Overview of Nucleocapsid-Targeting Vaccines against COVID-19.

The new SARS-CoV-2 coronavirus, which emerged in late 2019, is a highly variable causative agent of COVID-19, a contagious respiratory disease with potentially severe complications. Vaccination is considered the most effective measure to prevent the spread and complications of this infection. Spike (S) protein-based vaccines were very successful in preventing COVID-19 caused by the ancestral SARS-CoV-2 strain; however, their efficacy was significantly reduced when coronavirus variants antigenically different from the original strain emerged in circulation. This is due to the high variability of this major viral antigen caused by escape from the immunity caused by the infection or vaccination with spike-targeting vaccines. The nucleocapsid protein (N) is a much more conserved SARS-CoV-2 antigen than the spike protein and has therefore attracted the attention of scientists as a promising target for broad-spectrum vaccine development. Here, we summarized the current data on various N-based COVID-19 vaccines that have been tested in animal challenge models or clinical trials. Despite the high conservatism of the N protein, escape mutations gradually occurring in the N sequence can affect its protective properties. During the three years of the pandemic, at least 12 mutations have arisen in the N sequence, affecting more than 40 known immunogenic T-cell epitopes, so the antigenicity of the N protein of recent SARS-CoV-2 variants may be altered. This fact should be taken into account as a limitation in the development of cross-reactive vaccines based on N-protein.