Modelling the viral dynamics of the SARS-CoV-2 Delta and Omicron variants in different cell types (preprint)

We use viral kinetic models fitted to viral load data from in vitro studies to explain why the SARS-CoV-2 Omicron variant replicates faster than the Delta variant in nasal cells, but slower than Delta in lung cells, which could explain Omicron's higher transmission potential and lower severity. We find that in both nasal and lung cells, viral infectivity is higher for Omicron but the virus production rate is higher for Delta. However, the differences are unequal between cell types, and ultimately leads to the basic reproduction number and growth rate being higher for Omicron in nasal cells, and higher for Delta in lung cells. In nasal cells, Omicron alone can enter via a TMPRSS2-independent pathway, but it is primarily increased efficiency of TMPRSS2-dependent entry which accounts for Omicron's increased activity. This work paves the way for using within-host mathematical models to understand the transmission potential and severity of future variants.

Impact of antigen test target failure and testing strategies on the transmission of SARS-CoV-2 variants (preprint)

Population testing remains central to COVID-19 control and surveillance, with countries increasingly using antigen tests rather than molecular tests. Here we describe a SARS-CoV-2 variant that escapes N antigen tests due to multiple disruptive amino-acid substitutions in the N protein. By fitting a multistrain compartmental model to genomic and epidemiological data, we show that widespread antigen testing in the Italian region of Veneto favored the undetected spread of the antigen-escape variant compared to the rest of Italy. We highlight novel limitations of widespread antigen testing in the absence of molecular testing for diagnostic or confirmatory purposes. Critically, in the presence of a variant that escapes antigen testing, following up a proportion of negative antigen tests with a molecular test is the optimal testing strategy. Together, these findings highlight the importance of retaining molecular testing for surveillance purposes, also in contexts where the use of antigen tests is widespread.

Rapid longitudinal SARS-CoV-2 intra-host emergence of novel haplotypes regardless of immune deficiencies (preprint)

On February 2020, the municipality of Vo, a small town near Padua (Italy), was quarantined due to the first coronavirus disease 19 (COVID-19)-related death detected in Italy. The entire population was swab tested in two sequential surveys. Here we report the analysis of the viral genomes, which revealed that the unique ancestor haplotype introduced in Vo belongs to lineage B and, more specifically, to the subtype found at the end of January 2020 in two Chinese tourists visiting Rome and other Italian cities, carrying mutations G11083T and G26144T. The sequences, obtained for 87 samples, allowed us to investigate viral evolution while being transmitted within and across households and the effectiveness of the non-pharmaceutical interventions implemented in Vo. We report, for the first time, evidence that novel viral haplotypes can naturally arise intra-host within an interval as short as two weeks, in approximately 30% of the infected individuals, regardless of symptoms severity or immune system deficiencies. Moreover, both phylogenetic and minimum spanning network analyses converge on the hypothesis that the viral sequences evolved from a unique common ancestor haplotype, carried by an index case. The lockdown extinguished both viral spread and the emergence of new variants, confirming the efficiency of this containment strategy. The information gathered from household was used to reconstructs possible transmission events.

Refining reproduction number estimates to account for unobserved generations of infection in emerging epidemics (preprint)

BackgroundEstimating the transmissibility of infectious diseases is key to inform situational awareness and for response planning. Several methods tend to overestimate the basic (R0) and effective (Rt) reproduction numbers during the initial phases of an epidemic. The reasons driving the observed bias are unknown. In this work we explore the impact of incomplete observations and underreporting of the first generations of infections during the initial epidemic phase. MethodsWe propose a debiasing procedure which utilises a linear exponential growth model to infer unobserved initial generations of infections and apply it to EpiEstim. We assess the performance of our adjustment using simulated data, considering different levels of transmissibility and reporting rates. We also apply the proposed correction to SARS-CoV-2 incidence data reported in Italy, Sweden, the United Kingdom and the United States of America. ResultsIn all simulation scenarios, our adjustment outperforms the original EpiEstim method. The proposed correction reduces the systematic bias and the quantification of uncertainty is more precise, as better coverage of the true R0 values is achieved with tighter credible intervals. When applied to real world data, the proposed adjustment produces basic reproduction number estimates which closely match the estimates obtained in other studies while making use of a minimal amount of data. ConclusionsThe proposed adjustment refines the reproduction number estimates obtained with the current EpiEstim implementation by producing improved, more precise estimates earlier than with the original method. This has relevant public health implications. SummaryWe propose a back-imputation procedure tackling the issue of unobserved initial generations of infections to reduce the bias observed in the early R0 and Rt estimates and apply it to EpiEstim using simulated and reported COVID-19 data to evaluate it.

