Imperial College London

DrJohnLees

Faculty of MedicineSchool of Public Health

Visiting Researcher
 
 
 
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Contact

 

+44 (0)20 7594 2939j.lees Website

 
 
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Location

 

UG4Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

76 results found

Kremer PHC, Ferwerda B, Bootsma HJ, Rots NY, Wijmenga-Monsuur AJ, Sanders EAM, Trzcinski K, Wyllie AL, Turner P, van der Ende A, Brouwer MC, Bentley SD, van de Beek D, Lees JAet al., 2022, Pneumococcal genetic variability in age-dependent bacterial carriage, ELIFE, Vol: 11, ISSN: 2050-084X

Journal article

Stevens EJ, Morse DJ, Bonini D, Duggan S, Brignoli T, Recker M, Lees JA, Croucher NJ, Bentley S, Wilson DJ, Earle SG, Dixon R, Nobbs A, Jenkinson H, van Opijnen T, Thibault D, Wilkinson OJ, Dillingham MS, Carlile S, McLoughlin RM, Massey RCet al., 2022, Targeted control of pneumolysin production by a mobile genetic element in Streptococcus pneumoniae, MICROBIAL GENOMICS, Vol: 8, ISSN: 2057-5858

Journal article

Gladstone RA, Siira L, Brynildsrud OB, Vestrheim DF, Turner P, Clarke SC, Srifuengfung S, Ford R, Lehmann D, Egorova E, Voropaeva E, Haraldsson G, Kristinsson KG, McGee L, Breiman RF, Bentley SD, Sheppard CL, Fry NK, Corander J, Toropainen M, Steens Aet al., 2022, International links between Streptococcus pneumoniae vaccine serotype 4 sequence type (ST) 801 in Northern European shipyard outbreaks of invasive pneumococcal disease, VACCINE, Vol: 40, Pages: 1054-1060, ISSN: 0264-410X

Journal article

Zangari T, Zafar MA, Lees JA, Abruzzo AR, Bee GCW, Weiser JNet al., 2021, Pneumococcal capsule blocks protection by immunization with conserved surface proteins, NPJ VACCINES, Vol: 6

Journal article

Sonabend R, Whittles LK, Imai N, Perez Guzman PN, Knock E, Rawson T, Gaythorpe KA, Djaafara A, Hinsley W, Fitzjohn R, Lees JA, Thekke Kanapram D, Volz E, Ghani A, Ferguson NM, Baguelin M, Cori Aet al., 2021, Non-pharmaceutical interventions, vaccination, and the SARS-CoV-2 delta variant in England: a mathematical modelling study, The Lancet, Vol: 398, Pages: 1825-1835, ISSN: 0140-6736

Background:England's COVID-19 roadmap out of lockdown policy set out the timeline and conditions for the stepwise lifting of non-pharmaceutical interventions (NPIs) as vaccination roll-out continued, with step one starting on March 8, 2021. In this study, we assess the roadmap, the impact of the delta (B.1.617.2) variant of SARS-CoV-2, and potential future epidemic trajectories.Methods:This mathematical modelling study was done to assess the UK Government's four-step process to easing lockdown restrictions in England, UK. We extended a previously described model of SARS-CoV-2 transmission to incorporate vaccination and multi-strain dynamics to explicitly capture the emergence of the delta variant. We calibrated the model to English surveillance data, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework, then modelled the potential trajectory of the epidemic for a range of different schedules for relaxing NPIs. We estimated the resulting number of daily infections and hospital admissions, and daily and cumulative deaths. Three scenarios spanning a range of optimistic to pessimistic vaccine effectiveness, waning natural immunity, and cross-protection from previous infections were investigated. We also considered three levels of mixing after the lifting of restrictions.Findings:The roadmap policy was successful in offsetting the increased transmission resulting from lifting NPIs starting on March 8, 2021, with increasing population immunity through vaccination. However, because of the emergence of the delta variant, with an estimated transmission advantage of 76% (95% credible interval [95% CrI] 69–83) over alpha, fully lifting NPIs on June 21, 2021, as originally planned might have led to 3900 (95% CrI 1500–5700) peak daily hospital admissions under our central parameter scenario. Delaying until July 19, 2021, reduced peak hospital admissions by three fol

Journal article

Lees JA, Tonkin-Hill G, Yang Z, Corander Jet al., 2021, Mandrake: visualising microbial population structure by embedding millions of genomes into a low-dimensional representation

<jats:title>Abstract</jats:title><jats:p>In less than a decade, population genomics of microbes has progressed from the effort of sequencing dozens of strains to thousands, or even tens of thousands of strains in a single study. There are now hundreds of thousands of genomes available even for a single bacterial species and the number of genomes is expected to continue to increase at an accelerated pace given the advances in sequencing technology and widespread genomic surveillance initiatives. This explosion of data calls for innovative methods to enable rapid exploration of the structure of a population based on different data modalities, such as multiple sequence alignments, assemblies and estimates of gene content across different genomes. Here we present Mandrake, an efficient implementation of a dimensional reduction method tailored for the needs of large-scale population genomics. Mandrake is capable of visualising population structure from millions of whole genomes and we illustrate its usefulness with several data sets representing major pathogens. Our method is freely available both as an analysis pipeline (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/johnlees/mandrake">https://github.com/johnlees/mandrake</jats:ext-link>) and as a browser-based interactive application (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://gtonkinhill.github.io/mandrake-web/">https://gtonkinhill.github.io/mandrake-web/</jats:ext-link>).</jats:p>

