Estimation of Rift Valley fever virus spillover to humans during the Mayotte 2018-2019 epidemic.

Rift Valley fever (RVF) is an emerging, zoonotic, arboviral hemorrhagic fever threatening livestock and humans mainly in Africa. RVF is of global concern, having expanded its geographical range over the last decades. The impact of control measures on epidemic dynamics using empirical data has not been assessed. Here, we fitted a mathematical model to seroprevalence livestock and human RVF case data from the 2018-2019 epidemic in Mayotte to estimate viral transmission among livestock, and spillover from livestock to humans through both direct contact and vector-mediated routes. Model simulations were used to assess the impact of vaccination on reducing the epidemic size. The rate of spillover by direct contact was about twice as high as vector transmission. Assuming 30% of the population were farmers, each transmission route contributed to 45% and 55% of the number of human infections, respectively. Reactive vaccination immunizing 20% of the livestock population reduced the number of human cases by 30%. Vaccinating 1 mo later required using 50% more vaccine doses for a similar reduction. Vaccinating only farmers required 10 times as more vaccine doses for a similar reduction in human cases. Finally, with 52.0% (95% credible interval [CrI] [42.9-59.4]) of livestock immune at the end of the epidemic wave, viral reemergence in the next rainy season (2019-2020) is unlikely. Coordinated human and animal health surveillance, and timely livestock vaccination appear to be key to controlling RVF in this setting. We furthermore demonstrate the value of a One Health quantitative approach to surveillance and control of zoonotic infectious diseases.

A dynamic model of transmission and elimination of peste des petits ruminants in Ethiopia.

Peste des petits ruminants (PPR), a devastating viral disease of sheep and goats, has been targeted by the global community for eradication within the next 15 years. Although an efficacious attenuated live vaccine is available, the lack of knowledge about the transmission potential of PPR virus (PPRV) may compromise eradication efforts. By fitting a metapopulation model simulating PPRV spread to the results of a nationwide serological survey in Ethiopia, we estimated the level of viral transmission in an endemic setting and the vaccination coverage required for elimination. Results suggest that the pastoral production system as a whole acts as a viral reservoir, from which PPRV spills over into the sedentary production system, where viral persistence is uncertain. Estimated levels of PPRV transmission indicate that viral spread could be prevented if the proportion of immune small ruminants is kept permanently above 37% in at least 71% of pastoral village populations. However, due to the high turnover of these populations, maintaining the fraction of immune animals above this threshold would require high vaccine coverage within villages, and vaccination campaigns to be conducted annually. Adapting vaccination strategies to the specific characteristics of the local epidemiological context and small ruminant population dynamics would result in optimized allocation of limited resources and increase the likelihood of PPR eradication.

Assessing the performance of real-time epidemic forecasts: A case study of Ebola in the Western Area region of Sierra Leone, 2014-15.

Real-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles different components of forecasting ability using metrics that separately assess the calibration, sharpness and bias of forecasts. This makes it possible to assess not just how close a forecast was to reality but also how well uncertainty has been quantified. We used this approach to analyse the performance of weekly forecasts we generated in real time for Western Area, Sierra Leone, during the 2013-16 Ebola epidemic in West Africa. We investigated a range of forecast model variants based on the model fits generated at the time with a semi-mechanistic model, and found that good probabilistic calibration was achievable at short time horizons of one or two weeks ahead but model predictions were increasingly unreliable at longer forecasting horizons. This suggests that forecasts may have been of good enough quality to inform decision making based on predictions a few weeks ahead of time but not longer, reflecting the high level of uncertainty in the processes driving the trajectory of the epidemic. Comparing forecasts based on the semi-mechanistic model to simpler null models showed that the best semi-mechanistic model variant performed better than the null models with respect to probabilistic calibration, and that this would have been identified from the earliest stages of the outbreak. As forecasts become a routine part of the toolkit in public health, standards for evaluation of performance will be important for assessing quality and improving credibility of mathematical models, and for elucidating difficulties and trade-offs when aiming to make the most useful and reliable forecasts.

Near real-time forecasting for cholera decision making in Haiti after Hurricane Matthew.