Estimating the Protectiveness of Face Mask on Seasonal Influenza Transmissibility During COVID-19 Early Spread (preprint)

Background: After COVID-19 early expansion occurred in mainland China, seasonal influenza transmission in Hong Kong, which was growing initially, immediately plateaued, and then abruptly declined a few weeks later. These patterns correspond to the three phases of early COVID-19 spread from Wuhan to Hong Kong, i.e. the ordinary: before the occurrence in Wuhan; the awareness: after the evidence of human-to-human transmission was revealed; and the spreading: after the first local case was confirmed in Hong Kong. The available surveyed data on changes in precautionary behavior during these phases, i.e. face mask wearing and avoiding the crowd, provide an opportunity to estimate the protectiveness of face mask on influenza transmissibility. Methods: We developed a time-series susceptible-infected-recovered (TS-SIR) regression model to estimate the time-varying effective reproduction number Rt based on the weekly reported influenza cases. The reporting rate of influenza was adjusted under the assumption that patients with severe influenza were seeking medical care. After separating the effect from herd immunity, the percent reduction in Rt from each behavior was calculated as an indication of the protectiveness. Findings: The average Rt of winter influenza season in 2019/20 was estimated in the three phases: 1.29 (95%CI, 1.27 to 1.32) in the ordinary, 1.00 (95%CI, 0.99 to 1.00) in the awareness, and 0.73 (95%CI, 0.73 to 0.74) in the spreading. Our results showed that face mask wearing protected 22% from being transmitted, which was nearly half of the effect of avoiding the crowd (42%). If more than 79% of the people adopted both precautionary behaviors, the initial Rt reduced to less than one. Interpretation: The results suggested that mandatory face mask wearing along with social distancing practices could be effective in suppressing the transmission of influenza, which may also give hints on preventing COVID-19 infection.Funding Information: We declare no competing interests.Declaration of Interests: We acknowledge the support from grants funded by Health and Medical Research Fund [COVID190329415], City University of Hong Kong [7200573], andWellcome Trust and The Royal Society [213494/Z/18/3Z95].

Environmental drivers of SARS-CoV-2 lineage B.1.1.7 transmission in England, October to December 2020 (preprint)

Previous work has shown that environment affects SARS-CoV-2 transmission, but it is unclear whether emerging strains show similar responses. Here we show that lineage B.1.1.7 spread with greater transmission in colder and more densely populated parts of England. We also find evidence of B.1.1.7's transmission advantage at warmer temperatures versus other strains, implying that spring conditions may facilitate B.1.1.7's invasion in Europe and across the Northern hemisphere, undermining the effectiveness of public health interventions.

Environment influences SARS-CoV-2 transmission in the absence of non-pharmaceutical interventions (preprint)

As COVID-19 continues to spread across the world, it is increasingly important to understand the factors that influence its transmission. Seasonal variation driven by responses to changing environment has been shown to affect the transmission intensity of several coronaviruses. However, the impact of the environment on SARS-CoV-2 remains largely unknown, and thus seasonal variation remains a source of uncertainty in forecasts of SARS-CoV-2 transmission. Here we address this issue by assessing the association of temperature, humidity, UV radiation, and population density with estimates of transmission rate (R). Using data from the United States of America, we explore correlates of transmission across USA states using comparative regression and integrative epidemiological modelling. We find that policy intervention (`lockdown') and reductions in individuals' mobility are the major predictors of SARS-CoV-2 transmission rates, but in their absence lower temperatures and higher population densities are correlated with increased SARS-CoV-2 transmission. Our results show that summer weather cannot be considered a substitute for mitigation policies, but that lower autumn and winter temperatures may lead to an increase in transmission intensity in the absence of policy interventions or behavioural changes. We outline how this information may improve the forecasting of SARS-CoV-2, its future seasonal dynamics, and inform intervention policies.

State-level tracking of COVID-19 in the United States (preprint)

As of 1st June 2020, the US Centers for Disease Control and Prevention reported 104,232 confirmed or probable COVID-19-related deaths in the US. This was more than twice the number of deaths reported in the next most severely impacted country. We jointly modelled the US epidemic at the state-level, using publicly available death data within a Bayesian hierarchical semi-mechanistic framework. For each state, we estimate the number of individuals that have been infected, the number of individuals that are currently infectious and the time-varying reproduction number (the average number of secondary infections caused by an infected person). We used changes in mobility to capture the impact that non-pharmaceutical interventions and other behaviour changes have on the rate of transmission of SARS-CoV-2. Nationally, we estimated 3.7% [3.4%-4.0%] of the population had been infected by 1st June 2020, with wide variation between states, and approximately 0.01% of the population was infectious. We also demonstrated that good model forecasts of deaths for the next 3 weeks with low error and good coverage of our credible intervals.