Journal article

D'Aeth JC, van der Linden MPG, McGee L, De Lencastre H, Turner P, Song J-H, Lo SW, Gladstone RA, Sa-Leao R, Ko KS, Hanage WP, Breiman RF, Beall B, Bentley SD, Croucher NJ, GPS Consortiumet al., 2021, The role of interspecies recombinations in the evolution of antibiotic-resistant pneumococci, eLife, Vol: 10, ISSN: 2050-084X

The evolutionary histories of the antibiotic-resistant Streptococcus pneumoniae lineages PMEN3 and PMEN9 were reconstructed using global collections of genomes. In PMEN3, one resistant clade spread worldwide, and underwent 25 serotype switches, enabling evasion of vaccine-induced immunity. In PMEN9, only 9 switches were detected, and multiple resistant lineages emerged independently and circulated locally. In Germany, PMEN9’s expansion correlated significantly with the macrolide:penicillin consumption ratio. These isolates were penicillin sensitive but macrolide resistant, through a homologous recombination that integrated Tn1207.1 into a competence gene, preventing further diversification via transformation. Analysis of a species-wide dataset found 183 acquisitions of macrolide resistance, and multiple gains of the tetracycline-resistant transposon Tn916, through homologous recombination, often originating in other streptococcal species. Consequently, antibiotic selection preserves atypical recom- bination events that cause sequence divergence and structural variation throughout the S. pneumoniae chromosome. These events reveal the genetic exchanges between species normally counter-selected until perturbed by clinical interventions.

Journal article

Knock ES, Whittles LK, Lees JA, Perez-Guzman PN, Verity R, FitzJohn RG, Gaythorpe KAM, Imai N, Hinsley W, Okell LC, Rosello A, Kantas N, Walters CE, Bhatia S, Watson OJ, Whittaker C, Cattarino L, Boonyasiri A, Djaafara BA, Fraser K, Fu H, Wang H, Xi X, Donnelly CA, Jauneikaite E, Laydon DJ, White PJ, Ghani AC, Ferguson NM, Cori A, Baguelin M, Knock E, Whittles L, Lees J, Perez-Guzman P, Verity R, FitzJohn R, Gaythorpe KAM, Imai N, Hinsley W, Okell L, Rosello A, Kantas N, Walters C, Bhatia S, Watson O, Whittaker C, Cattarino L, Boonyasiri A, Djaafara B, Fraser K, Fu H, Wang H, Xi X, Donnelly C, Jauneikaite E, Laydon D, White P, Ghani A, Ferguson N, Cori A, Baguelin Met al., 2021, Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England, Science Translational Medicine, Vol: 13, Pages: 1-12, ISSN: 1946-6234

We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modelling framework allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rteff ) below 1 consistently; if introduced one week earlier it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 (95% credible interval [95%CrI]: 15,900-38,400). The infection fatality ratio decreased from 1.00% (95%CrI: 0.85%-1.21%) to 0.79% (95%CrI: 0.63%-0.99%), suggesting improved clinical care. The infection fatality ratio was higher in the elderly residing in care homes (23.3%, 95%CrI: 14.7%-35.2%) than those residing in the community (7.9%, 95%CrI: 5.9%-10.3%). On 2nd December 2020 England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95%CrI: 5.4%-10.2%) and 22.3% (95%CrI: 19.4%-25.4%) of the population. Therefore, any vaccination campaign will need to achieve high coverage and a high degree of protection in vaccinated individuals to allow non-pharmaceutical interventions to be lifted without a resurgence of transmission.

Journal article

Gladstone RA, McNally A, Pontinen AK, Tonkin-Hill G, Lees JA, Skyten K, Cleon F, Christensen MOK, Haldorsen BC, Bye KK, Gammelsrud KW, Hjetland R, Kummel A, Larsen HE, Lindemann PC, Lohr IH, Marvik A, Nilsen E, Noer MT, Simonsen GS, Steinbakk M, Tofteland S, Vattoy M, Bentley SD, Croucher NJ, Parkhill J, Johnsen PJ, Samuelsen O, Corander Jet al., 2021, Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002-17: a nationwide, longitudinal, microbial population genomic study, The Lancet Microbe, Vol: 2, Pages: E331-E341, ISSN: 2666-5247

BackgroundThe clonal diversity underpinning trends in multidrug resistant Escherichia coli causing bloodstream infections remains uncertain. We aimed to determine the contribution of individual clones to resistance over time, using large-scale genomics-based molecular epidemiology.MethodsThis was a longitudinal, E coli population, genomic, cohort study that sampled isolates from 22 512 E coli bloodstream infections included in the Norwegian surveillance programme on resistant microbes (NORM) from 2002 to 2017. 15 of 22 laboratories were able to share their isolates, and the first 22·5% of isolates from each year were requested. We used whole genome sequencing to infer the population structure (PopPUNK), and we investigated the clade composition of the dominant multidrug resistant clonal complex (CC)131 using genetic markers previously reported for sequence type (ST)131, effective population size (BEAST), and presence of determinants of antimicrobial resistance (ARIBA, PointFinder, and ResFinder databases) over time. We compared these features between the 2002–10 and 2011–17 time periods. We also compared our results with those of a longitudinal study from the UK done between 2001 and 2011.FindingsOf the 3500 isolates requested from the participating laboratories, 3397 (97·1%) were received, of which 3254 (95·8%) were successfully sequenced and included in the analysis. A significant increase in the number of multidrug resistant CC131 isolates from 71 (5·6%) of 1277 in 2002–10 to 207 (10·5%) of 1977 in 2011–17 (p<0·0001), was the largest clonal expansion. CC131 was the most common clone in extended-spectrum β-lactamase (ESBL)-positive isolates (75 [58·6%] of 128) and fluoroquinolone non-susceptible isolates (148 [39·2%] of 378). Within CC131, clade A increased in prevalence from 2002, whereas the global multidrug resistant clade C2 was not observed until 2007. Multiple de-n

