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Children exhibit a robust B-cell response to Omicron BA.2 after breakthrough infection with limited influence from the original antigenic sin

Cellular & Molecular Immunology volume 22, pages 127–130 (2025)Cite this article

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SARS-CoV-2 remains prevalent, with highly diverse strains carrying spike proteins with antigenic profiles distinct from those of the original strain (Wuhan Hu-1 or WT). Since November 2021, Omicron has acquired a remarkable capacity to outcompete previous SARS-CoV-2 and has become the dominant variant globally [1]. Extensive studies have provided insights into how the adult immune system, particularly humoral immunity, respond to SARS-CoV-2 and its variants, including Omicron [2]. A long-term study revealed that Omicron infections following previous Wuhan Hu-1 infections failed to increase the level of neutralizing antibodies against Omicron in adults [3]. This suggests an original antigenic sin (OAS), which tends to induce a recalled antibody response against preexposed antigens and weakens the response to new antigens, potentially explaining the frequent reinfections of SARS-CoV-2 variants. Other researchers have reported that the immune imprinting induced by WT vaccination biases antibody neutralization toward WT in Omicron breakthrough infections in adults [4, 5]. Previous research from our team has demonstrated the critical role of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 in interacting with ACE2 and inducing neutralizing antibodies. Furthermore, mutations in the RBD significantly influence the neutralizing activity of existing monoclonal antibodies (mAbs) [6]. We have also reported the characteristics of the immune response after WT infection in children, revealing the quick and potent induction of protective humoral immunity [7]. Nevertheless, the understanding of the antibody response against Omicron and other variants in children remains poorly understood.

We investigated whether prior WT vaccination affects the humoral immune response to the newly encountered variants in children. The neutralizing activities of plasma antibodies against the Omicron BA.2 and WT strains were analyzed in the primary and breakthrough BA.2 infection groups. Both groups presented high levels of neutralizing antibodies against BA.2, with the breakthrough infection group exhibiting slightly higher neutralizing titers (Fig. 1B, C). Interestingly, compared with adults infected with BA.2 after vaccination [4, 5], children presented much higher levels of neutralizing antibodies against Omicron BA.2 than against WT, indicating that the antibody response to BA.2 was not significantly influenced by the OAS of prior WT vaccination. We further investigated the contribution of RBD- and S2-specific antibodies induced by BA.2 immune boosting. The plasma antibody binding titer of the breakthrough infection group to BA.2 RBD was significantly greater than that in the primary infection group (Supplementary Fig. 1), suggesting that previous exposure to the WT antigen contributed to the recalled antibody response against shared RBD epitopes between WT and BA.2. The S2 domain of the spike protein is conserved and has been identified as the target of several broadly neutralizing antibodies (nAbs) against SARS-CoV-2 and other human coronaviruses [9,10,11]. Although the antibody binding response to the recombinant S2 subdomain protein was very high, the antibody titers against the two major S2 neutralizing epitopes were generally weak. Only a limited number of individuals showed high binding activity to the S2’ and fusion peptide epitopes, which are targeted by the pan-coronavirus human antibody 76E1 [9] (Supplementary Fig. 2). These findings suggest that the plasma polyclonal neutralizing activity was caused mainly by the antibodies targeting the RBD rather than the S2 domain. Overall, our data suggest that Omicron infection after previous WT vaccination induces strong neutralizing antibodies against Omicron, with no significant OAS effect observed in children.

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Fig. 1

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (Grant Nos. 2021YFC2701800 and 2022YFC2703603), the National Natural Science Foundation of China (Grant Nos. 32270991, 32100751 and 32100123), and the Shanghai Science and Technology Innovation Action (Grant Nos. 21JC1405800 and 21ZR1470600). We thank the Core Facilities of Chemical Biology, Cell Biology, and Molecular Biology of the Shanghai Institute of Biochemistry and Cell Biology for their technical support. We thank Dr. Xiao Lu of the CAS Center for Excellence in Molecular Cell Science for her assistance with the neutralization assay.

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Author notes

  1. These authors contributed equally: Zhiyang Ling, Zhangqian Zheng, Lingli Xu, Chunyan Yi.

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

    Zhiyang Ling, Chunyan Yi & Bing Sun

  2. Children’s Hospital of Fudan University, Shanghai, China

    Zhangqian Zheng, Lingli Xu, Xinran Dong & Bingbing Wu

  3. Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China

    Xiaoqiong Gu & Wenhao Zhou

  4. Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China

    Xiaoyu Sun

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  1. Zhiyang Ling
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Contributions

WHZ, BS, BBW, and XYS. initiated, designed, and supervised the study. ZYL, ZQZ, CYY, LLX, and XYS designed and performed all the experiments. XQG and ZQZ provided samples. LLX analyzed the scRNA-seq data. ZYL, CYY, XYS, and BS wrote the paper. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaoyu Sun, Bingbing Wu, Bing Sun or Wenhao Zhou.

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Competing interests

The authors declare that they have no competing interests. BS is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Ling, Z., Zheng, Z., Xu, L. et al. Children exhibit a robust B-cell response to Omicron BA.2 after breakthrough infection with limited influence from the original antigenic sin. Cell Mol Immunol 22, 127–130 (2025). https://doi.org/10.1038/s41423-024-01241-y

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