Since its emergence in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has developed into a global pandemic within a matter of months. While subunit vaccines are one of the prominent options for combating coronavirus disease 2019 (COVID‐19), the immunogenicity of spike protein‐based antigens remains unknown. When immunized in mice, the S1 domain induced much higher IgG and IgA antibody levels than the receptor‐binding domain (RBD) and more efficiently neutralized SARS‐CoV‐2 when adjuvanted with alum. It is inferred that a large proportion of these neutralization epitopes are located in the S1 domain but outside the RBD and that some of these are spatial epitopes. This finding indicates that expression systems with posttranslational modification abilities are important to maintain the natural configurations of recombinant spike protein antigens and are critical for effective COVID‐19 vaccines. Further, adjuvants prone to a Th1 response should be considered for S1‐based subunit COVID‐19 vaccines to reduce the potential risk of antibody‐dependent enhancement of infection. Highlights Antibodies induced by the S1 domain neutralized SARS‐Cov‐2 more efficiently than those induced by the receptor‐binding domain (RBD). Antibodies induced by the S1 domain produced from HEK293K cells neutralized SARS‐Cov‐2 more efficiently than those induced by the S1 domain produced from E. coli. Both the S1 domain and the RBD induced a highly Th2 response when adjuvanted with alum.