Scenario modelling for diminished influenza seasons during 2020/2021 and 2021/2022 in England (preprint)

Background There has been concern throughout the COVID-19 pandemic over highly stressed healthcare capacities being further pressured by seasonal influenza epidemics. Interventions to tackle the spread of SARS-CoV-2, the causative agent of COVID-19, have unsettled the respiratory pathogen landscape, including worldwide patterns of influenza activity. The implications of these disruptions for subsequent influenza seasons has been uncertain. Methods To conduct scenario analyses ahead of the 2020/2021 and 2021/2022 influenza seasons in England, we used a pre-existing age-structured, multi-strain compartmental model of influenza transmission and case severity, which included propagation of immunity between influenza seasons and had been previously fit to historical data. For the pre-2020/2021 influenza season, our scenarios varied the level of vaccine uptake and the inclusion/exclusion of nonpharmaceutical interventions (NPIs). We estimated the relative amount of health episode occurrences: symptomatic cases resulting in a GP consultation, hospital inpatient admissions, fatalities. In the pre-2021/2022 influenza season analysis, compared with a counterfactual case where influenza activity remained at historic levels in the 2020/2021 influenza season, we estimated the change in the same set of health episode occurrences in the 2021/2022 influenza season when assuming there was no influenza in circulation during the 2020/2021 influenza season. Results Attaining coverage of 75% in target groups for the 2020/2021 influenza season reduced health episode occurrences by 40–50% when compared to maintaining the 2019/2020 vaccination programme coverage and uptake levels. Having NPIs maintained throughout the entire influenza season saw 60-80% reductions in severe case outcomes. Combining an expanded vaccination programme and the use of NPIs could suppress the seasonal influenza epidemic, with reductions as much as 90–100%. In the absence of influenza transmission during the 2020/2021 influenza season, under our modelling assumption of mixing patterns returning to pre-2020 levels we projected a compensatory influenza epidemic with 1.2 to 2.2 times as many severe health episode occurrences in the subsequent 2021/2022 influenza season. Conclusions In the context of the time the work was originally conducted, the modelled scenarios indicated how bolstering vaccine coverage and reduction in contacts could likely allay resurgent seasonal influenza epidemics. Our analyses of the winter pressures that may be inflicted by other respiratory infections during the COVID-19 pandemic are one example of the modelling insights provided to the Scientific Pandemic Influenza Group on Modelling, Operational sub-group (SPI-M-O) for the Scientific Advisory Group for Emergencies (SAGE) in the UK.

Comparison of the 2021 COVID-19 Roadmap Projections against Public Health Data in England (preprint)

Control and mitigation of the COVID-19 pandemic in England has relied on a combination of vaccination and non-pharmaceutical interventions (NPIs). Some of these NPIs are extremely costly (economically and socially), so it was important to relax these promptly without overwhelming already burdened health services. The eventual policy was a Roadmap of four relaxation steps throughout 2021, taking England from lock-down to the cessation of all restrictions on social interaction. In a series of six Roadmap documents generated throughout 2021, models assessed the potential risk of each relaxation step. Here we show that the model projections generated a reliable estimation of medium-term hospital admission trends, with the data points up to September 2021 generally lying within our 95% prediction intervals. The greatest uncertainties in the modelled scenarios came from vaccine efficacy estimates against novel variants, and from assumptions about human behaviour in the face of changing restrictions and risk.

Short-term Projections based on Early Omicron Variant Dynamics in England (preprint)

Throughout the ongoing COVID-19 pandemic, the worldwide transmission and replication of SARS-COV-2, the causative agent of COVID-19 disease, has resulted in the opportunity for multiple mutations to occur that may alter the virus transmission characteristics, the effectiveness of vaccines and the severity of disease upon infection. The Omicron variant (B.1.1.529) was first reported to the WHO by South Africa on 24 November 2021 and was declared a variant of concern by the WHO on 26 November 2021. The variant was first detected in the UK on 27 November 2021 and has since been reported in a number of countries globally where it is frequently associated with rapid increase in cases. Here we present analyses of UK data showing the earliest signatures of the Omicron variant and mathematical modelling that uses the UK data to simulate the potential impact of this variant in the UK. In order to account for the uncertainty in transmission advantage, vaccine escape and severity at the time of writing, we carry out a sensitivity analysis to assess the impact of these variant characteristics on future risk.

