Unveiling a New Perspective on Distinguishing Omicron Breakthrough Cases and Postimmune COVID-19-Naive Individuals: Insights from Antibody Profiles

Abstract

In the situation of mass vaccination against COVID-19, few studies have reported on the early kinetics of specific antibodies (IgG/IgM/IgA) of vaccine breakthrough cases. There is still a lack of epidemiological evidence about the value of serological indicators in the auxiliary diagnosis of COVID-19 infection, especially when the nucleic acid results were undetectable. Omicron breakthrough cases post-inactivated vaccination (n = 456) and COVID-19-naive individuals with two doses of inactivated vaccination (n = 693) were enrolled. Blood samples were collected and tested for SARS-CoV-2 antibody levels based on the magnetic chemiluminescence enzyme immunoassay. Among Omicron breakthrough cases, the serum IgG antibody level was 36.34 Sample/CutOff (S/CO) (95% confidence interval [CI], 31.89 to 40.79) in the acute phase and 88.45 S/CO (95% CI, 82.79 to 94.12) in the recovery phase. Serum IgA can be detected in the first week post-symptom onset (PSO) and showed an almost linear increase within 5 weeks PSO. Compared with those of breakthrough cases, IgG and IgA titers of the postimmune group were much lower (4.70 S/CO and 0.46 S/CO, respectively). Multivariate regression showed that serum IgG and IgA levels in Omicron breakthrough cases were mainly affected by the weeks PSO (P < 0.001). Receiver operating characteristic ROC0 curve analysis showed that the area under the curve (AUC) was 0.744 and 0.806 when the cutoff values of IgA and IgG were 1 S/CO and 15 S/CO, respectively. Omicron breakthrough infection can lead to a further increase in IgG and IgA levels relative to those of the immunized population. When nucleic acid real-time PCR was negative, we would use the kinetics of IgG and IgA levels to distinguish the breakthrough cases from the immunized population. IMPORTANCE This study fills a gap in the epidemiological evidence by investigating the value of serological indicators, particularly IgG and IgA levels, in the auxiliary diagnosis of COVID-19 infections when nucleic acid results are undetectable. The findings reveal that among Omicron breakthrough cases, both IgG and IgA antibody levels exhibit significant changes. Serum IgG levels increase during the acute phase and rise further in the recovery phase. Serum IgA can be detected as early as the first week post-symptom onset (PSO), showing a consistent linear increase within 5 weeks PSO. Furthermore, receiver operating characteristic (ROC) curve analysis demonstrates the potential of IgG and IgA cutoff values as diagnostic markers. The study's conclusion underscores the importance of monitoring IgG and IgA kinetics in distinguishing Omicron breakthrough cases from vaccinated individuals. These findings contribute to the development of more accurate diagnostic approaches and help inform public health strategies during the ongoing COVID-19 pandemic.

Keywords: Omicron breakthrough infection; SARS-CoV-2; early kinetics; specific antibodies; vaccinated.

FIG 1

Comparison of IgG/IgM/IgA antibody levels in three groups of subjects. (A) IgG antibody levels in the acute phase and recovery phase of Omicron breakthrough cases and the postimmune population. (B) IgM antibody levels in the acute phase and recovery phase of Omicron breakthrough cases and the postimmune population. (C) IgA antibody levels in the acute phase and recovery phase of Omicron breakthrough cases and the postimmune population. P values were determined by applying a two-tailed Mann-Whitney U test. A P value of <0.05 was considered statistically significant; ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

FIG 2

Trends in specific antibody levels/positive rates in Omicron breakthrough cases and the postimmune population. (A) Time-varying kinetics of IgG/IgM/IgA antibody levels within 5 weeks after symptom onset in Omicron breakthrough cases. (B) Changes in antibody levels as the time interval between the last dose of vaccination and sampling increased in the postimmune population. (C) Kinetics of IgG/IgM/IgA seropositivity within 5 weeks after symptom onset in Omicron breakthrough cases. (D) Changes in IgG/IgM/IgA seropositivity as the time interval between the last dose of vaccination and sampling increased in the postimmune population.

FIG 3

Scatterplot between acute phase IgG levels and ratios of IgG recovery/IgG acute in Omicron breakthrough cases. The blue dots are independent samples selected to meet the conditions, the blue line is the nonlinear fitted curve, and the ratio of 4 on the vertical coordinate is drawn with a red dashed line. The correlation between the two indicators was calculated by Spearman correlation coefficient. A P value of <0.05 was considered statistically significant; ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.