The macroeconomic and epidemiological impacts of Covid-19 in Pakistan. (preprint)

'Coronavirus Disease 2019' (C19) is a respiratory illness caused by 'new Coronavirus' SARS-CoV-2. The C19 pandemic, which engulfed the world in 2021, also caused a national C19 epidemic in Pakistan, who responded with initial forced lockdowns (15-30 March 2020) and a subsequent switch to a smart lockdown strategy, and, by 31 December 2020, Pakistan had managed to limit confirmed cases and case fatalities to 482,506 (456 per 100,000) and 10,176 (4.8 per 100,000). The early switch to a smart lockdown strategy, and successful follow-up move to central coordination and effective communication and enforcement of Standard Operating Procedures, was motivated by a concern over how broad-based forced lockdowns would affect poor households and day-labour. The current study aims to investigate how the national Pakistan C19 epidemic would have unfolded under an uncontrolled baseline scenario and an alternative set of controlled non-pharmaceutical intervention (NPI) policy lockdown scenarios, including health and macroeconomic outcomes. We employ a dynamically-recursive version of the IFPRI Standard Computable General Equilibrium model framework (Lofgren, Lee Harris and Robinson 2002), and a, by now, well-established epidemiological transmission-dynamic model framework (Davies, Klepac et al 2020) using Pakistan-specific 5-year age-group contact matrices on four types of contact rates, including at home, at work, at school, and at other locations (Prem, Cook & Jit 2017), to characterize an uncontrolled spread of disease. Our simulation results indicate that an uncontrolled C19 epidemic, by itself, would have led to a 0.12% reduction in Pakistani GDP (-721mn USD), and a total of 0.65mn critically ill and 1.52mn severely ill C19 patients during 2020-21, while 405,000 Pakistani citizens would have lost their lives. Since the majority of case fatalities and symptomatic cases, respectively 345,000 and 35.9mn, would have occurred in 2020, the case fatality and confirmed case numbers, observed by 31. December 2020 represents an outcome which is far better than the alternative. Case fatalities by 31. December 2020 could possibly have been somewhat improved either via a more prolonged one-off 10 week forced lockdown (66% reduction) or a 1-month forced lockdown/2-months opening intermittent lockdown strategy (33% reduction), but both sets of strategies would have carried significant GDP costs in the order of 2.2%-6.2% of real GDP.

Estimating the increase in reproduction number associated with the Delta variant using local area dynamics in England (preprint)

Background: Local estimates of the time-varying effective reproduction number (Rt) of COVID-19 in England became increasingly heterogeneous during April and May 2021. This may have been attributable to the spread of the Delta SARS-CoV-2 variant. This paper documents real-time analysis that aimed to investigate the association between changes in the proportion of positive cases that were S-gene positive, an indicator of the Delta variant against a background of the previously predominant Alpha variant, and the estimated time-varying Rt at the level of upper-tier local authorities (UTLA). Method: We explored the relationship between the proportion of samples that were S-gene positive and the Rt of test-positive cases over time from the 23 February 2021 to the 25 May 2021. Effective reproduction numbers were estimated using the EpiNow2 R package independently for each local authority using two different estimates of the generation time. We then fit a range of regression models to estimate a multiplicative relationship between S-gene positivity and weekly mean Rt estimate. Results: We found evidence of an association between increased mean Rt estimates and the proportion of S-gene positives across all models evaluated with the magnitude of the effect increasing as model flexibility was decreased. Models that adjusted for either national level or NHS region level time-varying residuals were found to fit the data better, suggesting potential unexplained confounding. Conclusions: Our results indicated that even after adjusting for time-varying residuals between NHS regions, S-gene positivity was associated with an increase in the effective reproduction number of COVID-19. These findings were robust across a range of models and generation time assumptions, though the specific effect size was variable depending on the assumptions used. The lower bound of the estimated effect indicated that the reproduction number of Delta was above 1 in almost all local authorities throughout the period of investigation.

