Single-Dose Dendritic Cell-Targeted COVID-19 Vaccine Shows Exceptional Durability and Protection in Mice

Singapore & Melbourne, July 2024 — A groundbreaking study led by researchers from the Alonso group in the LSI Immunology Programme and Monash University has unveiled a promising next-generation COVID-19 vaccine that requires only a single dose to trigger long-lasting and broad immunity. The findings, published in Molecular Therapy, suggest that targeting vaccine candidates to a specific subset of dendritic cells could overcome critical limitations of existing COVID-19 vaccines. Current vaccines, while lifesaving, face challenges such as waning immunity, limited T cell responses, and poor protection at mucosal sites like the lungs. To address this, the team engineered a novel antibody-based construct, Clec9A-RBD, designed to deliver the SARS-CoV-2 receptor-binding domain (RBD) directly to conventional type 1 dendritic cells (cDC1).

These cells are powerful antigen-presenters that orchestrate robust antibody and T cell responses. In mouse studies, a single systemic injection of Clec9A-RBD induced remarkably durable immunity. Antibody responses remained strong for up to 21 months, with evidence of affinity maturation — meaning antibodies improved in strength and breadth over time. Importantly, these antibodies displayed neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity not only against ancestral SARS-CoV-2 but also across variants of concerns including pre-Omicron and Omicron lineages, as well as other related coronaviruses from the bat and pangolin lineages.

The vaccine also generated a sustained T cell response, including both CD4+ and CD8+ subsets. These responses were cross-reactive with all tested variants of concern, including Omicron subvariants, and a subset of polyfunctional T cells capable of producing multiple cytokines was detected. Notably, Clec9A-RBD stimulated significant mucosal immunity in the lungs, with tissue-resident memory T cells and protective antibodies present at respiratory surfaces. When vaccinated mice were challenged with ancestral SARS-CoV-2, they were fully protected, which correlated with significantly less weight loss and 100-fold lower viral loads in the lungs compared with unvaccinated controls.

The findings therefore suggest that Clec9A-RBD single shot immunization is expected to trigger robust and sustained, systemic and mucosal protective immunity against rapidly evolving SARS-CoV2 variants. With scalable antibody-based manufacturing, the Clec9A-taregting vaccine platform offers a cost-effective and rapidly deployable solution for future pandemics. As the equivalent of cDC1 subset exists in humans, the clinical application of this vaccine strategy is a realistic and exciting avenue.

Reference:
Cheang NYZ, Tan KS, Tan PS, et al. Single-shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad, durable and protective systemic and mucosal immunity in mice. Molecular Therapy. 2024. DOI: 10.1016/j.ymthe.2024.05.003