Differential immunity induced by Omicron sublineages in naïve and vaccine breakthrough infections

Categories: Disease & Virus

July 4, 2025

Study cohort

This study included 278 plasma samples collected from July 2021 through June 2023 from 170 COVID-19 patients, of whom 157 (92.4%) were hospitalized, 130 (76.5%) were fully vaccinated with 2 doses of the ancestral SARS-CoV-2 vaccine, 82 (48.2%) boosted with ≥ 1 additional dose of the ancestral vaccine, and 12 (7.1%) boosted with the BA.5 bivalent booster vaccine (Table 1 and Dataset 1). Additionally, the study included 25 plasma samples taken from 25 uninfected control subjects (“controls”), defined as patients who tested negative for SARS-CoV-2 admitted to the hospital for reasons other than COVID-19 who had remnant whole blood available and received the bivalent BA.5 booster vaccine prior to sample collection based on retrospective chart review (Table 2 and Dataset 1). Among the 170 COVID-19 patients, 132 were infected with an Omicron sublineage (77.6%), including 44 BA.1 (25.9%), 13 BA.2 (7.9%), 27 BA.4/BA.5 (15.9%), 5 BF (2.9%), 16 BQ.1 (9.4%), and 27 XBB.1 (15.9%) variants, while the remaining 38 patients were infected with the Delta variant (22.4%). Greater proportions of Delta-infected patients were unvaccinated and presented with severe disease than Omicron-infected patients (Table 3). Ten of the patients were pediatric patients (5.9%), 96 were male (56.5%), and 90 were immunocompetent (52.9%). 87 patients were asymptomatic or presented with mild SARS-CoV-2 respiratory infection (51.2%), most of whom were admitted for reasons other than COVID-19, while 83 (48.8%) had moderately severe or severe infection. Regarding the 25 uninfected controls, all were adults, 15 were female (60.0%), and 18 were immunocompetent (72.0%).

Table 1 Clinical and demographic data for the 170 COVID-19 patients in the study.

Table 2 Clinical and demographic data for the 25 uninfected controls in the study, hospitalized but COVID-19 negative.

Table 3 Clinical and demographic variables stratified by infecting variant for the 170 COVID-19 patients in the study.

Dataset 1 Deidentified patient and control data. A total of 278 plasma samples from 170 COVID-19 patients (first tab) and 25 plasma samples from 25 uninfected vaccinated control subjects (second tab) were included in this study.

Neutralizing antibody responses in boosted uninfected controls

In the control cohort of uninfected subjects who had received the bivalent BA.5 booster vaccine, neutralizing antibody titers against the wild-type ancestral strain (“WT”) were significantly higher than those against all the Omicron sublineages (p < 0.001) (Fig. 1A). Neutralizing antibody titers against BA.1, BA.2, and BA.5 were significantly higher than those against BQ.1.1 or XBB.1.5 (p < 0.001). Overall differences in neutralizing antibody titers against all variants between immunocompetent and immunocompromised controls were non-significant (Fig. 1B).

Self-neutralizing antibody responses in COVID-19 patients

We compared self-neutralizing antibody responses against the infecting variant or sublineage in patients stratified by immune status, vaccination status, and disease severity. Immunocompetent patients infected with BA.1, BA.2, BQ.1, or XBB.1 exhibited significantly higher self-neutralizing antibody titers than immunocompromised patients infected with the respective variant (p = 0.01–0.03) (Fig. 2), although this association was not significant for patients infected with Delta, BA.4/BA.5, or BF. Self-neutralizing antibody titers from Delta infections were significantly higher than those from Omicron variant infections, excluding BF, for all patients overall (p < 0.01) as well as for nearly all patient subgroups stratified by immunocompromised status, vaccination status, or COVID-19 severity (p < 0.001–0.024) (Fig. 3).

