Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Cheang, N. Y. Z.; Tan, P. S.; Purushotorman, K.; Yap, W. C.; Chua, B. Y. L.; Tan, K. S.; Tullett, K. M.; Yeoh, A. Y.-Y.; Tan, C. Q. H.; Qian, X.; Tay, D. J. W.; Caminschi, I.; Tan, Y. J.; MacAry, P. A.; Tan, C. W.; Lahoud, M. H.; Alonso, S.

doi:10.1101/2023.02.21.529344

bioRxiv · 10.1101/2023.02.21.529344

Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Cheang, N. Y. Z.·Tan, P. S.·Purushotorman, K.·Yap, W. C.·Chua, B. Y. L.·Tan, K. S.·Tullett, K. M.·Yeoh, A. Y.-Y.·Tan, C. Q. H.·Qian, X.·Tay, D. J. W.·Caminschi, I.·Tan, Y. J.·MacAry, P. A.·Tan, C. W.·Lahoud, M. H.·Alonso, S.

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Abstract

Current COVID-19 vaccines face certain limitations, which include waning immunity, immune escape by SARS-CoV-2 variants, limited CD8+ cellular response, and poor induction of mucosal immunity. Here, we engineered a Clec9A-RBD antibody construct that delivers the Receptor Binding Domain (RBD) from SARS-CoV-2 spike protein to conventional type 1 dendritic cells (cDC1). We showed that single dose immunization with Clec9A-RBD induced high RBD-specific antibody titers with a strong T-helper 1 (TH1) isotype profile and exceptional durability, whereby antibody titers were sustained for at least 21 months post-vaccination. Uniquely, affinity maturation of the antibody response was observed over time, as evidenced by enhanced neutralization potency and breadth across the sarbecovirus family. Consistently and remarkably, RBD-specific T-follicular helper cells and germinal center B cells were still detected at 12 months post-immunization. Increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the immune sera was also measured over time with comparable efficacy against ancestral SARS-CoV-2 and variants, including Omicron. Furthermore, Clec9A-RBD immunization induced a durable poly-functional TH1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants, including Omicron, and with robust CD8+ T cell signature. Lastly, Clec9A-RBD single dose systemic immunization primed effectively RBD-specific cellular and humoral mucosal immunity in lung. Taken together, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal immune responses against rapidly evolving SARS-CoV2 variants.

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Cheang, N. Y. Z., Tan, P. S., Purushotorman, K., Yap, W. C., Chua, B. Y. L., Tan, K. S., Tullett, K. M., Yeoh, A. Y.-Y., Tan, C. Q. H., Qian, X., Tay, D. J. W., Caminschi, I., Tan, Y. J., MacAry, P. A., Tan, C. W., Lahoud, M. H., Alonso, S.. 2023-02-21. Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses. https://doi.org/10.1101/2023.02.21.529344

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