AbstractThe structure‐based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen‐induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS‐CoV‐2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top‐scoring variant receptor binding domain‐G502E prevented spike‐induced cell‐to‐cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3‐fold in rabbit immunizations. We name our strategy BIBAX for body‐inert, B‐cell‐activating vaccines, which in the future may be applied beyond SARS‐CoV‐2 for the improvement of vaccines by design.