Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad, durable and protective systemic and mucosal immune responses in mice
(1) Zhi Cheang NY (2) Tan KS (3) Tan PS (4) Purushotorma K (5) Yap WC (6) Tullett KM (7) Leong Chua BY (8) Ying-Yan Yeoh A (9) Hui Tan CQ (10) Qian X (11) Chen H (12) Wen Tay DJ (13) Caminschi I (14) Tan YJ (15) Macary PA (16) Tan CW (17) Lahoud MH (18) Alonso S
(1) Zhi Cheang NY (2) Tan KS (3) Tan PS (4) Purushotorma K (5) Yap WC (6) Tullett KM (7) Leong Chua BY (8) Ying-Yan Yeoh A (9) Hui Tan CQ (10) Qian X (11) Chen H (12) Wen Tay DJ (13) Caminschi I (14) Tan YJ (15) Macary PA (16) Tan CW (17) Lahoud MH (18) Alonso S
Current COVID-19 vaccines face limitations including waning immunity, immune escape by SARS-CoV-2 variants, limited cellular response, and poor mucosal immunity. We engineered a Clec9A-Receptor Binding Domain (RBD) antibody construct that delivers the SARS-CoV-2 RBD to conventional type 1 dendritic cells. Compared to non-targeting approaches, single dose immunization in mice with Clec9A-RBD induced far higher RBD-specific antibody titers that were sustained for up to 21 months post-vaccination. Uniquely, increasing neutralizing and antibody-dependent cytotoxicity activities across the sarbecovirus family was observed, suggesting antibody affinity maturation over time. Consistently and remarkably, RBD-specific follicular T-helper cells and germinal center B cells persisted up to 12 months post-immunization. Furthermore, Clec9A-RBD immunization induced a durable mono- and poly-functional T(H)1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants of concern, including Omicron subvariants, and with robust CD8(+) T cell signature. Uniquely, Clec9A-RBD single-shot systemic immunization effectively primed RBD-specific cellular and humoral immunity in lung and resulted in significant protection against homologous SARS-CoV-2 challenge as evidenced by limited body weight loss and approx. 2 log(10) reduction in lung viral loads compared to non-immunized controls. Therefore, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal protective immunity against rapidly evolving SARS-CoV2 variants.
Author Info:
(1) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Imm
unology Programme, Life Sciences Institute, National University of Singapore, Singapore. (2) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (3) Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology; Monash University, Australia. (4) Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; Immunology Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (5) Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore. (6) Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology; Monash University, Australia. (7) Immunology Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (8) Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore. (9) Histology Core Facility, Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore. (10) Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; Immunology Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (11) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (12) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (13) Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology; Monash University, Australia; Dept. of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Melbourne, Australia. (14) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (15) Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; Immunology Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (16) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. (17) Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology; Monash University, Australia. (18) Infectious Diseases Translational Research Programme; Department of Microbiology & Immunology; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore. Electronic address: micas@nus.edu.sg.
