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Background: Shorter prophylactic vaccine schedules may offer more rapid protection against Ebola in resource-limited settings., Methods: This randomized, observer-blind, placebo-controlled, phase 2 trial conducted in 5 sub-Saharan African countries included people without human immunodeficiency virus (HIV) (PWOH, n = 249) and people with HIV (PWH, n = 250). Adult participants received 1 of 2 accelerated Ebola vaccine regimens (MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart [n = 79] or Ad26.ZEBOV, MVA-BN-Filo administered 28 days apart [n = 322]) or saline/placebo (n = 98). The primary endpoints were safety (adverse events [AEs]) and immunogenicity (Ebola virus [EBOV] glycoprotein-specific binding antibody responses). Binding antibody responders were defined as participants with a >2.5-fold increase from baseline or the lower limit of quantification if negative at baseline., Results: The mean age was 33.4 years, 52% of participants were female, and among PWH, the median CD4+ cell count was 560.0 (interquartile range, 418.0-752.0) cells/μL. AEs were generally mild/moderate with no vaccine-related serious AEs or remarkable safety profile differences by HIV status. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody response rates in vaccine recipients were 99% for the 14-day regimen (geometric mean concentrations [GMCs]: 5168 enzyme-linked immunosorbent assay units [EU]/mL in PWOH; 2509 EU/mL in PWH) and 98% for the 28-day regimen (GMCs: 6037 EU/mL in PWOH; 2939 EU/mL in PWH). At 12 months post-dose 2, GMCs in PWOH and PWH were 635 and 514 EU/mL, respectively, for the 14-day regimen and 331 and 360 EU/mL, respectively, for the 28-day regimen., Conclusions: Accelerated 14- and 28-day Ebola vaccine regimens were safe and immunogenic in PWOH and PWH in Africa. Clinical Trials Registration. NCT02598388., Competing Interests: Potential conflicts of interest. G. S., D. N. A., A. G., K. L., J. H., C. M., M. D., and C. R. were full-time employees of Janssen, Pharmaceutical Companies of Johnson & Johnson at the time of the study, and may own shares in Janssen, Pharmaceutical Companies of Johnson & Johnson. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Unlike adults, children experienced stronger and longer vector replication in plasma and shedding in saliva following rVSVΔG-ZEBOV-GP vaccination. The resulting risks of immunosuppression or immune hyperactivation leading to increased Adverse Events (AEs) and altered antibody responses are concerns that have been addressed in the present manuscript., Methods: Children aged 1-12 years living in Gabon received either rVSVΔG-ZEBOV-GP (ERVEBO®) vaccine or the varicella-zoster virus (VZV) vaccine (VZV). The concentration of rVSVΔG vector in blood and saliva, the occurrence of AEs up to day 28; the anti-rVSVΔG-ZEBOV-GP and anti-VZV IgG antibody titres, neutralising and avidity functions of anti-rVSVΔG-ZEBOV-GP by day 365; were assessed in serum. (PACTR202005733552021) FINDINGS: In the rVSVΔG-ZEBOV-GP group, 70% and 7% of children had >0 copies/ml of rVSVΔG respectively in plasma by day 3 and in saliva by day 14 after vaccination, with no detection on day 28. Significantly higher but transient AEs occurred in the rVSVΔG-ZEBOV-GP group. Both vaccines induced seroconversion on day 28 and sustainable IgG antibody titres by day 365. Avidity and neutralisation functions of the anti-rVSVΔG-ZEBOV-GP antibodies peaked at day 28 and were maintained by day 365., Interpretation: The replication and shedding do not affect the favourable risk-benefit balance of the rVSVΔG-ZEBOV-GP in children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Health-care providers and front-line workers are at risk of contracting Ebola virus disease during an Ebola virus outbreak and consequently of becoming drivers of the disease. We aimed to assess the long-term immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and the safety of and immune memory response to an Ad26.ZEBOV booster vaccination at 1 year or 2 years after the first dose in this at-risk population., Methods: This open-label, single-centre, randomised, phase 2 trial was conducted at one study site within a hospital in Boende, Democratic Republic of the Congo. Adult health-care providers and front-line workers, excluding those with a known history of Ebola virus disease, were vaccinated with a two-dose heterologous regimen administered at a 56-day interval via a 0·5 mL intramuscular injection in the