Evolution of neutralizing antibodies through vaccination and breakthrough infections in the era of COVID-19 endemicity

J Med Virol. 2023 Dec;95(12):e29285. doi: 10.1002/jmv.29285.


Despite a high vaccination rate, the COVID-19 pandemic continues with immune-evading Omicron variants. The success of additional antigenic stimulation through breakthrough infection (BI) and updated vaccination in overcoming antigenic imprinting needs to be determined. Participants in a long-term follow-up cohort of healthcare worker (HCW) vaccinee were categorized according to their infection/vaccination status. Anti-SARS-CoV-2 spike/nucleocapsid protein antibodies were measured, and plaque reduction neutralization tests (PRNTs) against wild-type (WT), BA.5, BN.1, and XBB.1.5 were conducted. The neutralization activity of intravenous immunoglobulin (IVIG) products was evaluated to assess the immune status of the general population. Ninety-five HCWs were evaluated and categorized into seven groups. The WT PRNT ND50 value was highest regardless of infection/vaccination status, and groups with recent antigenic stimulation showed high PRNT titers overall. Groups with double Omicron stimulation, either by BI plus BA.4/5 bivalent vaccination or repeated BI, exhibited significantly higher BA.5 and BN.1 PRNT to WT PRNT ratios than those with single Omicron stimulation. Overall group immunity was estimated to be boosted in January 2023, reflecting the effect of the BA.4/5 bivalent booster and additional BIs, but slightly declined in June 2023. A substantial increase in the antibody concentrations of IVIG products was noticed in 2022, and recently produced IVIG products exhibited a substantial level of cross-reactive neutralizing activity against emerging variants. Neutralizing activity against emerging variants could be enhanced by repeated antigenic stimulation via BI and/or updated vaccination. Overall group immunity was elevated accordingly, and IVIG products showed substantial activity against circulating strains.

Keywords: SARS-CoV-2 variants; antibodies; breakthrough infections; immunoglobulins; intravenous; neutralizing; vaccination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing*
  • Antibodies, Viral
  • Breakthrough Infections
  • COVID-19* / prevention & control
  • Humans
  • Immunoglobulins, Intravenous / therapeutic use
  • Pandemics
  • SARS-CoV-2
  • Vaccination


  • Antibodies, Neutralizing
  • Immunoglobulins, Intravenous
  • Antibodies, Viral

Supplementary concepts

  • SARS-CoV-2 variants