Imperial College London

DrLucyOkell

Faculty of MedicineSchool of Public Health

Lecturer/Royal Society Dorothy Hodgkin Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 3265l.okell Website

 
 
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Location

 

G24Medical SchoolSt Mary's Campus

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Summary

 

Publications

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66 results found

Winskill P, Whittaker C, Walker P, Watson O, Laydon D, Imai N, Cuomo-Dannenburg G, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Cattarino L, Ciavarella C, Cooper L, Coupland H, Cucunuba Perez Z, van Elsland S, Fitzjohn R, Flaxman S, Gaythorpe K, Green W, Hallett T, Hamlet A, Hinsley W, Knock E, Lees J, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Parag K, Thompson H, Unwin H, Wang Y, Whittles L, Xi X, Ferguson N, Donnelly C, Ghani Aet al., 2020, Report 22: Equity in response to the COVID-19 pandemic: an assessment of the direct and indirect impacts on disadvantaged and vulnerable populations in low- and lower middle-income countries, 22

The impact of the COVID-19 pandemic in low-income settings is likely to be more severe due to limited healthcare capacity. Within these settings, however, there exists unfair or avoidable differences in health among different groups in society – health inequities – that mean that some groups are particularly at risk from the negative direct and indirect consequences of COVID-19. The structural determinants of these are often reflected in differences by income strata, with the poorest populations having limited access to preventative measures such as handwashing. Their more fragile income status will also mean that they are likely to be employed in occupations that are not amenable to social-distancing measures, thereby further reducing their ability to protect themselves from infection. Furthermore, these populations may also lack access to timely healthcare on becoming ill. We explore these relationships by using large-scale household surveys to quantify the differences in handwashing access, occupation and hospital access with respect to wealth status in low-income settings. We use a COVID-19 transmission model to demonstrate the impact of these differences. Our results demonstrate clear trends that the probability of death from COVID-19 increases with increasing poverty. On average, we estimate a 32.0% (2.5th-97.5th centile 8.0%-72.5%) increase in the probability of death in the poorest quintile compared to the wealthiest quintile from these three factors alone. We further explore how risk mediators and the indirect impacts of COVID-19 may also hit these same disadvantaged and vulnerable the hardest. We find that larger, inter-generational households that may hamper efforts to protect the elderly if social distancing are associated with lower-income countries and, within LMICs, lower wealth status. Poorer populations are also more susceptible to food security issues - with these populations having the highest levels under-nourishment whilst also being

Report

Mellan T, Hoeltgebaum H, Mishra S, Whittaker C, Schnekenberg R, Gandy A, Unwin H, Vollmer M, Coupland H, Hawryluk I, Rodrigues Faria N, Vesga J, Zhu H, Hutchinson M, Ratmann O, Monod M, Ainslie K, Baguelin M, Bhatia S, Boonyasiri A, Brazeau N, Charles G, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Eaton J, van Elsland S, Fitzjohn R, Fraser K, Gaythorpe K, Green W, Hayes S, Imai N, Jeffrey B, Knock E, Laydon D, Lees J, Mangal T, Mousa A, Nedjati Gilani G, Nouvellet P, Olivera Mesa D, Parag K, Pickles M, Thompson H, Verity R, Walters C, Wang H, Wang Y, Watson O, Whittles L, Xi X, Okell L, Dorigatti I, Walker P, Ghani A, Riley S, Ferguson N, Donnelly C, Flaxman S, Bhatt Set al., 2020, Report 21: Estimating COVID-19 cases and reproduction number in Brazil

Brazil is an epicentre for COVID-19 in Latin America. In this report we describe the Brazilian epidemicusing three epidemiological measures: the number of infections, the number of deaths and the reproduction number. Our modelling framework requires sufficient death data to estimate trends, and wetherefore limit our analysis to 16 states that have experienced a total of more than fifty deaths. Thedistribution of deaths among states is highly heterogeneous, with 5 states—São Paulo, Rio de Janeiro,Ceará, Pernambuco and Amazonas—accounting for 81% of deaths reported to date. In these states, weestimate that the percentage of people that have been infected with SARS-CoV-2 ranges from 3.3% (95%CI: 2.8%-3.7%) in São Paulo to 10.6% (95% CI: 8.8%-12.1%) in Amazonas. The reproduction number (ameasure of transmission intensity) at the start of the epidemic meant that an infected individual wouldinfect three or four others on average. Following non-pharmaceutical interventions such as school closures and decreases in population mobility, we show that the reproduction number has dropped substantially in each state. However, for all 16 states we study, we estimate with high confidence that thereproduction number remains above 1. A reproduction number above 1 means that the epidemic isnot yet controlled and will continue to grow. These trends are in stark contrast to other major COVID19 epidemics in Europe and Asia where enforced lockdowns have successfully driven the reproductionnumber below 1. While the Brazilian epidemic is still relatively nascent on a national scale, our resultssuggest that further action is needed to limit spread and prevent health system overload.