Dosing interval strategies for two-dose COVID-19 vaccination in 13 low- and middle-income countries of Europe: health impact modelling and benefit-risk analysis (preprint)

Background: In settings where the COVID-19 vaccine supply is constrained, extending the intervals between the first and second doses of the COVID-19 vaccine could let more people receive their first doses earlier. Our aim is to estimate the health impact of COVID-19 vaccination alongside benefit-risk assessment of different dosing intervals for low- and middle-income countries of Europe. Methods: We fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 low- and middle-income countries in the World Health Organization European Region (Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Republic of Moldova, Russian Federation, Serbia, North Macedonia, Turkey, and Ukraine). A vaccine product with characteristics similar to the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies related to other COVID-19 vaccines. Both fixed dosing intervals at 4, 8, 12, 16, and 20 weeks and dose-specific intervals that prioritise specific doses for certain age groups were tested. Optimal intervals minimise COVID-19 mortality between March 2021 and December 2022. We incorporated the emergence of variants of concern into the model, and also conducted a benefit-risk assessment to quantify the trade-off between health benefits versus adverse events following immunisation. Findings: In 12 of the 13 countries, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20-59 years). These strategies lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.2% [range: 4.0% - 22.5%; n = 13 (countries)] more deaths. There is generally a negative association between dosing interval and COVID-19 mortality within the range we investigated. Assuming a shorter first dose waning duration of 120 days, as opposed to 360 days in the base case, led to shorter optimal dosing intervals of 8-12 weeks. Benefit-risk ratios were the highest for fixed dosing intervals of 8-12 weeks. Interpretation: We infer that longer dosing intervals of over six months, which are substantially longer than the current label recommendation for most vaccine products, could reduce COVID-19 mortality in low- and middle-income countries of WHO/Europe. Certain vaccine features, such as fast waning of first doses, significantly shorten the optimal dosing intervals.

Using high-resolution contact networks to evaluate SARS-CoV-2 transmission and control in large-scale multi-day events (preprint)

The emergence of the highly transmissible SARS-CoV-2 Delta variant has created a need to reassess the risk posed by increasing social contacts as countries resume pre-pandemic activities, particularly in the context of resuming large-scale events over multiple days. To examine how social contacts formed in different activity settings influences interventions required to control outbreaks, we combined high-resolution data on contacts among passengers and crew on cruise ships with network transmission models. We found passengers had a median of 20 (IQR 10-36) unique close contacts per day, and over 60% of their contact episodes were made in dining or sports areas where mask wearing is typically limited. In simulated outbreaks, we found that vaccination coverage and rapid antigen tests had a larger effect than mask mandates alone, indicating the importance of combined interventions against Delta to reduce event risk in the vaccine era.

Estimating the relationship between mobility, non-pharmaceutical interventions, and COVID-19 transmission in Ghana (preprint)

Governments around the world have implemented non-pharmaceutical interventions (NPIs), e.g. physical distancing and travel restrictions, to limit the transmission of COVID-19. While lockdowns and physical distancing have proven effective for reducing COVID-19 transmission, there is still limited understanding of the degree to which these interventions impact disease transmission, and how they are reflected in measures of human behaviour. Further, there is a lack of understanding about how new sources of data can be used to monitor NPIs, where these data have the potential to augment existing disease surveillance and modelling efforts. In this study, we assess the relationship between indicators of human mobility, NPIs, and estimates of Rt, a real-time measure of the intensity of COVID-19 transmission in subnational districts of Ghana using a multilevel generalised linear mixed model. We demonstrate a relationship between reductions in human mobility and decreases in Rt during the early stages of the COVID-19 epidemic in Ghana, and show how reductions in human mobility relate to increasing stringency of NPIs. We demonstrate the utility of combining local disease surveillance data with large scale human mobility data to augment existing surveillance capacity to estimate and monitor the effect of NPI policies.

