Immunogenicity of an Extended Dose Interval for the Ad26.ZEBOV, MVA-BN-Filo Ebola Vaccine Regimen in Adults and Children in the Democratic Republic of the Congo.

During the 2018-2020 Ebola virus disease outbreak in Democratic Republic of the Congo, a phase 3 trial of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine (DRC-EB-001) commenced in Goma, with participants being offered the two-dose regimen given 56 days apart. Suspension of trial activities in 2020 due to the COVID-19 pandemic led to some participants receiving a late dose 2 outside the planned interval. Blood samples were collected from adults, adolescents, and children prior to their delayed dose 2 vaccination and 21 days after, and tested for IgG binding antibodies against Ebola virus glycoprotein using the Filovirus Animal Nonclinical Group (FANG) ELISA. Results from 133 participants showed a median two-dose interval of 9.3 months. The pre-dose 2 antibody geometric mean concentration (GMC) was 217 ELISA Units (EU)/mL (95% CI 157; 301) in adults, 378 EU/mL (281; 510) in adolescents, and 558 EU/mL (471; 661) in children. At 21 days post-dose 2, the GMC increased to 22,194 EU/mL (16,726; 29,449) in adults, 37,896 EU/mL (29,985; 47,893) in adolescents, and 34,652 EU/mL (27,906; 43,028) in children. Participants receiving a delayed dose 2 had a higher GMC at 21 days post-dose 2 than those who received a standard 56-day regimen in other African trials, but similar to those who received the regimen with an extended interval.

Delivery and Safety of a Two-Dose Preventive Ebola Virus Disease Vaccine in Pregnant and Non-Pregnant Participants during an Outbreak in the Democratic Republic of the Congo.

During the 2018-2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.

Effectiveness of rVSV-ZEBOV vaccination during the 2018-20 Ebola virus disease epidemic in the Democratic Republic of the Congo: a retrospective test-negative study.

BACKGROUND: The recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) vaccine is the only WHO prequalified vaccine recommended for use to respond to outbreaks of Ebola virus (species Zaire ebolavirus) by WHO's Strategic Advisory Group of Experts on Immunization. Despite the vaccine's widespread use during several outbreaks, no real-world effectiveness estimates are currently available in the literature. METHODS: We conducted a retrospective test-negative analysis to estimate effectiveness of rVSV-ZEBOV vaccination against Ebola virus disease during the 2018-20 epidemic in the Democratic Republic of the Congo, using data on suspected Ebola virus disease cases collected from Ebola treatment centres. Those eligible for inclusion had an available Ebola virus RT-PCR result, available key data, were eligible for vaccination during the outbreak, and had symptom onset aligning with the period in which a ring-vaccination protocol was in use. After imputing missing data, each individual confirmed by RT-PCR to be Ebola virus disease-positive (defined as a case) was matched to one individual negative for Ebola virus disease (control) by sex, age, health zone, and month of symptom onset. Effectiveness was estimated from the odds ratio of being vaccinated (≥10 days before symptom onset) versus being unvaccinated among cases and controls, after adjusting for the matching factors. The imputation, matching and effectiveness estimation, was repeated 500 times. FINDINGS: 1273 (4·8%) of 26 438 eligible individuals were positive for Ebola virus disease (cases) and 25 165 (95·2%) were negative (controls). 40 (3·1%) cases and 1271 (5·1%) controls were reported as being vaccinated at least 10 days before symptom onset. After selecting individuals who reported exposure to an individual with Ebola virus disease within the 21 days before symptom onset and matching, the analysis datasets comprised a median of 309 cases and 309 controls. 10 days or more after vaccination, the effectiveness of rVSV-ZEBOV against Ebola virus disease was estimated to be 84% (95% credible interval 70-92). INTERPRETATION: This analysis is the first to provide estimates of the real-world effectiveness of the rVSV-ZEBOV vaccine against Ebola virus disease, amid the widespread use of the vaccine during a large Ebola virus disease outbreak. Our findings confirm that rVSV-ZEBOV is highly protective against Ebola virus disease and support its use during outbreaks, even in challenging contexts such as in the eastern Democratic Republic of the Congo. FUNDING: Médecins Sans Frontières. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

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.

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.

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.

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.

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.

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.

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.

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.

Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.

