Vaccines For Ebola Virus Disease Research Articles

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.

The economic burden of Ebola virus disease: a review and recommendations for analysis

Background Ebola virus disease (EVD) continues to be a major public health threat globally, particularly in the low-and-middle-income countries (LMICs) of Africa. The social and economic burdens of EVD are substantial and have triggered extensive research into prevention and control. We aim to highlight the impact and economic implications, identify research gaps, and offer recommendations for future economic studies pertaining to EVD. Method We conducted a comprehensive librarian-led search in PubMed/Medline, Embase, Google Scholar, EconLit and Scopus for economic evaluations of EVD. After study selection and data extraction, findings on the impact and economics of EVD were synthesized using a narrative approach, while identifying gaps, and recommending critical areas for future EVD economic studies. Results The economic evaluations focused on the burden of illness, vaccine cost-effectiveness, willingness-to-pay for a vaccine, EVD funding, and preparedness costs. The estimated economic impact of the 2014 EVD outbreak in Guinea, Liberia, and Sierra Leone across studies ranged from $30 billion to $50 billion. Facility construction and modification emerged as significant cost drivers for preparedness. The EVD vaccine demonstrated cost-effectiveness in a dynamic transmission model; resulting in an incremental cost-effectiveness ratio of about $96 per additional disability adjusted life year averted. Individuals exhibited greater willingness to be vaccinated if it incurred no personal cost, with a minority willing to pay about $1 for the vaccine. Conclusions The severe impact of EVD puts pressure on governments and the international community for better resource utilization and re-allocation. Several technical and methodological issues related to economic evaluation of EVD remain to be addressed, especially for LMICs. We recommend conducting cost-of-sequelae and cost-of-distribution analyses in addition to adapting existing economic analytical methods to EVD. Characteristics of the affected regions should be considered to provide evidence-based economic plans and economic-evaluation of mitigations that enhance resource allocation for prevention and treatment.

Perspectives on Advancing Countermeasures for Filovirus Disease: Report From a Multisector Meeting.

Although there are now approved treatments and vaccines for Ebola virus disease, the case fatality rate remains unacceptably high even when patients are treated with the newly approved therapeutics. Furthermore, these countermeasures are not expected to be effective against disease caused by other filoviruses. A meeting of subject-matter experts was held during the 10th International Filovirus Symposium to discuss strategies to address these gaps. Several investigational therapeutics, vaccine candidates, and combination strategies were presented. The greatest challenge was identified to be the implementation of well-designed clinical trials of safety and efficacy during filovirus disease outbreaks. Preparing for this will require agreed-upon common protocols for trials intended to bridge multiple outbreaks across all at-risk countries. A multinational research consortium including at-risk countries would be an ideal mechanism to negotiate agreement on protocol design and coordinate preparation. Discussion participants recommended a follow-up meeting be held in Africa to establish such a consortium.

Perceptions and Rumors About the Ebola Virus Disease Vaccine in the Ituri and Kivu Provinces of the Democratic Republic of Congo.

Perceptions and rumors about vaccinations can contribute to vaccine hesitancy. This study aimed to examine perceptions and rumors about the Ebola vaccine during the 10th Ebola Virus Disease outbreak in the Ituri and North Kivu provinces of the Democratic Republic of Congo. Eight hundred randomly selected respondents were surveyed with a uniform structured questionnaire. Further, we collected qualitative data through focus group discussions and using in-depth interview guides. Results revealed several misperceptions and rumors about the vaccine, which led to some level of vaccine hesitancy and refusal among the people. The acceptance rate of the vaccine was 67.3% (below the 80% threshold needed to create herd immunity in the population). More of the urban population (31.3%) than the rural population (10.4%) accepted the vaccine. Refusals were largely due to fear that the vaccine could activate other diseases in the body and could even kill. Some feared that it was a conspiracy of the government to reduce the population in the study area through forced fertility control and death, among other such concerns. In conclusion, these rumors increased mistrust, which challenged the efforts of the government and its partners to safeguard the health of the people.

