In a recent study posted to the Preprints with The Lancet* server, researchers determined the risk of breakthrough infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron and Delta variants in fully vaccinated individuals.

Study: Levels of SARS-CoV-2 Antibodies Among Fully-Vaccinated Individuals With Delta or Omicron Variant Breakthrough Infections: A Prospective Cohort Study. Image Credit: petovarga/Shutterstock
Study: Levels of SARS-CoV-2 Antibodies Among Fully-Vaccinated Individuals With Delta or Omicron Variant Breakthrough Infections: A Prospective Cohort Study. Image Credit: petovarga/Shutterstock


Coronavirus disease 2019 (COVID-19) vaccines that encode the proteins of the Wuhan strain of SARS-CoV-2 have been developed and deployed globally. However, multiple SARS-CoV-2 variants have emerged, which can erode the previous vaccine-induced immunity.

About the study

In the present study, researchers estimated the risk of Omicron breakthrough infections compared to those with the Delta variant in fully vaccinated individuals based on their anti-spike (S) immunoglobulin G (IgG) titers generated by prior COVID-19 vaccination. They also evaluated the frequency of severe SARS-CoV-2 infections among these individuals.

Data from the multicentric phase IV ENFORCE study, conducted between February and July 2021 at seven sites, covering all five Danish regions were obtained. Danish residents, aged over 18 years were recruited for the analysis before their first COVID-19 vaccination provided by the Danish COVID-19 vaccination program.

All the study participants were prime vaccinated with the BTN162b2, mRNA-1273, or ChAdOx1 vaccines before the commencement of the study and subsequently boosted by messenger ribonucleic acid (mRNA) vaccines.

Additionally, the PubMed database was searched without date or language restrictions for relevant literature on March 23, 2022, with the help of keywords such as “Omicron”, “B.1.1.529”, “SARS-CoV-2”, “COVID-19”, “antibody”, “serology” and “breakthrough infections”. Preprints were also included in the study. On data search, a letter to the editor, published on February 3, 2022, was obtained that reported anti-SARS-CoV-2 antibody titers in adults post one, two, or three COVID-19 mRNA vaccinations. 

If data on the variant type were unavailable, breakthrough infections that occurred between July 1 and December 1, 2021, were considered Delta infections, and those between December 21, 2021, and February 1, 2022, were considered Omicron infections based on the dominant strain during the periods. Data on severe COVID-19 infections were obtained from the Danish National Patient Register and confirmed using electronic patient records.

The rate of breakthrough infections diagnosed by polymerase chain reaction (PCR) post-14 days of the second prime dose was estimated using data from the Danish National Microbiology database (MiBa).

Serum samples were obtained from the participants to assess the antibody responses. The anti-S IgG titers of the study participants were evaluated using multi-antigen serological assays and were compared to that of controls matched for sex, age, and vaccination status, with a positive history of Delta breakthrough infections. The antibody titers were evaluated after 21 to 28 days, 90 days, and 180 days of follow-up. Additionally, the antibody response was also determined on day 7 and day 28 post-booster vaccination.

A Poisson regression model was used for determining the risk of breakthrough infections based on time-updated levels of SARS-CoV-2 transmission and time-updated anti-S IgG titers after adjusting for sex, age, and profession (healthcare workers).

The incidence rate ratio (IRR) for breakthrough infections by the Omicron and Delta variants was calculated for all the study participants. Additionally, the overall crude incidence rates (IR) among every 1000 person-days of follow-up were also determined.


A total of 6,076 participants (mean age 64 years) were included in the analysis. Breakthrough infections (n=504, IR 0.4, mean age 56 years) with the Omicron and Delta variants were detected in 363 (IR 1.98) and 127 (IR 0.1) vaccinated individuals, respectively.

The IRRs for breakthrough infections by the Delta variant reduced (IRR 0.3) with increased anti-S IgG titers. However, there were no substantial differences in IRRs of Omicron breakthrough infections.  This indicates that there was a gradual diminution in the risk of breakthrough infections observed with increasing anti-S IgG titers for the Delta variant but not for the Omicron variant.

Additionally, Delta breakthrough infection in only one patient caused severe disease and Omicron breakthrough infections caused severe disease in none of the patients.

The majority (90%) of the participants with Omicron breakthrough infections had anti-S IgG titers up to 6,967 binding antibody units/ml (BAU/ml), whereas the majority (90%) of participants with Delta breakthrough infections had anti-S IgG titers up to 2,905 BAU/ml. This indicates that Omicron breakthrough infections probably occur at higher anti-S IgG titers compared to Delta breakthrough infections.


To conclude, according to the study findings, the quantitative anti-S IgG titer levels have a limited impact on the risk of Omicron breakthrough infections. In addition, COVID-19 vaccines conferred strong protection against severe SARS-CoV-2 Omicron and Delta variant infections.

*Important notice

Preprints with The Lancet publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


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