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Signal Transduct Target Ther ; 7(1): 257, 2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1967591


Highly divergent SARS-CoV-2 variants have continuously emerged and spread around the world, and updated vaccines and innovative vaccination strategies are urgently needed to address the global SARS-COV2 pandemic. Here, we established a series of Ad5-vectored SARS-CoV-2 variant vaccines encoding multiple spike proteins derived from the Alpha, Beta, Gamma, Epsilon, Kappa, Delta and Omicron lineages and analyzed the antibody immune responses induced by single-dose and prime-boost vaccination strategies against emerging SARS-CoV-2 variants of concern (VOCs). Single-dose vaccination with SARS-CoV-2 variant vaccines tended to elicit the optimal self-matched neutralizing effects, and Ad5-B.1.351 produced more broad-spectrum cross-neutralizing antibodies against diverse variants. In contrast, prime-boost vaccination further strengthened and broadened the neutralizing antibody responses against highly divergent SARS-CoV-2 variants. The heterologous administration of Ad5-B.1.617.2 and Ad5-B.1.429 to Ad5-WT-primed mice resulted in superior antibody responses against most VOCs. In particular, the Omicron spike could only stimulate self-matched neutralizing antibodies with infrequent cross-reactivities to other variants used in single-dose vaccination strategies; moreover, with prime-boost regimens, this vaccine elicited an optimal specific neutralizing antibody response to Omicron, and prompted cross-antibody responses against other VOCs that were very similar to those obtained with Ad5-WT booster. Overall, this study delineated the unique characteristics of antibody responses to the SARS-CoV-2 VOC spikes with the single-dose or prime-boost vaccination strategies and provided insight into the vaccine development of next SARS-CoV-2 VOCs.

COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing/genetics , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Humans , Mice , RNA, Viral , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
Signal Transduct Target Ther ; 7(1): 139, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815514


The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection- and vaccination-induced antibodies, highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies (bnAbs). Here, we developed a panel of bnAbs against Omicron and other variants of concern (VOCs) elicited by vaccination of adenovirus-vectored COVID-19 vaccine (Ad5-nCoV). We also investigated the human longitudinal antibody responses following vaccination and demonstrated how the bnAbs evolved over time. A monoclonal antibody (mAb), named ZWD12, exhibited potent and broad neutralization against SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa, Delta, and Omicron by blocking the spike protein binding to the angiotensin-converting enzyme 2 (ACE2) and provided complete protection in the challenged prophylactic and therapeutic K18-hACE2 transgenic mouse model. We defined the ZWD12 epitope by determining its structure in complex with the spike (S) protein via cryo-electron microscopy. This study affords the potential to develop broadly therapeutic mAb drugs and suggests that the RBD epitope bound by ZWD12 is a rational target for the design of a broad spectrum of vaccines.

COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/genetics , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , COVID-19 Vaccines/genetics , Cryoelectron Microscopy , Epitopes , Humans , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Viral Envelope Proteins