deltoid muscle, comprising Ad26.ZEBOV as the first dose and MVA-BN-Filo as the second dose. After the initial vaccination on day 1, participants were randomly assigned (1:1) via randomisation envelopes, opened in a sequential order, to receive an Ad26.ZEBOV booster vaccination at 1 year (group 1) or 2 years (group 2) after the first dose. We present the secondary and exploratory objectives of the trial-results of the primary objective have been published elsewhere. We measured immunogenicity at six timepoints per group as geometric mean concentrations (GMCs) of Ebola virus glycoprotein-specific IgG binding antibodies, using the Filovirus Animal Non-Clinical Group ELISA. We assessed serious adverse events occurring up to 6 months after the last dose and local and systemic solicited and unsolicited adverse events reported for 7 days after the booster vaccination. Antibody responses were analysed per protocol, serious adverse events per full analysis set (FAS), and adverse events for all boosted FAS participants. This trial is registered as completed on ClinicalTrials.gov (NCT04186000)., Findings: Between Dec 18, 2019, and Feb 8, 2020, 699 health-care providers and front-line workers were enrolled and 698 were randomly assigned (350 to group 1 and 348 to group 2 [FAS]); 534 (77%) participants were male and 164 (23%) were female. 319 in group 1 and 317 in group 2 received the booster. 29 (8%) in group 1 and 26 (7%) in group 2 did not complete the study, mostly due to loss to follow-up or moving out of the study area. In both groups, injection-site pain or tenderness (87 [27%] of 319 group 1 participants vs 90 [28%] of 317 group 2 participants) and headache (91 [29%] vs 93 [29%]) were the most common solicited adverse events related to the investigational product. One participant (in group 2) had a related serious adverse event after booster vaccination (fever of ≥40·0°C). Before booster vaccination, Ebola virus glycoprotein-specific IgG binding antibody GMCs were 279·9 ELISA units (EU) per mL (95% CI 250·6-312·7) in 314 group 1 participants (1 year after first dose) and 274·6 EU/mL (242·1-311·5) in 310 group 2 participants (2 years after first dose). These values were 5·2 times higher in group 1 and 4·9 times higher in group 2 than before vaccination on day 1. 7 days after booster vaccination, these values increased to 10 781·6 EU/mL (9354·4-12 426·4) for group 1 and 10 746·9 EU/mL (9208·7-12 542·0) for group 2, which were approximately 39 times higher than before booster vaccination in both groups. 1 year after booster vaccination in 299 group 1 participants, a GMC that was 7·6-times higher than before booster vaccination was still observed (2133·1 EU/mL [1827·7-2489·7])., Interpretation: Overall, the vaccine regimen and booster dose were well tolerated. A similar and robust humoral immune response was observed for participants boosted 1 year and 2 years after the first dose, supporting the use of the regimen and flexibility of booster dose administration for prophylactic vaccination in at-risk populations., Funding: Innovative Medicines Initiative 2 Joint Undertaking and Coalition for Epidemic Preparedness Innovations., Competing Interests: Declaration of interests CR, MK, and CM were full-time employees of Janssen at the time of the study and report stock or stock options in Janssen. HM-M was appointed member of the advisory board of Janssen Global Services during the COVID-19 pandemic. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Understanding the knowledge, perception and attitudes towards Ebola vaccines is an important factor in ensuring future use of these vaccines. A qualitative methods study embedded in an Ebola vaccine immunogenicity and safety trial (NCT04028349) was conducted to explore the knowledge and perceptions of healthcare (HCWs) and frontline workers (FLWs), about Ebola vaccines and their willingness to participate or recommend participation in Uganda., Method: We carried out focus group discussions and semi-structured interviews before and after vaccination, with 70 HCWs and FLWs who consented to participate in the trial, and in the qualitative component, from August to September 2019. Data were analysed using thematic content analysis., Results: Respondents showed good knowledge about Ebola and the vaccines in general, and had wide access to information through several channels, including the study team. On prevention, particular attention was given to effective communication within health facilities. Misconceptions were