Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges

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1 Design Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges CLINICAL TRIALS Clinical Trials 2016, Vol. 13(1) Ó The Author(s) 2016 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / ctj.sagepub.com Stephen B Kennedy 1,2, James D Neaton 3, H Clifford Lane 4, Mark WS Kieh 1, Moses BF Massaquoi 1,2, Nancy A Touchette 4, Martha C Nason 4, Dean A Follmann 4, Fatorma K Boley 1,5, Melvin P Johnson 1, Gregg Larson 3, Francis N Kateh 2,6 and Tolbert G Nyenswah 2,6 Abstract The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a doubleblinded randomized controlled trial, in Liberia. Keywords Ebola virus disease, clinical trials, Liberia, epidemics, emerging and re-emerging infections, infectious diseases, social mobilization, partnership Introduction The first cases of the Ebola virus disease appeared in Liberia in March The epidemic peaked in Liberia between September and November 2014 and continued at lower levels through the first half of In September, Liberia was categorized as Ebola free 3 by the World Health Organization (WHO). To date, 10,672 cases and 4808 deaths have been reported in Liberia. 4 The Ebola outbreak in Liberia, as well as Guinea and Sierra Leone, was particularly devastating due to the poor health-care infrastructure; limited expertise in disease surveillance; limited capabilities for rapid response to emerging and re-emerging infectious diseases; limited training of health-care workers and emergency personnel in dealing with such an infectious and 1 Liberia US Clinical Trials Partnership Program, Partnership for Research on Ebola Vaccines in Liberia (PREVAIL), Monrovia, Liberia 2 Incident Management System (IMS), Emergency Operations Center (EoC), Ministry of Health (MoH), Monrovia, Liberia 3 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA 4 Division of Clinical Research, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA 5 Liberian Institute for Biomedical Research (LIBR), Margibi, Liberia 6 Ministry of Health (MoH), Monrovia, Liberia Corresponding author: Stephen B Kennedy, Liberia US Clinical Trials Partnership Program, Partnership for Research on Ebola Vaccines in Liberia (PREVAIL), Sinkor, Montserrado County, Monrovia, Liberia kennedys@lpgmc.org

2 50 Clinical Trials 13(1) deadly disease; and the lack of proven vaccines, therapeutics, or preventative measures. 5 8 Although several candidate vaccines and therapies were under development, none had been approved for use in humans or studied in populations at risk for Ebola In October 2014, a WHO Consultation endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. In November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to test scientifically advanced intervention strategies for treating, controlling, and preventing the disease in Liberia (Figure 1). The Joint Liberia US Partnership for Research on Ebola Virus in Liberia (PREVAIL) was established, and three high priority studies were designed and rapidly implemented as the beginning of a long-term collaborative partnership in clinical research between the two countries. The three initial studies are PREVAIL I, an Ebola vaccine clinical trial; PREVAIL II, a multi-country Ebola treatment trial; and PREVAIL III, an Ebola natural history study of survivors and their close contacts. As the partnership transitions from an emergency research strategy to a long-term sustainable post-ebola clinical research program, other studies of emerging and re-emerging infections will be undertaken. In addition, we expect to formulate a comprehensive governing framework to advance clinical research, bioethics, infrastructure, and capacity through the proposed establishment of a bio-bank to address the accumulation of increasing quantity of Ebola samples in the country. Following the agreement to form a partnership, a phase 2/3 clinical trial for studying vaccines was designed, sites for implementing the trial were chosen, and staff were hired and trained to carry out the trial. In late January, a dose for each vaccine was established based on phase 1 data, vaccines were shipped to Liberia, and the protocol was approved. In this article, we describe the clinical trial design, strategic approach, challenges, and implementation of PREVAIL I, a study designed to determine the efficacy Figure 1. Total Ebola cases per week reported in Liberia are plotted in red, based on the reports from the Ministry of Health. Lines in orange, green, and blue show the breakdown of weekly reported cases that were classified as confirmed, probable, or suspected, respectively. On the right, the black dotted line shows the cumulative enrollment in the PREVAIL I vaccine trial, scaled to the axis on the right side of the graph. Below the figure, important events are shown to give a sense of the timeline as the epidemic unfolded.

