Context-specific emergence and growth of the SARS-CoV-2 Delta variant.

The SARS-CoV-2 Delta (Pango lineage B.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide1,2. The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virus genomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chains that later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing-and not the number of importations-were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventions to reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529).

Efferocytosis perpetuates substance accumulation inside macrophage populations.

In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (104-[Formula: see text]) following their stimulation into an inflammatory state ex vivo. While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. As lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Consequently, enhanced macrophage cell death increased the rate and extent of foam cell formation. Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. As such, cannibalism has similar detrimental consequences in both cells and animals.

Investigation of P. vivax elimination via mass drug administration: A simulation study.

Plasmodium vivax is the most geographically widespread malaria parasite. P. vivax has the ability to remain dormant (as a hypnozoite) in the human liver and subsequently reactivate, which makes control efforts more difficult. Given the majority of P. vivax infections are due to hypnozoite reactivation, targeting the hypnozoite reservoir with a radical cure is crucial for achieving P. vivax elimination. Stochastic effects can strongly influence dynamics when disease prevalence is low or when the population size is small. Hence, it is important to account for this when modelling malaria elimination. We use a stochastic multiscale model of P. vivax transmission to study the impacts of multiple rounds of mass drug administration (MDA) with a radical cure, accounting for superinfection and hypnozoite dynamics. Our results indicate multiple rounds of MDA with a high-efficacy drug are needed to achieve a substantial probability of elimination. This work has the potential to help guide P. vivax elimination strategies by quantifying elimination probabilities for an MDA approach.

The Brazilian COVID-19 vaccination campaign: a modelling analysis of sociodemographic factors on uptake.

OBJECTIVE: Dose shortages delayed access to COVID-19 vaccination. We aim to characterise inequality in two-dose vaccination by sociodemographic group across Brazil. DESIGN: This is a cross-sectional study. SETTING: We used data retrieved from the Brazilian Ministry of Health databases published between 17 January 2021 and 6 September 2021. METHODS: We assessed geographical inequalities in full vaccination coverage and dose by age, sex, race and socioeconomic status. We developed a Campaign Optimality Index to characterise inequality in vaccination access due to premature vaccination towards younger populations before older and vulnerable populations were fully vaccinated. Generalised linear regression was used to investigate the risk of death and hospitalisation by age group, socioeconomic status and vaccination coverage. RESULTS: Vaccination coverage is higher in the wealthier South and Southeast. Men, people of colour and low-income groups were more likely to be only partially vaccinated due to missing or delaying a second dose. Vaccination started prematurely for age groups under 50 years which may have hindered uptake in older age groups. Vaccination coverage was associated with a lower risk of death, especially in older age groups (ORs 9.7 to 29.0, 95% CI 9. 4 to 29.9). Risk of hospitalisation was greater in areas with higher vaccination rates due to higher access to care and reporting. CONCLUSIONS: Vaccination inequality persists between states, age and demographic groups despite increasing uptake. The association between hospitalisation rates and vaccination is attributed to preferential delivery to areas of greater transmission and access to healthcare.

Epidemiological waves - Types, drivers and modulators in the COVID-19 pandemic.

Introduction: A discussion of 'waves' of the COVID-19 epidemic in different countries is a part of the national conversation for many, but there is no hard and fast means of delineating these waves in the available data and their connection to waves in the sense of mathematical epidemiology is only tenuous. Methods: We present an algorithm which processes a general time series to identify substantial, significant and sustained periods of increase in the value of the time series, which could reasonably be described as 'observed waves'. This provides an objective means of describing observed waves in time series. We use this method to synthesize evidence across different countries to study types, drivers and modulators of waves. Results: The output of the algorithm as applied to epidemiological time series related to COVID-19 corresponds to visual intuition and expert opinion. Inspecting the results of individual countries shows how consecutive observed waves can differ greatly with respect to the case fatality ratio. Furthermore, in large countries, a more detailed analysis shows that consecutive observed waves have different geographical ranges. We also show how waves can be modulated by government interventions and find that early implementation of NPIs correlates with a reduced number of observed waves and reduced mortality burden in those waves. Conclusion: It is possible to identify observed waves of disease by algorithmic methods and the results can be fruitfully used to analyse the progression of the epidemic.

Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) now arise in the context of heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron BA.1 genomes, we identified >6,000 introductions of the antigenically distinct VOC into England and analyzed their local transmission and dispersal history. We find that six of the eight largest English Omicron lineages were already transmitting when Omicron was first reported in southern Africa (22 November 2021). Multiple datasets show that importation of Omicron continued despite subsequent restrictions on travel from southern Africa as a result of export from well-connected secondary locations. Initiation and dispersal of Omicron transmission lineages in England was a two-stage process that can be explained by models of the country's human geography and hierarchical travel network. Our results enable a comparison of the processes that drive the invasion of Omicron and other VOCs across multiple spatial scales.

Quantifying the information in noisy epidemic curves.

Reliably estimating the dynamics of transmissible diseases from noisy surveillance data is an enduring problem in modern epidemiology. Key parameters are often inferred from incident time series, with the aim of informing policy-makers on the growth rate of outbreaks or testing hypotheses about the effectiveness of public health interventions. However, the reliability of these inferences depends critically on reporting errors and latencies innate to the time series. Here, we develop an analytical framework to quantify the uncertainty induced by under-reporting and delays in reporting infections, as well as a metric for ranking surveillance data informativeness. We apply this metric to two primary data sources for inferring the instantaneous reproduction number: epidemic case and death curves. We find that the assumption of death curves as more reliable, commonly made for acute infectious diseases such as COVID-19 and influenza, is not obvious and possibly untrue in many settings. Our framework clarifies and quantifies how actionable information about pathogen transmissibility is lost due to surveillance limitations.

Development of an influenza pandemic decision support tool linking situational analytics to national response policy.

National influenza pandemic plans have evolved substantially over recent decades, as has the scientific research that underpins the advice contained within them. While the knowledge generated by many research activities has been directly incorporated into the current generation of pandemic plans, scientists and policymakers are yet to capitalise fully on the potential for near real-time analytics to formally contribute to epidemic decision-making. Theoretical studies demonstrate that it is now possible to make robust estimates of pandemic impact in the earliest stages of a pandemic using first few hundred household cohort (FFX) studies and algorithms designed specifically for analysing FFX data. Pandemic plans already recognise the importance of both situational awareness i.e., knowing pandemic impact and its key drivers, and the need for pandemic special studies and related analytic methods for estimating these drivers. An important next step is considering how information from these situational assessment activities can be integrated into the decision-making processes articulated in pandemic planning documents. Here we introduce a decision support tool that directly uses outputs from FFX algorithms to present recommendations on response options, including a quantification of uncertainty, to decision makers. We illustrate this approach using response information from within the Australian influenza pandemic plan.

Higher risk of death from COVID-19 in low-income and non-White populations of São Paulo, Brazil.

INTRODUCTION: Little evidence exists on the differential health effects of COVID-19 on disadvantaged population groups. Here we characterise the differential risk of hospitalisation and death in São Paulo state, Brazil, and show how vulnerability to COVID-19 is shaped by socioeconomic inequalities. METHODS: We conducted a cross-sectional study using hospitalised severe acute respiratory infections notified from March to August 2020 in the Sistema de Monitoramento Inteligente de São Paulo database. We examined the risk of hospitalisation and death by race and socioeconomic status using multiple data sets for individual-level and spatiotemporal analyses. We explained these inequalities according to differences in daily mobility from mobile phone data, teleworking behaviour and comorbidities. RESULTS: Throughout the study period, patients living in the 40% poorest areas were more likely to die when compared with patients living in the 5% wealthiest areas (OR: 1.60, 95% CI 1.48 to 1.74) and were more likely to be hospitalised between April and July 2020 (OR: 1.08, 95% CI 1.04 to 1.12). Black and Pardo individuals were more likely to be hospitalised when compared with White individuals (OR: 1.41, 95% CI 1.37 to 1.46; OR: 1.26, 95% CI 1.23 to 1.28, respectively), and were more likely to die (OR: 1.13, 95% CI 1.07 to 1.19; 1.07, 95% CI 1.04 to 1.10, respectively) between April and July 2020. Once hospitalised, patients treated in public hospitals were more likely to die than patients in private hospitals (OR: 1.40%, 95% CI 1.34% to 1.46%). Black individuals and those with low education attainment were more likely to have one or more comorbidities, respectively (OR: 1.29, 95% CI 1.19 to 1.39; 1.36, 95% CI 1.27 to 1.45). CONCLUSIONS: Low-income and Black and Pardo communities are more likely to die with COVID-19. This is associated with differential access to quality healthcare, ability to self-isolate and the higher prevalence of comorbidities.