Journal article

FitzJohn RG, Knock ES, Whittles LK, Perez-Guzman PN, Bhatia S, Guntoro F, Watson OJ, Whittaker C, Ferguson NM, Cori A, Baguelin M, Lees JAet al., 2021, Reproducible parallel inference and simulation of stochastic state space models using odin, dust, and mcstate [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 5, ISSN: 2398-502X

State space models, including compartmental models, are used to model physical, biological and social phenomena in a broad range of scientific fields. A common way of representing the underlying processes in these models is as a system of stochastic processes which can be simulated forwards in time. Inference of model parameters based on observed time-series data can then be performed using sequential Monte Carlo techniques. However, using these methods for routine inference problems can be made difficult due to various engineering considerations: allowing model design to change in response to new data and ideas, writing model code which is highly performant, and incorporating all of this with up-to-date statistical techniques. Here, we describe a suite of packages in the R programming language designed to streamline the design and deployment of state space models, targeted at infectious disease modellers but suitable for other domains. Users describe their model in a familiar domain-specific language, which is converted into parallelised C++ code. A fast, parallel, reproducible random number generator is then used to run large numbers of model simulations in an efficient manner. We also provide standard inference and prediction routines, though the model simulator can be used directly if these do not meet the user's needs. These packages provide guarantees on reproducibility and performance, allowing the user to focus on the model itself, rather than the underlying computation. The ability to automatically generate high-performance code that would be tedious and time-consuming to write and verify manually, particularly when adding further structure to compartments, is crucial for infectious disease modellers. Our packages have been critical to the development cycle of our ongoing real-time modelling efforts in the COVID-19 pandemic, and have the potential to do the same for models used in a number of different domains.

Journal article

McCabe R, Kont M, Schmit N, Whittaker C, Lochen A, Baguelin M, Knock E, Whittles L, Lees J, Brazeau N, Walker P, Ghani A, Ferguson N, White P, Donnelly C, Hauck K, Watson Oet al., 2021, Modelling ICU capacity under different epidemiological scenarios of the COVID-19 pandemic in three western European countries, International Journal of Epidemiology, Vol: 50, Pages: 753-767, ISSN: 0300-5771

Background: The coronavirus disease 2019 (COVID-19) pandemic has placed enormous strain on intensive care units (ICUs) in Europe. Ensuring access to care, irrespective of COVID-19 status, in winter 2020/21 is essential.Methods: An integrated model of hospital capacity planning and epidemiological projections of COVID-19 patients is used to estimate the demand for and resultant spare capacity of ICU beds, staff, and ventilators under different epidemic scenarios in France, Germany, and Italy across the 2020/21 winter period. The effect of implementing lockdowns triggered by different numbers of COVID-19 patients in ICU under varying levels of effectiveness is examined, using a ‘dual-demand’ (COVID-19 and non-COVID-19) patient model.Results: Without sufficient mitigation, we estimate that COVID-19 ICU patient numbers will exceed those seen in the first peak, resulting in substantial capacity deficits, with beds being consistently found to be the most constrained resource. Reactive lockdowns could lead to large improvements in ICU capacity during the winter season, with pressure being most effectively alleviated when lockdown is triggered early and sustained under a higher level of suppression. The success of such interventions also depends on baseline bed numbers and average non-COVID-19 patient occupancy.Conclusions: Reductions in capacity deficits under different scenarios must be weighed against the feasibility and drawbacks of further lockdowns. Careful, continuous decision-making by national policymakers will be required across the winter period 2020/21.

Journal article

Hogan AB, Winskill P, Watson OJ, Walker PGT, Whittaker C, Baguelin M, Brazeau NF, Charles GD, Gaythorpe KAM, Hamlet A, Knock E, Laydon DJ, Lees JA, Løchen A, Verity R, Whittles LK, Muhib F, Hauck K, Ferguson NM, Ghani ACet al., 2021, Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: a mathematical modelling analysis, Vaccine, Vol: 39, Pages: 2995-3006, ISSN: 0264-410X

The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extended a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

Journal article

Watson O, Alhaffar M, Mehchy Z, Whittaker C, Akil Z, Brazeau N, Cuomo-Dannenburg G, Hamlet A, Thompson H, Baguelin M, Fitzjohn R, Knock E, Lees J, Whittles L, Mellan T, Winskill P, COVID-19 Response Team IC, Howard N, Clapham H, Checchi F, Ferguson N, Ghani A, Walker P, Beals Eet al., 2021, Leveraging community mortality indicators to infer COVID-19 mortality and transmission dynamics in Damascus, Syria, Nature Communications, Vol: 12, Pages: 1-10, ISSN: 2041-1723

The COVID-19 pandemic has resulted in substantial mortality worldwide. However, to date, countries in the Middle East and Africa have reported considerably lower mortality rates than in Europe and the Americas. Motivated by reports of an overwhelmed health system, we estimate the likely under-ascertainment of COVID-19 mortality in Damascus, Syria. Using all-cause mortality data, we fit a mathematical model of COVID-19 transmission to reported mortality, estimating that 1.25% of COVID-19 deaths (sensitivity range 1.00% – 3.00%) have been reported as of 2 September 2020. By 2 September, we estimate that 4,380 (95% CI: 3,250 – 5,550) COVID-19 deaths in Damascus may have been missed, with 39.0% (95% CI: 32.5% – 45.0%) of the population in Damascus estimated to have been infected. Accounting for under-ascertainment corroborates reports of exceeded hospital bed capacity and is validated by community-uploaded obituary notifications, which confirm extensive unreported mortality in Damascus.

