Protection of the receptor binding domain (RBD) dimer against SARS-CoV-2 and its variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant protein vaccines have been widely used in the real world and shown good protective effects. A vaccine prepared from the ancestral SARS-CoV-2 receptor-binding domain (RBD) homodimer was previously made a candidate in view of its effectiveness in rodents and nonhuman primates. Here, we report that the RBD homodimers of ancestral SARS-CoV-2 as well as the variant RBD dimers from the Beta, Delta, Lambda, Omicron, and Omicron sublineages, which were rapidly prepared using our universal dimeric protein platform, elicit both strong immunogenicity and good protection in vivo. The ancestral RBD vaccine was verified to provide cross-protection against the SARS-CoV-2 Delta variant from lethal challenge. A heterogeneous booster with Omicron BA.1 dimeric RBD vaccine based on a two-dose ancestral vaccine prime reduced the viral loads in Omicron BA.1 virus-challenged animals. In addition, vaccines prepared from dimeric Omicron XBB.1.5 RBD completely protected the mice from lethal challenge by Omicron XBB.1.16 and reduced the viral infection in the respiratory tract of Syrian hamsters. Thus, RBD homodimer vaccines can confer good protection against SARS-CoV-2 and its variants when used in homogeneous or heterogeneous boosting schemes. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants achieved immune escape and became less virulent and easily transmissible through rapid mutation in the spike protein, thus the efficacy of vaccines on the market or in development continues to be challenged. Updating the vaccine, exploring compromise vaccination strategies, and evaluating the efficacy of candidate vaccines for the emerging variants in a timely manner are important to combat complex and volatile SARS-CoV-2. This study reports that vaccines prepared from the dimeric receptor-binding domain (RBD) recombinant protein, which can be quickly produced using a mature and stable process platform, had both good immunogenicity and protection in vivo and could completely protect rodents from lethal challenge by SARS-CoV-2 and its variants, including the emerging Omicron XBB.1.16, highlighting the value of dimeric recombinant vaccines in the post-COVID-19 era.