Occurrence and significance of Omicron BA . 1 infection followed by 1 BA . 2 reinfection 2 3

42 The newly found Omicron SARS-CoV-2 variant of concern has rapidly spread worldwide. 43 Omicron carries numerous mutations in key regions and is associated with increased 44 transmissibility and immune escape. The variant has recently been divided into four 45 subvariants with substantial genomic differences, in particular between Omicron BA.1 and 46 BA.2. With the surge of Omicron subvariants BA.1 and BA.2, a large number of reinfections 47 from earlier cases has been observed, raising the question of whether BA.2 specifically can 48 escape the natural immunity acquired shortly after a BA.1 infection. 49 To investigate this, we selected a subset of samples from more than 1,8 million cases of 50 infections in the period from November 22, 2021, until February 11, 2022. Here, individuals 51 with two positive samples, more than 20 and less than 60 days apart, were selected. 52 From a total of 187 reinfection cases, we identified 47 instances of BA.2 reinfections shortly 53 after a BA.1 infection, mostly in young unvaccinated individuals with mild disease not 54 resulting in hospitalization or death. 55 In conclusion, we provide evidence that Omicron BA.2 reinfections do occur shortly after 56 BA.1 infections but are rare. 57 58 59 Introduction 60 Since the first report of a new SARS-CoV-2 variant of concern (VOC), Omicron (Pango 61 lineage B.1.1.529), on November 19, 2021, this VOC has rapidly disseminated globally and 62 now dominates in many countries. Omicron carries more than 30 mutations and deletions in 63 the spike gene compared to the original Wuhan strain and is associated with increased 64 transmissibility and immune escape. Studies indicate that the Omicron variant results in 65 less severe disease outcomes than Delta. Currently, Omicron is subdivided into four 66 subvariants, BA.1, BA.1.1, BA.2 and BA.3, where BA.1 is the dominating Omicron 67 subvariant worldwide (https://outbreak.info), and in Europe Omicron is estimated to account 68 for about 70% of all reported cases. In Denmark, we have observed a dramatic increase in 69 Omicron BA.2 case number since the beginning of early 2022, and BA.2 now accounts for 70 88% of all cases. Omicron BA.2 case numbers are also increasing in countries like the United 71 Kingdom, South Africa and Norway currently. Omicron BA.1 and BA.2 differ by up to 40 72 non-synonymous mutations and deletions including key mutations in the N-terminal and the 73 receptor binding domains of the spike gene, both regions that influence the immune response. 74 The diversity between Omicron BA.1 and BA.2 in the spike protein exceeds the variation 75 between the Wuhan and the Alpha variant. With the surge of both BA.1 and BA.2, a large 76 number of reinfections, as defined by the European Centre for Disease Prevention and 77 Control (ECDC) as two positive tests >60 days apart, has been observed, raising the question 78 if BA.2 can escape the natural immunity acquired shortly after a BA.1 infection, and if so, 79 whether these cases are associated with changes in disease severity. 80 Using whole genome sequencing (WGS), we investigate whether Omicron BA.2 reinfections 81 occurred within 20-60 days following initial infections with BA.1 in the time period when 82 these two subvariants emerged and became dominant in Denmark. Here we present evidence 83 that Omicron BA.2 reinfections indeed do occur relatively shortly after a BA.1 infection, 84 causing mostly mild disease in unvaccinated young individuals. 85 86 Methods 87 Epidemiological information 88 For the SARS-CoV-2 cases, we obtained data up to and including February 15, 2022, from 89 the Danish COVID-19 surveillance which includes information from multiple national 90 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271112 doi: medRxiv preprint