Convergence to the Equilibrium State in an Outbreak: When Can Growth Rates Accurately be Measured? (preprint)

We investigate sub-leading orders of the classic SEIR-model using contact matrices from modeling of the Omicron and Delta variants of COVID-19 in Denmark. The goal of this is to illustrate when the growth rate, and by extension the infectiousness, can be accurately measured in a new outbreak, e.g. after introduction of a new variant of a virus. We find that as long as susceptible depletion is a minor effect, the transients are gone within around 4 generations.

Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection (preprint)

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.

Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: Evidence from Danish Households (preprint)

The 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.

Effect of Vaccination on Household Transmission of SARS-CoV-2 Delta VOC (preprint)

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.

SARS-CoV-2 Omicron VOC Transmission in Danish Households (preprint)

The 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.

Evaluation of diagnostic test procedures for SARS-CoV-2 using latent class models: comparison of antigen test kits and sampling for PCR testing based on Danish national data registries (preprint)

Antigen test kits have been used extensively as a screening tool during the worldwide pandemic of coronavirus (SARS-CoV-2). While it is generally expected that taking samples for analysis with PCR testing gives more reliable results than using antigen test kits, the overall sensitivity and specificity of the two protocols in the field have not yet been estimated without assuming that the PCR test constitutes a gold standard. We use latent class models to estimate the in situ performance of both PCR and antigen testing, using data from the Danish national registries. The results are based on 240,000 paired tests results sub-selected from the 55 million test results that were obtained in Denmark during the period from February 2021 until June 2021. We found that the specificity of both tests is very high in our data sample (>99.7%), while the sensitivity of PCR sampling was estimated to be 95.7% (95% CI: 92.8-98.4%) and that of the antigen test kits used in Denmark over the study period was estimated at 53.8% (95% CI: 49.8-57.9%). Our findings can be used as supplementary information for consideration when implementing serial testing strategies that employ a confirmatory PCR sample following a positive result from an antigen test kit, such as the policy used in Denmark. We note that while this strategy reduces the number of false positives associated with antigen test screening, it also increases the false negatives. We demonstrate that the balance of trading false positives for false negatives only favours the use of serial testing when the expected true prevalence is low. Our results contain substantial uncertainty in the estimates for sensitivity due to the relatively small number of positive test results over this period: validation of our findings in a population with higher prevalence would therefore be highly relevant for future work.

Introduction and transmission of SARS-CoV-2 B.1.1.7 in Denmark (preprint)

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.

Increased Transmissibility of SARS-CoV-2 Lineage B.1.1.7 by Age and Viral Load: Evidence from Danish Households (preprint)

Aim The aim of this study was to estimate the household transmissibility of SARSCoV-2 for lineage B.1.1.7 compared with other lineages, by age and viral load. Furthermore, we wanted to estimate whether there is a multiplicative or additive effect of the increased transmissibility of B.1.1.7 compared with other lineages. Background New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 has been estimated to be more transmissible than other previously known lineages, but the association between transmissibility and risk factors, such as age of primary case and viral load is still unknown. Methods We used comprehensive administrative data from Denmark, comprising the full population, all SARS-CoV-2 RT-PCR tests, and all WGS lineage data (January 11 to February 7, 2021), to estimate household transmissibility stratified by lineage B.1.1.7 and other lineages. Results We included 5,241 households with primary cases; 808 were infected with SARS-CoV-2 lineage B.1.1.7 and 4,433 were infected with other lineages. The attack rate was 38% in households with a primary case infected with B.1.1.7 and 27% in households with a primary case infected with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5-1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load. Conclusions The results found in this study add new knowledge that can be used to mitigate the further spread of SARS-CoV-2 lineage B.1.1.7, which is becoming increasingly widespread in numerous countries. Our results clarify that the transmissibility of B.1.1.7 should be included as a multiplicative effect in mathematical models used as a tool for decision makers. The results may have important public health implications, as household transmission may serve as a bridge between otherwise separate transmission domains, such as schools and physical workplaces, despite implemented non-pharmaceutical interventions.

Communicate Hope to Motivate the Public During the COVID-19 Pandemic (preprint)

How should health authorities communicate to motivate the public to comply with health advice during a prolonged health crisis such as a pandemic? During the SARS-CoV-2 pandemic, for example, people have had to comply with successive restrictions as the world faced multiple races between controlling new waves of the virus and the development and implementation of vaccines. Here, we examine how health authorities and governments most effectively motivate the public by focusing on a specific race: between the Alpha variant and the implementation of the first generation of COVID-19 vaccinations in the winter of 2021. Following prior research on crisis communication, we focus on appeals to fear and hope using communicative aids in the form of visualizations based on epidemiological modelling. Using a population-based experiment conducted in United States (N = 3,022), we demonstrate that a hope-oriented visual communication aid, depicting the competing effects on the epidemic curve of (1) the more infectious variant and (2) vaccinations, motivates public action more effectively than a fear-oriented visual communication, focusing exclusively on the threat of the new variant. The importance of the implementation of such hope-oriented messages is further highlighted by cross-national representative surveys from eight countries (N = 3,995), which demonstrate that feelings of fear towards the Alpha variant alone were insufficient to activate strong compliance in isolation. Overall, these findings provide general insights into the importance of hope as a health communication strategy during the COVID-19 pandemic and beyond.

Fixed-time descriptive statistics underestimate extremes of epidemic curve ensembles (preprint)

Across the world, scholars are racing to predict the spread of the novel coronavirus, COVID-19. Such predictions are often pursued by numerically simulating epidemics with a large number of plausible combinations of relevant parameters. It is essential that any forecast of the epidemic trajectory derived from the resulting ensemble of simulated curves is presented with confidence intervals that communicate the uncertainty associated with the forecast. Here we argue that the state-of-the-art approach for summarizing ensemble statistics does not capture crucial epidemiological information. In particular, the current approach systematically suppresses information about the projected trajectory peaks. The fundamental problem is that each time step is treated separately in the statistical analysis. We suggest using curve-based descriptive statistics to summarize trajectory ensembles. The results presented allow researchers to report more representative confidence intervals, resulting in more realistic projections of epidemic trajectories and -- in turn -- enable better decision making in the face of the current and future pandemics.