Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody
Yi-Hsuan Chang, … , Shang-Te Danny Hsu, Kuo-I Lin
Yi-Hsuan Chang, … , Shang-Te Danny Hsu, Kuo-I Lin
Published May 22, 2024
Citation Information: JCI Insight. 2024;9(10):e179726. https://doi.org/10.1172/jci.insight.179726.
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Research Article COVID-19 Infectious disease

Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody

Abstract

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single–B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

Authors

Yi-Hsuan Chang, Min-Feng Hsu, Wei-Nan Chen, Min-Hao Wu, Wye-Lup Kong, Mei-Yeh Jade Lu, Chih-Heng Huang, Fang-Ju Chang, Lan-Yi Chang, Ho-Yang Tsai, Chao-Ping Tung, Jou-Hui Yu, Yali Kuo, Yu-Chi Chou, Li-Yang Bai, Yuan-Chih Chang, An-Yu Chen, Cheng-Cheung Chen, Yi-Hua Chen, Chun-Che Liao, Chih-Shin Chang, Jian-Jong Liang, Yi-Ling Lin, Takashi Angata, Shang-Te Danny Hsu, Kuo-I Lin

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Figure 6

O5C2 protects K18-hACE2 TG mice from BA.5 infection.

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O5C2 protects K18-hACE2 TG mice from BA.5 infection. (A) Flowchart of th...
(A) Flowchart of the experimental design of testing the prophylactic activity of O5C2 (15 mg/kg) to protect against challenge with BA.5 SARS-CoV-2 in K18-hACE2 TG mice. (B and C) Viral levels determined by PRNT (B) and real-time quantitative PCR (RT-qPCR) (C) in the lungs of infected mice with or without (PBS) pretreatment with O5C2. Data in B and C were analyzed by the 2-tailed Student’s t test to compare the results between treatment with PBS and O5C2 and are presented as the mean ± SEM (**P < 0.01, ***P < 0.001). (D) H&E staining showing the histopathology of the lungs in O5C2-pretreated mice on day 4 after BA.5 infection. Scale bar = 100 μm. (E–H) Transcriptome analysis by RNA-Seq. (E) Viral reads identified in the lungs of BA.5-infected mice receiving PBS or O5C2. (F) A volcano plot showing the DEGs as red dots, while green and gray dots represent nonsignificant and/or low (log2) fold-changes, respectively. The cutoff value for the DEGs was a P < 0.05 and log2 fold-change ≥ 1. (G) A heatmap of significant DEGs. (H) Bubble plots showing the top 20 biological process GO terms with the lowest overrepresented P value, where the plot on the left is based on upregulated genes, while the right plot is based on downregulated genes. The gene ratio on the x axis represents the percentage of genes under a GO term that are differentially expressed. The size of the point indicates the number of DEGs, while the blue color gradient represents the P value.