A mosaic RBD-nanoparticle pan-sarbecovirus vaccine elicits nanobodies that target highly conserved epitopes

The SARS-CoV-2 virus, responsible for COVID-19, frequently undergoes mutations, leading to the emergence of new variants of concern (VOCs). The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, a critical target for vaccines and therapeutic monoclonal antibodies, has experienced substitutions resulting in reduced vaccine and antibody effectiveness.

For instance, most anti-RBD therapeutic monoclonal antibodies previously authorized have become ineffective against newer VOCs such as Omicron. To tackle the impact of VOC substitutions on therapeutic antibody efficacy, researchers explored single-domain nanobodies (VHHs) targeting more conserved regions of the RBD across various variants of concern (VOCs).

They employed a Beacon optofluidic platform to isolate and analyze single memory B cells from llamas immunized with a mosaic RBD-nanoparticle immunogen designed to generate a broad antibody response against sarbecoviruses. Through multiplex binding assays and analysis of VHH-RBD complex structures, they discovered nanobodies that bind to spike RBDs from diverse sarbecovirus strains, including those inaccessible to conventional two-domain antibodies.

These single-domain nanobodies not only neutralize SARS-CoV-2 variants of concern but also protect against zoonotic sarbecoviruses, indicating their potential therapeutic utility in combating current and future outbreaks.