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Repeated vaccination of inactivated SARS-CoV-2 vaccine dampens neutralizing antibodies against Omicron variants in breakthrough infection

Bo Gao^1,2,† , Liheng He^1,† , Yujie Bao^3,† , Yingying Chen^1,4,5,† , Guanzhu Lu³ , Yu Zhang⁶ , Yingjie Xu⁶ , Bing Su^1,2,3,7 , Jie Xu^3,* , Ying Wang^1,4,5,8,* , Leng-Siew Yeap^1,2,*

¹Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
²Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
³Department of Infectious Diseases, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁴Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases (20dz2261100), Shanghai, China
⁵Key Laboratory of Parasite and Vector Biology, Ministry of Health, School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁶Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁷Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
⁸Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
^†These authors contributed equally: Bo Gao, Liheng He, Yujie Bao, Yingying Chen
* Correspondence: Jie Xu(xujie@shsmu.edu.cn)Ying Wang(ywangssmu@shsmu.edu.cn)Leng-Siew Yeap(yeaplengsiew@shsmu.edu.cn)

Dear Editor,

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the virus has continued to evolve resulting in new waves of infection and immune escape in the vaccinated population.1 The Omicron strains belong to newly prevailing variants of concern (VOCs). They acquired as many as 30 mutations in the spike (S) gene and half of which occur at the receptor-binding domain (RBD) of the S protein. Moreover, the Omicron variants can evade neutralization activity by most of the identified anti-SARS-CoV-2 antibodies.2,3 Several reports have suggested that three-dose vaccination mounted better neutralizing activity against Omicron than two-dose vaccination.4 However, it is not clear how breakthrough infection would affect the immune responses of those who had three-dose compared to two-dose vaccination. Here, we compared neutralizing antibody (nAb) levels according to a vesicular stomatitis virus (VSV) pseudovirus-based neutralization assay in people who experienced breakthrough infection after receiving either two or three doses of inactivated SARS-CoV-2 vaccine during the Omicron BA.2 wave in Shanghai between March and June 2022. Strikingly, we found that although nAb titers against SARS-CoV-2 were comparable between the 2-dose and the 3-dose groups of patients with BA.2 breakthrough infection, nAb titers against the Omicron BA.2, BA.4 and BA.5 variants were significantly lower in the 3-dose group. Our data suggest that repeated vaccination with inactivated virus vaccine back-boosts previous memory and dampens the immune response to a new antigenically related but distinct viral strain. Such vaccination-induced immune imprint could reflect the “original antigenic sin” doctrine described in the influenza field, whereby individuals infected with a new circulating viral strain developed a strong immune response to a priorly exposed strain.5 Thus, careful considerations in this aspect should be taken when designing future vaccination and booster strategies.

https://doi.org/10.1038/s41422-023-00781-8

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