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Researchers at the AIDS Institute, The University of Hong Kong (HKU), Department of Microbiology, School of Clinical Medicine, the LKS Faculty of Medicine of The University of Hong Kong (HKUMed) and the State Key Laboratory of Emerging Infectious Diseases, HKU, together with structural biologists at The Hong Kong University of Science and Technology (HKUST), have demonstrated that ZCB11, a broadly neutralising antibody derived from a local mRNA-vaccinee against the spreading Omicron variants of SARS-CoV-2, displays potent antiviral activities against all variants of concern (VOCs), including the dominantly spreading Omicron BA.1, BA1.1 and BA.2. Critically, either prophylactic or therapeutic ZCB11 administration protects lung infection against Omicron viral challenge in golden Syrian hamsters. The research paper is now published online in Nature Communications (link to publication).

Background
The strikingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variants have posed great challenges to the efficacy of current vaccines and antibody immunotherapy. In response to the continuous emergence of SARS-CoV-2 Omicron variants with unpredictable pathogenicity, universal masking, quarantine and endless viral testing have to be maintained, resulting in social anxiety and economic disruption. It is therefore important to investigate into whether host immune response can generate broadly neutralising antibodies, which is essential not only for antibody-based immunotherapy but also for vaccine optimisation to induce equally broad protection. 

Research methods and findings
In this study, the HKUMed team has established an effective platform of cloning technology that natively pairs antibody genes from individual human memory B cells. Using this technique, the research team successfully discovered ZCB11 after screening 34 BNT162b2-vaccinees in Hong Kong, and demonstrated that ZCB11 neutralises all VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2) and Omicron (B.1.1.529) by testing both pseudoviruses and authentic live viruses. Importantly, ZCB11 administration protects lung infection against both live Omicron and Delta viral challenges in golden Syrian hamsters respectively, under both prophylactic and therapeutic conditions. Furthermore, the HKUST collaborative team deciphered the complex structure of ZCB11 and spike protein at atomic resolution using single particle cryo-EM, revealing the unique molecular mode of ZCB11 action, which lays a solid foundation for upcoming structure-guided antibody and vaccine optimisation. 

Significance of the study
‘The findings suggested that ZCB11 is a promising antibody drug for biomedical interventions against pandemic SARS-CoV-2 variants of concern,’ remarked Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. ‘Although our findings implicate that the HKUMed team is at the world’s forefront of research and development of human antibody drugs and vaccines against COVID-19, we still urgently need to establish large-scale manufacturing capacity and clinical translational hubs in Hong Kong, in order to meet its aspiration of becoming an international innovation centre.’

‘The high-resolution structural information enabled us to understand the molecular mechanism of ZCB11 responding to a broad SARS-CoV-2 variant of concern,’ said Professor Dang Shangyu, Assistant Professor of Division of Life Science, HKUST. ‘This study relies on the state-of-the-art cryo-EM facility at HKUST, which demonstrated its capability to support not only research in structural biology, but also many other research fields, such as antibody development in this study.’

About the research team
The research is led by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed; and was conducted primarily by Mr Zhou Biao, PhD candidate. Dr Zhou Runhong, research officer; Dr Jasper Chan Fuk-woo, Clinical Associate Professor; Luo Mengxiao and Peng Qiaoli, PhD candidates; Dr Yuan Shuofeng, Assistant Professor at the Department of Microbiology, School of Clinical Medicine, HKUMed. Tang Bingjie and Liu Hang, MPhil students of Division of Life Science, HKUST, shared the first authorship.

This collaborative team also includes Dr Bobo Mok Wing-yee, Scientific Officer; Chen Bohao; Dr Wang Pui, Scientific Officer; Vincent Poon Kwok-man; Dr Chu Hin, Assistant Professor; Chris Chan Chung-sing, Jessica Tsang Oi-ling, Chris Chan Chun-yiu, Au Ka-kit, Man Hiu-on, Lu Lu, Dr Kelvin To Kai-wang, Chairperson and Clinical Associate Professor; Professor Chen Honglin; Professor Yuen Kwok-yung, Henry Fok Professor in Infectious Diseases and Chair of Infectious Diseases, Department of Microbiology, School of Clinical Medicine, HKUMed and Director of the State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong. Professor Dang Shangyu and Professor Chen Zhiwei shared the correspondence authorship.

Acknowledgements
This study was supported by the Hong Kong Research Grants Council - Collaborative Research Fund (C7156‐20GF, C1134‐20GF and C5110‐20GF) and Health and Medical Research Fund from the Food and Health Bureau (19181012); Shenzhen Science and Technology Program (JSGG20200225151410198 and JCYJ20210324131610027); the Hong Kong Health@InnoHK, Innovation and Technology Commission, the Government of the Hong Kong Special Administrative Region; and the China National Program on Key Research Project (2020YFC0860600, 2020YFA0707500 and 2020YFA0707504); and donations from the Friends of Hope Education Fund in Hong Kong. Professor Chen Zhiwei’s team was also partly supported by the Hong Kong Research Grants Council - Theme‐based Research Scheme (T11‐706/18‐N) and Wellcome Trust P86433.

All cryo-EM data were collected at the Biological Cryo-EM Center at HKUST, generously supported by a donation from the Lo Kwee Seong Foundation, together with support to Professor Dang Shangyu’s team from the Research Grants Council (RGC) of Hong Kong (ECS26101919, GRF16103321, C7009-20GF, C6001-21EF), Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) (SMSEGL20SC01-L), Guangdong Basic and Applied Basic Research Foundation (2021A1515012460), Shenzhen Special Fund for Local Science and Technology Development Guided by Central Government (2021Szvup140) and HKUST start-up and initiation grants.

About the Department of Microbiology, School of Clinical Medicine, HKUMed
The academic staff of Department of Microbiology are actively involved in clinical service and basic research. Postgraduate students may pursue studies on various aspects of microbiology and infectious diseases leading to an MPhil or PhD degree. The Master of Medical Sciences programme offers an opportunity to postgraduates interested in more in-depth studies on the biomedical aspects of clinical microbiology and infectious disease. In addition, the clinical staff of the Department also participate in the training of clinical microbiologists in Hong Kong and Shenzhen. The Infectious Disease Courses and Postgraduate Diploma Programme provides a unique avenue for the training of qualified medical practitioners in infectious diseases.

To promote knowledge exchange, research activities at the Department of Microbiology, School of Clinical Medicine, HKUMed can be viewed through http://www.microbiology.hku.hk/.

About HKUST Biological Cryo-EM Center
With a generous donation from the Lo Kwee Seong Foundation, the HKUST Biological Cryo-EM Center (https://cryo-em.hkust.edu.hk/) was established to allow local scientists to study biological macromolecules at atomic resolution. Currently, the Center hosts the modern state-of-the-art microscope, including Titan Krios, K3 direct electron detector and several other high-end equipment, providing dedicated users’ access to single particle analysis and cryo-electron tomography with technical supports.

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).