A Bivalent Bacterium-like Particles-Based Vaccine Induced Potent Immune Responses against the Sudan Virus and Ebola Virus in Mice

Ebola virus disease (EVD) is an acute viral hemorrhagic fever disease causing thousands of deaths. The large Ebola outbreak in 2014–2016 posed significant threats to global public health, requiring the development of multiple medical measures for disease control. Sudan virus (SUDV) and Zaire virus (EBOV) are responsible for severe disease and occasional deadly outbreaks in West Africa and Middle Africa. This study shows that bivalent bacterium-like particles (BLPs)-based vaccine, SUDV-EBOV BLPs (S/ZBLP + 2 + P), generated by mixing SUDV-BLPs and EBOV-BLPs at a 1 : 1 ratio, is immunogenic in mice. The SUDV-EBOV BLPs induced potent immune responses against SUDV and EBOV and elicited both T-helper 1 (Th1) and T-helper 2 (Th2) immune responses. The results indicated that SUDV-EBOV BLPs-based vaccine has the potential to be a promising candidate against SUDV and EBOV infections and provide a strategy to develop universal vaccines for EVD.

Protection, health seeking, or a laissez-passer: Participants’ decision-making in an EVD vaccine trial in the eastern Democratic Republic of the Congo

During the 10th Ebola virus disease (EVD) epidemic in the eastern Democratic Republic of the Congo (DRC) (2018–2020), two experimental EVD vaccines were deployed in North Kivu. This province has been at the centre of conflict in the region for the last 25 years. Amidst ambivalence towards protracted foreign intervention and controversy about introducing two experimental vaccines, the existing literature has focused on mistrust and ‘resistance’ towards the Ebola response and vaccines. In this article, we examine why people in the eastern DRC did decide to volunteer for a trial of a second EVD vaccine in North Kivu, despite the controversy. Drawing on ethnographic observation, interviews, and focus groups with trial participants conducted between September 2020 and April 2021, we analyse three motivations for participating: protection, health seeking, and expectations surrounding travel requirements. We make three points. First, participation in vaccine trials may be understood locally to have advantages which have not been considered by the trial, because they go beyond medical considerations and are specific to a particular social setting. Second, despite much of the literature focusing on a causal relationship between rumours and ‘vaccine hesitancy’, some rumours may in fact encourage participation. Third, material objects associated with trial participation - such as participant vaccine cards - can hold social and political meaning beyond the confines of the vaccine clinic, and influence decisions surrounding participation. Empirical investigation of how medical interventions become entangled in political economies is essential to understanding the perceived functions of participation, and thus the reasons why people volunteer in clinical trials. Participants' narratives about their decision-making provide an insight into how international bioethical debates interact with, but may also stand apart from, the situated social and economic realities driving decision-making around clinical trials on the ground. This highlights the need for ethical approaches that foreground the political, social, and economic context.

Economic evaluation using dynamic transition modeling of ebola virus vaccination in lower-and-middle-income countries

Background With the increasing occurrence of infectious diseases in lower-and-middle-income countries (LMICs), emergency preparedness is essential for rapid response and mitigation. Economic evaluations of mitigation technologies and strategies have been recommended for inclusion in emergency preparedness plans. We aimed to perform an economic evaluation using dynamic transition modeling of ebola virus disease (EVD) vaccination in a hypothetical community of 1,000 persons in the Democratic Republic of Congo (DRC). Method Using a modified SEIR (Susceptible, Exposed, Infectious, Recovered, with Death added [SEIR-D]) model that accounted for death and epidemiological data from an EVD outbreak in the DRC, we modeled the transmission of EVD in a hypothetical population of 1,000. With our model, we estimated the cost-effectiveness of an EVD vaccine and an EVD vaccination intervention. Results The results showed vaccinating 50% of the population at risk prevented 670 cases, 538 deaths, and 22,022 disability-adjusted life years (DALYs). The vaccine was found to be cost-effective with an incremental cost-effectiveness ratio (ICER) of $95.63 per DALY averted. We also determined the minimum required vaccination coverage for cost-effectiveness to be 40%. Sensitivity analysis showed our model to be fairly robust, assuring relatively consistent results even with variations in such input parameters as cost of screening, as well as transmission, infection, incubation, and case fatality rates. Conclusion EVD vaccination in our hypothetical population was found to be cost-effective from the payer perspective. Our model presents an efficient and reliable approach for conducting economic evaluations of infectious disease interventions as part of an emergency preparedness plan.

Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

IntroductionThe Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments.MethodsThis is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection.ResultsFrom April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those < 18 years of age included 549 (12%) aged 1 to 4 years, 750 (16%) 5 to 11 years, and 930 (19%) aged 12–17 years. At baseline, the median (25th, 75th percentile) antibody titer to Ebola virus glycoprotein for 1090 participants was 72 (50, 116) EU/mL.DiscussionThe PREVAC trial is evaluating—placebo-controlled—two promising Ebola candidate vaccines in advanced stages of development. The results will address unanswered questions related to short- and long-term safety and immunogenicity for three vaccine strategies in adults and children.Trial registrationClinicalTrials.gov NCT02876328. Registered on 23 August 2016.