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Vollmer M, Mishra S, Unwin H, Gandy A, Melan T, Bradley V, Zhu H, Coupland H, Hawryluk I, Hutchinson M, Ratmann O, Monod M, Walker P, Whittaker C, Cattarino L, Ciavarella C, Cilloni L, Ainslie K, Baguelin M, Bhatia S, Boonyasiri A, Brazeau N, Charles G, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Eaton J, van Elsland S, Fitzjohn R, Fraser K, Gaythorpe K, Green W, Hayes S, Imai N, Jeffrey B, Knock E, Laydon D, Lees J, Mangal T, Mousa A, Nedjati Gilani G, Nouvellet P, Olivera Mesa D, Parag K, Pickles M, Thompson H, Verity R, Walters C, Wang H, Wang Y, Watson O, Whittles L, Xi X, Ghani A, Riley S, Okell L, Donnelly C, Ferguson N, Dorigatti I, Flaxman S, Bhatt Set al., 2020, Report 20: A sub-national analysis of the rate of transmission of Covid-19 in Italy

Italy was the first European country to experience sustained local transmission of COVID-19. As of 1st May 2020, the Italian health authorities reported 28; 238 deaths nationally. To control the epidemic, the Italian government implemented a suite of non-pharmaceutical interventions (NPIs), including school and university closures, social distancing and full lockdown involving banning of public gatherings and non essential movement. In this report, we model the effect of NPIs on transmission using data on average mobility. We estimate that the average reproduction number (a measure of transmission intensity) is currently below one for all Italian regions, and significantly so for the majority of the regions. Despite the large number of deaths, the proportion of population that has been infected by SARS-CoV-2 (the attack rate) is far from the herd immunity threshold in all Italian regions, with the highest attack rate observed in Lombardy (13.18% [10.66%-16.70%]). Italy is set to relax the currently implemented NPIs from 4th May 2020. Given the control achieved by NPIs, we consider three scenarios for the next 8 weeks: a scenario in which mobility remains the same as during the lockdown, a scenario in which mobility returns to pre-lockdown levels by 20%, and a scenario in which mobility returns to pre-lockdown levels by 40%. The scenarios explored assume that mobility is scaled evenly across all dimensions, that behaviour stays the same as before NPIs were implemented, that no pharmaceutical interventions are introduced, and it does not include transmission reduction from contact tracing, testing and the isolation of confirmed or suspected cases. We find that, in the absence of additional interventions, even a 20% return to pre-lockdown mobility could lead to a resurgence in the number of deaths far greater than experienced in the current wave in several regions. Future increases in the number of deaths will lag behind the increase in transmission intensity and so a

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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, Report 19: The potential impact of the COVID-19 epidemic on HIV, TB and malaria in low- and middle-income countries

COVID-19 has the potential to cause disruptions to health services in different ways; through the health system becoming overwhelmed with COVID-19 patients, through the intervention used to slow transmission of COVID-19 inhibiting access to preventative interventions and services, and through supplies of medicine being interrupted. We aim to quantify the extent to which such disruptions in services for HIV, TB and malaria in high burden low- and middle-income countries could lead to additional loss of life. In high burden settings, HIV, TB and malaria related deaths over 5 years may be increased by up to 10%, 20% and 36%, respectively, compared to if there were no COVID-19 epidemic. We estimate the greatest impact on HIV to be from interruption to ART, which may occur during a period of high or extremely 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 a long period of COVID-19 suppression interventions; for malaria, we estimate that the greatest impact could come from reduced prevention activities including interruption of planned net campaigns, through all phases of the COVID-19 epidemic. In high burden settings, the impact of each type of disruption could be significant and lead to a 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. Maintaining the most critical prevention activities and healthcare services for HIV, TB and malaria could significantly reduce the overall impact of the COVID-19 epidemic.

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Sherrard-Smith E, Hogan A, Hamlet A, Watson OJ, Whittaker C, Winskill P, Verity R, Lambert B, Cairns M, Okell L, Slater H, Ghani A, Walker P, Churcher T, Imperial College COVID19 response teamet al., 2020, Report 18: The potential public health impact of COVID-19 on malaria in Africa.

The COVID-19 pandemic is likely to severely interrupt health systems in Sub-Saharan Africa (SSA) over the coming weeks and months. Approximately 90% of malaria deaths occur in this region of the world, with an estimated 380,000 deaths from malaria in 2018. Much of the gain made in malaria control over the last decade has been due to the distribution of long-lasting insecticide treated nets (LLINs). Many SSA countries planned to distribute these in 2020. We used COVID-19 and malaria transmission models to understand the likely impact that disruption to these distributions, alongside other core health services, could have on the malaria burden. Results indicate that if all malaria-control activities are highly disrupted then the malaria burden in 2020 could more than double that in the previous year, resulting in large malaria epidemics across the region. These will depend on the course of the COVID-19 epidemic and how it interrupts local health system. Our results also demonstrate that it is essential to prioritise the LLIN distributions either before or as soon as possible into local COVID-19 epidemics to mitigate this risk. Additional planning to ensure other malaria prevention activities are continued where possible, alongside planning to ensure basic access to antimalarial treatment, will further minimise the risk of substantial additional malaria mortality.