Computational models of cholera transmission can provide objective insights into the course of an ongoing epidemic and aid decision making on allocation of health care resources. However, models are typically designed, calibrated and interpreted post-hoc. Here, we report the efforts of a team from academia, field research and humanitarian organizations to model in near real-time the Haitian cholera outbreak after Hurricane Matthew in October 2016, to assess risk and to quantitatively estimate the efficacy of a then ongoing vaccination campaign. A rainfall-driven, spatially-explicit meta-community model of cholera transmission was coupled to a data assimilation scheme for computing short-term projections of the epidemic in near real-time. The model was used to forecast cholera incidence for the months after the passage of the hurricane (October-December 2016) and to predict the impact of a planned oral cholera vaccination campaign. Our first projection, from October 29 to December 31, predicted the highest incidence in the departments of Grande Anse and Sud, accounting for about 45% of the total cases in Haiti. The projection included a second peak in cholera incidence in early December largely driven by heavy rainfall forecasts, confirming the urgency for rapid intervention. A second projection (from November 12 to December 31) used updated rainfall forecasts to estimate that 835 cases would be averted by vaccinations in Grande Anse (90% Prediction Interval [PI] 476-1284) and 995 in Sud (90% PI 508-2043). The experience gained by this modeling effort shows that state-of-the-art computational modeling and data-assimilation methods can produce informative near real-time projections of cholera incidence. Collaboration among modelers and field epidemiologists is indispensable to gain fast access to field data and to translate model results into operational recommendations for emergency management during an outbreak. Future efforts should thus draw together multi-disciplinary teams to ensure model outputs are appropriately based, interpreted and communicated.

Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).

BACKGROUND: rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. METHODS: We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6-17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS: In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9-100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3-100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae. INTERPRETATION: The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. FUNDING: WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).

Measuring the impact of Ebola control measures in Sierra Leone.

Between September 2014 and February 2015, the number of Ebola virus disease (EVD) cases reported in Sierra Leone declined in many districts. During this period, a major international response was put in place, with thousands of treatment beds introduced alongside other infection control measures. However, assessing the impact of the response is challenging, as several factors could have influenced the decline in infections, including behavior changes and other community interventions. We developed a mathematical model of EVD transmission, and measured how transmission changed over time in the 12 districts of Sierra Leone with sustained transmission between June 2014 and February 2015. We used the model to estimate how many cases were averted as a result of the introduction of additional treatment beds in each area. Examining epidemic dynamics at the district level, we estimated that 56,600 (95% credible interval: 48,300-84,500) Ebola cases (both reported and unreported) were averted in Sierra Leone up to February 2, 2015 as a direct result of additional treatment beds being introduced. We also found that if beds had been introduced 1 month earlier, a further 12,500 cases could have been averted. Our results suggest the unprecedented local and international response led to a substantial decline in EVD transmission during 2014-2015. In particular, the introduction of beds had a direct impact on reducing EVD cases in Sierra Leone, although the effect varied considerably between districts.

Effectiveness of Ring Vaccination as Control Strategy for Ebola Virus Disease.

Using an Ebola virus disease transmission model, we found that addition of ring vaccination at the outset of the West Africa epidemic might not have led to containment of this disease. However, in later stages of the epidemic or in outbreaks with less intense transmission or more effective control, this strategy could help eliminate the disease.

Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.

BACKGROUND: A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. METHODS: For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. FINDINGS: Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. INTERPRETATION: The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. FUNDING: WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development.

Evaluation of the benefits and risks of introducing Ebola community care centers, Sierra Leone.

In some parts of western Africa, Ebola treatment centers (ETCs) have reached capacity. Unless capacity is rapidly scaled up, the chance to avoid a generalized Ebola epidemic will soon diminish. The World Health Organization and partners are considering additional Ebola patient care options, including community care centers (CCCs), small, lightly staffed units that could be used to isolate patients outside the home and get them into care sooner than otherwise possible. Using a transmission model, we evaluated the benefits and risks of introducing CCCs into Sierra Leone's Western Area, where most ETCs are at capacity. We found that use of CCCs could lead to a decline in cases, even if virus transmission occurs between CCC patients and the community. However, to prevent CCC amplification of the epidemic, the risk of Ebola virus-negative persons being exposed to virus within CCCs would have to be offset by a reduction in community transmission resulting from CCC use.

Extending the elderly- and risk-group programme of vaccination against seasonal influenza in England and Wales: a cost-effectiveness study.