Transmission dynamics of SARS-CoV-2 in a strictly-Orthodox Jewish community in the UK (preprint)

Some social settings such as households and workplaces, have been identified as high risk for SARS-CoV-2 transmission. Identifying and quantifying the importance of these settings is critical for designing interventions. A tightly-knit religious community in the UK experienced a very large COVID-19 epidemic in 2020, reaching 64.3% seroprevalence within 10 months, and we surveyed this community both for serological status and individual-level attendance at particular settings. Using these data, and a network model of people and places represented as a stochastic graph rewriting system, we estimated the relative contribution of transmission in households, schools and religious institutions to the epidemic, and the relative risk of infection in each of these settings. All congregate settings were important for transmission, with some such as primary schools and places of worship having a higher share of transmission than others. We found that the model needed a higher general-community transmission rate for women (3.3-fold), and lower susceptibility to infection in children to recreate the observed serological data. The precise share of transmission in each place was related to assumptions about the internal structure of those places. Identification of key settings of transmission can allow public health interventions to be targeted at these locations.

Comparative assessment of methods for short-term forecasts of COVID-19 admissions in England at the local level (preprint)

Background: Forecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources. Methods: We made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all, and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the Weighted Interval Score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known. Results: All models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons. Conclusions: Assuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.

The contribution of hospital-acquired infections to the COVID-19 epidemic in England in the first half of 2020 (preprint)

BackgroundSARS-CoV-2 spreads in hospitals, but the contribution of these settings to the overall COVID-19 burden at a national level is unknown. MethodsWe used comprehensive national English datasets and simulation modelling to determine the total burden (identified and unidentified) of symptomatic hospital-acquired infections. Those unidentified would either be 1) discharged before symptom onset ("missed"), or 2) have symptom onset 7 days or fewer from admission ("misclassified"). We estimated the contribution of "misclassified" cases and transmission from "missed" symptomatic infections to the English epidemic before 31st July 2020. FindingsIn our dataset of hospitalised COVID-19 patients in acute English Trusts with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired (with symptom onset 8 or more days after admission and before discharge). We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified. Misclassified cases and onward transmission from missed infections could account for 15% (mean, 95% range over 200 simulations: 14{middle dot}1%-15{middle dot}8%) of cases currently classified as community-acquired COVID-19. From this, we estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2%-20.7%) of all identified hospitalised COVID-19 cases. ConclusionsTransmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave", but fewer than 1% of all SARS-CoV-2 infections in England. Using symptom onset as a detection method for hospital-acquired SARS-CoV-2 likely misses a substantial proportion (>60%) of hospital-acquired infections. FundingNational Institute for Health Research, UK Medical Research Council, Society for Laboratory Automation and Screening, UKRI, Wellcome Trust, Singapore National Medical Research Council. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with the terms "((national OR country) AND (contribution OR burden OR estimates) AND ("hospital-acquired" OR "hospital-associated" OR "nosocomial")) AND Covid-19" for articles published in English up to July 1st 2021. This identified 42 studies, with no studies that had aimed to produce comprehensive national estimates of the contribution of hospital settings to the COVID-19 pandemic. Most studies focused on estimating seroprevalence or levels of infection in healthcare workers only, which were not our focus. Removing the initial national/country terms identified 120 studies, with no country level estimates. Several single hospital setting estimates exist for England and other countries, but the percentage of hospital-associated infections reported relies on identified cases in the absence of universal testing. Added value of this studyThis study provides the first national-level estimates of all symptomatic hospital-acquired infections with SARS-CoV-2 in England up to the 31st July 2020. Using comprehensive data, we calculate how many infections would be unidentified and hence can generate a total burden, impossible from just notification data. Moreover, our burden estimates for onward transmission suggest the contribution of hospitals to the overall infection burden. Implications of all the available evidenceLarge numbers of patients may become infected with SARS-CoV-2 in hospitals though only a small proportion of such infections are identified. Further work is needed to better understand how interventions can reduce such transmission and to better understand the contributions of hospital transmission to mortality.

