Homologous and heterologous serological response to the N‐terminal domain of SARS‐CoV‐2 in humans and mice

The increasing numbers of infected cases of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses serious threats to public health and the global economy. Most SARS‐CoV‐2 neutralizing antibodies target the receptor binding domain (RBD) and some the N‐terminal domain (NTD) of the spike protein, which is the major antigen of SARS‐CoV‐2. While the antibody response to RBD has been extensively characterized, the antigenicity and immunogenicity of the NTD protein are less well studied. Using 227 plasma samples from COVID‐19 patients, we showed that SARS‐CoV‐2 NTD‐specific antibodies could be induced during infection. As compared to the results of SARS‐CoV‐2 RBD, the serological response of SARS‐CoV‐2 NTD is less cross‐reactive with SARS‐CoV, a pandemic strain that was identified in 2003. Furthermore, neutralizing antibodies are rarely elicited in a mice model when NTD is used as an immunogen. We subsequently demonstrate that NTD has an altered antigenicity when expressed alone. Overall, our results suggest that while NTD offers a supplementary strategy for serology testing, it may not be suitable as an immunogen for vaccine development. Receptor binding domain (RBD) of the SARS‐CoV‐2 spike protein has been extensively studied in functional antibody screening and COVID‐19 vaccine design. To explore the function of N‐terminal domain (NTD) of spike protein, we reveal that NTD is a supplementary antigen for serology testing, but not a suitable immunogen for vaccine design.