Report 21: Estimating COVID-19 cases and reproduction number in Brazil (preprint)

Brazil is an epicentre for COVID-19 in Latin America. In this report we describe the Brazilian epidemic using three epidemiological measures: the number of infections, the number of deaths and the reproduction number. Our modelling framework requires sufficient death data to estimate trends, and we therefore limit our analysis to 16 states that have experienced a total of more than fifty deaths. The distribution of deaths among states is highly heterogeneous, with 5 states---Sao Paulo, Rio de Janeiro, Ceara, Pernambuco and Amazonas---accounting for 81% of deaths reported to date. In these states, we estimate that the percentage of people that have been infected with SARS-CoV-2 ranges from 3.3% (95% CI: 2.8%-3.7%) in Sao Paulo to 10.6% (95% CI: 8.8%-12.1%) in Amazonas. The reproduction number (a measure of transmission intensity) at the start of the epidemic meant that an infected individual would infect three or four others on average. Following non-pharmaceutical interventions such as school closures and decreases in population mobility, we show that the reproduction number has dropped substantially in each state. However, for all 16 states we study, we estimate with high confidence that the reproduction number remains above 1. A reproduction number above 1 means that the epidemic is not yet controlled and will continue to grow. These trends are in stark contrast to other major COVID-19 epidemics in Europe and Asia where enforced lockdowns have successfully driven the reproduction number below 1. While the Brazilian epidemic is still relatively nascent on a national scale, our results suggest that further action is needed to limit spread and prevent health system overload.

A comparative analysis of statistical methods to estimate the reproduction number in emerging epidemics with implications for the current COVID-19 pandemic (preprint)

As the SARS-CoV-2 pandemic continues its rapid global spread, quantification of local transmission patterns has been, and will continue to be, critical for guiding pandemic response. Understanding the accuracy and limitations of statistical methods to estimate the reproduction number, R0, in the context of emerging epidemics is therefore vital to ensure appropriate interpretation of results and the subsequent implications for control efforts. Using simulated epidemic data we assess the performance of 6 commonly-used statistical methods to estimate R0 as they would be applied in a real-time outbreak analysis scenario - fitting to an increasing number of data points over time and with varying levels of random noise in the data. Method comparison was also conducted on empirical outbreak data, using Zika surveillance data from the 2015-2016 epidemic in Latin America and the Caribbean. We find that all methods considered here frequently over-estimate R0 in the early stages of epidemic growth on simulated data, the magnitude of which decreases when fitted to an increasing number of time points. This trend of decreasing bias over time can easily lead to incorrect conclusions about the course of the epidemic or the need for control efforts. We show that true changes in pathogen transmissibility can be difficult to disentangle from changes in methodological accuracy and precision, particularly for data with significant over-dispersion. As localised epidemics of SARS-CoV-2 take hold around the globe, awareness of this trend will be important for appropriately cautious interpretation of results and subsequent guidance for control efforts. Significance StatementIn line with a real-time outbreak analysis we use simulated epidemic data to assess the performance of 6 commonly-used statistical methods to estimate the reproduction number, R0, at different time points during the epidemic growth phase. We find that estimates of R0 are frequently overestimated by these methods in the early stages of epidemic growth, with decreasing bias when fitting to an increasing number of time points. Reductions in R0 estimates obtained at sequential time points during early epidemic growth may reflect increased methodological accuracy rather than reductions in pathogen transmissibility or effectiveness of interventions. As SARS-CoV-2 continues its geographic spread, awareness of this bias will be important for appropriate interpretation of results and subsequent guidance for control efforts.

A sub-national analysis of the rate of transmission of COVID-19 in Italy (preprint)