Waning, Boosting and a Path to Endemicity for SARS-CoV-2 (preprint)

In many countries, an extensive vaccination programme has substantially reduced the public-health impact of SARS-CoV-2, limiting the number of hospital admissions and deaths compared to an unmitigated epidemic. Ensuring a low-risk transition from the current situation to one in which SARS-CoV-2 is endemic requires maintenance of high levels of population immunity. The observed waning of vaccine efficacy over time suggests that booster doses may be required to maintain population immunity especially in the most vulnerable groups. Here, using data and models for England, we consider the dynamics of COVID-19 over a two-year time-frame, and the role that booster vaccinations can play in mitigating the worst effects. We find that boosters are necessary to suppress the imminent wave of infections that would be generated by waning vaccine efficacy. Projecting further into the future, the optimal deployment of boosters is highly sensitive to their long-term action. If protection from boosters wanes slowly (akin to protection following infection) then a single booster dose to the over 50s may be all that is needed over the next two-years. However, if protection wanes more rapidly (akin to protection following second dose vaccination) then annual or even biannual boosters are required to limit subsequent epidemic peaks an reduce the pressure on public health services.

Quantifying within-school SARS-CoV-2 transmission and the impact of lateral flow testing in secondary schools in England (preprint)

Background To control within-school SARS-CoV-2 transmission in England, secondary school pupils have been encouraged to participate in twice weekly mass testing via lateral flow device tests (LFTs) from 8th March 2021, to complement an isolation of close contacts policy in place since 31st August 2020. Strategies involving the isolation of close contacts can lead to high levels of absences, negatively impacting pupils. Methods We fit a stochastic individual-based model of secondary schools to both community swab testing data and secondary school absences data. By simulating epidemics in secondary schools from 31st August 2020 until 21st May 2021, we quantify within-school transmission of SARS-CoV-2 in secondary schools in England, the impact of twice weekly mass testing on within-school transmission, and the potential impact of alternative strategies to the isolation of close contacts in reducing pupil absences. Findings The within-school reproduction number, R school , has remained below 1 from 31st August 2020 until 21st May 2021. Twice weekly mass testing using LFTs have helped to control within-school transmission in secondary schools in England. A strategy of serial contact testing alongside mass testing substantially reduces absences compared to strategies involving isolating close contacts, with only a marginal increase in within-school transmission. Interpretation Secondary school control strategies involving mass testing have the potential to control within-school transmission while substantially reducing absences compared to an isolation of close contacts policy.

Early epidemiological signatures of novel SARS-CoV-2 variants: establishment of B.1.617.2 in England (preprint)

The rapid emergence of SARS-CoV-2 mutants with new phenotypic properties is a critical challenge to the control of the ongoing pandemic. B.1.1.7 was monitored in the UK through routine testing and S-gene target failures (SGTF), comprising over 90% of cases by March 2021. Now, the reverse is occurring: SGTF cases are being replaced by an S-gene positive variant, which we associate with B.1.617.2. Evidence from the characteristics of S-gene positive cases demonstrates that, following importation, B.1.617.2 is transmitted locally, growing at a rate higher than B.1.1.7 and a doubling time between 5-14 days. S-gene positive cases should be prioritised for sequencing and aggressive control in any countries in which this variant is newly detected.

Solving Heterogeneous General Equilibrium Economic Models with Deep Reinforcement Learning (preprint)

General equilibrium macroeconomic models are a core tool used by policymakers to understand a nation's economy. They represent the economy as a collection of forward-looking actors whose behaviours combine, possibly with stochastic effects, to determine global variables (such as prices) in a dynamic equilibrium. However, standard semi-analytical techniques for solving these models make it difficult to include the important effects of heterogeneous economic actors. The COVID-19 pandemic has further highlighted the importance of heterogeneity, for example in age and sector of employment, in macroeconomic outcomes and the need for models that can more easily incorporate it. We use techniques from reinforcement learning to solve such models incorporating heterogeneous agents in a way that is simple, extensible, and computationally efficient. We demonstrate the method's accuracy and stability on a toy problem for which there is a known analytical solution, its versatility by solving a general equilibrium problem that includes global stochasticity, and its flexibility by solving a combined macroeconomic and epidemiological model to explore the economic and health implications of a pandemic. The latter successfully captures plausible economic behaviours induced by differential health risks by age.

Coughs, Colds and “Freshers’ Flu” Survey in the University of Cambridge, 2007-2008 (preprint)

Universities provide many opportunities for the spread of infectious respiratory illnesses. Students are brought together into close proximity from all across the world and interact with one another in their accommodation, through lectures and small group teaching and in social settings. The COVID-19 global pandemic has highlighted the need for sufficient data to help determine which of these factors are important for infectious disease transmission in universities and hence control university morbidity as well as community spillover. We describe the data from a previously unpublished self-reported university survey of coughs, colds and flu-like symptoms collected in Cambridge, UK, during winter 2007-2008. The online survey collected information on symptoms and socio-demographic, academic and lifestyle factors. There were 1076 responses, 97% from University of Cambridge students (5.7% of the total university student population), 3% from staff and <1% from other participants, reporting onset of symptoms between September 2007 and March 2008. Undergraduates are seen to report symptoms earlier in the term than postgraduates; differences in reported date of symptoms are also seen between subjects and accommodation types, although these descriptive results could be confounded by survey biases. Despite the historic and exploratory nature of the study, this is one of few recent detailed datasets of flu-like infection in a university context and is especially valuable to share now to improve understanding of potential transmission dynamics in universities during the current COVID-19 pandemic.