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Ainslie KEC, Walters CE, Fu H, Bhatia S, Wang H, Xi X, Baguelin M, Bhatt S, Boonyasiri A, Boyd O, Cattarino L, Ciavarella C, Cucunuba Z, Cuomo-Dannenburg G, Dighe A, Dorigatti I, van Elsland SL, FitzJohn R, Gaythorpe K, Ghani AC, Green W, Hamlet A, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Nedjati-Gilani G, Okell LC, Siveroni I, Thompson HA, Unwin HJT, Verity R, Vollmer M, Walker PGT, Wang Y, Watson OJ, Whittaker C, Winskill P, Donnelly CA, Ferguson NM, Riley Set al., Evidence of initial success for China exiting COVID-19 social distancing policy after achieving containment, Wellcome Open Research, Vol: 5, Pages: 81-81

<ns4:p><ns4:bold>Background</ns4:bold>: The COVID-19 epidemic was declared a Global Pandemic by WHO on 11 March 2020. By 24 March 2020, over 440,000 cases and almost 20,000 deaths had been reported worldwide. In response to the fast-growing epidemic, which began in the Chinese city of Wuhan, Hubei, China imposed strict social distancing in Wuhan on 23 January 2020 followed closely by similar measures in other provinces. These interventions have impacted economic productivity in China, and the ability of the Chinese economy to resume without restarting the epidemic was not clear.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: Using daily reported cases from mainland China and Hong Kong SAR, we estimated transmissibility over time and compared it to daily within-city movement, as a proxy for economic activity.</ns4:p><ns4:p> <ns4:bold>Results</ns4:bold>: Initially, within-city movement and transmission were very strongly correlated in the five mainland provinces most affected by the epidemic and Beijing. However, that correlation decreased rapidly after the initial sharp fall in transmissibility. In general, towards the end of the study period, the correlation was no longer apparent, despite substantial increases in within-city movement. A similar analysis for Hong Kong shows that intermediate levels of local activity were maintained while avoiding a large outbreak. At the very end of the study period, when China began to experience the re-introduction of a small number of cases from Europe and the United States, there is an apparent up-tick in transmission.</ns4:p><ns4:p> <ns4:bold>Conclusions:</ns4:bold> Although these results do not preclude future substantial increases in incidence, they suggest that after very intense social distancing (which resulted in containment), China successfully exited its lockdown to some degree. Elsewhere, movement data are being used as proxies for

Journal article

Grassly N, Pons Salort M, Parker E, White P, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Boyd O, Brazeau N, Cattarino L, Ciavarella C, Cooper L, Coupland H, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Dorigatti I, van Elsland S, Ferreira Do Nascimento F, Fitzjohn R, Fu H, Gaythorpe K, Geidelberg L, Green W, Hallett T, Hamlet A, Hayes S, Hinsley W, Imai N, Jorgensen D, 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, Ragonnet-Cronin M, Stopard I, Thompson H, 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, Ferguson Net al., 2020, Report 16: Role of testing in COVID-19 control

The World Health Organization has called for increased molecular testing in response to the COVID-19 pandemic, but different countries have taken very different approaches. We used a simple mathematical model to investigate the potential effectiveness of alternative testing strategies for COVID-19 control. Weekly screening of healthcare workers (HCWs) and other at-risk groups using PCR or point-of-care tests for infection irrespective of symptoms is estimated to reduce their contribution to transmission by 25-33%, on top of reductions achieved by self-isolation following symptoms. Widespread PCR testing in the general population is unlikely to limit transmission more than contact-tracing and quarantine based on symptoms alone, but could allow earlier release of contacts from quarantine. Immunity passports based on tests for antibody or infection could support return to work but face significant technical, legal and ethical challenges. Testing is essential for pandemic surveillance but its direct contribution to the prevention of transmission is likely to be limited to patients, HCWs and other high-risk groups.

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Flaxman S, Mishra S, Gandy A, Unwin H, Coupland H, Mellan T, Zhu H, Berah T, Eaton J, Perez Guzman P, Schmit N, Cilloni L, Ainslie K, Baguelin M, Blake I, Boonyasiri A, Boyd O, Cattarino L, Ciavarella C, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Dorigatti I, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Geidelberg L, Grassly N, Green W, Hallett T, Hamlet A, Hinsley W, Jeffrey B, Jorgensen D, Knock E, Laydon D, Nedjati Gilani G, Nouvellet P, Parag K, Siveroni I, Thompson H, Verity R, Volz E, Walters C, Wang H, Wang Y, Watson O, Winskill P, Xi X, Whittaker C, Walker P, Ghani A, Donnelly C, Riley S, Okell L, Vollmer M, Ferguson N, Bhatt Set al., 2020, Report 13: Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in 11 European countries

Following the emergence of a novel coronavirus (SARS-CoV-2) and its spread outside of China, Europe is now experiencing large epidemics. In response, many European countries have implemented unprecedented non-pharmaceutical interventions including case isolation, the closure of schools and universities, banning of mass gatherings and/or public events, and most recently, widescale social distancing including local and national lockdowns. In this report, we use a semi-mechanistic Bayesian hierarchical model to attempt to infer the impact of these interventions across 11 European countries. Our methods assume that changes in the reproductive number – a measure of transmission - are an immediate response to these interventions being implemented rather than broader gradual changes in behaviour. Our model estimates these changes by calculating backwards from the deaths observed over time to estimate transmission that occurred several weeks prior, allowing for the time lag between infection and death. One of the key assumptions of the model is that each intervention has the same effect on the reproduction number across countries and over time. This allows us to leverage a greater amount of data across Europe to estimate these effects. It also means that our results are driven strongly by the data from countries with more advanced epidemics, and earlier interventions, such as Italy and Spain. We find that the slowing growth in daily reported deaths in Italy is consistent with a significant impact of interventions implemented several weeks earlier. In Italy, we estimate that the effective reproduction number, Rt, dropped to close to 1 around the time of lockdown (11th March), although with a high level of uncertainty. Overall, we estimate that countries have managed to reduce their reproduction number. Our estimates have wide credible intervals and contain 1 for countries that have implemented all interventions considered in our analysis. This means that the reproducti