3 Kennedy et al. 51 and safety of two vaccines in preventing infections with Ebola virus in Liberia. Methods Overall study design PREVAIL I was designed as a randomized, doubleblind, placebo-controlled phase 2/3 clinical trial to evaluate the safety and efficacy of two Ebola vaccines among volunteers in the midst of the Ebola virus outbreak in Liberia. The study was designed to separately compare the safety and efficacy of the ChAd3 Ebola Zaire (EBO-Z) and VSVDG-Zaire Ebola virus (ZEBOV) vaccines versus a placebo in preventing definite Ebola infection 21 days or more following randomization. Since different volumes were required for each vaccine, two placebo preparations of normal saline were used in order to make the trial double-blind. PREVAIL was designed with a phase 2 sub-study embedded within it to evaluate safety and immunogenicity. The phase 2 sub-study was carried out at a single site and was undertaken because there were limited data from phase 1 studies on the safety of the two vaccines among volunteers in West Africa at the time the study was initiated. If the results of the phase 2 substudy indicated that the vaccines were safe and immunogenic, enrollment was to be expanded to several sites in Liberia with a simpler data collection plan focusing on the Ebola infection endpoint for the phase III efficacy trial. Randomization Eligible volunteers were randomized in a 2:1:2:1 allocation to ChAd3-EBO-Z (2 ml), 2 ml of placebo and VSVDG-ZEBOV (1 ml), 1 ml of placebo (Figure 2). Block randomization (block size of 12) was used to Figure 2. Study design overview: organogram describing the recruitment of subjects and study design in PREVAIL I.

4 52 Clinical Trials 13(1) ensure the desired allocation ratio for the four arms. Study volunteers and clinical staff monitoring participants for safety and efficacy outcomes were fully blinded. The randomization was implemented as follows: Each day at approximately 6 a.m., trained Liberian pharmacists removed vials of the vaccines from the freezers for thawing. Saline did not require thawing. After approximately min, 3-mL syringes were filled with the appropriate quantity of each vaccine or placebo. Bar-coded labels with unique syringe identification numbers corresponding to the randomization schedules were attached to each syringe. A total of 12 labelled syringes (4 of each vaccine and 4 with placebo, 2 each matching the different vaccine filled volumes) were placed in bags. With the use of a bar-coded scanner, the syringes were scanned, data from the scanner were uploaded to verify that the correct allocation ratios were present in the bag, and the bags were placed in temperature-controlled transport containers and taken to the Vaccination Center at Redemption Hospital. Syringes had to be used within 6 h. At the time of vaccination, one person randomly removed a syringe from the bag and handed the syringe to the person performing the vaccination. A tear-off portion of the bar-coded label on the syringe was attached to a case report form on which there was a participant ID code. This process provided the linkage of each syringe SID with the participant ID. Following randomization, participants visits were scheduled at 1 week, 1 month, and 2 months and every 2 months thereafter until the close of the study. At these visits, participants were asked questions to assess their health status and any unreported events, and blood samples were periodically collected. Shortly before the study ended, the protocol was amended to also include a week 2 follow-up visit to specifically evaluate these participants for joint problems. Study participants were encouraged to contact the Vaccination Center if they had experienced relevant symptoms or signs that are related to joint problems. Ethical and regulatory considerations Ethical approvals for PREVAIL I were obtained from the National Research Ethics Board in Liberia and the National Cancer Institute in the United States. In addition, regulatory approvals were obtained from the Liberia Medicines and Health Products Regulatory Authority in Liberia and the Food and Drug Administration in the United States, respectively. Study subjects recruitment Volunteers were recruited from high-risk communities that were proximal and distal to Redemption Hospital, the Vaccination Center identified for the phase 2 substudy. Redemption Hospital is a referral hospital situated in one of the hardest affected communities in Monrovia, Liberia s capital city. A widespread community-based social mobilization strategy about the trial was designed to provide knowledge about Ebola, the availability of experimental Ebola vaccines, the potential benefits and/or limitations of the proposed clinical trial, and to encourage volunteers to visit the proposed Vaccination Center. These outreach efforts targeted high-risk individuals based on the epidemiology of Ebola, including health-care workers and other high-risk frontline and community workers in contact with Ebola