Comparison between one and two dose SARS-CoV-2 vaccine prioritisation for a fixed number of vaccine doses (preprint)

The swift development of SARS-CoV-2 vaccines has been met with worldwide commendation. How-ever, in the context of an ongoing pandemic there is an interplay between infection and vaccination. Whilst infection can grow exponentially, vaccination rates are generally limited by supply and logistics. With the first SARS-CoV-2 vaccines receiving medical approval requiring two doses, there has been scrutiny on the spacing between doses; an elongated period between doses allows more of the population to receive a first vaccine dose in the short-term generating wide-spread partial immunity. Focusing on data from England, we investigated prioritisation of a one dose or two dose vaccination schedule given a fixed number of vaccine doses and with respect to a measure of maximising averted deaths. We optimised outcomes for two different estimates of population size and relative risk of mortality for at-risk groups within the Phase 1 vaccine priority order. Vaccines offering relatively high protection from the first dose favour strategies that prioritise giving more people one dose, although with increasing vaccine supply eventually those eligible and accepting vaccination will receive two doses. Whilst optimal dose timing can substantially reduce the overall mortality risk, there needs to be careful consideration of the logistics of vaccine delivery.

Vaccination and Non-Pharmaceutical Interventions: When Can the UK Relax About COVID-19? (preprint)

Background: The announcement of efficacious vaccine candidates against SARS-CoV-2 has been met with worldwide acclaim and relief. Many countries already have detailed plans for vaccine targeting based on minimising severe illness, death and healthcare burdens. Normally, relatively simple relationships between epidemiological parameters, vaccine efficacy and vaccine uptake predict the success of any immunisation programme. However, the dynamics of vaccination against SARS-CoV-2 is made more complex by age-dependent factors, changing levels of infection and the potential relaxation of non-pharmaceutical interventions (NPIs) as the perceived risk declines. Methods: In this study we use an age-structured mathematical model, matched to a range of epidemiological data, which also captures the roll-out of a two-dose vaccination programme targeted at specific age groups. Findings: We consider the interaction between the UK vaccination programme and future re- laxation (or removal) of NPIs. Our predictions highlight the population-level risks of early relaxation leading to a pronounced wave of infection, hospital admissions and deaths. Only vaccines that offer high transmission-blocking efficacy with high uptake in the general population allow relaxation of NPIs without a huge surge in deaths. Interpretation: While the novel vaccines against SARS-CoV-2 offer a potential exit strategy for this outbreak, this is highly contingent on the transmission blocking action of the vaccine and the population uptake, both of which need to be carefully monitored as vaccine programmes are rolled out in the UK and other countries.Funding Statement: This research was funded by the National Institute for Health Research (NIHR) [Policy Research Programme, Mathematical & Economic Modelling for Vaccination and Immunisation Evaluation, and Emergency Response; NIHR200411], the Medical Research Council through the COVID- 19 Rapid Response Rolling Call [grant number MR/V009761/1] and through the JUNIPER modelling consortium [grant number EP/V030477/1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of Interests: All authors declare that they have no competing interests.Ethics Approval Statement: The data were supplied from the CHESS database after anonymisation under strict data protection protocols agreed between the University of Warwick and Public Health England. The ethics of the use of these data for these purposes was agreed by Public Health England with the Government’s SPI-M(O) / SAGE committees.

Vaccination and Non-Pharmaceutical Interventions: When can the UK relax about COVID-19? (preprint)

