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SARS-CoV-2 S2P spike ages through distinct states with altered immunogenicity.
Journal of Biological Chemistry  (IF5.157),  Pub Date : 2021-08-27, DOI: 10.1016/j.jbc.2021.101127
Adam S Olia,Yaroslav Tsybovsky,Steven J Chen,Cuiping Liu,Alexandra F Nazzari,Li Ou,Lingshu Wang,Wing-Pui Kong,Kwan Leung,Tracy Liu,Tyler Stephens,I-Ting Teng,Shuishu Wang,Eun Sung Yang,Baoshan Zhang,Yi Zhang,Tongqing Zhou,John R Mascola,Peter D Kwong

The SARS-CoV-2 spike is the primary target of virus-neutralizing antibodies and critical to the development of effective vaccines against COVID-19. Here, we demonstrate that the prefusion-stabilized two-proline "S2P" spike-widely employed for laboratory work and clinical studies-unfolds when stored at 4 °C, physiological pH, as observed by electron microscopy (EM) and differential scanning calorimetry, but that its trimeric, native-like conformation can be reacquired by low pH treatment. When stored for approximately 1 week, this unfolding does not significantly alter antigenic characteristics; however, longer storage diminishes antibody binding, and month-old spike elicits virtually no neutralization in mice despite inducing high ELISA-binding titers. Cryo-EM structures reveal the folded fraction of spike to decrease with aging; however, its structure remains largely similar, although with varying mobility of the receptor-binding domain. Thus, the SARS-CoV-2 spike is susceptible to unfolding, which affects immunogenicity, highlighting the need to monitor its integrity.