Publications by authors named "Lilith K Whittles"

25 Publications

  • Page 1 of 1

Comparing the responses of the UK, Sweden and Denmark to COVID-19 using counterfactual modelling.

Sci Rep 2021 08 11;11(1):16342. Epub 2021 Aug 11.

MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, UK.

The UK and Sweden have among the worst per-capita COVID-19 mortality in Europe. Sweden stands out for its greater reliance on voluntary, rather than mandatory, control measures. We explore how the timing and effectiveness of control measures in the UK, Sweden and Denmark shaped COVID-19 mortality in each country, using a counterfactual assessment: what would the impact have been, had each country adopted the others' policies? Using a Bayesian semi-mechanistic model without prior assumptions on the mechanism or effectiveness of interventions, we estimate the time-varying reproduction number for the UK, Sweden and Denmark from daily mortality data. We use two approaches to evaluate counterfactuals which transpose the transmission profile from one country onto another, in each country's first wave from 13th March (when stringent interventions began) until 1st July 2020. UK mortality would have approximately doubled had Swedish policy been adopted, while Swedish mortality would have more than halved had Sweden adopted UK or Danish strategies. Danish policies were most effective, although differences between the UK and Denmark were significant for one counterfactual approach only. Our analysis shows that small changes in the timing or effectiveness of interventions have disproportionately large effects on total mortality within a rapidly growing epidemic.
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http://dx.doi.org/10.1038/s41598-021-95699-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358009PMC
August 2021

Children's role in the COVID-19 pandemic: a systematic review of early surveillance data on susceptibility, severity, and transmissibility.

Sci Rep 2021 07 6;11(1):13903. Epub 2021 Jul 6.

MRC Centre for Global Infectious Disease Analysis and WHO Collaborating Centre for Infectious Disease Modelling, Abdul Latif Jameel Institute for Disease and Emergency Analytics, Imperial College London, London, UK.

SARS-CoV-2 infections have been reported in all age groups including infants, children, and adolescents. However, the role of children in the COVID-19 pandemic is still uncertain. This systematic review of early studies synthesises evidence on the susceptibility of children to SARS-CoV-2 infection, the severity and clinical outcomes in children with SARS-CoV-2 infection, and the transmissibility of SARS-CoV-2 by children in the initial phases of the COVID-19 pandemic. A systematic literature review was conducted in PubMed. Reviewers extracted data from relevant, peer-reviewed studies published up to July 4th 2020 during the first wave of the SARS-CoV-2 outbreak using a standardised form and assessed quality using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. For studies included in the meta-analysis, we used a random effects model to calculate pooled estimates of the proportion of children considered asymptomatic or in a severe or critical state. We identified 2775 potential studies of which 128 studies met our inclusion criteria; data were extracted from 99, which were then quality assessed. Finally, 29 studies were considered for the meta-analysis that included information of symptoms and/or severity, these were further assessed based on patient recruitment. Our pooled estimate of the proportion of test positive children who were asymptomatic was 21.1% (95% CI: 14.0-28.1%), based on 13 included studies, and the proportion of children with severe or critical symptoms was 3.8% (95% CI: 1.5-6.0%), based on 14 included studies. We did not identify any studies designed to assess transmissibility in children and found that susceptibility to infection in children was highly variable across studies. Children's susceptibility to infection and onward transmissibility relative to adults is still unclear and varied widely between studies. However, it is evident that most children experience clinically mild disease or remain asymptomatically infected. More comprehensive contact-tracing studies combined with serosurveys are needed to quantify children's transmissibility relative to adults. With children back in schools, testing regimes and study protocols that will allow us to better understand the role of children in this pandemic are critical.
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http://dx.doi.org/10.1038/s41598-021-92500-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260804PMC
July 2021

Health-economic value of vaccination against group A Streptococcus in the United States.

Clin Infect Dis 2021 Jun 30. Epub 2021 Jun 30.

Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, California.

Background: Vaccines are needed to reduce the burden of group A Streptococcus (GAS). We assessed the potential health-economic value of GAS vaccines achievable through prevention of invasive disease and acute upper respiratory infections in the United States.