Characterising within-hospital SARS-CoV-2 transmission events: a retrospective analysis integrating epidemiological and viral genomic data from a UK tertiary care setting across two pandemic waves (preprint)

Objectives - To characterise within-hospital SARS-CoV-2 transmission across two waves of the COVID-19 pandemic. Design - A retrospective Bayesian modelling study to reconstruct transmission chains amongst 2181 patients and healthcare workers using combined viral genomic and epidemiological data. Setting - A large UK NHS Trust with over 1400 beds and employing approximately 17,000 staff. Participants - 780 patients and 522 staff testing SARS-CoV-2 positive between 1st March 2020 and 25th July 2020 (Wave 1); and 580 patients and 299 staff testing SARS-CoV-2 positive between 30th November 2020 and 24th January 2021 (Wave 2). Main outcome measures - Transmission pairs including who-infected-whom; location of transmission events in hospital; number of secondary cases from each individual, including differences in onward transmission from community and hospital onset patient cases. Results - Staff-to-staff transmission was estimated to be the most frequent transmission type during Wave 1 (31.6% of observed hospital-acquired infections; 95% CI 26.9 to 35.8%), decreasing to 12.9% (95% CI 9.5 to 15.9%) in Wave 2. Patient-to-patient transmissions increased from 27.1% in Wave 1 (95% CI 23.3 to 31.4%) to 52.1% (95% CI 48.0 to 57.1%) in Wave 2, to become the predominant transmission type. Over 50% of hospital-acquired infections were concentrated in 8/120 locations in Wave 1 and 10/93 locations in Wave 2. Approximately 40% to 50% of hospital-onset patient cases resulted in onward transmission compared to less than 4% of definite community-acquired cases. Conclusions - Prevention and control measures that evolved during the COVID-19 pandemic may have had a significant impact on reducing infections between healthcare workers, but were insufficient during the second wave to prevent a high number of patient-to-patient transmissions. As hospital-acquired cases appeared to drive most onward transmissions, more frequent and rapid identification and isolation of these cases will be required to break hospital transmission chains in subsequent pandemic waves

Optimising health and economic impacts of COVID-19 vaccine prioritisation strategies in the WHO European Region (preprint)

BackgroundCountries in the World Health Organization (WHO) European Region differ in terms of the COVID-19 vaccine roll-out speed. We evaluated the health and economic impact of different age-based vaccine prioritisation strategies across this demographically and socio-economically diverse region. MethodsWe fitted country-specific age-stratified compartmental transmission models to reported COVID-19 mortality in the WHO European Region to inform the immunity level before vaccine roll-out. Building upon broad recommendations from the WHO Strategic Advisory Group of Experts on Immunisation (SAGE), we examined four strategies that prioritise: all adults (V+), younger (20-59 year-olds) followed by older adults (60+) (V20), older followed by younger adults (V60), and the oldest adults (75+) (V75) followed by incremental expansion to successively younger five-year age groups. We explored four roll-out scenarios based on projections or recent observations (R1-4) - the slowest scenario (R1) covers 30% of the total population by December 2022 and the fastest (R4) 80% by December 2021. Five decision-making metrics were summarised over 2021-22: mortality, morbidity, and losses in comorbidity-adjusted life expectancy (cLE), comorbidity- and quality-adjusted life years (cQALY), and the value of human capital (HC). Six sets of infection-blocking and disease-reducing vaccine efficacies were considered. FindingsThe optimal age-based vaccine prioritisation strategies were sensitive to country characteristics, decision-making metrics and roll-out speeds. Overall, V60 consistently performed better than or comparably to V75. There were greater benefits in prioritising older adults when roll-out is slow and when VE is low. Under faster roll-out, V+ was the most desirable option. InterpretationA prioritisation strategy involving more age-based stages (V75) does not necessarily lead to better health and economic outcomes than targeting broad age groups (V60). Countries expecting a slow vaccine roll-out may particularly benefit from prioritising older adults. FundingWorld Health Organization, Bill and Melinda Gates Foundation, the Medical Research Council (United Kingdom), the National Institute of Health Research (United Kingdom), the European Commission, the Foreign, Commonwealth and Development Office (United Kingdom), Wellcome Trust Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and medRxiv for articles published in English from inception to 9 Jun 2021, with the search terms: ("COVID-19" OR "SARS-CoV-2") AND ("priorit*) AND ("model*") AND ("vaccin*") and identified 66 studies on vaccine prioritization strategies. Of the 25 studies that compared two or more age-based prioritisation strategies, 12 found that targeting younger adults minimised infections while targeting older adults minimised mortality; an additional handful of studies found similar outcomes between different age-based prioritisation strategies where large outbreaks had already occurred. However, only two studies have explored age-based vaccine prioritisation using models calibrated to observed outbreaks in more than one country, and no study has explored the effectiveness of vaccine prioritisation strategies across settings with different population structures, contact patterns, and outbreak history. Added-value of this studyWe evaluated various age-based vaccine prioritisation strategies for 38 countries in the WHO European Region using various health and economic outcomes for decision-making, by parameterising models using observed outbreak history, known epidemiologic and vaccine characteristics, and a range of realistic vaccine roll-out scenarios. We showed that while targeting older adults was generally advantageous, broadly targeting everyone above 60 years might perform better than or comparably to a more detailed strategy that targeted the oldest age group above 75 years followed by those in the next younger five-year age band. Rapid vaccine roll-out has only been observed in a small number of countries. If vaccine coverage can reach 80% by the end of 2021, prioritising older adults may not be optimal in terms of health and economic impact. Lower vaccine efficacy was associated with greater relative benefits only under relatively slow roll-out scenarios considered. Implication of all the available evidenceCOVID-19 vaccine prioritization strategies that require more precise targeting of individuals of a specific and narrow age range may not necessarily lead to better outcomes compared to strategies that prioritise populations across broader age ranges. In the WHO European Region, prioritising all adults equally or younger adults first will only optimise health and economic impact when roll-out is rapid, which may raise between-country equity issues given the global demand for COVID-19 vaccines.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust (preprint)

