SARS-CoV-2 is continually evolving with new variants to evade protective immunity and cause new infections. This study aimed to assess infection-acquired immunity and hybrid immunity against re-infection or severe COVID-19.

During 2020–2023, we collected 890 serum samples from individuals infected with SARS-CoV-2 variants including wild type, D614G, Alpha, Delta, BA.1, BA.2, BA.2.76, BA.5.2, BF.7, XBB, and EG.5. The levels of serum neutralizing antibodies (NAbs) against 18 diverse SARS-CoV-2 variants were determined using a bead-based high-throughput broad neutralizing-antibody assay.

In the initial wave of the COVID-19 pandemic, >75% of the patients demonstrated robust NAb responses against the ancestral SARS-CoV-2, during a period when vaccines were not yet available. After the emergence of the Omicron variant, the seroprevalence of anti-Omicron NAbs among the patients increased rapidly. By April 2023, when XBB variant was predominant, approximately 80% of the patients demonstrated >50% neutralization against the highly immune-evasive XBB lineages. Three serotypes of SARS-CoV-2, namely non-Omicron, Omicron, and XBB serotypes, were identified, with the strong likelihood of further changes occurring as the virus mutating. Generally, NAbs elicited by a previous serotype could not typically effectively protect against another serotype that emerges later in the evolutionary stages.

Our results firstly demonstrated the synergistic evolution between host immunity and SARS-CoV-2 variants in the real world, which would be helpful to develop future vaccines and public health strategies.