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Abstract/Summary
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Vaccination with different vaccines has been implemented globally to counter the continuous COVID-19 pandemic.
However, the vaccine-elicited antibodies have reduced efficiency against the highly mutated Omicron sub-variants.
Previously, we developed a protein subunit COVID-19 vaccine called ZF2001, based on the dimeric receptor-binding
domain (RBD). This vaccine has been administered using different dosing intervals in real-world setting. Some
individuals received three doses of ZF2001, with a one-month interval between each dose, due to urgent clinical
requirements. Others had an extended dosing interval of up to five months between the second and third dose, a
standard vaccination regimen for the protein subunit vaccine against hepatitis B. In this study, we profile B cell
responses in individuals who received three doses of ZF2001, and compared those with long or short dosing intervals.
We observed that the long-interval group exhibited higher and broader serologic antibody responses. These
responses were associated with the increased size and evolution of vaccine-elicited B-cell receptor repertoires,
characterized by the elevation of expanded clonotypes and somatic hypermutations. Both groups of individuals
generated substantial amounts of broadly neutralizing antibodies (bnAbs) against various SARS-CoV-2 variants,
including Omicron sub-variants such as XBB. These bnAbs target four antigenic sites within the RBD. To determine the
vulnerable site of SARS-CoV-2, we employed cryo-electron microscopy to identify the epitopes of highly potent bnAbs
that targeted two major sites. Our findings provide immunological insights into the B cell responses elicited by RBDbased vaccine, and suggest that a vaccination regimen of prolonging time interval should be used in practice.
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