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Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PGT, Fu H, Dighe A, Griffin JT, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunubá Z, FitzJohn R, Gaythorpe K, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati-Gilani G, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Xi X, Donnelly CA, Ghani AC, Ferguson NMet al., 2020, Estimates of the severity of coronavirus disease 2019: a model-based analysis., Lancet Infectious Diseases, ISSN: 1473-3099

BACKGROUND: In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases. METHODS: We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation. FINDINGS: Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9-19·2) and to hospital discharge to be 24·7 days (22·9-28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70 117), we estimated a crude case fatality ratio (adjusted for cen

Journal article

Walker P, Whittaker C, Watson O, Baguelin M, Ainslie K, Bhatia S, Bhatt S, Boonyasiri A, Boyd O, Cattarino L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Donnelly C, Dorigatti I, van Elsland S, Fitzjohn R, Flaxman S, Fu H, Gaythorpe K, Geidelberg L, Grassly N, Green W, Hamlet A, Hauck K, Haw D, Hayes S, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Mishra S, Nedjati Gilani G, Okell L, Riley S, Thompson H, Unwin H, Verity R, Vollmer M, Walters C, Wang H, Wang Y, Winskill P, Xi X, Ferguson N, Ghani Aet al., 2020, Report 12: The global impact of COVID-19 and strategies for mitigation and suppression

The world faces a severe and acute public health emergency due to the ongoing COVID-19 global pandemic. How individual countries respond in the coming weeks will be critical in influencing the trajectory of national epidemics. Here we combine data on age-specific contact patterns and COVID-19 severity to project the health impact of the pandemic in 202 countries. We compare predicted mortality impacts in the absence of interventions or spontaneous social distancing with what might be achieved with policies aimed at mitigating or suppressing transmission. Our estimates of mortality and healthcare demand are based on data from China and high-income countries; differences in underlying health conditions and healthcare system capacity will likely result in different patterns in low income settings. We estimate that in the absence of interventions, COVID-19 would have resulted in 7.0 billion infections and 40 million deaths globally this year. Mitigation strategies focussing on shielding the elderly (60% reduction in social contacts) and slowing but not interrupting transmission (40% reduction in social contacts for wider population) could reduce this burden by half, saving 20 million lives, but we predict that even in this scenario, health systems in all countries will be quickly overwhelmed. This effect is likely to be most severe in lower income settings where capacity is lowest: our mitigated scenarios lead to peak demand for critical care beds in a typical low-income setting outstripping supply by a factor of 25, in contrast to a typical high-income setting where this factor is 7. As a result, we anticipate that the true burden in low income settings pursuing mitigation strategies could be substantially higher than reflected in these estimates. Our analysis therefore suggests that healthcare demand can only be kept within manageable levels through the rapid adoption of public health measures (including testing and isolation of cases and wider social distancing meas

Report

Ainslie K, Walters C, Fu H, Bhatia S, Wang H, Baguelin M, Bhatt S, Boonyasiri A, Boyd O, Cattarino L, Ciavarella C, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Dorigatti I, van Elsland S, Fitzjohn R, Gaythorpe K, Geidelberg L, Ghani A, Green W, Hamlet A, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Nedjati Gilani G, Okell L, Siveroni I, Thompson H, Unwin H, Verity R, Vollmer M, Walker P, Wang Y, Watson O, Whittaker C, Winskill P, Xi X, Donnelly C, Ferguson N, Riley Set al., 2020, Report 11: Evidence of initial success for China exiting COVID-19 social distancing policy after achieving containment

The COVID-19 epidemic was declared a Global Pandemic by WHO on 11 March 2020. As of 20 March 2020, over 254,000 cases and 10,000 deaths had been reported worldwide. The outbreak began in the Chinese city of Wuhan in December 2019. In response to the fast-growing epidemic, China imposed strict social distancing in Wuhan on 23 January 2020 followed closely by similar measures in other provinces. At the peak of the outbreak in China (early February), there were between 2,000 and 4,000 new confirmed cases per day. For the first time since the outbreak began there have been no new confirmed cases caused by local transmission in China reported for five consecutive days up to 23 March 2020. This is an indication that the social distancing measures enacted in China have led to control of COVID-19 in China. These interventions have also impacted economic productivity in China, and the ability of the Chinese economy to resume without restarting the epidemic is not yet clear. Here, we estimate transmissibility from reported cases and compare those estimates with daily data on within-city movement, as a proxy for economic activity. Initially, within-city movement and transmission were very strongly correlated in the 5 provinces most affected by the epidemic and Beijing. However, that correlation is no longer apparent even though within-city movement has started to increase. A similar analysis for Hong Kong shows that intermediate levels of local activity can be maintained while avoiding a large outbreak. These results do not preclude future epidemics in China, nor do they allow us to estimate the maximum proportion of previous within-city activity that will be recovered in the medium term. However, they do suggest that after very intense social distancing which resulted in containment, China has successfully exited their stringent social distancing policy to some degree. Globally, China is at a more advanced stage of the pandemic. Policies implemented to reduce the spread of CO