BACKGROUND: In March, 2016, a flare-up of Ebola virus disease was reported in Guinea, and in response ring vaccination with the unlicensed rVSV-ZEBOV vaccine was introduced under expanded access, the first time that an Ebola vaccine has been used in an outbreak setting outside a clinical trial. Here we describe the safety of rVSV-ZEBOV candidate vaccine and operational feasibility of ring vaccination as a reactive strategy in a resource-limited rural setting. METHODS: Approval for expanded access and compassionate use was rapidly sought and obtained from relevant authorities. Vaccination teams and frozen vaccine were flown to the outbreak settings. Rings of contacts and contacts of contacts were defined and eligible individuals, who had given informed consent, were vaccinated and followed up for 21 days under good clinical practice conditions. FINDINGS: Between March 17 and April 21, 2016, 1510 individuals were vaccinated in four rings in Guinea, including 303 individuals aged between 6 years and 17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among the vaccinees. Adverse events following vaccination were reported in 47 (17%) 6-17 year olds (all mild) and 412 (36%) adults (individuals older than 18 years; 98% were mild). Children reported fewer arthralgia events than adults (one [<1%] of 303 children vs 81 [7%] of 1207 adults). No severe vaccine-related adverse events were reported. INTERPRETATION: The results show that a ring vaccination strategy can be rapidly and safely implemented at scale in response to Ebola virus disease outbreaks in rural settings. FUNDING: WHO, Gavi, and the World Food Programme.

Drivers for Rift Valley fever emergence in Mayotte: A Bayesian modelling approach.

Rift Valley fever (RVF) is a major zoonotic and arboviral hemorrhagic fever. The conditions leading to RVF epidemics are still unclear, and the relative role of climatic and anthropogenic factors may vary between ecosystems. Here, we estimate the most likely scenario that led to RVF emergence on the island of Mayotte, following the 2006-2007 African epidemic. We developed the first mathematical model for RVF that accounts for climate, animal imports and livestock susceptibility, which is fitted to a 12-years dataset. RVF emergence was found to be triggered by the import of infectious animals, whilst transmissibility was approximated as a linear or exponential function of vegetation density. Model forecasts indicated a very low probability of virus endemicity in 2017, and therefore of re-emergence in a closed system (i.e. without import of infected animals). However, the very high proportion of naive animals reached in 2016 implies that the island remains vulnerable to the import of infectious animals. We recommend reinforcing surveillance in livestock, should RVF be reported is neighbouring territories. Our model should be tested elsewhere, with ecosystem-specific data.

The impact of control strategies and behavioural changes on the elimination of Ebola from Lofa County, Liberia.

The Ebola epidemic in West Africa was stopped by an enormous concerted effort of local communities and national and international organizations. It is not clear, however, how much the public health response and behavioural changes in affected communities, respectively, contributed to ending the outbreak. Here, we analyse the epidemic in Lofa County, Liberia, lasting from March to November 2014, by reporting a comprehensive time line of events and estimating the time-varying transmission intensity using a mathematical model of Ebola transmission. Model fits to the epidemic show an alternation of peaks and troughs in transmission, consistent with highly heterogeneous spread. This is combined with an overall decline in the reproduction number of Ebola transmission from early August, coinciding with an expansion of the local Ebola treatment centre. We estimate that healthcare seeking approximately doubled over the course of the outbreak, and that isolation of those seeking healthcare reduced their reproduction number by 62% (mean estimate, 95% credible interval (CI) 59-66). Both expansion of bed availability and improved healthcare seeking contributed to ending the epidemic, highlighting the importance of community engagement alongside clinical intervention.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.

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.

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).

Comparative Analysis of Dengue and Zika Outbreaks Reveals Differences by Setting and Virus.

The pacific islands of Micronesia have experienced several outbreaks of mosquito-borne diseases over the past decade. In outbreaks on small islands, the susceptible population is usually well defined, and there is no co-circulation of pathogens. Because of this, analysing such outbreaks can be useful for understanding the transmission dynamics of the pathogens involved, and particularly so for yet understudied pathogens such as Zika virus. Here, we compared three outbreaks of dengue and Zika virus in two different island settings in Micronesia, the Yap Main Islands and Fais, using a mathematical model of transmission dynamics and making full use of commonalities in disease and setting between the outbreaks. We found that the estimated reproduction numbers for Zika and dengue were similar when considered in the same setting, but that, conversely, reproduction number for the same disease can vary considerably by setting. On the Yap Main Islands, we estimated a reproduction number of 8.0-16 (95% Credible Interval (CI)) for the dengue outbreak and 4.8-14 (95% CI) for the Zika outbreak, whereas for the dengue outbreak on Fais our estimate was 28-102 (95% CI). We further found that the proportion of cases of Zika reported was smaller (95% CI 1.4%-1.9%) than that of dengue (95% CI: 47%-61%). We confirmed these results in extensive sensitivity analysis. They suggest that models for dengue transmission can be useful for estimating the predicted dynamics of Zika transmission, but care must be taken when extrapolating findings from one setting to another.