Structural biologists at the Hong Kong University of Science and Technology (HKUST) in collaboration with researchers from the AIDS Institute, the University of Hong Kong (HKU), the Department of Microbiology, the School of Clinical Medicine, University of Hong Kong LKS Faculty of Medicine (HKUMed) and State Key Laboratory of Emerging Infectious Diseases, HKU demonstrated that ZCB11, a broadly neutralizing antibody derived from a local mRNA vaccine against spreading Omicron variants of SARS-CoV-2, displays potent antiviral activities against all variants of concern (COVs), including the dominantly spreading Omicron BA.1, BA1.1 and BA.2. Critically, prophylactic or therapeutic administration of ZCB11 protects lung infection against Omicron virus challenge in golden Syrian hamsters. The research paper is now published online in Nature Communications (link to publication).
The surprisingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variants have posed great challenges to the effectiveness of current vaccines and antibody immunotherapy. In response to the continued emergence of SARS-CoV-2 Omicron variants with unpredictable pathogenicity, universal masking, quarantine, and endless viral testing must be maintained, resulting in social anxiety and economic disruption. It is therefore important to determine whether the host immune response can generate broadly neutralizing antibodies, which is essential not only for antibody-based immunotherapy, but also for vaccine optimization to induce a equally broad protection.
Research methods and results
In this study, the HKUMed team implemented an efficient cloning technology platform that natively matches the antibody genes of 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 neutralizes 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 pseudovirus and authentic live virus. Importantly, administration of ZCB11 protected lung infection against Omicron and Delta live viral challenges in golden Syrian hamsters, respectively, under prophylactic and therapeutic conditions. Additionally, the HKUST collaborative team deciphered the complex structure of ZCB11 and the spike protein at atomic resolution using a single cryo-EM particle, revealing the unique molecular mode of action of ZCB11, which lays a solid foundation for the future optimization of structure-guided antibodies and vaccines.
Significance of the study
“The results suggest that ZCB11 is a promising antibody for biomedical interventions against the concerning variants of pandemic SARS-CoV-2,” remarked Professor CHEN Zhiwei, Director of the AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, which led the study. “While our findings imply that the HKUMed team is at the global forefront of research and development of human antibodies and vaccines against COVID-19, we still urgently need to establish a capacity to large-scale manufacturing and clinical translation centers in Hong Kong, in order to fulfill its aspiration to become an international center of innovation.
“The high-resolution structural information allowed us to understand the molecular mechanism of ZCB11 responding to a concerning broad variant of SARS-CoV-2,” said Prof. DANG Shangyu, Assistant Professor, Division of Life Sciences, HKUST . “This study builds on HKUST’s state-of-the-art cryo-EM facility, which has demonstrated its ability to support not only structural biology research, but also many other research areas, such as antibody development in this study.”
About the research team
The research is led by Professor Chen Zhiwei, Director of the AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed; and was conducted mainly by Mr. ZHOU Biao, PhD student. Dr. ZHOU Runhong, Research Officer; Dr. Jasper CHAN Fuk-Woo, Associate Clinical Professor; LUO Mengxiao and PENG Qiaoli, doctoral students; Dr. YUAN Shuofeng, Assistant Professor, Department of Microbiology, School of Clinical Medicine, HKUMed. TANG Bingjie and LIU Hang, master’s students from the Division of Life Sciences, HKUST, shared the first authorship.
This collaborative team also includes Dr. Bobo MOK Wing-Yee, Scientific Officer; CHEN Bohao; Dr WANG Pui, Scientific Manager; Dr. 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, President and Associate Clinical Professor; Professor CHEN Honglin; Professor YUEN Kwok-Yung, Henry Fok Professor of Infectious Diseases and Chairman of Infectious Diseases, Department of Microbiology, School of Clinical Medicine, HKUMed and Director of State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong. Professor Dang Shangyu and Professor Chen Zhiwei shared authorship of the correspondence.
This study was supported by the Hong Kong Research Grants Council – Collaborative Research Fund (C7156‐20GF, C1134‐20GF and C5110‐20GF) and the Health and Medical Research Fund of the Food and Health Bureau (19181012); Shenzhen Science and Technology Program (JSGG20200225151410198 and JCYJ20210324131610027); Hong Kong [email protected], Innovation and Technology Commission, Hong Kong Special Administrative Region Government; and the Chinese national program on the 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 partially supported by the Hong Kong Research Grants Council – Theme‐based Research Scheme (T11‐706/18‐N) and the Wellcome Trust P86433.
All cryo-EM data was collected at the Biological Cryo-EM Center at HKUST, generously supported by a donation from the Lo Kwee Seong Foundation, as well as team support from Professor Dang Shangyu of 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 Seed and Initiation Grants (2021Szvup140) and HKUST.
About HKUST Cryo-EM Biological Center
Thanks to a generous donation from the Lo Kwee Seong Foundation, the Cryo-EM Biological Center at HKUST (http://cryoem.hkust.edu.hk/) was established to enable local scientists to study biological macromolecules at atomic resolution. Currently, the Center houses the modern state-of-the-art microscope, including the Titan Krios, the K3 Direct Electron Detector and several other high-end equipment, providing dedicated users with access to single particle analysis and to cryo-electron tomography with technical supports.
About the Department of Microbiology, HKUMed
The academic staff of the Department of Microbiology is actively involved in clinical services and basic research. Postgraduate students can pursue studies in various aspects of microbiology and infectious diseases leading to a master’s or doctoral degree. The Master of Medical Sciences program provides an opportunity for postgraduate students interested in more in-depth studies of the biomedical aspects of clinical microbiology and infectious diseases. In addition, the Department’s clinical staff are also involved in training clinical microbiologists in Hong Kong and Shenzhen. The Infectious Diseases Courses and Postgraduate Diploma Program provide a unique pathway for the training of qualified infectious disease physicians.
To promote knowledge exchange, research activities of the Department of Microbiology, School of Clinical Medicine, HKUMed can be viewed at https://www.microbiology.hku.hk/.