For individuals who have been vaccinated with COVID-19 or have been infected with SARS-CoV-2, serum from them already contains specific IgG and IgM antibodies explicitly targeting the Wuhan strain of SARS-CoV-2. The results of this study showed that after breakthrough infection with Omicron-BA.2, the antibody levels of specific IgM against the Wuhan strain and specific IgG against Omicron were not significantly elevated within 27 days of onset. While for the unvaccinated population, the aforementioned antibody levels also did not show enhancements during the observational period, indicating that the antibodies cannot be used as indicators for Omicron breakthrough infection. Specific IgM antibodies to the Wuhan strain were not significantly increased, which may be due to the fact that the currently popular Omicron variant processes many mutations on the key antigenic spike protein, Omicron-specific IgM antibodies possessed weak reaction activity to the Wuhan strain. Therefore, current vaccines based on the original Wuhan strain confer very little protection against Omicron variant [6]. Interestingly, in this study, the levels of humoral immunity against Omicron-specific IgM were significantly increased after breakthrough infection, suggesting that the detection of Omicron-specific IgM antibodies can be used as a test criterion of Omicron breakthrough infection. As we know, IgM antibodies are produced at a very early stage of infection, then the antibody isotype switch from IgM to IgG usually occurs with the progression of the humoral immune response development [7]. Therefore, IgM antibodies are generated in the early stages of infection, then IgG is a signal for the latter stages of infection. This could be the reason for the lack of significantly increased affinity to IgG antibodies against BA.2 in our research. As the observation period was relatively short, if observation times were extended, the IgG will be increased later. In addition, we observed that serums from unvaccinated individuals and the majority of vaccinated infections (23/32) possessed only low or no neutralizing activity against Omicron (GMT 24.3) at the onset of Omicron breakthrough infections, suggesting that Omicron-BA.2 can largely escape vaccine-induced immune protection, which produces breakthrough infections, and these findings are consistent with other publications [8,9,10,11]. At the later stage of Omicron breakthrough infection, antibody neutralization levels against the Wuhan strain were elevated in infected individuals. Similarly, the mean neutralization titers of late serum against Omicron were significantly higher than those of early Omicron infection or pre-infection serum, suggesting that breakthrough infection with the Omicron strain enhances the specific antibody response to SARS-CoV-2 titers, and the induced neutralizing antibodies may be able to neutralize Omicron and Wuhan strains broadly. These results suggest that Omicron-associated antigens may have potential as candidate antigens for vaccine booster shots, which is consistent with our previous findings on Omicron booster shots at the animal level [12]. Besides that, when comparing the late stage of infection to the early stage of infection in the immunized group, no significant increases in binding antibody titers against the Wuhan strain were seen, but there was a substantial rise in neutralizing antibodies. This indicates that breakthrough Omicron infection could not increase the total antibody titers against the Wuhan strain, but it might improve the neutralizing antibody titers during our observation. This inspires us when evaluating immune responses to COVID-19 booster vaccinations not only based on the binding antibody titers but also by neutralizing antibody levels. In conclusion, the findings of this study provide important clues for the diagnosis of Omicron breakthrough infections, antibody characterization studies, and the design of next-generation vaccines for COVID-19. This study has a limitation, due to the insufficient number of samples in this study, we could not describe the difference in antibody response in vaccinees who had 3 doses and 2 doses with breakthrough infections, further elaborating on the comparative analysis of the antibody responses between these different vaccinees would be helpful.