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Ferguson N, Laydon D, Nedjati Gilani G, Imai N, Ainslie K, Baguelin M, Bhatia S, Boonyasiri A, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Dorigatti I, Fu H, Gaythorpe K, Green W, Hamlet A, Hinsley W, Okell L, van Elsland S, Thompson H, Verity R, Volz E, Wang H, Wang Y, Walker P, Walters C, Winskill P, Whittaker C, Donnelly C, Riley S, Ghani Aet al., 2020, Report 9: Impact of non-pharmaceutical interventions (NPIs) to reduce COVID19 mortality and healthcare demand

The global impact of COVID-19 has been profound, and the public health threat it represents is the most serious seen in a respiratory virus since the 1918 H1N1 influenza pandemic. Here we present the results of epidemiological modelling which has informed policymaking in the UK and other countries in recent weeks. In the absence of a COVID-19 vaccine, we assess the potential role of a number of public health measures – so-called non-pharmaceutical interventions (NPIs) – aimed at reducing contact rates in the population and thereby reducing transmission of the virus. In the results presented here, we apply a previously published microsimulation model to two countries: the UK (Great Britain specifically) and the US. We conclude that the effectiveness of any one intervention in isolation is likely to be limited, requiring multiple interventions to be combined to have a substantial impact on transmission. Two fundamental strategies are possible: (a) mitigation, which focuses on slowing but not necessarily stopping epidemic spread – reducing peak healthcare demand while protecting those most at risk of severe disease from infection, and (b) suppression, which aims to reverse epidemic growth, reducing case numbers to low levels and maintaining that situation indefinitely. Each policy has major challenges. We find that that optimal mitigation policies (combining home isolation of suspect cases, home quarantine of those living in the same household as suspect cases, and social distancing of the elderly and others at most risk of severe disease) might reduce peak healthcare demand by 2/3 and deaths by half. However, the resulting mitigated epidemic would still likely result in hundreds of thousands of deaths and health systems (most notably intensive care units) being overwhelmed many times over. For countries able to achieve it, this leaves suppression as the preferred policy option. We show that in the UK and US context, suppression will minimally requi

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Gaythorpe K, Imai N, Cuomo-Dannenburg G, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Perez Z, Dighe A, Dorigatti I, Fitzjohn R, Fu H, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati Gilani G, Okell L, Riley S, Thompson H, van Elsland S, Volz E, Wang H, Wang Y, Whittaker C, Xi X, Donnelly C, Ghani A, Ferguson Net al., 2020, Report 8: Symptom progression of COVID-19

The COVID-19 epidemic was declared a Public Health Emergency of International Concern (PHEIC) by WHO on 30th January 2020 [1]. As of 8 March 2020, over 107,000 cases had been reported. Here, we use published and preprint studies of clinical characteristics of cases in mainland China as well as case studies of individuals from Hong Kong, Japan, Singapore and South Korea to examine the proportional occurrence of symptoms and the progression of symptoms through time.We find that in mainland China, where specific symptoms or disease presentation are reported, pneumonia is the most frequently mentioned, see figure 1. We found a more varied spectrum of severity in cases outside mainland China. In Hong Kong, Japan, Singapore and South Korea, fever was the most frequently reported symptom. In this latter group, presentation with pneumonia is not reported as frequently although it is more common in individuals over 60 years old. The average time from reported onset of first symptoms to the occurrence of specific symptoms or disease presentation, such as pneumonia or the use of mechanical ventilation, varied substantially. The average time to presentation with pneumonia is 5.88 days, and may be linked to testing at hospitalisation; fever is often reported at onset (where the mean time to develop fever is 0.77 days).

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Thompson H, Imai N, Dighe A, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Perez Z, Cuomo-Dannenburg G, Dorigatti I, Fitzjohn R, Fu H, Gaythorpe K, Ghani A, Green W, Hamlet A, Hinsley W, Laydon D, Nedjati Gilani G, Okell L, Riley S, van Elsland S, Volz E, Wang H, Yuanrong W, Whittaker C, Xi X, Donnelly C, Ferguson Net al., 2020, Report 7: Estimating infection prevalence in Wuhan City from repatriation flights

Since the end of January 2020, in response to the growing COVID-19 epidemic, 55 countries have repatriated over 8000 citizens from Wuhan City, China. In addition to quarantine measures for returning citizens, many countries implemented PCR screening to test for infection regardless of symptoms. These flights therefore give estimates of infection prevalence in Wuhan over time. Between 30th January and 1st February (close to the peak of the epidemic in Wuhan), infection prevalence was 0.87% (95% CI: 0.32% - 1.89%). As countries now start to repatriate citizens from Iran and northern Italy, information from repatriated citizens could help inform the level of response necessary to help control the outbreaks unfolding in newly affected areas.