One-step single-tube accelerated quantitative nucleoprotein gene-specific reverse transcription loop-mediated isothermal gene amplification (RT-LAMP) assay for rapid, real-time & reliable clinical detection of Ebola virus.

Background & objectives:Due to the absence of specific drugs or vaccines for Ebola virus disease, rapid, sensitive and reliable diagnostic methods are required to control the transmission chain of the disease and for better patient management. Isothermal amplification of nucleic acids has emerged as a promising alternative in which rapid and efficient amplification is achieved at a constant temperature without the thermal cycling required in PCR.Methods:A one-step single-tube accelerated quantitative reverse trascription loop-mediated isothermal amplification (RT-LAMP) assay was developed by targeting the NP gene of 2014 Zaire Ebola virus (ZEBOV). The RT-LAMP assay was found to be specific for ZEBOV, without having any cross-reactivity with related haemorrhagic fever viral agents.Results:The comparative evaluation of Ebola virus NP gene-specific RT-LAMP assay with reverse transcription (RT) - PCR and TaqMan real-time RT-PCR demonstrated that RT-LAMP was 10-1000 folds more sensitive than TaqMan real-time RT-PCR and conventional RT-PCR, respectively, with a detection limit of 1 copy number. In the absence of real-world clinical samples, the feasibility of Ebola virus RT-LAMP assay for clinical diagnosis was evaluated with different body fluids including serum, urine, saliva, semen and stool samples from healthy human volunteers spiked with gamma-irradiated ZEBOV 2014 obtained from Robert Koch Institute, Berlin, Germany, through the European Network for Diagnostics of Imported Viral Diseases. The Ebola virus RT-LAMP assay could correctly be picked up the spiked samples up to 1 copy of viral RNA without having any matrix interference. The monitoring of gene amplification can also be visualized with the naked eye by using SYBR Green I fluorescent dye.Interpretation & conclusions:Thus, due to easy operation without a requirement of sophisticated equipment and skilled personnel, the RT-LAMP assay reported here is a valuable tool as a point-of-care diagnosis for the rapid and real-time detection of Ebola virus in resource-limited healthcare settings of developing countries.

Safety and immunogenicity of vesicular stomatitis virus-based vaccines for Ebola virus disease

Safety and immunogenicity of vesicular stomatitis virus-based vaccines for Ebola virus disease

Modeling the Impact of Vaccine Delivery on the 2018-2019 North Kivu &amp; Ituri Ebola Outbreak

Background: The reemergence of Ebola in the Democratic Republic of Congo (DRC) has developed into the largest and most challenging Ebola Virus Disease (EVD) outbreak in the country's history. Violence has hindered response efforts, including the administration of the investigational EVD vaccine, rVSV-ZEBOV. During a crisis of this magnitude, decision-makers often look to predictive models to inform operational strategy. Methods: We used an agent-based model to forecast the additional EVD case burden in North Kivu & Ituri health zones, by the end of July 2019, at different levels of vaccine administration and contact-finding. Our model incorporated countermeasure strategies like social distancing, school closure, hospital isolation, and ring vaccination, while varying rates of contact-finding and vaccine administration to generate case incidence estimates. Findings: Our model estimated that if the response continues as-is, approximately 1,039 additional cases will occur between May 20th and July 31st, for a cumulative total of 2,688 EVD cases by the end of July. If vaccine administration were discontinued, we estimated a 13.4% higher incidence of EVD cases by the end of July. Increased contact-finding and vaccination administration resulted in 10.3% fewer additional EVD cases. Interpretation: Near real-time forecasting can generate potential outbreak trajectories dependent on the magnitude and success of public health response efforts. Although the ongoing vaccination campaign has reduced the overall number of EVD cases that would be expected in the ongoing outbreak, simultaneous delivery of other countermeasures at high rates is necessary to bring the outbreak to a close. While our projections should be interpreted cautiously due to evolving outbreak dynamics, the estimated magnitude can be used to inform public health response planning for the international community. Funding Statement: This study was funded by the Defense Threat Reduction Agency's (DTRA) Technical Reachback contract, (HDTRA1-09-D-0009-0003) and the contract to Virginia Polytechnic Institute and State University (HDTRA1-17-D-0023-0001). Declaration of Interests: All authors declare they have nothing to disclose.

