Publications
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Lipsitch M, Donnelly CA, Fraser C, et al., 2015, Potential biases in estimating absolute and relative case-fatality risks during outbreaks, PLOS Neglected Tropical Diseases, Vol: 9, ISSN: 1935-2735
Walker PGT, White MT, Griffin JT, et al., 2015, Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis, Lancet Infectious Diseases, Vol: 15, Pages: 825-832, ISSN: 1473-3099
BackgroundThe ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease.MethodsWe estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand.FindingsIf malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43–49) in Guinea, 88% (83–93) in Sierra Leone, and 140% (135–147) in Liberia in 2014. This increase is equivalent to 3·5 million (95% credible interval 2·6 million to 4·9 million) additional untreated cases, with 10 900 (5700–21 400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria.InterpretationThese findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems.
Lambrechts L, Ferguson NM, Harris E, et al., 2015, Assessing the epidemiological effect of wolbachia for dengue control, LANCET INFECTIOUS DISEASES, Vol: 15, Pages: 862-866, ISSN: 1473-3099
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- Citations: 53
Dorigatti I, Aguas R, Donnelly CA, et al., 2015, Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and South East Asia., Vaccine, Vol: 33, Pages: 3746-3751, ISSN: 1873-2518
BACKGROUND: The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine. METHODS: We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models. RESULTS: We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor. We find that the CYD-TDV vaccine generates similar titres against all serotypes following the third dose, though DENV4 is immunodominant after the first dose. CONCLUSIONS: This study contributes to a better understanding of the immunological responses elicited by CYD-TDV. The recent availability of phase-3 data is a unique opportunity to further investigate the immunogenicity and efficacy of the CYD-TDV vaccine, especially in subjects with different levels of pre-existing immunity against DENV. Modelling multiple immunological outcomes with a single multivariate model offers advantages over traditional approaches, capturing correlations between response variables, and the statistical method adopted in this study can be applied to a variety of infections with interacting strains.
Van Kerkhove MD, Bento AI, Mills HL, et al., 2015, A review of epidemiological parameters from Ebola outbreaks to inform early public health decision-making., Scientific Data, Vol: 2, Pages: 150019-150019, ISSN: 2052-4463
The unprecedented scale of the Ebola outbreak in West Africa has, as of 29 April 2015, resulted in more than 10,884 deaths among 26,277 cases. Prior to the ongoing outbreak, Ebola virus disease (EVD) caused relatively small outbreaks (maximum outbreak size 425 in Gulu, Uganda) in isolated populations in central Africa. Here, we have compiled a comprehensive database of estimates of epidemiological parameters based on data from past outbreaks, including the incubation period distribution, case fatality rate, basic reproduction number (R 0 ), effective reproduction number (R t ) and delay distributions. We have compared these to parameter estimates from the ongoing outbreak in West Africa. The ongoing outbreak, because of its size, provides a unique opportunity to better understand transmission patterns of EVD. We have not performed a meta-analysis of the data, but rather summarize the estimates by virus from comprehensive investigations of EVD and Marburg outbreaks over the past 40 years. These estimates can be used to parameterize transmission models to improve understanding of initial spread of EVD outbreaks and to inform surveillance and control guidelines.
Rodriguez-Barraquer I, Mier-y-Teran-Romero L, Ferguson N, et al., 2015, Differential efficacy of dengue vaccine by immune status, LANCET, Vol: 385, Pages: 1726-1726, ISSN: 0140-6736
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- Citations: 11
Gambhir M, Clark TA, Cauchemez S, et al., 2015, A Change in Vaccine Efficacy and Duration of Protection Explains Recent Rises in Pertussis Incidence in the United States, PLOS Computational Biology, Vol: 11, ISSN: 1553-734X
Over the past ten years the incidence of pertussis in the United States (U.S.) has risen steadily, with 2012 seeing the highest case number since 1955. There has also been a shift over the same time period in the age group reporting the largest number of cases (aside from infants), from adolescents to 7–11 year olds. We use epidemiological modelling and a large case incidence dataset to explain the upsurge. We investigate several hypotheses for the upsurge in pertussis cases by fitting a suite of dynamic epidemiological models to incidence data from the National Notifiable Disease Surveillance System (NNDSS) between 1990–2009, as well as incidence data from a variety of sources from 1950–1989. We find that: the best-fitting model is one in which vaccine efficacy and duration of protection of the acellular pertussis (aP) vaccine is lower than that of the whole-cell (wP) vaccine, (efficacy of the first three doses 80% [95% CI: 78%, 82%] versus 90% [95% CI: 87%, 94%]), increasing the rate at which disease is reported to NNDSS is not sufficient to explain the upsurge and 3) 2010–2012 disease incidence is predicted well. In this study, we use all available U.S. surveillance data to: 1) fit a set of mathematical models and determine which best explains these data and 2) determine the epidemiological and vaccine-related parameter values of this model. We find evidence of a difference in efficacy and duration of protection between the two vaccine types, wP and aP (aP efficacy and duration lower than wP). Future refinement of the model presented here will allow for an exploration of alternative vaccination strategies such as different age-spacings, further booster doses, and cocooning.