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Okell L, Bretscher MT, Dahal P, Griffin J, stepniewska K, Bassat Q, Baudin E, D'Alessandro U, Djimde A, Dorsey G, Espie E, Fofana B, Gonzalez R, Juma E, Karema C, Lasry E, Lell B, Lima N, Menendez C, Mombo-Ngoma G, Moreira C, Nikiema F, Ouedraogo J, Staedke S, Tinto H, Valea I, Yeka A, Ghani A, Guerin Pet al., 2020, The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data, BMC Medicine, Vol: 18, Pages: 1-17, ISSN: 1741-7015

Background: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programmes combined with sulfadoxine-pyrimethamine. Whilst artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n=4214 individuals). The time to PCR-confirmed re-infection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to re-infection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to re-infection in multivariate models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~2-fold longer protection than AL. Conversely at a higher prevalence of 86Y and 76T mutant parasites (>80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protec

Journal article

Bhatia S, Imai N, Cuomo-Dannenburg G, Baguelin M, Boonyasiri A, Cori A, Cucunuba Perez Z, Dorigatti I, Fitzjohn R, Fu H, Gaythorpe K, Ghani A, Hamlet A, Hinsley W, Laydon D, Nedjati Gilani G, Thompson H, Okell L, Riley S, van Elsland S, Volz E, Wang H, Wang Y, Whittaker C, Xi X, Donnelly C, Ferguson Net al., 2020, Report 6: Relative sensitivity of international surveillance, Report 6: Relative sensitivity of international surveillance

Since the start of the COVID-19 epidemic in late 2019, there are now 29 affected countries with over 1000 confirmed cases outside of mainland China. In previous reports, we estimated the likely epidemic size in Wuhan City based on air traffic volumes and the number of detected cases internationally. Here we analysed COVID-19 cases exported from mainland China to different regions and countries, comparing the country-specific rates of detected and confirmed cases per flight volume to estimate the relative sensitivity of surveillance in different countries. Although travel restrictions from Wuhan City and other cities across China may have reduced the absolute number of travellers to and from China, we estimated that about two thirds of COVID-19 cases exported from mainland China have remained undetected worldwide, potentially resulting in multiple chains of as yet undetected human-to-human transmission outside mainland China.

Report

Volz E, Baguelin M, Bhatia S, Boonyasiri A, Cori A, Cucunuba Perez Z, Cuomo-Dannenburg G, Donnelly C, Dorigatti I, Fitzjohn R, Fu H, Gaythorpe K, Ghani A, Hamlet A, Hinsley W, Imai N, Laydon D, Nedjati Gilani G, Okell L, Riley S, van Elsland S, Wang H, Wang Y, Xi X, Ferguson Net al., 2020, Report 5: Phylogenetic analysis of SARS-CoV-2

Genetic diversity of SARS-CoV-2 (formerly 2019-nCoV), the virus which causes COVID-19, provides information about epidemic origins and the rate of epidemic growth. By analysing 53 SARS-CoV-2 whole genome sequences collected up to February 3, 2020, we find a strong association between the time of sample collection and accumulation of genetic diversity. Bayesian and maximum likelihood phylogenetic methods indicate that the virus was introduced into the human population in early December and has an epidemic doubling time of approximately seven days. Phylodynamic modelling provides an estimate of epidemic size through time. Precise estimates of epidemic size are not possible with current genetic data, but our analyses indicate evidence of substantial heterogeneity in the number of secondary infections caused by each case, as indicated by a high level of over-dispersion in the reproduction number. Larger numbers of more systematically sampled sequences – particularly from across China – will allow phylogenetic estimates of epidemic size and growth rate to be substantially refined.

Report

Dorigatti I, Okell L, Cori A, Imai N, Baguelin M, Bhatia S, Boonyasiri A, Cucunuba Perez Z, Cuomo-Dannenburg G, Fitzjohn R, Fu H, Gaythorpe K, Hamlet A, Hinsley W, Hong N, Kwun M, Laydon D, Nedjati Gilani G, Riley S, van Elsland S, Volz E, Wang H, Walters C, Xi X, Donnelly C, Ghani A, Ferguson Net al., 2020, Report 4: Severity of 2019-novel coronavirus (nCoV)

We present case fatality ratio (CFR) estimates for three strata of 2019-nCoV infections. For cases detected in Hubei, we estimate the CFR to be 18% (95% credible interval: 11%-81%). For cases detected in travellers outside mainland China, we obtain central estimates of the CFR in the range 1.2-5.6% depending on the statistical methods, with substantial uncertainty around these central values. Using estimates of underlying infection prevalence in Wuhan at the end of January derived from testing of passengers on repatriation flights to Japan and Germany, we adjusted the estimates of CFR from either the early epidemic in Hubei Province, or from cases reported outside mainland China, to obtain estimates of the overall CFR in all infections (asymptomatic or symptomatic) of approximately 1% (95% confidence interval 0.5%-4%). It is important to note that the differences in these estimates does not reflect underlying differences in disease severity between countries. CFRs seen in individual countries will vary depending on the sensitivity of different surveillance systems to detect cases of differing levels of severity and the clinical care offered to severely ill cases. All CFR estimates should be viewed cautiously at the current time as the sensitivity of surveillance of both deaths and cases in mainland China is unclear. Furthermore, all estimates rely on limited data on the typical time intervals from symptom onset to death or recovery which influences the CFR estimates.