BackgroundWe aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity. MethodsHCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99{middle dot}47%, specificity 99{middle dot}56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model. FindingsAs of 12th June 2020, 24{middle dot}4% (n=311/1275) HCWs were seropositive. Of these, 39{middle dot}2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41{middle dot}1%, 95% CrI 30{middle dot}0-52{middle dot}9) and in Physiotherapists and Occupational Therapists (39{middle dot}2%, 95% CrI 24{middle dot}4-56{middle dot}5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those [≤]30 years. InterpretationHCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for studies published up to March 6th 2021, using the terms "COVID", "SARS-CoV-2", "seroprevalence", and "healthcare workers", and in addition for articles of antibody titres in different age groups against coronaviruses using "coronavirus", "SARS-CoV-2, "antibody", "antibody tires", "COVID" and "age". We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised. Added value of this studyIn this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 "Red Zones" and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity. Implications of all the available evidenceThere are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates. Author Contributions O_TBL View this table: org.highwire.dtl.DTLVardef@77acb4org.highwire.dtl.DTLVardef@eb9b35org.highwire.dtl.DTLVardef@1af298org.highwire.dtl.DTLVardef@12cf3e1org.highwire.dtl.DTLVardef@3f6476_HPS_FORMAT_FIGEXP M_TBL C_TBL

Population disruption: estimating changes in population distribution in the UK during the COVID-19 pandemic (preprint)

Mobility data have demonstrated major changes in human movement patterns in response to COVID-19 and associated interventions in many countries. This can involve sub-national redistribution, short-term relocations as well as international migration. In this paper, we combine detailed location data from Facebook measuring the location of approximately 6 million daily active Facebook users in 5km2 tiles in the UK with census-derived population estimates to measure population mobility and redistribution. We provide time-varying population estimates and assess spatial population changes with respect to population density and four key reference dates in 2020 (First lockdown, End of term, Beginning of term, Christmas). We also show how the timing and magnitude of observed population changes can impact the size of epidemics using a deterministic model of COVID-19 transmission. We estimate that between March 2020 and March 2021, the total population of the UK has declined and we identify important spatial variations in this population change, showing that low-density areas have experienced lower population decreases than urban areas. We estimate that, for the top 10% highest population tiles, the population has decreased by 6.6%. Further, we provide evidence that geographic redistributions of population within the UK coincide with dates of non-pharmaceutical interventions including lockdowns and movement restrictions, as well as seasonal patterns of migration around holiday dates. The methods used in this study reveal significant changes in population distribution at high spatial and temporal resolutions that have not previously been quantified by available demographic surveys in the UK. We found early indicators of potential longer-term changes in the population distribution of the UK although it is not clear how these changes may persist after the COVID-19 pandemic.

Date of introduction and epidemiologic patterns of SARS-CoV-2 in Mogadishu, Somalia: estimates from transmission modelling of 2020 excess mortality data (preprint)

IntroductionIn countries with weak surveillance systems confirmed COVID-19 deaths are likely to underestimate the death toll of the pandemic. Many countries also have incomplete vital registration systems, hampering excess mortality estimation. Here, we fitted a dynamic transmission model to satellite imagery data on burial patterns in Mogadishu, Somalia during 2020 to estimate the date of introduction, transmissibility and other epidemiologic characteristics of SARS-CoV-2 in this low-income, crisis-affected setting. MethodsWe performed Markov chain Monte Carlo (MCMC) fitting with an age-structured compartmental COVID-19 model to provide median estimates and credible intervals for the date of introduction, the basic reproduction number (R0) and the effect of non-pharmaceutical interventions in Mogadishu up to September 2020. ResultsUnder the assumption that excess deaths in Mogadishu February-September 2020 were directly attributable to SARS-CoV-2 infection we arrived at median estimates of October-November 2019 for the date of introduction and low R0 estimates (1.3-1.5) stemming from the early and slow rise of excess deaths. The effect of control measures on transmissibility appeared small. ConclusionSubject to study assumptions, a very early SARS-CoV-2 introduction event may have occurred in Somalia. Estimated transmissibility in the first epidemic wave was lower than observed in European settings.

Quarantine and testing strategies to reduce transmission risk from imported SARS-CoV-2 infections: a global modelling study (preprint)

Background Many countries require incoming air travellers to quarantine on arrival and/or undergo testing to limit importation of SARS-CoV-2. Methods We developed mathematical models of SARS-CoV-2 viral load trajectories over the course of infection to assess the effectiveness of quarantine and testing strategies. We consider the use of Polymerase Chain Reaction (PCR) and lateral flow testing (LFT) both pre-flight, to reduce the number of infectious arrivals and when exiting quarantine, and daily testing of arrivals with LFTs. We also estimate the effect of each strategy relative to domestic incidence, and limits of achievable risk reduction, for 99 countries where flight data and case numbers are estimated. Results We find that immediately pre-flight LFTs are more effective than PCR tests 3 days before departure in decreasing the number of departing infectious travellers. Pre-flight LFTs and post-flight quarantines, with tests to release, may prevent the majority of transmission from infectious arrivals while reducing the required duration of quarantine; a pre-flight LFT followed by 5 days in quarantine with a test to release would reduce the expected number of secondary cases generated by an infected traveller compared to symptomatic self-isolation alone, Rs, by 85% (95% UI: 74%, 96%) for PCR and 85% (95% UI: 70%, 96%) for LFT, even assuming imperfect adherence to quarantine (28% of individuals) and self-isolation following a positive test (86%). Under the same adherence assumptions, 5 days of daily LFT testing would reduce Rs by 91% (95% UI: 75%, 98%). Conclusions Strategies aimed at reducing the risk of imported cases should be considered with respect to: domestic incidence, transmission, and susceptibility; measures in place to support quarantining travellers; and incidence of new variants of concern in travellers' origin countries. Daily testing with LFTs for 5 days is comparable to 5 days of quarantine with a test on exit or 14 days with no test.

Serial intervals observed in SARS-CoV-2 B.1.617.2 variant cases (preprint)

Rapid growth of the B.1.617.2 variant of SARS-CoV-2 has been observed in many countries. Broadly, the factors driving the recent rapid growth of COVID-19 cases could be attributed to shorten generation intervals or higher transmissibility (effective reproduction number, R), or both. As such, establishing reasons for the observed rapid growth will allow countries to know how best to enhance their outbreak control measures. In this study, we analysed the serial interval of household transmission pairs infected with SARS-CoV-2 B.1.617.2 variant and compared with those who were infected prior to the occurrence of the major global SARS-CoV-2 variants. After controlling for confounding factors, our findings suggest no significant changes in the serial intervals for SARS-CoV-2 cases infected with the B.1.617.2 variant. This in turn lends support for a hypothesis of a higher R for B.1.617.2 cases.

How immunity from and interaction with seasonal coronaviruses can shape SARS-CoV-2 epidemiology (preprint)

We hypothesised that cross-protection from seasonal epidemics of human coronaviruses (HCoVs) could have affected SARS-CoV-2 transmission, including generating reduced susceptibility in children. To determine what the pre-pandemic distribution of immunity to HCoVs was, we fitted a mathematical model to 6 years of seasonal coronavirus surveillance data from England and Wales. We estimated a duration of immunity to seasonal HCoVs of 7.3 years (95%CI 6.8 - 7.9) and show that, while cross-protection between HCoV and SARS-CoV-2 may contribute to the age distribution, it is insufficient to explain the age pattern of SARS-CoV-2 infections in the first wave of the pandemic in England and Wales. Projections from our model illustrate how different strengths of cross-protection between circulating coronaviruses could determine the frequency and magnitude of SARS-CoV-2 epidemics over the coming decade, as well as the potential impact of cross-protection on future seasonal coronavirus transmission.

SARS-CoV-2 infection risk during delivery of childhood vaccination campaigns: a modelling study (preprint)

BackgroundThe COVID-19 pandemic has disrupted delivery of immunisation services globally. Many countries have postponed vaccination campaigns out of concern about infection risks to staff delivering vaccination, the children being vaccinated and their families. The World Health Organization recommends considering both the benefit of preventive campaigns and the risk of SARS-CoV-2 transmission when making decisions about campaigns during COVID-19 outbreaks, but there has been little quantification of the risks. MethodsWe modelled excess SARS-CoV-2 infection risk to vaccinators, vaccinees and their caregivers resulting from vaccination campaigns delivered during a COVID-19 epidemic. Our model used population age-structure and contact patterns from three exemplar countries (Burkina Faso, Ethiopia, and Brazil). It combined an existing compartmental transmission model of an underlying COVID-19 epidemic with a Reed-Frost model of SARS-CoV-2 infection risk to vaccinators and vaccinees. We explored how excess risk depends on key parameters governing SARS-CoV-2 transmissibility, and aspects of campaign delivery such as campaign duration, number of vaccinations, and effectiveness of personal protective equipment (PPE) and symptomatic screening. ResultsInfection risks differ considerably depending on the circumstances in which vaccination campaigns are conducted. A campaign conducted at the peak of a SARS-CoV-2 epidemic with high prevalence and without special infection mitigation measures could increase absolute infection risk by 32% to 45% for vaccinators, and 0.3% to 0.5% for vaccinees and caregivers. However, these risks could be reduced to 3.6% to 5.3% and 0.1% to 0.2% respectively by use of PPE that reduces transmission by 90% (as might be achieved with N95 respirators or high-quality surgical masks) and symptomatic screening. ConclusionsSARS-CoV-2 infection risks to vaccinators, vaccinees and caregivers during vaccination campaigns can be greatly reduced by adequate PPE, symptomatic screening, and appropriate campaign timing. Our results support the use of adequate risk mitigation measures for vaccination campaigns held during SARS-CoV-2 epidemics, rather than cancelling them entirely.

Estimating the impact of reopening schools on the reproduction number of SARS-CoV-2 in England, using weekly contact survey data (preprint)

Background Schools have been closed in England since the 4th of January 2021 as part of the national restrictions to curb transmission of SARS-CoV-2. The UK Government plans to reopen schools on the 8th of March. Although there is evidence of lower individual-level transmission risk amongst children compared to adults, the combined effects of this with increased contact rates in school settings are not clear. Methods We measured social contacts when schools were both open or closed, amongst other restrictions. We combined these data with estimates of the susceptibility and infectiousness of children compared with adults to estimate the impact of reopening schools on the reproduction number. Results Our results suggest that reopening all schools could increase R from an assumed baseline of 0.8 to between 1.0 and 1.5, or to between 0.9 and 1.2 reopening primary or secondary schools alone. Conclusion Our results suggest that reopening schools is likely to halt the fall in cases observed in recent months and risks returning to rising infections, but these estimates rely heavily on the current estimates or reproduction number and the current validity of the susceptibility and infectiousness profiles we use.

Health impact and cost-effectiveness of COVID-19 vaccination in Sindh Province, Pakistan (preprint)

Background Multiple COVID-19 vaccines appear to be safe and efficacious, but only high-income countries have the resources to procure sufficient vaccine doses for most of their eligible populations. The World Health Organization has published guidelines for vaccine prioritisation, but most vaccine impact projections have focused on high-income countries, and few incorporate economic considerations. To address this evidence gap, we projected the health and economic impact of different vaccination scenarios in Sindh province, Pakistan (population: 48 million). Methods We fitted a compartmental transmission model to COVID-19 cases and deaths in Sindh from 30 April to 15 September 2020 using varying assumptions about the timing of the first case and the duration of infection-induced immunity. We then projected cases and deaths over 10 years under different vaccine scenarios. Finally, we combined these projections with a detailed economic model to estimate incremental costs (from healthcare and partial societal perspectives), disability adjusted life years (DALYs), and cost-effectiveness for each scenario. Findings A one-year vaccination campaign using an infection-blocking vaccine at $3/dose with 70% efficacy and 2.5 year duration of protection is projected to avert around 0.93 (95% Credible Interval: 0.91, 1.0) million cases, 7.3 (95% CrI: 7.2, 7.4) thousand deaths and 85.1 (95% CrI: 84.6, 86.8) thousand DALYs, and be net cost saving from the health system perspective. However, paying a high price for vaccination ($10/dose) may not be cost-effective. Vaccinating the older (65+) population first would prevent slightly more deaths and a similar number of cases as vaccinating everyone aged 15+ at the same time, at similar cost-effectiveness. Interpretation COVID-19 vaccination can have a considerable health impact, and is likely to be cost-effective if more optimistic vaccine scenarios apply. Preventing severe disease is an important contributor to this impact, but the advantage of focusing initially on older, high-risk populations may be smaller in generally younger populations where many people have already been infected, typical of many low- and -middle income countries, as long as vaccination gives good protection against infection as well as disease.

Increased hazard of death in community-tested cases of SARS-CoV-2 Variant of Concern 202012/01 (preprint)

VOC 202012/01, a SARS-CoV-2 variant first detected in the United Kingdom in September 2020, has spread to multiple countries worldwide. Several studies have established that this novel variant is more transmissible than preexisting variants of SARS-CoV-2, but have not identified whether the new variant leads to any change in disease severity. We analyse a large database of SARS-CoV-2 community test results and COVID-19 deaths for England, representing approximately 47% of all SARS-CoV-2 community tests and 7% of COVID-19 deaths in England from 1 September 2020 to 22 January 2021. Fortuitously, these SARS-CoV-2 tests can identify VOC 202012/01 because mutations in this lineage prevent PCR amplification of the spike gene target (S gene target failure, SGTF). We estimate that the hazard of death among SGTF cases is 30% (95% CI 9-56%) higher than among non-SGTF cases after adjustment for age, sex, ethnicity, deprivation level, care home residence, local authority of residence and date of test. In absolute terms, this increased hazard of death corresponds to the risk of death for a male aged 55-69 increasing from 0.56% to 0.73% (95% CI 0.60-0.86%) over the 28 days following a positive SARS-CoV-2 test in the community. Correcting for misclassification of SGTF, we estimate a 35% (12-64%) higher hazard of death associated with VOC 202012/01. Our analysis suggests that VOC 202012/01 is not only more transmissible than preexisting SARS-CoV-2 variants but may also cause more severe illness.