A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

Wang, K.; Cao, Y. R.; Zhou, Y.; Wu, J.; Jia, Z.; Hu, Y.; Yisimayi, A.; Fu, W.; Wang, L.; Liu, P.; Fan, K.; Chen, R.; Jing, L.; Wang, Y.; Ge, X.; Zhang, Q.; Wang, N.; Wu, W.; Gao, Y.; Miao, J.; Jiang, Y.; Qin, L.; Zhu, L.; Huang, W.; Zhang, Y.; Zhang, H.; Li, B.; Gao, Q.; Xie, X. S.; Wang, Q.; Wang, X.

Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-refractory and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.