Role of Antibodies in Protection Against Ebola Virus in Nonhuman Primates Immunized With Three Vaccine Platforms.

Several vaccine platforms have been successfully evaluated for prevention of Ebola virus (EBOV) disease (EVD) in nonhuman primates and humans. Despite remarkable efficacy by multiple vaccines, the immunological correlates of protection against EVD are incompletely understood. We systematically evaluated the antibody response to various EBOV proteins in 79 nonhuman primates vaccinated with various EBOV vaccine platforms. We evaluated the serum immunoglobulin (Ig)G titers against EBOV glycoprotein (GP), the ability of the vaccine-induced antibodies to bind GP at acidic pH or to displace ZMapp, and virus neutralization titers. The correlation of these outcomes with survival from EVD was evaluated by appropriate statistical methods. Irrespective of the vaccine platform, protection from EVD strongly correlated with anti-GP IgG titers. The GP-directed antibody levels required for protection in animals vaccinated with virus-like particles (VLPs) lacking nucleoprotein (NP) was significantly higher than animals immunized with NP-containing VLPs or adenovirus-expressed GP, platforms that induce strong T-cell responses. Furthermore, protective immune responses correlated with anti-GP antibody binding strength at acidic pH, neutralization of GP-expressing pseudovirions, and the ability to displace ZMapp components from GP. These findings suggest key quantitative and qualitative attributes of antibody response to EVD vaccines as potential correlates of protection.

Efficacy of Galidesivir against Ebola Virus Disease in Rhesus Monkeys

BackgroundThe recent re-emergence of Ebola virus in the Democratic Republic of the Congo serves as a stark reminder of the 2013–2016 Ebola virus (EBOV), which resulted in >11,000 deaths. To date, there are no approved therapeutics or vaccines for EBOV disease (EVD). Galidesivir (BCX4430) is an adenosine nucleoside analogue designed to inhibit viral RNA polymerase activity indirectly through non-obligate RNA chain termination. Galidesivir exhibits in vitro antiviral activity against a broad spectrum of negative- and positive-sense RNA viruses. In vivo, galidesivir has shown antiviral activity against various viruses and provides 100% protection against Marburg virus disease in cynomolgus macaques, when administered either 1 or 2 days post infection. Initial exploratory studies in a rhesus macaque model of EVD showed that 25 mg/kg galidesivir administered twice daily (BID) IM beginning immediately following viral challenge protected 100% (6 of 6) of animals.MethodsPharmacokinetic modeling based on galidesivir levels in healthy and EBOV-infected animals predicted that a loading-dose regimen could decrease time to steady-state, potentially advantageous when extending the time of treatment initiation. To test the efficacy of a loading dose regimen, 100 mg/kg was administered BID either 2 or 3 days after challenge, followed by maintenance doses of 25 mg/kg BID for a total duration of 11 days.ResultsSix of 6 (100%) rhesus monkeys survived after receiving loading doses on day 2, and 4 of 6 (67%) animals survived after receiving loading doses beginning day 3. In the dosing regimen that conferred 100% protection, the animals exhibited either no behavioral depression or only mild and transient behavioral depression. In all treated groups, there was a significant reduction of plasma viral RNA concentrations during the acute phase of disease.ConclusionGalidesivir protects rhesus monkeys against an otherwise lethal EBOV challenge. Administered by IM injection, Phase 1 human clinical studies of single and multiple ascending doses have shown galidesivir to be generally safe and well tolerated up to 10 mg/kg daily for seven days. Additional clinical studies are planned to evaluate the safety and tolerability of galidesivir administered by IV infusion. Supported by NIAID (NIH), HHSN272201300017C.Disclosures S. MacLennan, BioCryst: Employee, Salary. A. Mathis, BioCryst Pharmaceuticals: Employee, Salary. E. Giuliano, BioCryst: Employee, Salary. R. Taylor, BioCryst Pharmaceuticals: Employee, Salary. W. Sheridan, BioCryst Pharmaceuticals: Employee, Salary.

