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Mol Ther ; 32(7): 2299-2315, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38715364

ABSTRACT

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.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Dendritic Cells , Immunity, Mucosal , Lectins, C-Type , SARS-CoV-2 , Animals , Mice , Dendritic Cells/immunology , SARS-CoV-2/immunology , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Antibodies, Viral/immunology , Antibodies, Neutralizing/immunology , Humans , Female , Spike Glycoprotein, Coronavirus/immunology , Receptors, Mitogen/immunology , Antibody-Dependent Cell Cytotoxicity/immunology , Receptors, Immunologic
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