Report

van Lenthe M, van der Meulen R, Lassovski M, Ouabo A, Bakula E, Badio C, Cibenda D, Okell L, Piriou E, Grignard L, Lanke K, Rao B, Bousema T, Roper Cet al., 2019, Markers of sulfadoxine-pyrimethamine resistance in Eastern Democratic Republic of Congo; implications for malaria chemoprevention, Malaria Journal, Vol: 18, Pages: 1-9, ISSN: 1475-2875

BackgroundSulfadoxine–pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap.MethodsDried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays.ResultsAcross populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5–25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3–87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7–47.2%). The dhfr I164L mutation was found in one sample.ConclusionsThe prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DR

Journal article

Challenger J, Goncalves BP, Bradley J, Bruxvoort K, Tiono AB, Drakeley C, Bousema T, Ghani AC, Okell LCet al., How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study, BMJ Global Health, Vol: 4, ISSN: 2059-7908

IntroductionArtemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicatedPlasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routinehealthcare settings, however, its effectiveness can be diminished by delayed access to treatmentand poor adherence. As well as affecting clinical outcomes, these factors can lead to increasedtransmission, which is the focus of this study.MethodsWe extend a within-host model of Plasmodium falciparum to include gametocytes, the parasiteforms responsible for onward transmission. The model includes a pharmacokineticpharmacodynamic model of AL, calibrated against both immature and mature gametocytes usingindividual-level patient data, to estimate the impact that delayed access and imperfect adherence totreatment can have on onward transmission of the parasite to mosquitoes.ResultsUsing survey data from 7 African countries to determine the time taken to acquire antimalarialsfollowing fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared to patients treated after 24 hours. Realistic adherence behaviour, based on datafrom a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold,compared to a perfectly-adherent cohort. This was driven largely by increased rates of treatmentfailure leading to chronic infection, rather than prolonged gametocytaemia in patients who haveslower, but still successful, clearance of parasites after imperfect adherence to treatment. Ourmodel estimated that the mean infectivity of untreated infections was 29-51 times higher than thatof treated infections (assuming perfect drug adherence), underlining the importance of improvingtreatment coverage.ConclusionUsing mathematical modelling, we quantify how delayed treatment and non-adherent treatmentcan increase transmission compared to prompt effective treatment. We also highlight thattransmission from the large proporti

Journal article

Slater HC, Ross A, Felger I, Hofmann NE, Robinson L, Cook J, Goncalves BP, Bjorkman A, Ouedraogo AL, Morris U, Msellem M, Koepfli C, Mueller I, Tadesse F, Gadisa E, Das S, Domingo G, Kapulu M, Midega J, Owusu-Agyei S, Nabet C, Piarroux R, Doumbo O, Doumbo SN, Koram K, Lucchi N, Udhayakumar V, Mosha J, Tiono A, Chandramohan D, Gosling R, Mwingira F, Sauerwein R, Paul R, Riley EM, White NJ, Nosten F, Imwong M, Bousema T, Drakeley C, Okell LCet al., 2019, Author Correction: The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density, Nature Communications, Vol: 10, ISSN: 2041-1723

Correction to: Nature Communications https://doi.org/10.1038/s41467-019-09441-1; published online 29 March 2019

Journal article

van Eijk AM, Larsen DA, Kayentao K, Koshy G, Slaughter DEC, Roper C, Okell LC, Desai M, Gutman J, Khairallah C, Rogerson SJ, Hopkins Sibley C, Meshnick SR, Taylor SM, Ter Kuile FOet al., 2019, Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis., Lancet Infectious Diseases, Vol: 19, Pages: 546-556, ISSN: 1473-3099

BACKGROUND: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. METHODS: For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. FINDINGS: Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and

Journal article

Slater H, Ross A, Felger I, Hofmann N, Robinson L, Cook J, Goncalves, Bjorkman, Ouedraogo, Morris, Msellem, Koepfli, Mueller, Tadesse, Gadisa, Das, Domingo, Kapulu, Midega J, Owusu-Agyei, Nabet, Piarroux, Doumbo, Doumbo, Koram, Lucchi, Udhayakumar, Mosha, Tiono, Chandramohan, Gosling, Mwingira, Sauerwein, Riley, White, Nosten, Imwong, Bousema, Drakeley, Okell Let al., 2019, The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density, Nature Communications, Vol: 10, ISSN: 2041-1723

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

Journal article

van Eijk AM, Larsen D, Kayentao K, Koshy G, Slaughter D, Roper C, Okell L, Desai M, Gutman J, Khairallah C, Rogerson S, Sibley C, Meshnick S, Taylor S, ter Kuile Fet al., Impact of Plasmodium falciparum Sulphadoxine-Pyrimethamine Resistance on the Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy in Africa: A Systematic Review and Meta-Analysis, Lancet Infectious Diseases, ISSN: 1473-3099