Establishment and lineage dynamics of the SARS-CoV-2 epidemic in the UK.

The United Kingdom's COVID-19 epidemic during early 2020 was one of world's largest and was unusually well represented by virus genomic sampling. We determined the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes, including 26,181 from the UK sampled throughout the country's first wave of infection. Using large-scale phylogenetic analyses combined with epidemiological and travel data, we quantified the size, spatiotemporal origins, and persistence of genetically distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown tended to be larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, whereas lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.

Context-specific emergence and growth of the SARS-CoV-2 Delta variant.

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes to reconstruct the emergence of Delta, and quantify its introduction to and regional dissemination across England, in the context of changing travel and social restrictions. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter-regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta’s invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

Context-specific emergence and growth of the SARS-CoV-2 Delta variant.

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases 1-3 . The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions 4,5 . Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes to reconstruct the emergence of Delta, and quantify its introduction to and regional dissemination across England, in the context of changing travel and social restrictions. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter-regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta's invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

Crowding and the shape of COVID-19 epidemics.

The coronavirus disease 2019 (COVID-19) pandemic is straining public health systems worldwide, and major non-pharmaceutical interventions have been implemented to slow its spread1-4. During the initial phase of the outbreak, dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was primarily determined by human mobility from Wuhan, China5,6. Yet empirical evidence on the effect of key geographic factors on local epidemic transmission is lacking7. In this study, we analyzed highly resolved spatial variables in cities, together with case count data, to investigate the role of climate, urbanization and variation in interventions. We show that the degree to which cases of COVID-19 are compressed into a short period of time (peakedness of the epidemic) is strongly shaped by population aggregation and heterogeneity, such that epidemics in crowded cities are more spread over time, and crowded cities have larger total attack rates than less populated cities. Observed differences in the peakedness of epidemics are consistent with a meta-population model of COVID-19 that explicitly accounts for spatial hierarchies. We paired our estimates with globally comprehensive data on human mobility and predict that crowded cities worldwide could experience more prolonged epidemics.

Epidemiological data from the COVID-19 outbreak, real-time case information.

Cases of a novel coronavirus were first reported in Wuhan, Hubei province, China, in December 2019 and have since spread across the world. Epidemiological studies have indicated human-to-human transmission in China and elsewhere. To aid the analysis and tracking of the COVID-19 epidemic we collected and curated individual-level data from national, provincial, and municipal health reports, as well as additional information from online reports. All data are geo-coded and, where available, include symptoms, key dates (date of onset, admission, and confirmation), and travel history. The generation of detailed, real-time, and robust data for emerging disease outbreaks is important and can help to generate robust evidence that will support and inform public health decision making.

Influencing public health policy with data-informed mathematical models of infectious diseases: Recent developments and new challenges.

Modern data and computational resources, coupled with algorithmic and theoretical advances to exploit these, allow disease dynamic models to be parameterised with increasing detail and accuracy. While this enhances models' usefulness in prediction and policy, major challenges remain. In particular, lack of identifiability of a model's parameters may limit the usefulness of the model. While lack of parameter identifiability may be resolved through incorporation into an inference procedure of prior knowledge, formulating such knowledge is often difficult. Furthermore, there are practical challenges associated with acquiring data of sufficient quantity and quality. Here, we discuss recent progress on these issues.

Epidemiological and clinical characteristics of the COVID-19 epidemic in Brazil.

The first case of COVID-19 was detected in Brazil on 25 February 2020. We report and contextualize epidemiological, demographic and clinical findings for COVID-19 cases during the first 3 months of the epidemic. By 31 May 2020, 514,200 COVID-19 cases, including 29,314 deaths, had been reported in 75.3% (4,196 of 5,570) of municipalities across all five administrative regions of Brazil. The R0 value for Brazil was estimated at 3.1 (95% Bayesian credible interval = 2.4-5.5), with a higher median but overlapping credible intervals compared with some other seriously affected countries. A positive association between higher per-capita income and COVID-19 diagnosis was identified. Furthermore, the severe acute respiratory infection cases with unknown aetiology were associated with lower per-capita income. Co-circulation of six respiratory viruses was detected but at very low levels. These findings provide a comprehensive description of the ongoing COVID-19 epidemic in Brazil and may help to guide subsequent measures to control virus transmission.