Methods: We estimated annual incidence of invasive GAS disease and associated costs incurred from hospitalization and management of long-term sequelae, as well as productivity losses resulting from acute illness, long-term disability, and mortality. We also estimated healthcare and productivity costs associated with GAS pharyngitis, sinusitis, and acute otitis media. We estimated costs averted by prevention of invasive disease and acute upper respiratory infections for vaccines with differing efficacy profiles; our base case considered vaccines meeting the World Health Organization Preferred Product Profile (WHO-PPP) with a 6-year average duration of protection.

Results: Costs of invasive GAS disease and acute upper respiratory infections totaled $6.08 (95% confidence interval: 5.33-6.86) billion annually. Direct effects of vaccines meeting WHO-PPP characteristics and administered at ages 12 and 18 months would avert $609 (558-663) million in costs annually, primarily by preventing non-invasive disease; with an additional dose at age 5y, averted costs would total $869 (798-945) million annually. Adult vaccination at age 65y would avert $326 (271-387) million in annual costs associated with invasive GAS disease. Indirect effects of vaccination programs reducing incidence of GAS diseases across all ages by 20% would avert roughly $1 billion in costs each year.

Conclusions: The economic burden of GAS is substantial. Our findings should inform prioritization of GAS vaccine development and evaluation.
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http://dx.doi.org/10.1093/cid/ciab597DOI Listing
June 2021

Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England.

Sci Transl Med 2021 07 22;13(602). Epub 2021 Jun 22.

MRC Centre for Global Infectious Disease Analysis, Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health, Imperial College London, London W2 1PG, UK.

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 modeling 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 ( ) below 1 consistently; if introduced 1 week earlier, it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 [95% credible interval (CrI): 15,900 to 38,400]. The infection fatality ratio decreased from 1.00% (95% CrI: 0.85 to 1.21%) to 0.79% (95% CrI: 0.63 to 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 to 35.2%) than those residing in the community (7.9%, 95% CrI: 5.9 to 10.3%). On 2 December 2020, England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95% CrI: 5.4 to 10.2%) and 22.3% (95% CrI: 19.4 to 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 nonpharmaceutical interventions to be lifted without a resurgence of transmission.
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http://dx.doi.org/10.1126/scitranslmed.abg4262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432953PMC
July 2021

Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: A mathematical modelling analysis.

Vaccine 2021 05 8;39(22):2995-3006. Epub 2021 Apr 8.

MRC Centre for Global Infectious Disease Analysis, and the Abdul Latif Jameel Institute for Disease and Emergency Analytics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, United Kingdom. Electronic address:

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 extend 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 identify optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We find 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.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030738PMC
May 2021

Leveraging community mortality indicators to infer COVID-19 mortality and transmission dynamics in Damascus, Syria.

Nat Commun 2021 04 22;12(1):2394. Epub 2021 Apr 22.

MRC Centre for Global Infectious Disease Analysis, Jameel Institute for Disease and Emergency Analytics, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1038/s41467-021-22474-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062464PMC
April 2021

Modelling intensive care unit capacity under different epidemiological scenarios of the COVID-19 pandemic in three Western European countries.

Int J Epidemiol 2021 07;50(3):753-767

MRC Centre for Global Infectious Disease Analysis & WHO Collaborating Centre for Infectious Disease Modelling, Abdul Latif Jameel Institute for Disease and Emergency Analytics, Imperial College London, St Mary's Campus, Norfolk Place, London, UK.

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 2020-2021 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 2020-2021 winter period. The effect of implementing lockdowns triggered by different numbers of COVID-19 patients in ICUs 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.

Conclusion: 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 2020-2021.
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http://dx.doi.org/10.1093/ije/dyab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083295PMC
July 2021

Reduction in mobility and COVID-19 transmission.

Nat Commun 2021 02 17;12(1):1090. Epub 2021 Feb 17.

MRC Centre for Global Infectious Disease Analysis, J-IDEA, Department of Infectious Disease Epidemiology, Imperial College London, St Mary's Campus, London, UK.

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.
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http://dx.doi.org/10.1038/s41467-021-21358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889876PMC
February 2021

Inference of Naturally Acquired Immunity Using a Self-matched Negative-Control Design.