Virus-Vectored Ebola Vaccines

The Ebola virus disease (EVD) is one of the most dangerous infections affecting humans and animals. The first EVD outbreaks occurred in 1976 in Sudan and Zaire. Since then, more than 20 outbreaks have occurred; the largest of which (2014-2016) evolved into an epidemic in West Africa and claimed the lives of more than 11,000 people. Although vaccination is the most effective way to prevent epidemics, there was no licensed vaccine for EVD at the beginning of the latest outbreak. The development of the first vaccines for EVD started in 1980 and has come a long technological way, from inactivated to genetically engineered vaccines based on recombinant viral vectors. This review focuses on virus-vectored Ebola vaccines that have demonstrated the greatest efficacy in preclinical trials and are currently under different phases of clinical trial. Particular attention is paid to the mechanisms of immune response development, which are important for protection from EVD, and the key vaccine parameters necessary for inducing long-term protective immunity against EVD.

Conventional Wisdom versus Actual Outcomes: Challenges in the Conduct of an Ebola Vaccine Trial in Liberia during the International Public Health Emergency.

.Clinical trials are challenging endeavors. Planning and implementing an investigational vaccine trial in Liberia, in the midst of an Ebola virus disease (EVD) epidemic that World Health Organization classified a public health emergency of international concern, presented extraordinary challenges. Normally, years of preparation and a litany of tasks lay the groundwork for a successful, randomized, blinded, placebo-controlled trial focused on safety and efficacy. Difficult research settings, unpredictable events, and other unique circumstances can add complexity. The setting in Liberia was especially problematic due to an infrastructure still badly damaged following a lengthy civil war and a very fragile health-care system that was further devastated by the EVD outbreak. The Partnership for Research on Vaccines in Liberia I EVD vaccine trial was planned and implemented in less than 3 months by a Liberian and U.S. research partnership, and its Phase II substudy was fully enrolled 3 months later. Contrasting conventional wisdom with trial outcomes offers an opportunity to compare early assumptions, barriers encountered, and adaptive strategies used, with end results. Understanding what was learned can inform future trial responses when disease outbreaks, especially in resource-poor locations with minimal infrastructure, pose a significant threat to public health.

Leading Ebola Vaccine Candidates

The ongoing outbreak of Ebola Virus Disease (EVD) in West Africa is the largest outbreak ever recorded with a total number of 28,602 confirmed, probable, or suspected cases in Guinea, Liberia, and Sierra Leone, including 11,301 reported deaths since December 2013 (as of January 17, 2016).1 A meeting convened by the World Health Organization (WHO) in September, 2014, concluded that an urgent unmet need exists for efficacy and safety testing of the EVD vaccine candidates and that clinical trials should be expedited. These vaccines could be used both in an outbreak setting and to provide long-term protection in populations at risk of sporadic outbreaks.

Real-time dynamic modelling for the design of a cluster-randomized phase 3 Ebola vaccine trial in Sierra Leone

BackgroundDeclining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013–16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size. MethodsIn real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning. ResultsEVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time. ConclusionsThis analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined.

Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model.

BackgroundDuring the 2014 Ebola virus disease (EVD) outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT) was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel “ordered stepped-wedge cluster trial” (OSWCT) designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor.Methodology/Principal FindingsWe constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model’s projection of first case occurrence was robust to changes in disease natural history parameters.Conclusions/SignificanceOrdering clusters in a step-wedge trial based on the cluster’s underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints.

Ebola Virus Infection: Overview and Update on Prevention and Treatment.

In 2014 and 2015, the largest Ebola virus disease (EVD) outbreak in history affected large populations across West Africa. The goal of this report is to provide an update on the epidemic and review current progress in the development, evaluation and deployment of prevention and treatment strategies for EVD. Relevant information was identified through a comprehensive literature search using Medline, PubMed and CINAHL Complete and using the search terms Ebola, Ebola virus disease, Ebola hemorrhagic fever, West Africa outbreak, Ebola transmission, Ebola symptoms and signs, Ebola diagnosis, Ebola treatment, vaccines for Ebola and clinical trials on Ebola. Through 22 July 2015, a total of 27,741 EVD cases and 11,284 deaths were reported from all affected countries. Several therapeutic agents and novel vaccines for EVD have been developed and are now undergoing evaluation. Concurrent with active case investigation, contact tracing, surveillance and supportive care to patients and communities, there has been rapid progress in the development of new therapies and vaccines against EVD. Continued focus on strengthening clinical and public health infrastructure will have direct benefits in controlling the spread of EVD and will provide a strong foundation for deployment of new drugs and vaccines to affected countries when they become available. The unprecedented West Africa Ebola outbreak, response measures, and ensuing drug and vaccine development suggest that new tools for Ebola control may be available in the near future.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0079-5) contains supplementary material, which is available to authorized users.