Humoral Response Kinetics and Cross-Immunity in Hospitalized Patients with SARS-CoV-2 WT, Delta, or Omicron Infections: A Comparison between Vaccinated and Unvaccinated Cohorts

With the ongoing evolution of severe acute respiratory virus-2 (SARS-CoV-2), the number of confirmed COVID-19 cases continues to rise. This study aims to investigate the impact of vaccination status, SARS-CoV-2 variants, and disease severity on the humoral immune response, including cross-neutralizing activity, in hospitalized COVID-19 patients. This retrospective cohort study involved 122 symptomatic COVID-19 patients hospitalized in a single center. Patients were categorized based on the causative specific SARS-CoV-2 variants (33 wild-type (WT), 54 Delta and 35 Omicron) and their vaccination history. Sequential samples were collected to assess binding antibody responses (anti-S/RBD and anti-N) and surrogate virus neutralization tests (sVNTs) against WT, Omicron BA.1, and BA.4/5. The vaccinated breakthrough infection group (V) exhibited higher levels of anti-S/RBD compared to the variant-matched unvaccinated groups (UVs). The Delta infection resulted in a more rapid production of anti-S/RBD levels compared to infections with WT or Omicron variants. Unvaccinated severe WT or Delta infections had higher anti-S/RBD levels compared to mild cases, but this was not the case with Omicron infection. In vaccinated patients, there was no difference in antibody levels between mild and severe infections. Both Delta (V) and Omicron (V) groups showed strong cross-neutralizing activity against WT and Omicron (BA.1 and BA.4/5), ranging from 79.3% to 97.0%. WT (UV) and Delta (UV) infections had reduced neutralizing activity against BA.1 (0.8% to 12.0%) and BA.4/5 (32.8% to 41.0%). Interestingly, patients who received vaccines based on the ancestral spike exhibited positive neutralizing activity against BA.4/5, even though none of the study participants had been exposed to BA.4/5 and it is antigenically more advanced. Our findings suggest that a previous vaccination enhanced the humoral immune response and broadened cross-neutralizing activity to SARS-CoV-2 variants in hospitalized COVID-19 patients.