Epidemiology 2021 03;32(2):168-178

From the Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, CA.

Host adaptive immune responses may protect against infection or disease when a pathogen is repeatedly encountered. The hazard ratio of infection or disease, given previous infection, is typically sought to estimate the strength of protective immunity. However, variation in individual exposure or susceptibility to infection may introduce frailty bias, whereby a tendency for infections to recur among individuals with greater risk confounds the causal association between previous infection and susceptibility. We introduce a self-matched "case-only" inference method to control for unmeasured individual heterogeneity, making use of negative-control endpoints not attributable to the pathogen of interest. To control for confounding, this method compares event times for endpoints due to the pathogen of interest and negative-control endpoints during counterfactual risk periods, defined according to individuals' infection history. We derive a standard Mantel-Haenszel (matched) odds ratio conveying the effect of prior infection on time to recurrence. We compare performance of this approach to several proportional hazards modeling frameworks and estimate statistical power of the proposed strategy under various conditions. In an example application, we use the proposed method to reestimate naturally acquired protection against rotavirus gastroenteritis using data from previously published cohort studies. This self-matched negative-control design may present a flexible alternative to existing approaches for analyzing naturally acquired immunity, as well as other exposures affecting the distribution of recurrent event times.
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http://dx.doi.org/10.1097/EDE.0000000000001305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850593PMC
March 2021

State-level tracking of COVID-19 in the United States.

Nat Commun 2020 12 3;11(1):6189. Epub 2020 Dec 3.

MRC Centre for Global Infectious Disease Analysis, Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), Imperial College, London, UK.

As of 1st June 2020, the US Centres 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 death data within a Bayesian hierarchical semi-mechanistic framework. For each state, we estimate the number of individuals that have been infected, the number of individuals that are currently infectious and the time-varying reproduction number (the average number of secondary infections caused by an infected person). We use changes in mobility to capture the impact that non-pharmaceutical interventions and other behaviour changes have on the rate of transmission of SARS-CoV-2. We estimate that R was 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.
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http://dx.doi.org/10.1038/s41467-020-19652-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712910PMC
December 2020

Database of epidemic trends and control measures during the first wave of COVID-19 in mainland China.

Int J Infect Dis 2021 Jan 31;102:463-471. Epub 2020 Oct 31.

Department of Mathematics, Imperial College London, London, UK.

Objectives: In this data collation study, we aimed to provide a comprehensive database describing the epidemic trends and responses during the first wave of coronavirus disease 2019 (COVID-19) throughout the main provinces in China.

Methods: From mid-January to March 2020, we extracted publicly available data regarding 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 descriptive analyses of the epidemic 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 differed among provinces. Compared with 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 the local transmission of COVID-19 declined, switching the focus of measures to the testing and quarantine of inbound travellers may have helped 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 containing these indicators and information regarding control measures is a useful resource for further research and policy planning in response to the COVID-19 epidemic.
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http://dx.doi.org/10.1016/j.ijid.2020.10.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603985PMC
January 2021

Using rapid point-of-care tests to inform antibiotic choice to mitigate drug resistance in gonorrhoea.

Euro Surveill 2020 10;25(43)

GlaxoSmithKline, Collegeville, Pennsylvania, United States.

BackgroundThe first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the 'stepping-stone' mutation to gepotidacin resistance.AimTo investigate how POCTs detecting resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.MethodsWe use individual-based stochastic simulations to formally investigate the aim.ResultsThe level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1-13%.ConclusionMutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.43.1900210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596916PMC
October 2020

Response to COVID-19 in South Korea and implications for lifting stringent interventions.

BMC Med 2020 10 9;18(1):321. Epub 2020 Oct 9.

MRC Centre for Global Infectious Disease Analysis, Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), Imperial College London, London, UK.

Background: After experiencing a sharp growth in COVID-19 cases early in the pandemic, South Korea rapidly controlled transmission while implementing less stringent national social distancing measures than countries in Europe and the USA. This has led to substantial interest in their "test, trace, isolate" strategy. However, it is important to understand the epidemiological peculiarities of South Korea's outbreak and characterise their response before attempting to emulate these measures elsewhere.

