Dynamics of Crossed Acquired Immunity Against SARS-CoV-2 Variants: From Vaccine to Hybrid Immunity in China

The immune response to evolving Omicron variants in China, especially after booster doses and breakthrough infections post-Zero-COVID-19 policy, is poorly understood. In a 14-month cohort of 206 adults, baseline assessments were conducted the day before the third COVID-19 vaccine dose (Visit 1), with follow-ups at 1 (Visit 2), 3 (Visit 3), 6 (Visit 4), 9 (Visit 5), and 14 (Visit 6) months after the dose. The lifting of Zero-COVID-19 policy coincided with a surge in Omicron breakthrough infections among our participants, occurring 12 months after the third vaccine dose. We assessed neutralizing antibodies (NAbs) against prototype/variant strains and T cell responses to BA.5 Spike and conserved peptide pools (CPPs) in PBMCs. NAbs and T-cell responses significantly increased after policy's cessation, surpassing levels seen 1 month post-third dose. Over 90% of participants showed notable NAb increases between Visit 5 and 6 without additional boosters, suggesting probable SARS-CoV-2 infections. Cross-reactive NAbs decreased for BA.5 (1.5-fold), XBB.1.5 (15.4-fold), and JN.1 (44.8-fold) compared to the prototype strain. T-cell responses to BA.5 Spike and CPPs remained stable. From vaccine to hybrid immunity, sustained cellular immunity protects against severe outcomes despite reduced NAb cross-reactivity. Updated variant-targeted vaccines remain crucial, especially for those with weaker immune responses.