patients (e.g. ambulance drivers and burial workers). Inclusion criteria were based on a broader context to reflect the target population that would eventually receive an efficacious vaccine. Volunteers were included if they were 18 years of age or older, signed an informed consent, and were likely to be in the surrounding area of the Vaccination Center for at least 1 year. Potential volunteers were excluded if they had a fever greater than 38.0 C or a self-reported history of Ebola virus disease, were pregnant or breastfeeding, or had any condition that would limit the participant s ability to meet the study protocol requirements. The informed consent process consisted of two components. The first part consisted of a group information session at which the study requirements, risks, and benefits were discussed using a series of flip charts. This was a very interactive session with many questions asked by participants. This was followed by individual consent in a private room with each participant. Social mobilization strategy The social mobilization strategy employed to promote the clinical trial and enhance the enrollment of consenting participants consisted of four distinct pillars: advocacy, communication, community engagement, and monitoring and evaluation, respectively. The goal of the advocacy pillar was to mobilize key community decision makers, opinion leaders, and political leaders to seek approval and support for the implementation of the vaccine trial within the targeted high-risk communities. The communication pillar included many types of communication. Targeted messages (e.g. frequently asked questions and press releases) were directed at the local media to supplement increased and accurate information for print and broadcast media dissemination and to dispel local myths and misconceptions. Regular press conferences were organized to brief the nation and its people about the status of the Liberia United States partnership and the resultant vaccine trial. In addition, distribution of flyers, preparation and airing of jingles and songs on television and radio, and distribution of text messages by telecommunication companies targeting subscribers were used to reach as many

5 Kennedy et al. 53 people as possible. The community engagement pillar consisted of community outreach programs directed at the targeted population, especially community, religious, and traditional leaders, through meetings, and the utilization of community mobilizers and communicators as change agents to encourage participation in the study. Finally, the fourth pillar monitored and evaluated the messaging and outreach strategies with a joint review mechanism that incorporated community leaders, diverse community groups, and government partners to ensure that the output, impact, and challenges of the social mobilization campaign were identified and changes instituted to address existing gaps. Measurements and data collection Data collected for participants in the trial included baseline data (birth date and gender; pregnancy test results), high-risk occupation status, location of home, contact information, history of contact with an Ebolainfected person, and contact information for two additional individuals who would know the participant s whereabouts. Other information collected included body temperature, height and weight, targeted selfreported medical history, and HIV and syphilis serostatus. Blood samples were collected at baseline, 1 week, and 1 month for assessing electrolytes, blood chemistries, antibody levels against Ebola and for storage. At 6 and 12 months, blood was collected for antibody levels and storage. Volunteers were questioned to assess the possibility of unreported Ebola or serious adverse events during all follow-up visits. Safety and adverse event reporting An adverse event was defined as any untoward medical occurrence in a randomized consenting volunteer, whether or not it was considered related to the vaccination. Study participants were monitored closely during the first week following vaccination and were seen at 1 week, 1 month, and 2 months and then at 2-month intervals following vaccination. During this time period, vaccine injection site reactions, symptoms and signs of any severity grade, and serious adverse events were reported. Participants were asked about specific symptoms of interest and any signs and symptoms reported by consenting volunteers who were not on the targeted checklist were also recorded. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA Ò ). The primary safety endpoint was a safety or adverse event occurring within 30 days of vaccination. Clinical management Study participants were provided information on whom to contact if they experienced adverse events or symptoms of Ebola infection, which would be managed according to local standards. This information was provided on the back of a picture identification card made for each participant at the time of vaccination. This card also identified the person as a participant in the vaccine trial in the event they were hospitalized. Participants testing positive for HIV or syphilis at study entry were counseled and referred for treatment. Participants were to be followed up to 12 months after vaccination for Ebola and adverse events. Participants were allowed to withdraw from follow-up at any time at their request and resume participation at any time. Women reporting pregnancy in the first 30 days of follow-up after vaccination were followed through their pregnancy, and outcomes were reported on a case report form. Sample size considerations The phase 3 trial was designed as an event-driven trial with 112 primary events for each of the two vaccines versus placebo comparisons. The following assumptions were made in computing the event targets and sample size: The primary analysis would be a modified intention-to-treat analysis using Ebola outcomes that occur 21 days or more following randomization; a Cox model for time to Ebola infection with a single indicator for the active vaccine will be used to estimate the hazard ratio (HR) for each pairwise comparison: ChAd3 EBO-Z vaccine versus pooled placebo and VSVDG-ZEBOV versus pooled placebo; For each primary comparison, there is 1:1 allocation for vaccine and placebo (1 and 2 ml placebo groups would be pooled); Type 1 error = (two sided), adjusted for the two primary comparisons (0.05/2); Power = 0.90 to detect vaccine efficacy of 50%, corresponding to a HR of 0.5; Based on these assumptions, the target number of primary events is 112 for each vaccine versus pooled placebo comparison; 1.0% of volunteers in the pooled placebo group would develop Ebola virus disease after 12 months; Volunteers would be enrolled over a 4-month period and followed for a minimum of 8 months (average follow-up is 10 months and range is 8 12 months); Deaths unrelated to Ebola and losses to follow-up would occur at the rate of 1% per month. With these additional assumptions, 28,170 volunteers, 9390 per active vaccine arm, and 4695 per each of the two placebo groups were estimated to be needed to obtain the required number of primary events.

6 54 Clinical Trials 13(1) The phase 2 sub-study was powered to detect differences in the rates of grades 3 and 4 adverse events between each vaccine and the placebo and to estimate Ebola virus antibody responses. With 600 participants (200 given each vaccine and 200 in the pooled placebo groups), power was good (80% or greater) to detect a difference in rates for an adverse event that occurs in at least 6% of participants given one of the vaccines and no more than 1% of volunteers in the pooled placebo group. For an adverse event that occurs in no more than 5% of those in the pooled placebo group, the study would have at least 80% power to detect a difference in rate if that adverse event occurs in at least 13% of the vaccine recipients in either group. With this sample size, if 70% of the 200 participants assigned to one of the vaccine groups had a positive immune response, the 95% confidence interval for the true response rate will be from 63% to 76%. Data analysis The primary endpoint was definite Ebola infection occurring 21 days or more following randomization with separate analysis of each vaccine versus the placebo. An important secondary endpoint was Ebola events at any time following randomization (the intention-to-treat analysis). The analysis plan for both the primary and safety endpoints and all secondary endpoints included time-to-event methods, log-rank tests, proportional hazards regression analysis, and Kaplan Meier cumulative event curves. As part of these analyses, the proportional hazards assumption is to be assessed. The primary analysis is based on a Cox model with a single indicator for the vaccine group. Vaccine efficacy is to be estimated as (1 2 HR) where HR is the vaccine-to-placebo HR estimate based on the Cox model. For the 600 participants in the phase 2 sub-study, Barnard s test would be used to compare each vaccine versus the pooled placebo group for the proportions with targeted and volunteered adverse events. For these 600 participants, the percent with an antibody response and log-transformed antibody titer levels would be compared at week 1 and month 1 among those who did not test positive for Ebola antibodies at baseline. The primary comparison of antibodies would be based on the 1-month data. Data monitoring An independent Data Safety Monitoring Board (DSMB) reviewed the study design and regularly reviews the data for safety and other related concerns. Specifically, the DSMB reviews the safety data and makes recommendations. As a guideline for efficacy, the upper boundary to establish the benefit of each vaccine will be based on the Lan-DeMets spending function analog of the O Brien-Fleming boundary to preserve a one-sided level of significance. For each pairwise comparison of vaccine versus pooled placebo, the event target is 112 definite Ebola virus disease