Methods: We systematically extracted numbers of suspected cases tested, PCR-confirmed cases, deaths, isolated confirmed cases, and numbers of confirmed cases with an identified epidemiological link from publicly available data. We estimated the time-varying reproduction number, R, using an established Bayesian framework, and reviewed the package of interventions implemented by South Korea using our extracted data, plus published literature and government sources.

Results: We estimated that after the initial rapid growth in cases, R dropped below one in early April before increasing to a maximum of 1.94 (95%CrI, 1.64-2.27) in May following outbreaks in Seoul Metropolitan Region. By mid-June, R was back below one where it remained until the end of our study (July 13th). Despite less stringent "lockdown" measures, strong social distancing measures were implemented in high-incidence areas and studies measured a considerable national decrease in movement in late February. Testing the capacity was swiftly increased, and protocols were in place to isolate suspected and confirmed cases quickly; however, we could not estimate the delay to isolation using our data. Accounting for just 10% of cases, individual case-based contact tracing picked up a relatively minor proportion of total cases, with cluster investigations accounting for 66%.

Conclusions: Whilst early adoption of testing and contact tracing is likely to be important for South Korea's successful outbreak control, other factors including regional implementation of strong social distancing measures likely also contributed. The high volume of testing and the low number of deaths suggest that South Korea experienced a small epidemic relative to other countries. Caution is needed in attempting to replicate the South Korean response in populations with larger more geographically widespread epidemics where finding, testing, and isolating cases that are linked to clusters may be more difficult.
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http://dx.doi.org/10.1186/s12916-020-01791-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544529PMC
October 2020

The potential public health consequences of COVID-19 on malaria in Africa.

Nat Med 2020 09 7;26(9):1411-1416. Epub 2020 Aug 7.

MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, UK.

The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-2. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs), with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.
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http://dx.doi.org/10.1038/s41591-020-1025-yDOI Listing
September 2020

Potential impact of the COVID-19 pandemic on HIV, tuberculosis, and malaria in low-income and middle-income countries: a modelling study.

Lancet Glob Health 2020 09 13;8(9):e1132-e1141. Epub 2020 Jul 13.

Medical Research Council Centre for Global Infectious Disease Analysis, Abdul Latif Jameel Institute for Disease and Emergency Analytics, Imperial College London, London, UK.

Background: COVID-19 has the potential to cause substantial disruptions to health services, due to cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions to services for HIV, tuberculosis, and malaria in low-income and middle-income countries with high burdens of these diseases could lead to additional loss of life over the next 5 years.

Methods: Assuming a basic reproduction number of 3·0, we constructed four scenarios for possible responses to the COVID-19 pandemic: no action, mitigation for 6 months, suppression for 2 months, or suppression for 1 year. We used established transmission models of HIV, tuberculosis, and malaria to estimate the additional impact on health that could be caused in selected settings, either due to COVID-19 interventions limiting activities, or due to the high demand on the health system due to the COVID-19 pandemic.

Findings: In high-burden settings, deaths due to HIV, tuberculosis, and malaria over 5 years could increase by up to 10%, 20%, and 36%, respectively, compared with if there was no COVID-19 pandemic. The greatest impact on HIV was estimated to be from interruption to antiretroviral therapy, which could occur during a period of high health system demand. For tuberculosis, the greatest impact would be from reductions in timely diagnosis and treatment of new cases, which could result from any prolonged period of COVID-19 suppression interventions. The greatest impact on malaria burden could be as a result of interruption of planned net campaigns. These disruptions could lead to a loss of life-years over 5 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 and tuberculosis epidemics.

Interpretation: Maintaining the most critical prevention activities and health-care services for HIV, tuberculosis, and malaria could substantially reduce the overall impact of the COVID-19 pandemic.

Funding: Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development, and Medical Research Council.
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http://dx.doi.org/10.1016/S2214-109X(20)30288-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357988PMC
September 2020

Naturally Acquired Protection Against Upper Respiratory Symptoms Involving Group A Streptococcus in a Longitudinal Cohort Study.