mainly around route of transmission, animal origin and types of vaccines. Previous fears were based on rumours circulating in the community, mainly about the presence of the virus in the vaccine, side effects and intention to harm (e.g. by "the whites"), ultimately insisting on transparency, trust and involvement of local leaders. Acceptability of participation was motivated by the need to protect self and others, and the willingness to advance research. Majority were willing to recommend participation to their community., Conclusions: Overall, information sharing leads to a better understanding and acceptance of vaccine trials and a positive vaccination experience can be a deciding factor in the acceptance of others. Particular attention should be paid to involving the community in addressing misconceptions and fears, while ensuring that participants have access to vaccination sites in terms of transport, and that they are properly accommodated at the study site including staying for a reasonable period of time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

Background: The long-term retention of information disclosed during the informed consent in clinical trials lasting over a year cannot be guaranteed for all volunteers. This study aimed to assess the level of participants' retention and understanding of the trial information after two years of participation in a vaccine trial., Methods: In total, 699 health care providers (HCPs) and frontline workers were enrolled in the EBL2007 vaccine trial conducted between February 2019 and September 2022 in the Health District of Boende, Democratic Republic of the Congo (DRC). Individual scores obtained from a questionnaire (test of understanding, TOU), specifically designed to assess the understanding of the consent at baseline, were collected before the clinical trial started and at one-year and two-year intervals., Results: TOU scores were high in the beginning of the trial (median TOU = 10/10), but significantly decreased in both the first and second years following (median TOU = 8/10 in year 1 and median TOU = 9/10 in year 2, p-value < 0.0001). The decrease in scores was significantly higher among individuals with occupations requiring shorter education such as midwives (median TOU = 7/10 in year 1 and 8/10 in year 2, pvalue = 0.025). Furthermore, older participants exhibited poorer retention of information compared to younger individuals (median TOU = 8/10 vs 9/10, p-value = 0.007)., Conclusion: We observed a significant decline in the informational knowledge of informed consent, specifically in terms of basic knowledge on the study vaccine and trial procedures. As participant safety and understanding is a paramount ethical concern for researchers, it is crucial for participants to fully comprehend the study's objectives and potential risks. Therefore, our findings suggest the need for clinical researchers to re-explain participants to optimize the protection of their rights and wellbeing during the research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Potential conflicts of interest All authors attest they meet the ICMJE criteria for authorship., (Copyright © 2023. Published by Elsevier Ltd.)

Background: This review aimed to systematically evaluate the immunogenicity and safety of the candidate Ebola virus vaccine (EVV)., Methods: We searched five databases for randomized controlled trials (RCTs) evaluating the effects of EVV on healthy adults. The primary outcomes were relative risk (RR) of sero-conversion or sero-response of EVV in healthy adults between the groups that received EVV and the controls., Results: Twenty-nine RCTs ( n  = 23573) were included. There was a significant difference in RR of sero-conversion of EVV (RR 13.18; 95% CI 11.28-15.41; I 2  = 33%; P  < 0.01) between the two groups. There was a significant difference in RR of adverse events (AEs) of EVV (RR 1.49; 95% CI 1.27-1.74; I 2  = 88%; P  < 0.01), although no difference in RR of serious AE (SAE) between the two groups. Subgroup analysis showed that there was no significant difference in RR of AEs for DNAEBO, EBOV-GP, MVA, and rVSVN4CT1 vaccines, compared with controls., Conclusions: The DNAEBO, EBOV-GP, MVA, and rVSVN4CT1 vaccines are likely to be safe and immunogenic, tending to support the vaccination against Ebola disease. These findings should provide much-needed evidence for public health policy makers to develop preventive measures based on disease prevalence features and socio-economic conditions.

