In Denmark, Omicron reinfections reveal ineffective post-COVID-19 immunity

In a recent study posted to the medRxiv* preprint server, researchers investigated variant-wise SARS-CoV-2 reinfection cases in Denmark.

The evolution of SARS-CoV-2 has led to the emergence of multiple variants of concern (VOC) with increased transmissibility and immune-evasiveness such as Omicron, leading to an upsurge of SARS-CoV-2 reinfections and difficulties in COVID-19 mitigation globally. Studies have investigated SARS-CoV-2 reinfection frequencies but were restricted to reverse transcriptase polymer chain reaction (RT-PCR) analysis data, in which SARS-CoV-2 Pango lineages are not specified. In addition, a genomic sequencing report is typically categorized as either initial infection or reinfection, but next-generation sequencing (NGS) data for an initial infection and reinfection are rarely reported together for an individual.

Study: Increasing Cases of SARS-CoV-2 Omicron Reinfection Reveals Ineffective Post-COVID-19 Immunity in Denmark and Conveys the Need for Continued Next-Generation Sequencing. Image Credit: Noiel / Shutterstock

About the study

In the present study, researchers characterized SARS-CoV-2 reinfections by variant based on the integration of RT-PCR analysis and next-genome sequencing (NGS) analysis of sequences obtained from Danish SARS-CoV-2-positive individuals and the GISAID (global initiative on sharing avian influenza data) database.

NGS data and clinical metadata of primary SARS-CoV-2 infections and reinfections from the same individual residing in Denmark were analyzed. In total, 21,708 entries of reinfections were available between 1 March 2020 and 28 August 2022, with data on the dates of sample collection about primary SARS-CoV-2 infections and reinfections.

The team documented clinical SARS-CoV-2 metadata as the time points of initial and subsequent SARS-CoV-2 infections to measure the duration between the initial and subsequent SARS-CoV-2 infections. In addition, RT-PCR analysis results and NGS analysis results were available for primary infections and reinfections, respectively. 

The team excluded 70 case entries (

Reinfection cases were stratified by variant and subvariant. The GISAID database was accessed for two files: one set of files comprising current metadata for >12 million SARS-CoV-2 sequences and the second set comprising filtered metadata files of only Denmark residents with two associated SARS-CoV-2 infections documented.


Primary infection and reinfection with Omicron (i.e., Omicron-Omicron infections) were reported to occur within a short period (even within three weeks, an average of 22 weeks) than non-Omicron-Omicron infections. Omicron reinfections within ten weeks of initial Omicron infection were largely reported due to BA.1 followed by BA.2.

Reinfection frequency was significantly higher with Omicron (25%, N=1875) after primary infections with any VOC. No Alpha VOC-induced reinfection cases were reported, whereas Delta VOC caused reinfections in 2.3% (n=169) of cases. Pre-Omicron estimates of natural infection-induced immunity were above 90%, which dropped to below 10% in three to four months.

Among individuals with Delta-induced primary infections, reinfections due to Delta variant <1% (n=18) but for Omicron reinfections were 41% (n=3060 cases). Further, reinfections with the same VOC but differing subvariants were only 0.3% (n=24), except for Omicron (4.6%, n=340). 93% of individuals reinfected from March 2020 had Omicron reinfections, indicating that initial SARS-CoV-2 infection with the Wuhan-Hu-1 strain, Alpha VOC, or Delta VOC variant was unable to confer adequate immune protection against reinfections, especially for Omicron reinfections.

Omicron reinfections were reported among 62% (n=211), 20%, (n=68), and 30% (n=102) of cases in which primary SARS-CoV-2 infections were caused by Omicron BA.1, BA.2, and BA.5, respectively, Individuals with primary BA.2 infections demonstrated high reinfection frequencies (38%, n=129) with the Omicron BA.5 subvariant (26%, n=89). The findings indicated that even though the SARS-CoV-2 spike (S) protein of the three Omicron subvariants are similar, differences in the Omicron subvariants were adequate to prevent Omicron BA.1/2 infection-induced nAbs (neutralizing antibodies) from binding with Omicron BA.5 S.


The study findings showed that most SARS-CoV-2 reinfection cases occurred due to Omicron. Omicron reinfections among those with primary Omicron infection happened within a short period, as less as three weeks. The findings indicated that primary infections with non-Omicron VOCs were inadequate in providing immune protection to prevent reinfections with Omicron.

Further, the findings highlight the transmissibility and immune-evasiveness of Omicron and the need for updated SARS-CoV-2 vaccines, continued SARS-CoV-2 surveillance, and SARS-CoV-2 evolutionary assessments to guide policy-making for improved public health across the globe. In addition, the analysis underscores the need for analyzing individual-level NGS data to provide precise estimates of SARS-CoV-2 reinfection risks.

*Important notice

medRxiv publishes 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.