2017) PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization. Journal of Immunology. 199:1846-55 (*: co-corresponding authors)  
[7] Chan CP, Yuen CK, Cheung PH, Fung SY, Lui PY, Chen H, Kok* KH, Jin DY. (2018) Antiviral activity of double-stranded RNA-binding protein PACT against influenza A virus mediated via suppression of viral RNA polymerase. FASEB Journal. 32:4380-4393 (*: co-corresponding authors)  
[8] Lui, WY, Yuen CK, Li C, Wong WM, Lui PY, Lin CH, Chan KH, Zhao H, Chen H, To KK, Zhang AJ, Yuen KY, Kok* KH. (2019) SMRT sequencing revealed the diversity and characteristics of defective interfering RNAs in influenza A (H7N9) virus infection. Emerging Microbes & Infections 8:662-674.  
[9] Chan JF, Yuan S, Kok* KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, Tsoi HW, Lo SK, Chan KH, Poon VK, Chan WM, Ip JD, Cai JP, Cheng VC, Chen H, Hui CK, Yuen KY. (2020) A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 395:514-523. (*: co-first author)  
[10] Chan JF, Kok* KH, Zhu Z, Chu H, To KK, Yuan S, Yuen KY. (2020) Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 9:221-236. (*: co-first and co-corresponding author)  
[11] Wang X, Lam JY, Wong WM, Yuen CK, Cai JP, Au SW, Chan JF, To KKW, Kok* KH, Yuen KY. (2020) Accurate Diagnosis of COVID-19 by a Novel Immunogenic Secreted SARS-CoV-2 orf8 Protein. mBio. 11:e02431-20. (*:co-corresponding author)  
[12] Wang X, Lam JY, Chen L, Au SW, To KKW, Yuen KY, Kok KH. (2021) Mining of linear B cell epitopes of SARS-CoV-2 ORF8 protein from COVID-19 patients. Emerg Microbes Infect. 10:1016-1023.
[13] Yuen CK, Wong WM, Mak LF, Wang X, Chu H, Yuen KY, Kok KH. (2021) Suppression of SARS-CoV-2 infection in ex-vivo human lung tissues by targeting class III phosphoinositide 3-kinase. J Med Virol. 93:2076-2083.  
[14] Yuen CK, Lam JY, Wong WM, Mak LF, Wang X, Chu H, Cai JP, Jin DY, To KK, Chan JF, Yuen KY, Kok KH. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect. 2020 9:1418-1428.  
[15] Lam JY, Yuen CK, Ip JD, Wong WM, To KK, Yuen KY, Kok KH. (2020) Loss of orf3b in the circulating SARS-CoV-2 strains. Emerg Microbes Infect. 9:2685-2696.  
[16] Lam JY, Ng YY, Yuen CK, Wong WM, Yuen KY, Kok KH. (2022) A nasal omicron vaccine booster elicits potent neutralizing antibody response against emerging SARS-CoV-2 variants. Emerg Microbes Infect. 11:964-967.
[17] Lam JY, Wong WM, Yuen CK, Ng YY, San CH, Yuen KY, Kok KH (2023) An RNA-Scaffold Protein Subunit Vaccine for Nasal Immunization. Vaccines 11(10):1550. 
[18] Yuen CT, Wong WM, Mak LF, Lam JY, Cheung LY, Cheung DT, Ng YY, Lee AC, Zhong N, Yuen KY, Kok KH (2023) An interferon-integrated mucosal vaccine provides pan-sarbecovirus protection in small animal models. Nature Communications 14(1):6762.