Journal article

Lees J, Ccroucher NJ, Anderson D, Stajich Jet al., 2021, johnlees/PopPUNK: PopPUNK v2.4.0

Minimum sketchlib version for this release is v1.7.0

Software

Pontinen AK, Top J, Arredondo-Alonso S, Tonkin-Hill G, Freitas AR, Novais C, Gladstone RA, Pesonen M, Meneses R, Pesonen H, Lees JA, Jamrozy D, Bentley SD, Lanza VF, Torres C, Peixe L, Coque TM, Parkhill J, Schurch AC, Willems RJL, Corander Jet al., 2021, Apparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era, NATURE COMMUNICATIONS, Vol: 12

Journal article

Kremer PHC, Ferwerda B, Bootsma HJ, Rots NY, Wijmega-Monsuur AJ, Sanders EAM, Trzciński K, Wyllie AL, Turner P, van der Ende A, Brouwer MC, Bentley SD, van de Beek D, Lees JAet al., 2021, Pneumococcal genetic variability influences age-dependent bacterial carriage

<jats:title>Abstract</jats:title><jats:p>The pneumococcal conjugate vaccine (PCV) primarily reduces disease burden in adults through a reduction in carriage prevalence of invasive serotypes in children. Current vaccine formulations are the same for both adults and children, but tailoring these formulations to age category could optimize vaccine efficacy. Identification of specific pneumococcal genetic factors associated with carriage in younger or older age groups may suggest alternative formulations and contribute to a better mechanistic understanding of immunity. Here, we used whole genome sequencing to dissect pneumococcal variation associated with age. We performed genome sequencing in a large carriage cohort, and conducted a meta-analysis with an existing carriage study. We compiled a dictionary of pathogen genetic variation including serotype, sequence cluster, sequence elements, SNPs, burden combined rare variants, and clusters of orthologous genes (COGs) for each cohort – all of which used in a genome-wide association with host age. Age-dependent colonization had some heritability, though this varied between cohorts (h<jats:sup>2</jats:sup> = 0.10, 0.00 – 0.69 95% CI in the first; h<jats:sup>2</jats:sup> = 0.46, 0.33 – 0.60 95% CI in the second cohort). We found that serotypes and genetic background (strain) explained most of the heritability in each cohort (h<jats:sup>2</jats:sup><jats:sub>serotype</jats:sub> = 0.06 and h<jats:sup>2</jats:sup><jats:sub>GPSC</jats:sub> = 0.04 in the first; h<jats:sup>2</jats:sup><jats:sub>serotype</jats:sub> = 0.20 and h<jats:sup>2</jats:sup><jats:sub>GPSC</jats:sub> = 0.23 in the second cohort). We found one candidate association (p = 1.2×10<jats:sup>−9</jats:sup>) upstream of an accessory Sec-dependent serine-rich glycoprotein adhesin. Overall, a

Journal article

Nouvellet P, Bhatia S, Cori A, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Brazeau N, Cattarino L, Cooper L, Coupland H, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Dorigatti I, Eales O, van Elsland S, NASCIMENTO F, Fitzjohn R, Gaythorpe K, Geidelberg L, green W, Hamlet A, Hauck K, Hinsley W, Imai N, Jeffrey, Jeffrey B, Knock E, Laydon D, Lees J, Mangal T, Mellan T, Nedjati Gilani G, Parag K, Pons Salort M, Ragonnet-Cronin M, Riley S, Unwin H, Verity R, Vollmer M, Volz E, Walker P, Walters C, Wang H, Watson O, Whittaker C, Whittles L, Xi X, Ferguson N, Donnelly Cet al., 2021, Reduction in mobility and COVID-19 transmission, Nature Communications, Vol: 12, ISSN: 2041-1723

In response to the COVID-19 pandemic, countries have sought to control SARS-CoV-2 transmission by restricting population movement through social distancing interventions, thus reducing the number of contacts.Mobility data represent an important proxy measure of social distancing, and here, we characterise the relationship between transmission and mobility for 52 countries around the world.Transmission significantly decreased with the initial reduction in mobility in 73% of the countries analysed, but we found evidence of decoupling of transmission and mobility following the relaxation of strict control measures for 80% of countries. For the majority of countries, mobility explained a substantial proportion of the variation in transmissibility (median adjusted R-squared: 48%, interquartile range - IQR - across countries [27-77%]). Where a change in the relationship occurred, predictive ability decreased after the relaxation; from a median adjusted R-squared of 74% (IQR across countries [49-91%]) pre-relaxation, to a median adjusted R-squared of 30% (IQR across countries [12-48%]) post-relaxation.In countries with a clear relationship between mobility and transmission both before and after strict control measures were relaxed, mobility was associated with lower transmission rates after control measures were relaxed indicating that the beneficial effects of ongoing social distancing behaviours were substantial.

Journal article

Croucher N, Harrow G, Lees J, Hanage W, Lipsitch M, Corander J, Colijn Cet al., 2021, Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures, The ISME Journal: multidisciplinary journal of microbial ecology, Vol: 15, Pages: 1523-1538, ISSN: 1751-7362

Streptococcus pneumoniae can be divided into many strains, each a distinct set of isolates sharing similar core and accessorygenomes, which co-circulate within the same hosts. Previous analyses suggested the short-term vaccine-associated dynamicsof S. pneumoniae strains may be mediated through multi-locus negative frequency-dependent selection (NFDS), whichmaintains accessory loci at equilibrium frequencies. Long-term simulations demonstrated NFDS stabilised clonally-evolvingmulti-strain populations through preventing the loss of variation through drift, based on polymorphism frequencies,pairwise genetic distances and phylogenies. However, allowing symmetrical recombination between isolates evolving undermulti-locus NFDS generated unstructured populations of diverse genotypes. Replication of the observed data improvedwhen multi-locus NFDS was combined with recombination that was instead asymmetrical, favouring deletion of accessoryloci over insertion. This combination separated populations into strains through outbreeding depression, resulting fromrecombinants with reduced accessory genomes having lower fitness than their parental genotypes. Although simplisticmodelling of recombination likely limited these simulations’ ability to maintain some properties of genomic data asaccurately as those lacking recombination, the combination of asymmetrical recombination and multi-locus NFDS couldrestore multi-strain population structures from randomised initial populations. As many bacteria inhibit insertions into theirchromosomes, this combination may commonly underlie the co-existence of strains within a niche.

Journal article

Fu H, Wang H, Xi X, Boonyasiri A, Wang Y, Hinsley W, Fraser KJ, McCabe R, Olivera Mesa D, Skarp J, Ledda A, Dewé T, Dighe A, Winskill P, van Elsland SL, Ainslie KEC, Baguelin M, Bhatt S, Boyd O, Brazeau NF, Cattarino L, Charles G, Coupland H, Cucunubá ZM, Cuomo-Dannenburg G, Donnelly CA, Dorigatti I, Eales OD, Fitzjohn RG, Flaxman S, Gaythorpe KAM, Ghani AC, Green WD, Hamlet A, Hauck K, Haw DJ, Jeffrey B, Laydon DJ, Lees JA, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Parag KV, Ragonnet-Cronin M, Riley S, Schmit N, Thompson HA, Unwin HJT, Verity R, Vollmer MAC, Volz E, Walker PGT, Walters CE, Waston OJ, Whittaker C, Whittles LK, Imai N, Bhatia S, Ferguson NMet al., 2021, A database for the epidemic trends and control measures during the first wave of COVID-19 in mainland China, International Journal of Infectious Diseases, Vol: 102, Pages: 463-471, ISSN: 1201-9712

Objectives: This data collation effort aims to provide a comprehensive database to describe the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19)across main provinces in China. Methods: From mid-January to March 2020, we extracted publicly available data on the spread and control of COVID-19 from 31 provincial health authorities and major media outlets in mainland China. Based on these data, we conducted a descriptive analysis of the epidemics in the six most-affected provinces. Results: School closures, travel restrictions, community-level lockdown, and contact tracing were introduced concurrently around late January but subsequent epidemic trends were different across provinces. Compared to Hubei, the other five most-affected provinces reported a lower crude case fatality ratio and proportion of critical and severe hospitalised cases. From March 2020, as local transmission of COVID-19 declined, switching the focus of measures to testing and quarantine of inbound travellers could help to sustain the control of the epidemic. Conclusions: Aggregated indicators of case notifications and severity distributions are essential for monitoring an epidemic. A publicly available database with these indicators and information on control measures provides useful source for exploring further research and policy planning for response to the COVID-19 epidemic.

Journal article

Knock E, Whittles L, Lees J, Perez Guzman P, Verity R, Fitzjohn R, Gaythorpe K, Imai N, Hinsley W, Okell L, Rosello A, Kantas N, Walters C, Bhatia S, Watson O, Whittaker C, Cattarino L, Boonyasiri A, Djaafara A, Fraser K, Fu H, Wang H, Xi X, Donnelly C, Jauneikaite E, Laydon D, White P, Ghani A, Ferguson N, Cori A, Baguelin Met al., 2020, Report 41: The 2020 SARS-CoV-2 epidemic in England: key epidemiological drivers and impact of interventions

England has been severely affected by COVID-19. We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional 2020 surveillance data. Only national lockdown brought the reproduction number below 1 consistently; introduced one week earlier in the first wave it could have reduced mortality by 23,300 deaths on average. The mean infection fatality ratio was initially ~1.3% across all regions except London and halved following clinical care improvements. The infection fatality ratio was two-fold lower throughout in London, even when adjusting for demographics. The infection fatality ratio in care homes was 2.5-times that in the elderly in the community. Population-level infection-induced immunity in England is still far from herd immunity, with regional mean cumulative attack rates ranging between 4.4% and 15.8%.

Report

Unwin H, Mishra S, Bradley V, Gandy A, Mellan T, Coupland H, Ish-Horowicz J, Vollmer M, Whittaker C, Filippi S, Xi X, Monod M, Ratmann O, Hutchinson M, Valka F, Zhu H, Hawryluk I, Milton P, Ainslie K, Baguelin M, Boonyasiri A, Brazeau N, Cattarino L, Cucunuba Z, Cuomo-Dannenburg G, Dorigatti I, Eales O, Eaton J, van Elsland S, Fitzjohn R, Gaythorpe K, Green W, Hinsley W, Jeffrey B, Knock E, Laydon D, Lees J, Nedjati-Gilani G, Nouvellet P, Okell L, Parag K, Siveroni I, Thompson H, Walker P, Walters C, Watson O, Whittles L, Ghani A, Ferguson N, Riley S, Donnelly C, Bhatt S, Flaxman S, Unwin H, Mishra S, Bradley VC, Gandy A, Vollmer M, Mellan T, Coupland H, Ainslie K, Whittaker C, Ish-Horowicz J, Filippi S, Xi X, Monod M, Ratmann O, Hutchinson M, Valka F, Zhu H, Hawryluk I, Milton P, Baguelin M, Boonyasiri A, Brazeau N, Cattarino L, Charles G, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Djaafara A, Dorigatti I, Eales O, Eaton J, van Elsland S, Fitzjohn R, Gaythorpe K, Green W, Hallett T, Hinsley W, Imai N, Jeffrey B, Knock E, Laydon D, Lees J, Nedjati Gilani G, Nouvellet P, Okell L, Ower A, Parag K, Siveroni I, Thompson H, Verity R, Walker P, Walters C, Wang Y, Watson O, Whittles L, Ghani A, Ferguson N, Riley S, Donnelly C, Bhatt S, Flaxman Set al., 2020, State-level tracking of COVID-19 in the United States, Nature Communications, Vol: 11, Pages: 1-9, ISSN: 2041-1723

As of 1st June 2020, the US Centers for Disease Control and Prevention reported 104,232 confirmed or probable COVID-19-related deaths in the US. This was more than twice the number of deaths reported in the next most severely impacted country. We jointly model the US epidemic at the state-level, using publicly available deathdata within a Bayesian hierarchical semi-mechanistic framework. For each state, we estimate the number of individuals that have been infected, the number of individuals that are currently infectious and the time-varying reproduction number (the average number of secondary infections caused by an infected person). We use changes in mobility to capture the impact that non-pharmaceutical interventions and other behaviour changes have on therate of transmission of SARS-CoV-2. We estimate thatRtwas only below one in 23 states on 1st June. We also estimate that 3.7% [3.4%-4.0%] of the total population of the US had been infected, with wide variation between states, and approximately 0.01% of the population was infectious. We demonstrate good 3 week model forecasts of deaths with low error and good coverage of our credible intervals.

Journal article

Thompson H, Imai N, Dighe A, Ainslie K, Baguelin M, Bhatia S, Bhatt S, Boonyasiri A, Boyd O, Brazeau N, Cattarino L, Cooper L, Coupland H, Cucunuba Z, Cuomo-Dannenburg G, Djaafara B, Dorigatti I, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Green W, Hallett T, Hamlet A, Haw D, Hayes S, Hinsley W, Jeffrey B, Knock E, Laydon D, Lees J, Mangal T, Mellan T, Mishra S, Mousa A, Nedjati-Gilani G, Nouvellet P, Okell L, Parag K, Ragonnet-Cronin M, Riley S, Unwin H, Verity R, Vollmer M, Volz E, Walker P, Walters C, Wang H, Wang Y, Watson O, Whittaker C, Whittles L, Winskill P, Xi X, Donnelly C, Ferguson Net al., 2020, SARS-CoV-2 infection prevalence on repatriation flights from Wuhan City, China, Journal of Travel Medicine, Vol: 27, Pages: 1-3, ISSN: 1195-1982

We estimated SARS-CoV-2 infection prevalence in cohorts of repatriated citizens from Wuhan to be 0.44% (95% CI: 0.19%–1.03%). Although not representative of the wider population we believe these estimates are helpful in providing a conservative estimate of infection prevalence in Wuhan City, China, in the absence of large-scale population testing early in the epidemic.

Journal article

Lees J, Fitzjohn R, 2020, mrc-ide/mcstate: v0.6.0

This is an archive of v0.6.0 of mcstate, as used to produce version 2 of the associated publication.Monte-Carlo State Space Models

Software

Lees J, Fitzjohn R, 2020, mrc-ide/odin-dust-plots: Plots at submission

This is an archive of code to create plots at initial submission

Software

McCabe R, Kont M, Schmit N, Whittaker C, Lochen A, Baguelin M, Knock E, Whittles L, Lees J, Walker P, Ghani A, Ferguson N, White P, Donnelly C, Hauck K, Watson Oet al., 2020, Report 36: Modelling ICU capacity under different epidemiological scenarios of the COVID-19 pandemic in three western European countries

The coronavirus disease 2019 (COVID-19) pandemic has placed enormous strain on healthcare systems, particularly intensive care units (ICUs), with COVID-19 patient care being a key concern of healthcare system planning for winter 2020/21. Ensuring that all patients who require intensive care, irrespective of COVID-19 status, can access it during this time is essential. This study uses an integrated model of hospital capacity planning and epidemiological projections of COVID-19 patients to estimate the spare capacity of key ICU resources under different epidemic scenarios in France, Germany and Italy across the winter period of 2020/21. In particular, we examine the effect of implementing suppression strategies of varying effectiveness, triggered by different numbers of COVID-19 patients in ICU. The use of a ‘dual-demand’ (COVID-19 and non-COVID-19) patient model and the consideration of multiple ICU resources that determine capacity (beds, doctors, nurses and ventilators) and the interdependencies between them, provides a detailed insight into potential capacity constraints this winter. Without sufficient mitigation, we estimate that COVID-19 ICU patient numbers will exceed those seen in the first peak, resulting in substantial capacity deficits, with beds being consistently found to be the most constrained resource across countries. Lockdowns triggered based on ICU capacity could lead to large improvements in spare capacity during the winter season, with pressure being most effectively alleviated when lockdown is triggered early and implemented at a higher level of suppression. In many cases, maximum deficits are reduced to lower levels which can then be managed by expanding supply-side hospital capacity, to ensure that all patients can receive treatment. The success of such interventions also depends on baseline ICU bed numbers and average non-COVID-19 patient occupancy. We find that lockdowns of longer duration reduce the total number of days in defic