Clin Infect Dis 2020 11;71(8):e244-e254

Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Pharyngitis due to group A Streptococcus (GAS) represents a major cause of outpatient visits and antibiotic use in the United States. A leading vaccine candidate targets 30 of the > 200 emm types of GAS. We aimed to assess natural protection conferred by GAS against respiratory symptoms.

Methods: In a 5-year study among school-aged children in Pittsburgh, Pennsylvania, pharyngeal cultures were obtained from children at 2-week intervals, and active surveillance was conducted for respiratory illnesses. We assessed protection via the relative odds of previous detection of homologous strains (defined by field-inversion gel electrophoresis banding pattern), emm types, and emm clusters at visits where GAS was detected with symptoms, vs visits where GAS was detected without symptoms. We used a cluster bootstrap of children to adjust estimates for repeated sampling.

Results: At visits where previously detected GAS emm types were identified, we estimated 81.8% (95% confidence interval [CI], 67.1%-91.7%) protection against typical pharyngitis symptoms among children reacquiring the same strain, and 94.5% (95% CI, 83.5%-98.6%) protection among children acquiring a distinct strain. We estimated 77.1% (95% CI, 33.7%-96.3%) protection against typical symptoms among children acquiring partially heterologous emm types belonging to a previously detected emm cluster. Protection was evident after both symptomatic and asymptomatic detections of GAS. We did not identify strong evidence of protection against atypical respiratory symptoms.

Conclusions: Within a 5-year longitudinal study, previous detection of GAS emm types was associated with protection against typical symptoms when homologous strains were subsequently detected. Naturally acquired protection against partially heterologous types suggests that emm type-based vaccines may have broader strain coverage than what has been previously assumed.
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http://dx.doi.org/10.1093/cid/ciaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750950PMC
November 2020

Assessment of the Potential of Vaccination to Combat Antibiotic Resistance in Gonorrhea: A Modeling Analysis to Determine Preferred Product Characteristics.

Clin Infect Dis 2020 11;71(8):1912-1919

School of Life Sciences, University of Warwick, Coventry, United Kingdom.

Background: Gonorrhea incidence is increasing rapidly in many countries, while antibiotic resistance is making treatment more difficult. Combined with evidence that two meningococcal vaccines are likely partially protective against gonorrhea, this has renewed interest in a gonococcal vaccine, and several candidates are in development. Key questions are how protective and long-lasting a vaccine needs to be, and how to target it. We assessed vaccination's potential impact and the feasibility of achieving the World Health Organization's (WHO) target of reducing gonorrhea incidence by 90% during 2018-2030, by comparing realistic vaccination strategies under a range of scenarios of vaccine efficacy and duration of protection, and emergence of extensively-resistant gonorrhea.

Methods: We developed a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behavior in men who have sex with men (MSM). We used data from England, which has a comprehensive, consistent nationwide surveillance system. Using particle Markov chain Monte Carlo methods, we fitted to gonorrhea incidence in 2008-2017, then used Bayesian forecasting to examine an extensive range of scenarios.

Results: Even in the worst-case scenario of untreatable infection emerging, the WHO target is achievable if all MSM attending sexual health clinics receive a vaccine offering ≥ 52% protection for ≥ 6 years. A vaccine conferring 31% protection (as estimated for MeNZB) for 2-4 years could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if > 70% of resistant gonorrhea remains treatable.

Conclusions: Even a partially-protective vaccine, delivered through a realistic targeting strategy, could substantially reduce gonorrhea incidence, despite antibiotic resistance.
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http://dx.doi.org/10.1093/cid/ciz1241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643747PMC
November 2020

A dynamic power-law sexual network model of gonorrhoea outbreaks.

PLoS Comput Biol 2019 03 8;15(3):e1006748. Epub 2019 Mar 8.

School of Life Sciences, University of Warwick, Coventry, United Kingdom.

Human networks of sexual contacts are dynamic by nature, with partnerships forming and breaking continuously over time. Sexual behaviours are also highly heterogeneous, so that the number of partners reported by individuals over a given period of time is typically distributed as a power-law. Both the dynamism and heterogeneity of sexual partnerships are likely to have an effect in the patterns of spread of sexually transmitted diseases. To represent these two fundamental properties of sexual networks, we developed a stochastic process of dynamic partnership formation and dissolution, which results in power-law numbers of partners over time. Model parameters can be set to produce realistic conditions in terms of the exponent of the power-law distribution, of the number of individuals without relationships and of the average duration of relationships. Using an outbreak of antibiotic resistant gonorrhoea amongst men have sex with men as a case study, we show that our realistic dynamic network exhibits different properties compared to the frequently used static networks or homogeneous mixing models. We also consider an approximation to our dynamic network model in terms of a much simpler branching process. We estimate the parameters of the generation time distribution and offspring distribution which can be used for example in the context of outbreak reconstruction based on genomic data. Finally, we investigate the impact of a range of interventions against gonorrhoea, including increased condom use, more frequent screening and immunisation, concluding that the latter shows great promise to reduce the burden of gonorrhoea, even if the vaccine was only partially effective or applied to only a random subset of the population.
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http://dx.doi.org/10.1371/journal.pcbi.1006748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426262PMC
March 2019

Epidemiological Trends of Antibiotic Resistant Gonorrhoea in the United Kingdom.

Antibiotics (Basel) 2018 Jul 13;7(3). Epub 2018 Jul 13.

Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London W2 1PG, UK.

Gonorrhoea is one of the most common sexually-transmitted bacterial infections, globally and in the United Kingdom. The levels of antibiotic resistance in gonorrhoea reported in recent years represent a critical public health issue. From penicillins to cefixime, the gonococcus has become resistant to all antibiotics that have been previously used against it, in each case only a matter of years after introduction as a first-line therapy. After each instance of resistance emergence, the treatment recommendations have required revision, to the point that only a few antibiotics can reliably be prescribed to treat infected individuals. Most countries, including the UK, now recommend that gonorrhoea be treated with a dual therapy combining ceftriaxone and azithromycin. While this treatment is still currently effective for the vast majority of cases, there are concerning signs that this will not always remain the case, and there is no readily apparent alternative. Here, we review the use of antibiotics and epidemiological trends of antibiotic resistance in gonorrhoea from surveillance data over the past 15 years in the UK and describe how surveillance could be improved.
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http://dx.doi.org/10.3390/antibiotics7030060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165062PMC
July 2018

Testing for gonorrhoea should routinely include the pharynx.

Lancet Infect Dis 2018 07;18(7):716-717

MRC Centre for Outbreak Analysis and Modelling and NIHR Health Protection Research Unit in Modelling Methodology, Imperial College London, London, W2 1PG, UK; Modelling and Economics Unit, National Infection Service, Public Health England, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(18)30341-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349805PMC
July 2018

Estimating the fitness cost and benefit of cefixime resistance in Neisseria gonorrhoeae to inform prescription policy: A modelling study.

PLoS Med 2017 Oct 31;14(10):e1002416. Epub 2017 Oct 31.

Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom.

Background: Gonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men (MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined.

Methods And Findings: We developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%-52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%-93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%-99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%-36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%-66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process.

Conclusions: Our study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels.
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http://dx.doi.org/10.1371/journal.pmed.1002416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663337PMC
October 2017

Model-based analysis of an outbreak of bubonic plague in Cairo in 1801.

J R Soc Interface 2017 06;14(131)

Bioterrorism and Emerging Disease Analysis, Emergency Response Department, Health Protection and Medical Directorate, Public Health England, Porton Down SP4 0JG, UK.