BACKGROUND: The present study aims to evaluate the cost-effectiveness of extending the pre-2013 influenza immunisation programme for high-risk and elderly individuals to those at low risk of developing complications following infection with seasonal influenza. METHODS: We performed an economic evaluation comparing different extensions of the pre-2013 influenza programme to seven possible age groups of low-risk individuals (aged 2-4 years, 50-64 years, 5-16 years, 2-4 and 50-64 years, 2-16 years, 2-16 and 50-64 years, and 2-64 years). These extensions are evaluated incrementally on four base scenarios (no vaccination, risk group only with coverage as observed between 1995 and 2009, risk group and 65+, and risk group with 75% coverage and 65+). Impact of vaccination is assessed using a transmission model built and parameterised from a previously published study. The study population is all individuals of all ages in England and Wales representing an average total of 52.6 million people over 14 influenza seasons (1995-2009). RESULTS: The influenza programme (risk group and elderly) prior to 2013 is likely to be cost effective (incremental cost effectiveness ratio: 7,475 £/QALY, net benefit: 253 M£ [15-829]). Extension to any one of the low-risk target groups defined earlier is likely to be cost-effective. However, strategies that do not include vaccination of school-aged children are less likely to be cost-effective. The most efficient strategy is extension to the 5-16 year age group while universal vaccination (extension to all low-risk individuals over 2 years) will achieve the highest net benefit. While extension to the 2-16 year age group is likely to be very cost effective, the cost-effectiveness of extensions beyond 2-16 years is very uncertain. Extension to the 5-16 year age group would likely remain cost-effective even without herd immunity effects to other age groups. As our study includes a strong historical component, our results depend on the efficacy of the influenza vaccine remaining at levels similar to the ones achieved in the past over a long-period of time (assumed to vary between 28% and 70% depending of the circulating strains and age groups). CONCLUSIONS: Making use of surveillance data from over a decade in conjunction with a dynamic model, we find that vaccination of children in the United Kingdom is likely to be highly cost-effective, not only for their own benefit but also to reduce the disease burden in the rest of the community.

Duration of Ebola virus RNA persistence in semen of survivors: population-level estimates and projections.

Ebola virus can persist in semen after recovery, potentially for months, which may impact the duration of enhanced surveillance required after interruption of transmission. We combined recent data on viral RNA persistence with weekly disease incidence to estimate the current number of semen-positive men in affected West African countries. We find the number is low, and since few reported sexual transmission events have occurred, the future risk is also likely low, although sexual health promotion remains critical.

Assessing optimal target populations for influenza vaccination programmes: an evidence synthesis and modelling study.

BACKGROUND: Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality. METHODS AND FINDINGS: Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34-0.45) infections per dose of vaccine and 1.74 (1.16-3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5-16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52-0.81) infections per dose and 1.95 (1.28-3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50-64-y-olds) would prevent only 0.43 (0.35-0.52) infections per dose and 1.77 (1.15-3.14) deaths per 1,000 doses. CONCLUSIONS: This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults. Please see later in the article for the Editors' Summary.

A prospective, multi-site, cohort study to estimate incidence of infection and disease due to Lassa fever virus in West African countries (the Enable Lassa research programme)-Study protocol.

BACKGROUND: Lassa fever (LF), a haemorrhagic illness caused by the Lassa fever virus (LASV), is endemic in West Africa and causes 5000 fatalities every year. The true prevalence and incidence rates of LF are unknown as infections are often asymptomatic, clinical presentations are varied, and surveillance systems are not robust. The aim of the Enable Lassa research programme is to estimate the incidences of LASV infection and LF disease in five West African countries. The core protocol described here harmonises key study components, such as eligibility criteria, case definitions, outcome measures, and laboratory tests, which will maximise the comparability of data for between-country analyses. METHOD: We are conducting a prospective cohort study in Benin, Guinea, Liberia, Nigeria (three sites), and Sierra Leone from 2020 to 2023, with 24 months of follow-up. Each site will assess the incidence of LASV infection, LF disease, or both. When both incidences are assessed the LASV cohort (nmin = 1000 per site) will be drawn from the LF cohort (nmin = 5000 per site). During recruitment participants will complete questionnaires on household composition, socioeconomic status, demographic characteristics, and LF history, and blood samples will be collected to determine IgG LASV serostatus. LF disease cohort participants will be contacted biweekly to identify acute febrile cases, from whom blood samples will be drawn to test for active LASV infection using RT-PCR. Symptom and treatment data will be abstracted from medical records of LF cases. LF survivors will be followed up after four months to assess sequelae, specifically sensorineural hearing loss. LASV infection cohort participants will be asked for a blood sample every six months to assess LASV serostatus (IgG and IgM). DISCUSSION: Data on LASV infection and LF disease incidence in West Africa from this research programme will determine the feasibility of future Phase IIb or III clinical trials for LF vaccine candidates.

Protocol for a phase 3 trial to evaluate the effectiveness and safety of a heterologous, two-dose vaccine for Ebola virus disease in the Democratic Republic of the Congo.

