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BackgroundThe continued occurrence of more contagious SARS-CoV-2 variants and waning immunity over time require ongoing re-evaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in two age groups (12-59 and 60 years or above) of two and three vaccine doses (BNT162b2 mRNA or mRNA-1273 vaccine) by time since vaccination against SARS-CoV-2 infection and COVID-19-related hospitalization in an Alpha, Delta and Omicron dominated period. MethodsA Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron variants. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all residents in Denmark aged 12 years or above (18 years or above for the analysis of three doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021) and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models with adjustments for age, sex and geographical region. Vaccination status was included as a time-varying exposure. FindingsIn the oldest age group, VE against infection after two doses was 91.0% (95% CI: 88.5; 92.9) for the Alpha variant, 82.2% (95% CI: 75.3; 87.1) for the Delta variant and 39.9% (95% CI: 26.4; 50.9) for the Omicron variant 14-30 days since vaccination. The VE waned over time and was 71.5% (95% CI: 54.7; 82.8), 49.8% (95% CI: 46.5; 52.8) and 4.7% (95% CI: 0.2; 8.9) >120 days since vaccination against the three variants, respectively. Higher estimates were observed after the third dose with VE estimates against infection of 86.0% (Delta, 95% CI: 83.3; 88.3) and 57.6% (Omicron, 95% CI: 55.8; 59.4) 14-30 days since vaccination. Among both age groups, VE against COVID-19-related hospitalization 14-30 days since vaccination with two or three doses was 94.8% or above for the Alpha and Delta variants, whereas among the youngest age group, VE estimates against the Omicron variant after two and three doses were 62.4% (95% CI: 46.3; 73.6) and 89.8% (95% CI: 87.9; 91.3), respectively. ConclusionsTwo vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha and Delta variants with protection waning over time. Two vaccine doses provided only limited protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Omicron variant. The third vaccine dose substantially increased the protection against Delta and Omicron.
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The newly found Omicron SARS-CoV-2 variant of concern has rapidly spread worldwide. Omicron carries numerous mutations in key regions and is associated with increased transmissibility and immune escape. The variant has recently been divided into four subvariants with substantial genomic differences, in particular between Omicron BA.1 and BA.2. With the surge of Omicron subvariants BA.1 and BA.2, a large number of reinfections from earlier cases has been observed, raising the question of whether BA.2 specifically can escape the natural immunity acquired shortly after a BA.1 infection. To investigate this, we selected a subset of samples from more than 1,8 million cases of infections in the period from November 22, 2021, until February 11, 2022. Here, individuals with two positive samples, more than 20 and less than 60 days apart, were selected. From a total of 187 reinfection cases, we identified 47 instances of BA.2 reinfections shortly after a BA.1 infection, mostly in young unvaccinated individuals with mild disease not resulting in hospitalization or death. In conclusion, we provide evidence that Omicron BA.2 reinfections do occur shortly after BA.1 infections but are rare.
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1The Omicron SARS-CoV-2 variant of concern (VOC lineage B.1.1.529), which became dominant in many countries during early 2022, includes several subvariants with strikingly different genetic characteristics. Several countries, including Denmark, have observed the two Omicron subvariants: BA.1 and BA.2. In Denmark the latter has rapidly replaced the former as the dominant subvariant. Based on nationwide Danish data, we estimate the transmission dynamics of BA.1 and BA.2 following the spread of Omicron VOC within Danish households in late December 2021 and early January 2022. Among 8,541 primary household cases, of which 2,122 were BA.2, we identified a total of 5,702 secondary infections among 17,945 potential secondary cases during a 1-7 day follow-up period. The secondary attack rate (SAR) was estimated as 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively. We found BA.2 to be associated with an increased susceptibility of infection for unvaccinated individuals (Odds Ratio (OR) 2.19; 95%-CI 1.58-3.04), fully vaccinated individuals (OR 2.45; 95%-CI 1.77-3.40) and booster-vaccinated individuals (OR 2.99; 95%-CI 2.11-4.24), compared to BA.1. We also found an increased transmissibility from unvaccinated primary cases in BA.2 households when compared to BA.1 households, with an OR of 2.62 (95%-CI 1.96-3.52). The pattern of increased transmissibility in BA.2 households was not observed for fully vaccinated and booster-vaccinated primary cases, where the OR of transmission was below 1 for BA.2 compared to BA.1. We conclude that Omicron BA.2 is inherently substantially more transmissible than BA.1, and that it also possesses immune-evasive properties that further reduce the protective effect of vaccination against infection, but do not increase its transmissibility from vaccinated individuals with breakthrough infections.
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1The SARS-CoV-2 Delta variant of concern (VOC), which has shown increased transmission compared with previous variants, emerged rapidly globally during the first half of 2021, and became one of the most widespread SARS-CoV-2 variants worldwide. We utilized total population data from 24,693 Danish households with 53,584 potential secondary cases to estimate household transmission of the Delta VOC in relation to vaccination status. We found that the vaccine effectiveness against susceptibility (VES) was 61% (95%-CI: 59-63) and that the vaccine effectiveness against transmissibility (VET) was 42% (95%-CI: 39-45). We also found that unvaccinated individuals with an infection exhibited a higher viral load (one third of a standard deviation) compared to fully vaccinated individuals with a breakthrough infection. Our results imply that vaccinations reduce susceptibility as well as transmissibility. The results are important for policy makers to select strategies for reducing transmission of SARS-CoV-2.
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1The Omicron variant of concern (VOC) is a rapidly spreading variant of SARS-CoV-2 that is likely to overtake the previously dominant Delta VOC in many countries by the end of 2021. We estimated the transmission dynamics following the spread of Omicron VOC within Danish households during December 2021. We used data from Danish registers to estimate the household secondary attack rate (SAR). Among 11,937 households (2,225 with the Omicron VOC), we identified 6,397 secondary infections during a 1-7 day follow-up period. The SAR was 31% and 21% in households with the Omicron and Delta VOC, respectively. We found an increased transmission for unvaccinated individuals, and a reduced transmission for booster-vaccinated individuals, compared to fully vaccinated individuals. Comparing households infected with the Omicron to Delta VOC, we found an 1.17 (95%-CI: 0.99-1.38) times higher SAR for unvaccinated, 2.61 times (95%-CI: 2.34-2.90) higher for fully vaccinated and 3.66 (95%-CI: 2.65-5.05) times higher for booster-vaccinated individuals, demonstrating strong evidence of immune evasiveness of the Omicron VOC. Our findings confirm that the rapid spread of the Omicron VOC primarily can be ascribed to the immune evasiveness rather than an inherent increase in the basic transmissibility.
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In early 2021, the SARS-CoV-2 lineage B.1.1.7 became dominant across large parts of the world. In Denmark, comprehensive and real-time test, contact-tracing, and sequencing efforts were applied to sustain epidemic control. Here, we use these data to investigate the transmissibility, introduction, and onward transmission of B.1.1.7 in Denmark. In a period with stable restrictions, we estimated an increased B.1.1.7 transmissibility of 58% (95% CI: [56%,60%]) relative to other lineages. Epidemiological and phylogenetic analyses revealed that 37% of B.1.1.7 cases were related to the initial introduction in November 2020. Continuous introductions contributed substantially to case numbers, highlighting the benefit of balanced travel restrictions and self-isolation procedures coupled with comprehensive surveillance efforts, to sustain epidemic control in the face of emerging variants.