BackgroundPlasmodium falciparum resistance to sulphadoxine-pyrimethamine (SP) threatens the efficacy of intermittent preventive treatment (IPTp) for malaria in pregnancy in Africa. We conducted a meta-analysis to assess the impact of SP resistance on IPTp-SP effectiveness.MethodsWe searched databases (1990 to March-01-2018) for clinical studies (aggregated data) or surveys (individual-participant data) containing information on low birthweight (LBW, primary outcome) and malaria by IPTp-SP dose, and for studies reporting SP-resistance molecular markers. We performed random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarized dose-response data (Relative-Risk-Reduction:RRR) and multivariate meta-regression to explore modifying effects of SP-resistance (dhps substitutions A437G, K540E, A581G). FindingsOf 1097 records, 57 studies were included in the aggregated-data meta-analysis (59,457 births). The RRR for LBW declined with increasing prevalence of Pfdhps-K540E (P-trend=0.0060) but not with Pfdhps-A437G (P-trend=0.35). The RRR in areas of high (Pfdhps-K540E >90%, n=11), moderate (Central/West Africa:Pfdhps-A437G≥90% or East/southern Africa:Pfdhps-K540E 30-90%, n=16) and low SP-resistances (n=30) were 7% (95% CI 0-13), 21% (14-29) and 27% (21-33) respectively (P-trend=0.0054, I2=69.5%). In the individual-participant analysis of 13 surveys (42,394 births), IPTp-SP was associated with reduced LBW in areas with Pfdhps-K540E>90% & Pfdhps-A581G<10% (RRR=10%, 7-12), but not those with Pfdhps-A581G>=10% (pooled Pfdhps-A581G prevalence:37%, range 29-46) (RRR=0.5%, -16-14, n=3). InterpretationThe effectiveness of IPTp-SP is reduced in areas with high SP-resistance, but IPTp-SP remains associated with reduced LBW in areas where Pfdhps-K540E prevalence exceeds 90%. IPTp-SP is not effective in areas with ≥37% prevalence of the highly-resistant sextuple Pfdhps-A581G-containing genotype.

Journal article

Okell L, Reiter LM, Ebbe LS, Baraka V, Bisanzio D, Watson O, Bennett A, Verity R, Gething P, Roper C, Alifrangis Met al., 2018, Emerging implications of policies on malaria treatment: genetic changes in the Pfmdr-1 gene affecting susceptibility to artemether-lumefantrine and artesunate-amodiaquine in Africa, BMJ Global Health, Vol: 3, ISSN: 2059-7908

Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of −0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=−0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7–10 years after AL introduction. Observed rates of selection have implications for pla

Journal article

Tadesse FG, Slater HC, Chali W, Teelen K, Lanke K, Belachew M, Menberu T, Shumie G, Shitaye G, Okell LC, Graumans W, van Gemert G-J, Kedir S, Tesfaye A, Belachew F, Abebe W, Mamo H, Sauerwein R, Balcha T, Aseffa A, Yewhalaw D, Gadisa E, Drakeley C, Bousema Tet al., 2018, The relative contribution of symptomatic and asymptomatic Plasmodium vivax and Plasmodium falciparum infections to the infectious reservoir in a low-endemic setting in Ethiopia, Clinical Infectious Diseases, Vol: 66, Pages: 1883-1891, ISSN: 1058-4838

Background: The majority of P. vivax and P. falciparum infections in low-endemic settings are asymptomatic. The relative contribution to the infectious reservoir of these infections, often of low-parasite-density, compared to clinical malaria cases, is currently unknown but important for malaria elimination strategies. Methods: We assessed infectivity of passively-recruited symptomatic malaria patients (n=41) and community-recruited asymptomatic individuals with microscopy- (n=41) and PCR-detected infections (n=82) using membrane feeding assays with Anopheles arabiensis mosquitoes in Adama, Ethiopia. Malaria incidence and prevalence data was used to estimate the contributions of these populations to the infectious reservoir. Results: Overall, 34.9% (29/83) of P. vivax and 15.1% (8/53) P. falciparum infected individuals infected ≥1 mosquitoes. Mosquito infection rates were strongly correlated with asexual parasite density for P. vivax (ρ = 0.63; P < .001) but not for P. falciparum (ρ = 0.06; P = .770). P. vivax symptomatic infections were more infectious to mosquitoes (infecting 46.5% of mosquitoes, 307/660) compared to asymptomatic microscopy-detected (infecting 12.0% of mosquitoes, 80/667; P = .005) and PCR-detected infections (infecting 0.8% of mosquitoes, 6/744; P < .001). Adjusting for population prevalence, symptomatic, asymptomatic microscopy- and PCR-detected infections were responsible for 8.0%, 76.2% and 15.8% of the infectious reservoir for P. vivax, respectively. For P. falciparum, mosquito infections were sparser and also predominantly from asymptomatic infections. Conclusions: In this low-endemic setting aiming for malaria elimination, asymptomatic infections are highly prevalent and responsible for the majority of onward mosquito infections. The early identification and treatment of asymptomatic infections might thus accelerate elimination efforts.

Journal article

Challenger J, Bruxvoort K, Ghani AC, Okell LCet al., 2017, Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling, Nature Communications, Vol: 8, ISSN: 2041-1723

Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub-optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates data on the human immune response to the parasite, and AL’s pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers.

Journal article

Brady OJ, Slater HC, Pemberton-Ross P, Wenger E, Maude RJ, Ghani AC, Penny MA, Gerardin J, White LJ, Chitnis N, Aguas R, Hay SI, Smith DL, Stuckey EM, Okiro EA, Smith TA, Okell LCet al., 2017, Model citizen Reply, LANCET GLOBAL HEALTH, Vol: 5, Pages: E974-E974, ISSN: 2214-109X

Journal article

Bretscher MT, Griffin JT, Ghani AC, Okell LCet al., 2017, Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment, MALARIA JOURNAL, Vol: 16, ISSN: 1475-2875

BackgroundAnti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission—with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings.MethodsA mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission-blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide-prevalence in 2–10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA).ResultsTransmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10–40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long durat

Journal article

Okell L, Griffin JT, Roper C, 2017, Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa, Scientific Reports, Vol: 7, ISSN: 2045-2322

Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.

Journal article

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