INTRODUCTION: Ebola virus disease (EVD) continues to be a significant public health problem in sub-Saharan Africa, especially in the Democratic Republic of the Congo (DRC). Large-scale vaccination during outbreaks may reduce virus transmission. We established a large population-based clinical trial of a heterologous, two-dose prophylactic vaccine during an outbreak in eastern DRC to determine vaccine effectiveness. METHODS AND ANALYSIS: This open-label, non-randomised, population-based trial enrolled eligible adults and children aged 1 year and above. Participants were offered the two-dose candidate EVD vaccine regimen VAC52150 (Ad26.ZEBOV, Modified Vaccinia Ankara (MVA)-BN-Filo), with the doses being given 56 days apart. After vaccination, serious adverse events (SAEs) were passively recorded until 1 month post dose 2. 1000 safety subset participants were telephoned at 1 month post dose 2 to collect SAEs. 500 pregnancy subset participants were contacted to collect SAEs at D7 and D21 post dose 1 and at D7, 1 month, 3 months and 6 months post dose 2, unless delivery was before these time points. The first 100 infants born to these women were given a clinical examination 3 months post delivery. Due to COVID-19 and temporary suspension of dose 2 vaccinations, at least 50 paediatric and 50 adult participants were enrolled into an immunogenicity subset to examine immune responses following a delayed second dose. Samples collected predose 2 and at 21 days post dose 2 will be tested using the Ebola viruses glycoprotein Filovirus Animal Non-Clinical Group ELISA. For qualitative research, in-depth interviews and focus group discussions were being conducted with participants or parents/care providers of paediatric participants. ETHICS AND DISSEMINATION: Approved by Comité National d'Ethique et de la Santé du Ministère de la santé de RDC, Comité d'Ethique de l'Ecole de Santé Publique de l'Université de Kinshasa, the LSHTM Ethics Committee and the MSF Ethics Review Board. Findings will be presented to stakeholders and conferences. Study data will be made available for open access. TRIAL REGISTRATION NUMBER: NCT04152486.

Explaining rapid reinfections in multiple-wave influenza outbreaks: Tristan da Cunha 1971 epidemic as a case study.

Influenza usually spreads through the human population in multiple-wave outbreaks. Successive reinfection of individuals over a short time interval has been explicitly reported during past pandemics. However, the causes of rapid reinfection and the role of reinfection in driving multiple-wave outbreaks remain poorly understood. To investigate these issues, we focus on a two-wave influenza A/H3N2 epidemic that occurred on the remote island of Tristan da Cunha in 1971. Over 59 days, 273 (96%) of 284 islanders experienced at least one attack and 92 (32%) experienced two attacks. We formulate six mathematical models invoking a variety of antigenic and immunological reinfection mechanisms. Using a maximum-likelihood analysis to confront model predictions with the reported incidence time series, we demonstrate that only two mechanisms can be retained: some hosts with either a delayed or deficient humoral immune response to the primary influenza infection were reinfected by the same strain, thus initiating the second epidemic wave. Both mechanisms are supported by previous empirical studies and may arise from a combination of genetic and ecological causes. We advocate that a better understanding and account of heterogeneity in the human immune response are essential to analysis of multiple-wave influenza outbreaks and pandemic planning.

Control of Ebola virus disease outbreaks: Comparison of health care worker-targeted and community vaccination strategies.

BACKGROUND: Health care workers (HCW) are at risk of infection during Ebola virus disease outbreaks and therefore may be targeted for vaccination before or during outbreaks. The effect of these strategies depends on the role of HCW in transmission which is understudied. METHODS: To evaluate the effect of HCW-targeted or community vaccination strategies, we used a transmission model to explore the relative contribution of HCW and the community to transmission. We calibrated the model to data from multiple Ebola outbreaks. We quantified the impact of ahead-of-time HCW-targeted strategies, and reactive HCW and community vaccination. RESULTS: We found that for some outbreaks (we call "type 1″) HCW amplified transmission both to other HCW and the community, and in these outbreaks prophylactic vaccination of HCW decreased outbreak size. Reactive vaccination strategies had little effect because type 1 outbreaks ended quickly. However, in outbreaks with longer time courses ("type 2 outbreaks"), reactive community vaccination decreased the number of cases, with or without prophylactic HCW-targeted vaccination. For both outbreak types, we found that ahead-of-time HCW-targeted strategies had an impact at coverage of 30%. CONCLUSIONS: The vaccine strategies tested had a different impact depending on the transmission dynamics and previous control measures. Although we will not know the characteristics of a new outbreak, ahead-of-time HCW-targeted vaccination can decrease the total outbreak size, even at low vaccine coverage.