Accounting for Healthcare-Seeking Behaviours and Testing Practices in Real-Time Influenza Forecasts.

For diseases such as influenza, where the majority of infected persons experience mild (if any) symptoms, surveillance systems are sensitive to changes in healthcare-seeking and clinical decision-making behaviours. This presents a challenge when trying to interpret surveillance data in near-real-time (e.g., to provide public health decision-support). Australia experienced a particularly large and severe influenza season in 2017, perhaps in part due to: (a) mild cases being more likely to seek healthcare; and (b) clinicians being more likely to collect specimens for reverse transcription polymerase chain reaction (RT-PCR) influenza tests. In this study, we used weekly Flutracking surveillance data to estimate the probability that a person with influenza-like illness (ILI) would seek healthcare and have a specimen collected. We then used this estimated probability to calibrate near-real-time seasonal influenza forecasts at each week of the 2017 season, to see whether predictive skill could be improved. While the number of self-reported influenza tests in the weekly surveys are typically very low, we were able to detect a substantial change in healthcare seeking behaviour and clinician testing behaviour prior to the high epidemic peak. Adjusting for these changes in behaviour in the forecasting framework improved predictive skill. Our analysis demonstrates a unique value of community-level surveillance systems, such as Flutracking, when interpreting traditional surveillance data. These methods are also applicable beyond the Australian context, as similar community-level surveillance systems operate in other countries.

Anatomy of a seasonal influenza epidemic forecast

Bayesian methods have been used to predict the timing of infectious disease epidemics in various settings and for many infectious diseases, including seasonal influenza. But integrating these techniques into public health practice remains an ongoing challenge, and requires close collaboration between modellers, epidemiologists, and public health staff. During the 2016 and 2017 Australian influenza seasons, weekly seasonal influenza forecasts were produced for cities in the three states with the largest populations: Victoria, New South Wales, and Queensland. Forecast results were presented to Health Department disease surveillance units in these jurisdictions, who provided feedback about the plausibility and public health utility of these predictions. In earlier studies we found that delays in reporting and processing of surveillance data substantially limited forecast performance, and that incorporating climatic effects on transmission improved forecast performance. In this study of the 2016 and 2017 seasons, we sought to refine the forecasting method to account for delays in receiving the data, and used meteorological data from past years to modulate the force of infection. We demonstrate how these refinements improved the forecast's predictive capacity, and use the 2017 influenza season to highlight challenges in accounting for population and clinician behaviour changes in response to a severe season.

Model selection for seasonal influenza forecasting.

Epidemics of seasonal influenza inflict a huge burden in temperate climes such as Melbourne (Australia) where there is also significant variability in their timing and magnitude. Particle filters combined with mechanistic transmission models for the spread of influenza have emerged as a popular method for forecasting the progression of these epidemics. Despite extensive research it is still unclear what the optimal models are for forecasting influenza, and how one even measures forecast performance. In this paper, we present a likelihood-based method, akin to Bayes factors, for model selection when the aim is to select for predictive skill. Here, "predictive skill" is measured by the probability of the data after the forecasting date, conditional on the data from before the forecasting date. Using this method we choose an optimal model of influenza transmission to forecast the number of laboratory-confirmed cases of influenza in Melbourne in each of the 2010-15 epidemics. The basic transmission model considered has the susceptible-exposed-infectious-recovered structure with extensions allowing for the effects of absolute humidity and inhomogeneous mixing in the population. While neither of the extensions provides a significant improvement in fit to the data they do differ in terms of their predictive skill. Both measurements of absolute humidity and a sinusoidal approximation of those measurements are observed to increase the predictive skill of the forecasts, while allowing for inhomogeneous mixing reduces the skill. We discuss how our work could be integrated into a forecasting system and how the model selection method could be used to evaluate forecasts when comparing to multiple surveillance systems providing disparate views of influenza activity.