Imai N, Dorigatti I, Cauchemez S, et al., 2015, Estimating Dengue Transmission Intensity from Sero-Prevalence Surveys in Multiple Countries, PLOS Neglected Tropical Diseases, Vol: 9, ISSN: 1935-2735
BackgroundEstimates of dengue transmission intensity remain ambiguous. Since the majority of infectionsare asymptomatic, surveillance systems substantially underestimate true rates of infection.With advances in the development of novel control measures, obtaining robustestimates of average dengue transmission intensity is key for assessing both the burden ofdisease from dengue and the likely impact of interventions.Methodology/Principal FindingsThe force of infection (λ) and corresponding basic reproduction numbers (R0) for denguewere estimated from non-serotype (IgG) and serotype-specific (PRNT) age-stratified seroprevalencesurveys identified from the literature. The majority of R0 estimates ranged from1–4. Assuming that two heterologous infections result in complete immunity produced up totwo-fold higher estimates of R0 than when tertiary and quaternary infections were included.λ estimated from IgG data were comparable to the sum of serotype-specific forces of infectionderived from PRNT data, particularly when inter-serotype interactions were allowed for.Conclusions/SignificanceOur analysis highlights the highly heterogeneous nature of dengue transmission. How underlyingassumptions about serotype interactions and immunity affect the relationship betweenthe force of infection and R0 will have implications for control planning. While PRNTdata provides the maximum information, our study shows that even the much cheaperELISA-based assays would provide comparable baseline estimates of overall transmissionintensity which will be an important consideration in resource-constrained settings.
Agua-Agum J, Ariyarajah A, Blake IM, et al., 2015, Ebola virus disease among children in West Africa, New England Journal of Medicine, Vol: 372, Pages: 1274-1277, ISSN: 1533-4406
Ferguson NM, Duong THK, Clapham H, et al., 2015, Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti, Science Translational Medicine, Vol: 7, ISSN: 1946-6234
Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact.
Agua-Agum J, Ariyarajah A, Aylward B, et al., 2015, West African Ebola epidemic after one year - slowing but not yet under control, New England Journal of Medicine, Vol: 372, Pages: 584-587, ISSN: 1533-4406
Dye C, 2015, Goal-Directed Resuscitation in Septic Shock, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 372, Pages: 189-189, ISSN: 0028-4793
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- Citations: 11
Lessler J, Rodriguez-Barraquer I, Cummings T, et al., 2014, Estimating potential incidence of MERS-CoV associated with Hajj pilgrims to Saudi Arabia, 2014, PLoS Currents, Vol: Edition 1, ISSN: 2157-3999
Between March and June 2014 the Kingdom of Saudi Arabia (KSA) had a large outbreak of MERS-CoV, renewing fears of a major outbreak during the Hajj this October. Using KSA Ministry of Health data, the MERS-CoV Scenario and Modeling Working Group forecast incidence under three scenarios. In the expected incidence scenario, we estimate 6.2 (95% Prediction Interval [PI]: 1–17) pilgrims will develop MERS-CoV symptoms during the Hajj, and 4.0 (95% PI: 0–12) foreign pilgrims will be infected but return home before developing symptoms. In the most pessimistic scenario, 47.6 (95% PI: 32–66) cases will develop symptoms during the Hajj, and 29.0 (95% PI: 17–43) will be infected but return home asymptomatic. Large numbers of MERS-CoV cases are unlikely to occur during the 2014 Hajj even under pessimistic assumptions, but careful monitoring is still needed to detect possible mass infection events and minimize introductions into other countries.
Pelat C, Ferguson NM, White PJ, et al., 2014, Optimizing the Precision of Case Fatality Ratio Estimates Under the Surveillance Pyramid Approach, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 180, Pages: 1036-1046, ISSN: 0002-9262
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- Citations: 8
Whitty CJM, Farrar J, Ferguson N, et al., 2014, Tough choices to reduce Ebola transmission, NATURE, Vol: 515, Pages: 192-194, ISSN: 0028-0836
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- Citations: 43
Okell LC, Cairns M, Griffin JT, et al., 2014, Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis, Nature Communications, Vol: 5, ISSN: 2041-1723
There are currently several recommended drug regimens for uncomplicated falciparummalaria in Africa. Each has different properties that determine its impact on diseaseburden. Two major antimalarial policy options are artemether–lumefantrine (AL) anddihydroartemisinin–piperaquine (DHA–PQP). Clinical trial data show that DHA–PQP provideslonger protection against reinfection, while AL is better at reducing patient infectiousness.Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducingeffects and cost into a mathematical model and simulate malaria transmission and treatmentin Africa, using geographically explicit data on transmission intensity and seasonality,population density, treatment access and outpatient costs. DHA–PQP has a modestly higherestimated impact than AL in 64% of the population at risk. Given current higher costestimates for DHA–PQP, there is a slightly greater cost per case averted, except in areas withhigh, seasonally varying transmission where the impact is particularly large. We find that alocally optimized treatment policy can be highly cost effective for reducing clinical malariaburden.