outcomes. The monitoring boundaries for each comparison will be determined at each of seven planned efficacy interim reviews before the end of the study. The timing of these reviews will be based on the fraction of the primary endpoints that have accrued (i.e. after approximately 12.5%, 25%, 37.5%, 50%, 62.5%, 75%, and 87.5% of information is available). Since each vaccine is being compared with the placebo group, early stopping of one vaccine versus the placebo comparison could impact the ability to determine the safety and efficacy of the other vaccine. For example, if one of the vaccines was found to have clear and substantial efficacy compared to the placebo at an interim analysis (e.g. crosses the upper boundary for efficacy) and the other vaccine does not, the DSMB could be asked to weigh the safety profiles of each vaccine (assess risk benefit). They could recommend continuing the study (both vaccine arms) in order to obtain more information on a less effective but safer vaccine or stop the study and immediately provide the effective vaccine to all eligible study volunteers. For this decision, the DSMB could consider the conditional power estimates for the vaccine that does not have a clear and substantial efficacy. If randomization is ongoing and one vaccine has an unacceptable rate of serious adverse events or a rate of Ebola and/or all-cause mortality that is greater than the placebo, enrollment to that arm could be terminated and the allocation will be 1:1 for subsequent enrollments to the other vaccine and placebo. Results Study summary Recruitment targets. The initial target to recruit 600 adults to the phase 2 sub-study was achieved in early March As the trial was approaching its recruitment target of 600 volunteers, it became clear that it would not be possible to enroll a cohort in Liberia with an adequate number of subsequent Ebola virus infections to determine efficacy. Thus, based on the recommendation of the US Food and Drug Administration and with concurrence by the independent DSMB and the two institutional review boards of record, the phase 2 sub-study was subsequently expanded to 1500 participants with follow-up for 12 months in order to obtain more safety and immunogenicity data and a better representation of women. Additional immunogenicity testing is being carried out at 6 and 12 months after vaccination. The sample size of 1500 consenting adults was achieved on 30 April Participant retention. Consistent with the principle of the intent to treat, consenting adult participants enrolled in

7 Kennedy et al. 55 Table 1. Number of volunteers expected to complete follow-up visits (second column), and the completion rate (third column). Designated visits (after innoculation) Number of visits expected c Attended/completed (%) Week Month Month Month Month 6 a Any visit b EVD: Ebola virus disease. a Window period for follow-up and monitoring of the participants has not closed. b Average follow-up to date. c Follow-up is ongoing and for some participants follow-up visit windows have not yet opened. the study are expected to be followed for 12 months to determine the long-term adverse effects and durability of the immune response, where applicable. The completion rates for follow-up visits through month 4, which is now complete, have been excellent, and those for the later follow-up visits, which are ongoing, have also been very good (Table 1). We attribute this excellent retention in part to a well-organized group of individuals called trackers who maintain regular contacts with each participant. In addition, a number of reports are prepared for the staff at Redemption Hospital on upcoming scheduled visits and missed visits that are used on a daily basis. Conclusion During the implementation of the clinical trial, there were several lessons learned. Below, we describe the challenges and proffered strategies we have employed to address them. The challenges are categorized under three major groups: infrastructure, capacity enhancement, and fear and myths. Infrastructure The infrastructure of the Vaccination Center was strengthened to accommodate the flow of eligible and consenting study participants, including areas for laboratory, vaccination, and monitoring. The issues encountered were overcrowding and scarcity of space. For example, many more eligible participants than expected showed up to volunteer for enrollment. The study educator had to conduct several information sections per day to accommodate the large influx of people. Since there was a cap on the number of participants to be vaccinated per day due to the daily limit of vaccine syringes prepared, all interested participants could not be individually consented and vaccinated each day. To address this issue, the team provided reservations to additional participants in the order that they were provided information and volunteered to participate. This strategy helped the team schedule participants for future consenting, eligibility assessment, baseline