Report

Kremer PHC, Lees JA, Ferwerda B, van de Ende A, Brouwer MC, Bentley SD, van de Beek Det al., 2020, Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis, FRONTIERS IN MEDICINE, Vol: 7

Journal article

Hogan A, Winskill P, Watson O, Walker P, Whittaker C, Baguelin M, Haw D, Lochen A, Gaythorpe K, Ainslie K, Bhatt S, Boonyasiri A, Boyd O, Brazeau N, Cattarino L, Charles G, Cooper L, Coupland H, Cucunuba Perez Z, Cuomo-Dannenburg G, Donnelly C, Dorigatti I, Eales O, van Elsland S, Ferreira Do Nascimento F, Fitzjohn R, Flaxman S, Green W, Hallett T, Hamlet A, Hinsley W, Imai N, Jauneikaite E, Jeffrey B, Knock E, Laydon D, Lees J, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Ower A, Parag K, Ragonnet-Cronin M, Siveroni I, Skarp J, Thompson H, Unwin H, Verity R, Vollmer M, Volz E, Walters C, Wang H, Wang Y, Whittles L, Xi X, Muhib F, Smith P, Hauck K, Ferguson N, Ghani Aet al., 2020, Report 33: Modelling the allocation and impact of a COVID-19 vaccine

Several SARS-CoV-2 vaccine candidates are now in late-stage trials, with efficacy and safety results expected by the end of 2020. Even under optimistic scenarios for manufacture and delivery, the doses available in 2021 are likely to be limited. Here we identify optimal vaccine allocation strategies within and between countries to maximise health (avert deaths) under constraints on dose supply. We extended an existing mathematical model of SARS-CoV-2 transmission across different country settings to model the public health impact of potential vaccines, using a range of target product profiles developed by the World Health Organization. We show that as supply increases, vaccines that reduce or block infection – and thus transmission – in addition to preventing disease have a greater impact than those that prevent disease alone, due to the indirect protection provided to high-risk groups. We further demonstrate that the health impact of vaccination will depend on the cumulative infection incidence in the population when vaccination begins, the duration of any naturally acquired immunity, the likely trajectory of the epidemic in 2021 and the level of healthcare available to effectively treat those with disease. Within a country, we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly and other high-risk groups. However, if a larger supply is available, the optimal strategy switches to targeting key transmitters (i.e. the working age population and potentially children) to indirectly protect the elderly and vulnerable. Given the likely global dose supply in 2021 (2 billion doses with a two-dose vaccine), we find that a strategy in which doses are allocated to countries in proportion to their population size is close to optimal in averting deaths. Such a strategy also aligns with the ethical principles agreed in pandemic preparedness planning.

Report

Monod M, Blenkinsop A, Xi X, Herbert D, Bershan S, Tietze S, Bradley V, Chen Y, Coupland H, Filippi S, Ish-Horowicz J, McManus M, Mellan T, Gandy A, Hutchinson M, Unwin H, Vollmer M, Weber S, Zhu H, Bezancon A, Ferguson N, Mishra S, Flaxman S, Bhatt S, Ratmann O, Ainslie K, Baguelin M, Boonyasiri A, Boyd O, Cattarino L, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Djaafara A, Dorigatti I, van Elsland S, Fitzjohn R, Gaythorpe K, Geidelberg L, Green W, Hamlet A, Jeffrey B, Knock E, Laydon D, Nedjati Gilani G, Nouvellet P, Parag K, Siveroni I, Thompson H, Verity R, Walters C, Donnelly C, Okell L, Bhatia S, Brazeau N, Eales O, Haw D, Imai N, Jauneikaite E, Lees J, Mousa A, Olivera Mesa D, Skarp J, Whittles Let al., 2020, Report 32: Targeting interventions to age groups that sustain COVID-19 transmission in the United States, Pages: 1-32

Following ini􀀂al declines, in mid 2020, a resurgence in transmission of novel coronavirus disease (COVID-19) has occurred in the United States and parts of Europe. Despite the wide implementa􀀂on of non-pharmaceu􀀂cal inter-ven􀀂ons, it is s􀀂ll not known how they are impacted by changing contact pa􀀁erns, age and other demographics. As COVID-19 disease control becomes more localised, understanding the age demographics driving transmission and how these impact the loosening of interven􀀂ons such as school reopening is crucial. Considering dynamics for the United States, we analyse aggregated, age-specific mobility trends from more than 10 million individuals and link these mechanis􀀂cally to age-specific COVID-19 mortality data. In contrast to previous approaches, we link mobility to mortality via age specific contact pa􀀁erns and use this rich rela􀀂onship to reconstruct accurate trans-mission dynamics. Contrary to anecdotal evidence, we find li􀀁le support for age-shi􀀃s in contact and transmission dynamics over 􀀂me. We es􀀂mate that, un􀀂l August, 63.4% [60.9%-65.5%] of SARS-CoV-2 infec􀀂ons in the United States originated from adults aged 20-49, while 1.2% [0.8%-1.8%] originated from children aged 0-9. In areas with con􀀂nued, community-wide transmission, our transmission model predicts that re-opening kindergartens and el-ementary schools could facilitate spread and lead to considerable excess COVID-19 a􀀁ributable deaths over a 90-day period. These findings indicate that targe􀀂ng interven􀀂ons to adults aged 20-49 are an important con-sidera􀀂on in hal􀀂ng resurgent epidemics, and preven􀀂ng COVID-19-a􀀁ributable deaths when kindergartens and elementary schools reopen.

