Single-shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad, durable and protective systemic and mucosal immunity in mice
Authors:
- Cheang, Nicholas You Zhi
- Tan, Kai Sen
- Tan, Peck Szee
- Purushotorma, Kiren
- Yap, Wee Chee
- Tullett, Kirsteen McInnes
- Chua, Benson Yen Leong
- Yeoh, Aileen Ying-Yan
- Tan, Caris Qi Hui
- Qian, Xinlei
- Chen, Huixin
- Tay, Douglas Jie Wen
- Caminschi, Irina
- Tan, Yee Joo
- Macary, Paul Anthony
- Tan, Chee Wah
- Lahoud, Mireille Hanna
- Alonso, Sylvie
Details:
Molecular Therapy, Volume 32, Issue 7, 2024-07-03
Article Link: Click here
Current coronavirus disease 2019 vaccines face limitations including waning immunity, immune escape by severe acute respiratory syndrome coronavirus 2 (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 with 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 after 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 after immunization. Furthermore, Clec9A-RBD immunization induced a durable mono- and poly-functional T-helper 1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants of concern, including Omicron subvariants, and with a 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 approximately 2 log10 decrease in lung viral loads compared with 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.