Italy was the first European country to experience sustained local transmission of COVID-19. As of 1st May 2020, the Italian health authorities reported 28,238 deaths nationally. To control the epidemic, the Italian government implemented a suite of non-pharmaceutical interventions (NPIs), including school and university closures, social distancing and full lockdown involving banning of public gatherings and non essential movement. In this report, we model the effect of NPIs on transmission using data on average mobility. We estimate that the average reproduction number (a measure of transmission intensity) is currently below one for all Italian regions, and significantly so for the majority of the regions. Despite the large number of deaths, the proportion of population that has been infected by SARS-CoV-2 (the attack rate) is far from the herd immunity threshold in all Italian regions, with the highest attack rate observed in Lombardy (13.18% [10.66%-16.70%]). Italy is set to relax the currently implemented NPIs from 4th May 2020. Given the control achieved by NPIs, we consider three scenarios for the next 8 weeks: a scenario in which mobility remains the same as during the lockdown, a scenario in which mobility returns to pre-lockdown levels by 20%, and a scenario in which mobility returns to pre-lockdown levels by 40%. The scenarios explored assume that mobility is scaled evenly across all dimensions, that behaviour stays the same as before NPIs were implemented, that no pharmaceutical interventions are introduced, and it does not include transmission reduction from contact tracing, testing and the isolation of confirmed or suspected cases. New interventions, such as enhanced testing and contact tracing are going to be introduced and will likely contribute to reductions in transmission; therefore our estimates should be viewed as pessimistic projections. We find that, in the absence of additional interventions, even a 20% return to pre-lockdown mobility could lead to a resurgence in the number of deaths far greater than experienced in the current wave in several regions. Future increases in the number of deaths will lag behind the increase in transmission intensity and so a second wave will not be immediately apparent from just monitoring of the daily number of deaths. Our results suggest that SARS-CoV-2 transmission as well as mobility should be closely monitored in the next weeks and months. To compensate for the increase in mobility that will occur due to the relaxation of the currently implemented NPIs, adherence to the recommended social distancing measures alongside enhanced community surveillance including swab testing, contact tracing and the early isolation of infections are of paramount importance to reduce the risk of resurgence in transmission.

Suppression of COVID-19 outbreak in the municipality of Vo, Italy (preprint)

On the 21st of February 2020 a resident of the municipality of Vo, a small town near Padua, died of pneumonia due to SARS-CoV-2 infection. This was the first COVID-19 death detected in Italy since the emergence of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days. We collected information on the demography, clinical presentation, hospitalization, contact network and presence of SARS-CoV-2 infection in nasopharyngeal swabs for 85.9% and 71.5% of the population of Vo at two consecutive time points. On the first survey, which was conducted around the time the town lockdown started, we found a prevalence of infection of 2.6% (95% confidence interval (CI) 2.1-3.3%). On the second survey, which was conducted at the end of the lockdown, we found a prevalence of 1.2% (95% CI 0.8-1.8%). Notably, 43.2% (95% CI 32.2-54.7%) of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic. The mean serial interval was 6.9 days (95% CI 2.6-13.4). We found no statistically significant difference in the viral load (as measured by genome equivalents inferred from cycle threshold data) of symptomatic versus asymptomatic infections (p-values 0.6 and 0.2 for E and RdRp genes, respectively, Exact Wilcoxon-Mann-Whitney test). Contact tracing of the newly infected cases and transmission chain reconstruction revealed that most new infections in the second survey were infected in the community before the lockdown or from asymptomatic infections living in the same household. This study sheds new light on the frequency of asymptomatic SARS-CoV-2 infection and their infectivity (as measured by the viral load) and provides new insights into its transmission dynamics, the duration of viral load detectability and the efficacy of the implemented control measures.

Estimates of the severity of COVID-19 disease (preprint)

Background: A range of case fatality ratio (CFR) estimates for COVID 19 have been produced that differ substantially in magnitude. Methods: We used individual-case data from mainland China and cases detected outside mainland China to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the CFR by relating the aggregate distribution of cases by dates of onset to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for the demography of the population, and age and location-based under ascertainment. We additionally estimated the CFR from individual linelist data on 1,334 cases identified outside mainland China. We used data on the PCR prevalence in international residents repatriated from China at the end of January 2020 to obtain age-stratified estimates of the infection fatality ratio (IFR). Using data on age stratified severity in a subset of 3,665 cases from China, we estimated the proportion of infections that will likely require hospitalisation. Findings: We estimate the mean duration from onset-of-symptoms to death to be 17.8 days (95% credible interval, crI 16.9,19.2 days) and from onset-of-symptoms to hospital discharge to be 22.6 days (95% crI 21.1,24.4 days). We estimate a crude CFR of 3.67% (95% crI 3.56%,3.80%) in cases from mainland China. Adjusting for demography and under-ascertainment of milder cases in Wuhan relative to the rest of China, we obtain a best estimate of the CFR in China of 1.38% (95% crI 1.23%,1.53%) with substantially higher values in older ages. Our estimate of the CFR from international cases stratified by age (under 60 or 60 and above) are consistent with these estimates from China. We obtain an overall IFR estimate for China of 0.66% (0.39%,1.33%), again with an increasing profile with age. Interpretation: These early estimates give an indication of the fatality ratio across the spectrum of COVID-19 disease and demonstrate a strong age-gradient in risk.