Summary Background The announcement of efficacious vaccine candidates against SARS-CoV-2 has been met with worldwide acclaim and relief. Many countries already have detailed plans for vaccine targeting based on minimising severe illness, death and healthcare burdens. Normally, relatively simple relationships between epidemiological parameters, vaccine efficacy and vaccine uptake predict the success of any immunisation programme. However, the dynamics of vaccination against SARS-CoV-2 is made more complex by age-dependent factors, changing levels of infection and the potential relaxation of non-pharmaceutical interventions (NPIs) as the perceived risk declines. Methods In this study we use an age-structured mathematical model, matched to a range of epidemiological data in the UK, that also captures the roll-out of a two-dose vaccination programme targeted at specific age groups. Findings We consider the interaction between the UK vaccination programme and future relaxation (or removal) of NPIs. Our predictions highlight the population-level risks of early relaxation leading to a pronounced wave of infection, hospital admissions and deaths. Only vaccines that offer high infection-blocking efficacy with high uptake in the general population allow relaxation of NPIs without a huge surge in deaths. Interpretation While the novel vaccines against SARS-CoV-2 offer a potential exit strategy for this outbreak, this is highly contingent on the infection-blocking (or transmission-blocking) action of the vaccine and the population uptake, both of which need to be carefully monitored as vaccine programmes are rolled out in the UK and other countries. Research in context Evidence before this study Vaccination has been seen as a key tool in the fight against SARS-CoV-2. The vaccines already developed represent a major technological achievement and have been shown to generate significant immune responses, as well as offering considerable protection against disease. However, to date there is limited information on the degree of infection-blocking these vaccines are likely to induce. Mathematical models have already successfully been used to consider age- and risk-structured targeting of vaccination, highlighting the importance of prioritising older and high-risk individuals. Added value of this study Translating current knowledge and uncertainty of vaccine behaviour into meaningful public health messages requires models that fully capture the within-country epidemiology as well as the complex roll-out of a two-dose vaccination programme. We show that under reasonable assumptions for vaccine efficacy and uptake the UK is unlikely to reach herd immunity, which means that non-pharmaceutical interventions cannot be released without generating substantial waves of infection. Implications of all the available evidence Vaccination is likely to provide substantial individual protection to those receiving two doses, but the degree of protection to the wider population is still uncertain. While substantial immunisation of the most vulnerable groups will allow for some relaxation of controls, this must be done gradually to prevent large scale public health consequences.

Predictions of COVID-19 dynamics in the UK: short-term forecasting and analysis of potential exit strategies (preprint)

BackgroundEfforts to suppress transmission of SARS-CoV-2 in the UK have seen non-pharmaceutical interventions being invoked. The most severe measures to date include all restaurants, pubs and cafes being ordered to close on 20th March, followed by a "stay at home" order on the 23rd March and the closure of all non-essential retail outlets for an indefinite period. Government agencies are presently analysing how best to develop an exit strategy from these measures and to determine how the epidemic may progress once measures are lifted. Mathematical models are currently providing short and long term forecasts regarding the future course of the COVID-19 outbreak in the UK to support evidence-based policymaking. MethodsWe present a deterministic, age-structured transmission model that uses real-time data on confirmed cases requiring hospital care and mortality to provide up-to-date predictions on epidemic spread in ten regions of the UK. The model captures a range of age-dependent heterogeneities, reduced transmission from asymptomatic infections and produces a good fit to the key epidemic features over time. We simulated a suite of scenarios to assess the impact of differing approaches to relaxing social distancing measures from 7th May 2020, on the estimated number of patients requiring inpatient and critical care treatment, and deaths. With regard to future epidemic outcomes, we investigated the impact of reducing compliance, ongoing shielding of elder age groups, reapplying stringent social distancing measures using region based triggers and the role of asymptomatic transmission. FindingsWe find that significant relaxation of social distancing measures from 7th May onwards can lead to a rapid resurgence of COVID-19 disease and the health system being quickly overwhelmed by a sizeable, second epidemic wave. In all considered age-shielding based strategies, we projected serious demand on critical care resources during the course of the pandemic. The reintroduction and release of strict measures on a regional basis, based on ICU bed occupancy, results in a long epidemic tail, until the second half of 2021, but ensures that the health service is protected by reintroducing social distancing measures for all individuals in a region when required. DiscussionOur work confirms the effectiveness of stringent non-pharmaceutical measures in March 2020 to suppress the epidemic. It also provides strong evidence to support the need for a cautious, measured approach to relaxation of lockdown measures, to protect the most vulnerable members of society and support the health service through subduing demand on hospital beds, in particular bed occupancy in intensive care units.

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells (preprint)

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

A dynamic nomenclature proposal for SARS-CoV-2 to assist genomic epidemiology

The ongoing pandemic spread of a novel human coronavirus, SARS-COV-2, associated with severe pneumonia disease (COVID-19), has resulted in the generation of thousands of virus genome sequences. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding phylogenetic diversity of SARS-CoV-2. We present a rational and dynamic virus nomenclature that uses a phylogenetic framework to identify those lineages that contribute most to active spread. Our system is made tractable by constraining the number and depth of hierarchical lineage labels and by flagging and declassifying virus lineages that become unobserved and hence are likely inactive. By focusing on active virus lineages and those spreading to new locations this nomenclature will assist in tracking and understanding the patterns and determinants of the global spread of SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.