data collection, and vaccination, and deal with the overcrowding caused by the influx of volunteers. Capacity enhancement Rigorous clinical research is relatively new to the Liberian staff of PREVAIL I. The Liberia US partnership established a buddy system for key positions per the organogram where comparable Liberians and US partners were paired. This system provided an effective fulcrum for information and technology sharing needed to conduct a structured research study within a Vaccination Center. The exchange of perspectives of the US partners, sharing their trial experiences and insights on implementation feasibility, and the Liberian partners, sharing their cultural familiarity regarding the delivery of information to participants and the operation of clinical trial in a local hospital setting, was essential. This buddy system was effective in marshalling the different backgrounds and experiences to address the intricacies of a study that many thought could never happen in resource-limited settings during outbreaks of emerging and re-emerging infectious diseases. Each partner contributed invaluable experiences which led to the successful implementation of the ongoing vaccine clinical trial. Fear and myths The study began just when Liberia was experiencing a decline in the incidence of Ebola. Accordingly, many potential participants were afraid to be among the first group of consenting volunteers, fearing they could obtain the Ebola virus from the vaccine. In addition, some consenting volunteers during the early phase of the clinical trial had post-inoculation psychological reactions, similar to the signs and symptoms experienced by participants from the phase I trials. Accordingly, there were many calls to the medical monitors with questions about the perceived relationships of those signs and symptoms to the vaccines they

8 56 Clinical Trials 13(1) had received. To address this challenge, the team decided that the monitors should call all newly inoculated participants before the end of the workday to inquire about any reactions and provide reassurance regarding current knowledge about the side effects and safety of the vaccines. In summary, we demonstrated that a rigorously designed clinical trial could be effectively conducted during a rapidly spreading epidemics in a resourcelimited setting. We also demonstrated that ethical and regulatory clearances can be obtained, and adherence to procedures and protocols can be maintained, during emergency outbreaks from emerging and re-emerging infectious diseases. Most importantly, we demonstrated that a joint collaborative, joint, clinical research partnership can be developed, and successfully employed to conduct high-quality research programs during the peak of major epidemics associated with virulent pathogens. Acknowledgements The authors acknowledge the contributions of the consenting and non-consenting volunteers to the advancement of clinical research in Liberia, the staff of the PREVAIL I Ebola virus disease Vaccination Center at Redemption Hospital, and the entire PREVAIL I EVD Study Team. Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. World Health Organization. Global alert & response: Ebola virus disease (EVD), 2014, csr/don/2014_03_30_ebola_lbr/en/ 2. World Health Organization. The Ebola outbreak in Liberia is over, statements/2015/liberia-ends-ebola/en/ (2015, accessed 11 November 2015). 3. World Health Organization. Ebola transmission in Liberia over. Nation enters 90-day intensive surveillance period, (2015, accessed 11 November 2015). 4. World Health Organization. Ebola situation report, 16 September 2015, (accessed 11 November 2015). 5. Buseh AG, Stevens PE, Bromberg M, et al. The Ebola epidemic in West Africa: challenges, opportunities, and policy priority areas. Nurs Outlook 2015; 63: Siedner MJ, Gostin LO, Cranmer HH, et al. Strengthening the detection of and response to public health emergencies: lessons from the West African Ebola epidemic. PLoS Med 2015; 12: e Gostin LO and Friedman EA. A retrospective and prospective analysis of the West African Ebola virus disease epidemic: Robust national health systems at the foundation and an empowered WHO at the apex. Lancet 2015; 385: Kennedy SB and Nisbett RA. The Ebola epidemic: a transformative moment for global health. Bull World Health Organ 2015; 93: Agnandji ST, Huttner A, Zinser ME, et al. Phase I trials of rvsv Ebola vaccine in Africa and Europe: preliminary report. N Engl J Med. Epub ahead of print 1 April DOI: /NEJMoa Kibuuka H, Berkowitz NM, Millard M, et al. Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1B, randomised, double-blind, placebo-controlled clinical trial. Lancet 2015; 385: Ledgerwood JE, DeZure AD, Stanley DA, et al. Chimpanzee adenovirus vector Ebola vaccine preliminary report. NEnglJMed. Epub ahead of print 26 November DOI: /NEJMoa Stanley DA, Honko AN, Asiedu C, et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against Ebola virus challenge. Nat Med 2014; 20: