RESUMO
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.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Células Dendríticas , Imunidade nas Mucosas , Lectinas Tipo C , SARS-CoV-2 , Animais , Camundongos , Células Dendríticas/imunologia , SARS-CoV-2/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Humanos , Feminino , Glicoproteína da Espícula de Coronavírus/imunologia , Receptores Mitogênicos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Receptores ImunológicosRESUMO
SignificanceAlthough the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24-amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.