Bubonic plague has caused three deadly pandemics in human history: from the mid-sixth to mid-eighth century, from the mid-fourteenth to the mid-eighteenth century and from the end of the nineteenth until the mid-twentieth century. Between the second and the third pandemics, plague was causing sporadic outbreaks in only a few countries in the Middle East, including Egypt. Little is known about this historical phase of plague, even though it represents the temporal, geographical and phylogenetic transition between the second and third pandemics. Here we analysed in detail an outbreak of plague that took place in Cairo in 1801, and for which epidemiological data are uniquely available thanks to the presence of medical officers accompanying the Napoleonic expedition into Egypt at that time. We propose a new stochastic model describing how bubonic plague outbreaks unfold in both rat and human populations, and perform Bayesian inference under this model using a particle Markov chain Monte Carlo. Rat carcasses were estimated to be infectious for approximately 4 days after death, which is in good agreement with local observations on the survival of infectious rat fleas. The estimated transmission rate between rats implies a basic reproduction number of approximately 3, causing the collapse of the rat population in approximately 100 days. Simultaneously, the force of infection exerted by each infected rat carcass onto the human population increases progressively by more than an order of magnitude. We also considered human-to-human transmission via pneumonic plague or human specific vectors, but found this route to account for only a small fraction of cases and to be significantly below the threshold required to sustain an outbreak.
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http://dx.doi.org/10.1098/rsif.2017.0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493801PMC
June 2017

Genomic Analysis and Comparison of Two Gonorrhea Outbreaks.

mBio 2016 Jun 28;7(3). Epub 2016 Jun 28.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom

Unlabelled: Gonorrhea is a sexually transmitted disease causing growing concern, with a substantial increase in reported incidence over the past few years in the United Kingdom and rising levels of resistance to a wide range of antibiotics. Understanding its epidemiology is therefore of major biomedical importance, not only on a population scale but also at the level of direct transmission. However, the molecular typing techniques traditionally used for gonorrhea infections do not provide sufficient resolution to investigate such fine-scale patterns. Here we sequenced the genomes of 237 isolates from two local collections of isolates from Sheffield and London, each of which was resolved into a single type using traditional methods. The two data sets were selected to have different epidemiological properties: the Sheffield data were collected over 6 years from a predominantly heterosexual population, whereas the London data were gathered within half a year and strongly associated with men who have sex with men. Based on contact tracing information between individuals in Sheffield, we found that transmission is associated with a median time to most recent common ancestor of 3.4 months, with an upper bound of 8 months, which we used as a criterion to identify likely transmission links in both data sets. In London, we found that transmission happened predominantly between individuals of similar age, sexual orientation, and location and also with the same HIV serostatus, which may reflect serosorting and associated risk behaviors. Comparison of the two data sets suggests that the London epidemic involved about ten times more cases than the Sheffield outbreak.

Importance: The recent increases in gonorrhea incidence and antibiotic resistance are cause for public health concern. Successful intervention requires a better understanding of transmission patterns, which is not uncovered by traditional molecular epidemiology techniques. Here we studied two outbreaks that took place in Sheffield and London, United Kingdom. We show that whole-genome sequencing provides the resolution to investigate direct gonorrhea transmission between infected individuals. Combining genome sequencing with rich epidemiological information about infected individuals reveals the importance of several transmission routes and risk factors, which can be used to design better control measures.
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http://dx.doi.org/10.1128/mBio.00525-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937209PMC
June 2016

Epidemiological analysis of the Eyam plague outbreak of 1665-1666.

Proc Biol Sci 2016 05;283(1830)

Department of Infectious Disease Epidemiology, Imperial College London, London, UK

Plague, caused by the bacterium Yersinia pestis, is one of the deadliest infectious diseases in human history, and still causes worrying outbreaks in Africa and South America. Despite the historical and current importance of plague, several questions remain unanswered concerning its transmission routes and infection risk factors. The plague outbreak that started in September 1665 in the Derbyshire village of Eyam claimed 257 lives over 14 months, wiping out entire families. Since previous attempts at modelling the Eyam plague, new data have been unearthed from parish records revealing a much more complete record of the disease. Using a stochastic compartmental model and Bayesian analytical methods, we found that both rodent-to-human and human-to-human transmission played an important role in spreading the infection, and that they accounted, respectively, for a quarter and three-quarters of all infections, with a statistically significant seasonality effect. We also found that the force of infection was stronger for infectious individuals living in the same household compared with the rest of the village. Poverty significantly increased the risk of disease, whereas adulthood decreased the risk. These results on the Eyam outbreak contribute to the current debate on the relative importance of plague transmission routes.
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http://dx.doi.org/10.1098/rspb.2016.0618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874723PMC
May 2016
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