Journal article

van Elsland S, Watson O, Alhaffar M, Mehchy Z, Whittaker C, Akil Z, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Boyd O, Brazeau N, Cattarino L, Charles G, Ciavarella C, Cooper L, Coupland H, Cucunuba Perez Z, Cuomo-Dannenburg G, Djaafara A, Donnelly C, Dorigatti I, Eales O, van Elsland S, Nascimento F, Fitzjohn R, Flaxman S, Forna A, Fu H, Gaythorpe K, Green W, Hamlet A, Hauck K, Haw D, Hayes S, Hinsley W, Imai N, Jeffrey B, Johnson R, Jorgensen D, Knock E, Laydon D, Lees J, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Olivera Mesa D, Pons Salort M, Ragonnet-Cronin M, Siveroni I, Stopard I, Thompson H, Unwin H, Verity R, Vollmer M, Volz E, Walters C, Wang H, Wang Y, Whittles L, Winskill P, Xi X, Ferguson N, Beals E, Walker P, Anonymous Authorset al., 2020, Report 31: Estimating the burden of COVID-19 in Damascus, Syria: an analysis of novel data sources to infer mortality under-ascertainment

The COVID-19 pandemic has resulted in substantial mortality worldwide. However, to date, countries in the Middle East and Africa have reported substantially lower mortality rates than in Europe and the Americas. One hypothesis is that these countries have been ‘spared’, but another is that deaths have been under-ascertained (deaths that have been unreported due to any number of reasons, for instance due to limited testing capacity). However, the scale of under-ascertainment is difficult to assess with currently available data. In this analysis, we estimate the potential under-ascertainment of COVID-19 mortality in Damascus, Syria, where all-cause mortality data has been reported between 25th July and 1st August. We fit a mathematical model of COVID-19 transmission to reported COVID-19 deaths in Damascus since the beginning of the pandemic and compare the model-predicted deaths to reported excess deaths. Exploring a range of different assumptions about under-ascertainment, we estimate that only 1.25% of deaths (sensitivity range 1% - 3%) due to COVID-19 are reported in Damascus. Accounting for under-ascertainment also corroborates local reports of exceeded hospital bed capacity. To validate the epidemic dynamics inferred, we leverage community-uploaded obituary certificates as an alternative data source, which confirms extensive mortality under-ascertainment in Damascus between July and August. This level of under-ascertainment suggests that Damascus is at a much later stage in its epidemic than suggested by surveillance reports, which have repo. We estimate that 4,340 (95% CI: 3,250 - 5,540) deaths due to COVID-19 in Damascus may have been missed as of 2nd September 2020. Given that Damascus is likely to have the most robust surveillance in Syria, these findings suggest that other regions of the country could have experienced similar or worse mortality rates due to COVID-19.

Report

Hogan A, Jewell B, Sherrard-Smith E, Watson O, Whittaker C, Hamlet A, Smith J, Winskill P, Verity R, Baguelin M, Lees J, Whittles L, Ainslie K, Bhatt S, Boonyasiri A, Brazeau N, Cattarino L, Cooper L, Coupland H, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Eaton J, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Green W, Haw D, Hayes S, Hinsley W, Imai N, Laydon D, Mangal T, Mellan T, Mishra S, Parag K, Thompson H, Unwin H, Vollmer M, Walters C, Wang H, Ferguson N, Okell L, Churcher T, Arinaminpathy N, Ghani A, Walker P, Hallett T, Hogan A, Jewell B, Sherrard-Smith E, Vesga J, Watson O, Whittaker C, Hamlet A, Smith J, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Brazeau N, Cattarino L, Charles G, Cooper L, Coupland H, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Dorigatti I, Eaton J, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Green W, Haw D, Hayes S, Hinsley W, Imai N, Knock E, Laydon D, Lees J, Mangal T, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Ower A, Parag K, Pickles M, Stopard I, Thompson H, Unwin H, Verity R, Vollmer M, Walters C, Wang H, Wang Y, Whittles L, Winskill P, Xi X, Ferguson N, Churcher T, Arinaminpathy N, Ghani A, Walker P, Hallett Tet al., 2020, Potential impact of the COVID-19 pandemic on HIV, TB and malaria in low- and middle-income countries: a modelling study, The Lancet Global Health, Vol: 8, Pages: e1132-e1141, ISSN: 2214-109X

Background: COVID-19 has the potential to cause substantial disruptions to health services, including by cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions in services for human immunodeficiency virus (HIV), tuberculosis (TB) and malaria in low- and middle-income countries with high burdens of those disease could lead to additional loss of life. Methods: We constructed plausible scenarios for the disruptions that could be incurred during the COVID-19 pandemic and used established transmission models for each disease to estimate the additional impact on health that could be caused in selected settings.Findings: In high burden settings, HIV-, TB- and malaria-related deaths over five years may increase by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 pandemic. We estimate the greatest impact on HIV to be from interruption to antiretroviral therapy, which may occur during a period of high health system demand. For TB, we estimate the greatest impact is from reductions in timely diagnosis and treatment of new cases, which may result from any prolonged period of COVID-19 suppression interventions. We estimate that the greatest impact on malaria burden could come from interruption of planned net campaigns. These disruptions could lead to loss of life-years over five years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV/TB epidemics.Interpretation: Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 pandemic.Funding: Bill & Melinda Gates Foundation, The Wellcome Trust, DFID, MRC

Journal article

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