Omicron BA. 2 reinfections can occur shortly following BA.1 infection

In a recent study posted to the medRxiv* preprint server, an interdisciplinary team of researchers from Denmark investigated the probability of Omicron BA.2 reinfections following Omicron BA.1 initial infection by whole genomic sequencing (WGS), in the period of dominance of these subvariants in Denmark.

Study: Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection. Image Credit: Dkoi/Shutterstock

Study: Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection. Image Credit: Dkoi/Shutterstock

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has recently been categorized by the World Health Organization (WHO) into four subvariants - BA.1, BA.1.1, BA.2, and BA.3 - with considerable genomic differences. Currently, in Denmark, Omicron BA.2 accounts for 88% of all SARS-CoV-2 cases.

Omicron BA.1 and BA.2 sublineages have a difference of up to 40 deletions and mutations, with the major mutations in the receptor-binding domain and N-terminal domain of the spike gene. With the surge of Omicron BA.1 and BA.2 subvariants, a large number of reinfections have been observed in Europe. This raised the concern for the ability of the Omicron BA.2 subvariant to escape natural immunity acquired after BA.1 infection.

Study design

In this study, the researchers obtained data of SARS-CoV-2 cases between 21 November, 2021, to 11 February, 2022, from Danish coronavirus disease 2019 (COVID-19) surveillance containing information from multiple Danish registries like National Patient Registry, National Microbiology Database (MiBA), and the National Vaccination Registry. Samples were collected from the individuals infected with Omicron lineages, 20 to 60 days apart with SARS-CoV-2-positive samples for WGS.

In this study, Illumina technology was used to perform WGS by using a panel of ARTIC v3 amplicons. Sequencing of samples was performed on either NextSeq or NovaSeq platforms, and subvariants were sequenced using the Pangolin version. For genomic and case analysis Omicron BA.1.1 was paired with the BA.1.

The authors randomly selected Omicron BA. 1 and BA. 2 genomes from the national data and performed MAFT alignment including Omicron BA.1 and BA.2 reinfection genomes and the reference sequence of Wuhan-Hu-1. These were used to form a phylogeny of maximum likelihood in IQ-TREE of 1000 bootstraps.

The researchers assessed reads having a 5´-untranslated region (UTR) sequence from 55-69 position in the sequencing data against Wuhan-Hu-1 reference genome using Jupyter Notebook of the SARS-CoV-2-leader.


Based on genomic data, 54 cases with high-quality sequences of Omicron BA.2 were detected, which had also shown non-sequenced samples post 20-60 days. The researchers observed that a majority of 88% of Omicron BA.1 to BA.1 cases (15/17) were identical with zero to one single nucleotide polymorphism (SNP), with only two cases showing a larger difference of seven to eight SNPs. While regarding three cases of Omicron BA.2 to BA.2, two cases were identical and one case had four different SNPs.

In comparison to the initial Omicron BA.1 infections, Omicron BA.2 reinfections had higher cycle threshold (Ct) values reflecting a reduced viral concentration. Similarly, Ct values were also higher for the BA.1 to BA.1 Omicron cases. In this context, the researchers observed no difference in the viral load of BA.1 and BA.2 as reflected by the Ct values of their genome.

The findings revealed that during the Omicron BA.1 infection, no case was observed with >38 years of age and over 70% of the cases were <20 years of age. Regarding the vaccination status, over 89% of cases were non-vaccinated, 6% were vaccinated twice, and 4% vaccinated once. In Denmark, 81% of the population were vaccinated twice and 62% received the booster dose. Interestingly, the researchers observed 26 reinfections in Delta to Omicron BA.1 and 140 in Delta to Omicron BA.2. For Delta to BA.2 reinfection cases, the median age was 16 years and over 68% were unvaccinated.

During the follow-up period, the team observed that among the 47 subjects with Omicron BA.1 to BA.2 reinfections, none were hospitalized or died. Over 85% of the cases had mild symptoms after Omicron BA.2 reinfections, with a mean duration of four days between both infection rounds. During the first infection, for over 53% of cases, the primary evidence for testing was exposure as close contact with a SARS-CoV-2 positive person, while for the second infection, 47% of cases had experienced symptoms as a major indication for testing.

On comparing the phylogeny of the Omicron BA.1 and BA.2 paired genome with the randomly sampled genomes of Danish BA.1 and BA.2, no specific variant was responsible for reinfection nor were any major clusters of Omicron BA.1 causing reinfections observed.

In the Omicron BA.2 cases, the spike protein showed no mutations. During the initial Omicron BA.1 infection, no differences were observed between the viral genomic ribonucleic acid (RNA) levels and for the mapped spike and nucleoprotein subgenomic RNA between the study population and BA.1 samples selected randomly for comparison. In contrast, for Omicron BA.2 infection, there was a predominance of genomic RNA and reduced spike and nucleoprotein subgenomic RNAs in the study population as compared to the BA.2 random samples.

Further, the researchers observed that in the Omicron BA.2 samples, both the study and random population had an increased viral genomic RNA and reduced levels of subgenomic RNA of spike and nucleoprotein as compared to the study and random samples of Omicron BA.1.


The results of this study provided evidence for the occurrence of Omicron BA.2 reinfections quickly after a former Omicron BA.1 infection, which caused mild disease in young unvaccinated individuals. The Omicron BA.2 reinfections were more prevalent in individuals who tested SARS-CoV-2 positive for more than one time and caused widespread community transmission.

*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.

Journal reference:
Sangeeta Paul

Written by

Sangeeta Paul

Sangeeta Paul is a researcher and medical writer based in Gurugram, India. Her academic background is in Pharmacy; she has a Bachelor’s in Pharmacy, a Master’s in Pharmacy (Pharmacology), and Ph.D. in Pharmacology from Banasthali Vidyapith, Rajasthan, India. She also holds a post-graduate diploma in Drug regulatory affairs from Jamia Hamdard, New Delhi, and a post-graduate diploma in Intellectual Property Rights, IGNOU, India.


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