Real-time forecasting of infectious disease dynamics with a stochastic semi-mechanistic model.

Real-time forecasts of infectious diseases can help public health planning, especially during outbreaks. If forecasts are generated from mechanistic models, they can be further used to target resources or to compare the impact of possible interventions. However, paremeterising such models is often difficult in real time, when information on behavioural changes, interventions and routes of transmission are not readily available. Here, we present a semi-mechanistic model of infectious disease dynamics that was used in real time during the 2013-2016 West African Ebola epidemic, and show fits to a Ebola Forecasting Challenge conducted in late 2015 with simulated data mimicking the true epidemic. We assess the performance of the model in different situations and identify strengths and shortcomings of our approach. Models such as the one presented here which combine the power of mechanistic models with the flexibility to include uncertainty about the precise outbreak dynamics may be an important tool in combating future outbreaks.

Cholera epidemic in Yemen, 2016-18: an analysis of surveillance data.

BACKGROUND: In war-torn Yemen, reports of confirmed cholera started in late September, 2016. The disease continues to plague Yemen today in what has become the largest documented cholera epidemic of modern times. We aimed to describe the key epidemiological features of this epidemic, including the drivers of cholera transmission during the outbreak. METHODS: The Yemen Health Authorities set up a national cholera surveillance system to collect information on suspected cholera cases presenting at health facilities. Individual variables included symptom onset date, age, severity of dehydration, and rapid diagnostic test result. Suspected cholera cases were confirmed by culture, and a subset of samples had additional phenotypic and genotypic analysis. We first conducted descriptive analyses at national and governorate levels. We divided the epidemic into three time periods: the first wave (Sept 28, 2016, to April 23, 2017), the increasing phase of the second wave (April 24, 2017, to July 2, 2017), and the decreasing phase of the second wave (July 3, 2017, to March 12, 2018). We reconstructed the changes in cholera transmission over time by estimating the instantaneous reproduction number, Rt. Finally, we estimated the association between rainfall and the daily cholera incidence during the increasing phase of the second epidemic wave by fitting a spatiotemporal regression model. FINDINGS: From Sept 28, 2016, to March 12, 2018, 1 103 683 suspected cholera cases (attack rate 3·69%) and 2385 deaths (case fatality risk 0·22%) were reported countrywide. The epidemic consisted of two distinct waves with a surge in transmission in May, 2017, corresponding to a median Rt of more than 2 in 13 of 23 governorates. Microbiological analyses suggested that the same Vibrio cholerae O1 Ogawa strain circulated in both waves. We found a positive, non-linear, association between weekly rainfall and suspected cholera incidence in the following 10 days; the relative risk of cholera after a weekly rainfall of 25 mm was 1·42 (95% CI 1·31-1·55) compared with a week without rain. INTERPRETATION: Our analysis suggests that the small first cholera epidemic wave seeded cholera across Yemen during the dry season. When the rains returned in April, 2017, they triggered widespread cholera transmission that led to the large second wave. These results suggest that cholera could resurge during the ongoing 2018 rainy season if transmission remains active. Therefore, health authorities and partners should immediately enhance current control efforts to mitigate the risk of a new cholera epidemic wave in Yemen. FUNDING: Health Authorities of Yemen, WHO, and Médecins Sans Frontières.

Aedes aegypti Control Through Modernized, Integrated Vector Management.

INTRODUCTION: In the context of the ongoing, unprecedented Zika virus outbreak in the Americas, the World Health Organization has expressed its support for developing and up-scaling three novel approaches to controlling the Aedes aegypti mosquito: the Sterile Insect Technique (SIT), the Release of Insects carrying Dominant Lethal genes (RIDL) and the release of Wolbachia-infected mosquitoes. Whereas the former two approaches are temporary insect population suppression strategies, Wolbachia infection is a self-sustaining, invasive strategy that uses inherited endosymbiotic bacteria to render natural mosquito populations arbovirus resistant. METHODS: A mathematical model is parameterised with new, Brazilian field data informing the mating competitiveness of mass-reared, released insects; and simulations compare and contrast projections of vector control achieved with the alternative approaches. RESULTS: Important disadvantages of Wolbachia and SIT are identified: both strategies result in mosquitoes ovipositing non-viable eggs and, by alleviating intense larval competition, can cause an overall increase in survival to the adult stage. However, it is demonstrated that strategically combining the suppression methods with Wolbachia can generate a sustained control while mitigating the risks of inadvertent exacerbation of the wild mosquito population. DISCUSSION: This initial analysis demonstrates potential for good synergy when combining novel mosquito approaches in a modernized, integrated vector control programme.