Cross-Neutralization Responses and Persistent Symptoms After SARS-CoV-2 Breakthrough Infections

The rapid succession of Omicron sub-variant waves has generated a complex and evolving humoral immune landscape in previously infected populations. To characterize the post-COVID-19 humoral immune landscape in China, we conducted a cross-sectional study evaluating cross-neutralizing antibody profile and associated epidemiological factors in a Chinese cohort. Serum samples and epidemiological questionnaire data were collected from 273 convalescent volunteers. SARS-CoV-2 infection history, vaccination background, and persistent symptoms were obtained via structured surveys. Serum neutralizing antibody (NAb) titers were measured against pseudoviruses representing B.1, BA.2, BA.5, XBB.1.16, JN.1, and KP.3.1.1. Associations of infection frequency, vaccination status, and epidemic era on NAb responses were evaluated. Persistent symptoms lasting ≥ 30 days were reported by 58.97% of participants, most commonly fatigue/malaise (32.60%) and chronic cough (23.08%). NAb titers remained high against B.1, BA.2, and BA.5, a marked 5- to 27-fold reduction was observed against XBB.1.16, JN.1, and KP.3.1.1. Neutralization against KP.3.1.1 showed the greatest reduction, with 42.90% of serum samples below the lower limit of detection. Compared with individuals with one infection, those with repeated infections showed relatively higher titers against later Omicron sub-variants, particularly XBB.1.16, JN.1, and KP.3.1.1, whereas neutralization against earlier variants was not consistently increased neutralizing profiles also varied by epidemic era of infection, although some subgroup analyzes were limited by small sample sizes. Together, these findings define the cross-NAb landscape in a real-world Chinese population after a 3-year zero-COVID strategy. Despite modest broadening of humoral immunity following multiple exposures, antigenic divergence of emerging Omicron sub-variants continues to limit cross-protection, supporting the need for variant-adapted vaccination strategies.