Cross-neutralizing antibody responses in COVID-19 patients

For each infecting sublineage, we compared neutralization antibody titers against cultured isolates representing the BA.1, BA.2, BA.5, BQ.1.1, and XBB.1.5 Omicron sublineages (Fig. 4A). Overall, cross-neutralizing titers were robust against earlier Omicron sublineages, with PRNT50 values > 1:100, but were much weaker against later sublineages, especially if these sublineages emerged after the infecting sublineage. For BA.2 infections, cross-neutralizing antibody titers were significantly lower against BQ.1.1 than BA.1 (p = 0.011) and BA.2 (p = 0.008), while cross-neutralizing titers were significantly lower against XBB.1.5 than BA.1 (p = 0.005), BA.2 (p = 0.004), and BA.5 (p = 0.042). For BA.4/BA.5 infections, cross-neutralizing titers were significantly lower against BQ.1.1 than BA.2 (p = 0.009), while cross-neutralizing titers were significantly lower against XBB.1.1 than BA.1 (p = 0.003), BA.2 (p < 0.001), and BA.5 (p = 0.004). For BQ.1 infections, self-neutralization titers were significantly lower against BQ.1.1 than cross-neutralizing titers against BA.1 (p = 0.039), BA.2 (p = 0.023), and BA.5 (p = 0.017), while cross-neutralizing titers were significantly lower against XBB.1.5 than BA.1 (p = 0.003), BA.2 (p < 0.001), and BA.5 (p = 0.003). In XBB.1 infections, cross-neutralizing antibody titers were significantly lower against BQ.1.1 than BA.2 (p = 0.012) and BA.4/BA.5 (p = 0.013), while self-neutralizing antibody titers against XBB.1.5 were significantly lower than cross-neutralizing antibody titers against BA.2 (p = 0.033) and BA.4/BA.5 (p = 0.040),

We compared relative neutralizing antibody titers in patients infected with different Omicron sublineages. Neutralizing antibody titers against BQ.1.1 were significantly higher in BQ.1 and XBB.1 infections compared to those in BA.2 infections (p = 0.046 and p = 0.009, respectively) (Fig. 4B). Neutralizing antibody titers against XBB.1.5 were significantly higher in XBB.1 infections compared to those in BA.2 infections (p < 0.001), BA.4/BA.5 infections (p = 0.016), and BQ.1 infections (p = 0.046).

Effect of prior infection and vaccination on neutralizing antibody responses

Next, we plotted mean neutralizing antibody titers against wild-type, Delta, and Omicron lineages in infected patients by collection month (Fig. 5A,B,D–I).@@ We also plotted in parallel the emergence of the Delta and Omicron sublineage waves by collection month and annotated the graph with population-level statewide seroprevalence data (Fig. 5C)⁹. At the onset of the Omicron BA.1 and BA.4/BA.5 waves, only 8% and 2% of the population, respectively, were seronegative. This observation is consistent with the finding of robust neutralizing antibody titers (PRNT50 ≥ 10³) against WT across all variant and sublineage infections (Fig. 5A). Notably, whereas Delta-infected patients generated robust neutralizing Abs versus Delta (Fig. 5B), this was not generally the case for patients infected with Omicron sublineages. Among these sublineages, robust neutralizing antibody titers were only observed for BA-2 infected patients against BA.1, BA.2, BA.4/BA.5, and BF.7 (Fig. 5D–G) and for XBB.1 infected patients against the other lineages (Fig. 5D–I).

Longitudinal analyses of neutralizing antibody responses

Samples collected at various days post-infection based on the date of symptom onset or first positive SARS-CoV-2 PCR test were available for longitudinal analyses of neutralizing antibody titers from 132 patients infected with Omicron sublineages from January 2022 through June 2023 (Fig. 6). In BA.1 and BF infections, neutralizing antibody titers increased more slowly and to lower peak levels over time compared to infections from other Omicron variants. In addition, neutralizing antibody titers from infection by earlier Omicron variants (BA.1 and BA.2) waned more quickly than those from infection by later Omicron variants (BA.4/BA.5, BF, BQ.1, and XBB.1).