WHO Ebola Response Team, 2014, Ebola virus disease in West Africa — The first 9 months of the epidemic and forward projections, New England Journal of Medicine, Vol: 371, Pages: 1481-1495, ISSN: 0028-4793
BACKGROUNDOn March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a “public health emergency of international concern.”METHODSBy September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa — Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14.RESULTSThe majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R0) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total.CONCLUSIONSThese data indicate that without drastic improvements in control measures, the numbers of
Cauchemez S, Ferguson NM, Fox A, et al., 2014, Determinants of Influenza Transmission in South East Asia: Insights from a Household Cohort Study in Vietnam, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 30
Clapham HE, Tricou V, Nguyen VVC, et al., 2014, Within-host viral dynamics of dengue serotype 1 infection, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 11, ISSN: 1742-5689
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- Citations: 72
Ferguson NM, Cummings DAT, 2014, How season and serotype determine dengue transmissibility, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: 9370-9371, ISSN: 0027-8424
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- Citations: 6
Hayward AC, Fragaszy EB, Bermingham A, et al., 2014, Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study, LANCET RESPIRATORY MEDICINE, Vol: 2, Pages: 445-454, ISSN: 2213-2600
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- Citations: 264
Garske T, Van Kerkhove MD, Yactayo S, et al., 2014, Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data, PLoS Medicine, Vol: 11, ISSN: 1548-7091
BackgroundYellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.Methods and FindingsGeneralised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000–380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000–180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaign
Jombart T, Aanensen DM, Baguelin M, et al., 2014, OutbreakTools: A new platform for disease outbreak analysis using the R software, Epidemics, Vol: 7, Pages: 28-34, ISSN: 1755-4365
The investigation of infectious disease outbreaks relies on the analysis of increasingly complex and diverse data, which offer new prospects for gaining insights into disease transmission processes and informing public health policies. However, the potential of such data can only be harnessed using a number of different, complementary approaches and tools, and a unified platform for the analysis of disease outbreaks is still lacking. In this paper, we present the new R package OutbreakTools, which aims to provide a basis for outbreak data management and analysis in R. OutbreakTools is developed by a community of epidemiologists, statisticians, modellers and bioinformaticians, and implements classes and methods for storing, handling and visualizing outbreak data. It includes real and simulated outbreak datasets. Together with a number of tools for infectious disease epidemiology recently made available in R, OutbreakTools contributes to the emergence of a new, free and open-source platform for the analysis of disease outbreaks.
Voeroes J, Urbanek A, Rautureau GJP, et al., 2014, Large-Scale Production and Structural and Biophysical Characterizations of the Human Hepatitis B Virus Polymerase, JOURNAL OF VIROLOGY, Vol: 88, Pages: 2584-2599, ISSN: 0022-538X
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- Citations: 23
Griffin JT, Ferguson NM, Ghani AC, 2014, Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa, Nature Communications, Vol: 5, ISSN: 2041-1723
Estimating the changing burden of malaria disease remains difficult owing to limitations inhealth reporting systems. Here, we use a transmission model incorporating acquisition andloss of immunity to capture age-specific patterns of disease at different transmissionintensities. The model is fitted to age-stratified data from 23 sites in Africa, and we thenproduce maps and estimates of disease burden. We estimate that in 2010 there were 252(95% credible interval: 171–353) million cases of malaria in sub-Saharan Africa that activecase finding would detect. However, only 34% (12–86%) of these cases would be observedthrough passive case detection. We estimate that the proportion of all cases of clinicalmalaria that are in under-fives varies from above 60% at high transmission to below 20% atlow transmission. The focus of some interventions towards young children may need to bereconsidered, and should be informed by the current local transmission intensity.
Ferguson NM, Van Kerkhove MD, 2014, Identification of MERS-CoV in dromedary camels, LANCET INFECTIOUS DISEASES, Vol: 14, Pages: 93-94, ISSN: 1473-3099
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- Citations: 31
Jombart T, Cori A, Didelot X, et al., 2014, Bayesian Reconstruction of Disease Outbreaks by Combining Epidemiologic and Genomic Data, PLOS COMPUTATIONAL BIOLOGY, Vol: 10, ISSN: 1553-734X
Cauchemez S, Fraser C, Van Kerkhove MD, et al., 2014, Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility, LANCET INFECTIOUS DISEASES, Vol: 14, Pages: 50-56, ISSN: 1473-3099
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- Citations: 226
Otete EH, Ahankari AS, Jones H, et al., 2013, Parameters for the Mathematical Modelling of <i>Clostridium difficile</i> Acquisition and Transmission: A Systematic Review, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 10
Ferguson N, 2013, High schools, race, and America's future: What students can teach us about morality, diversity and community, JOURNAL OF MORAL EDUCATION, Vol: 42, Pages: 516-517, ISSN: 0305-7240
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