Introduction: The rVSVDG-ZEBOV-GP (Ervebo®) vaccine is both immunogenic and protective against Ebola. However, the vaccine can cause a broad range of transient adverse reactions, from headache to arthritis. Identifying baseline reactogenicity signatures can advance personalized vaccinology and increase our understanding of the molecular factors associated with such adverse events., Methods: In this study, we developed a machine learning approach to integrate prevaccination gene expression data with adverse events that occurred within 14 days post-vaccination., Results and Discussion: We analyzed the expression of 144 genes across 343 blood samples collected from participants of 4 phase I clinical trial cohorts: Switzerland, USA, Gabon, and Kenya. Our machine learning approach revealed 22 key genes associated with adverse events such as local reactions, fatigue, headache, myalgia, fever, chills, arthralgia, nausea, and arthritis, providing insights into potential biological mechanisms linked to vaccine reactogenicity., Competing Interests: Author IM was employed by the company Microbiotec Srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Gonzalez Dias Carvalho, Dominguez Crespo Hirata, Mano Alves, Moscardini, do Nascimento, Costa-Martins, Sorgi, Harandi, Ferreira, Vianello, Haks, Ottenhoff, Santoro, Martinez-Murillo, Huttner, Siegrist, Medaglini and Nakaya.)

Background: This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone., Methods: In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069)., Findings: From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded)., Interpretation: Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination., Funding: Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests Janssen Vaccines & Prevention was the vaccine manufacturer and donated the vaccine for this study. BK, WvD, AG, DA, CM, ML, KL, CR, and MD were full-time employees of Janssen Pharmaceuticals at the time of the study and hold stock or stock options in Janssen Pharmaceuticals. All other authors declare funding from the Innovative Medicines Initiative 2 Joint Undertaking., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: From 2019 to 2021, Rwandan residents of the border with the Democratic Republic of the Congo were offered the Ad26.ZEBOV (adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein) and MVA-BN-Filo (modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and nucleoprotein from Tai Forest viruses) Ebola vaccine regimen., Methods: Nonpregnant persons aged ≥2 years were eligible. Unsolicited adverse events (UAEs) were reported through phone calls or visits, and serious adverse events (SAEs) were recorded per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines., Results: Following Ad26.ZEBOV, UAEs were reported by 0.68% of 216 113 vaccinees and were more common in younger children (aged 2-8 years, 1.2%) compared with older children (aged 9-17 years, 0.4%) and adults (aged ≥18 years, 0.7%). Fever and headache were the most reported symptoms. All 17 SAEs related to vaccine were in children aged 2-8 years (10 postvaccination febrile convulsions ± gastroenteritis and 7 fever and/or gastroenteritis). The incidence of febrile seizures was 8 of 26 062 (0.031%) prior to initiation of routine acetaminophen in December 2020 and 2 of 15 897 (0.013%) thereafter. Nonobstetric SAEs were similar in males and females. All 20 deaths were unrelated to vaccination. Young girls and adult women with UAEs were less likely to receive the second dose than those without UAEs. Seven unrelated SAEs occurred in 203 267 MVA-BN-Filo recipients., Conclusions: Postvaccination febrile convulsions in young children were rare but not previously described after Ad26.ZEBOV and were reduced with routine acetaminophen. The regimen was otherwise safe and well-tolerated., Competing Interests: Potential conflicts of interest. J. No. is an employee of J&J Global Public Health R&D, engaged by Janssen Vaccines & Prevention, the manufacturer of the 2-dose Ebola vaccine regimen utilized in the UMURINZI campaign. N. H. and M. K. are employees of Janssen Vaccines & Prevention, the manufacturer of the 2-dose Ebola vaccine regimen utilized in the UMURINZI campaign. C. R. is currently a retired employee of Janssen Vaccines & Prevention but served as the medical leader during the conduct of this campaign. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Risks to mother and fetus following Ebola virus infection are very high. Evaluation of safety and immunogenicity of non-replicating Ebola vaccine candidates is a priority for use in pregnant women. This is the protocol for a randomized, open-label, single-center phase 3 clinical trial of the safety, reactogenicity, and immunogenicity of the 2-dose Ebola vaccine regimen in healthy adult pregnant women. This 2-dose regimen has been shown to be safe, judged effective, and approved in non-pregnant populations., Methods: A total of 2000 adult (≥ 18 years of age) pregnant women will be enrolled from antenatal care facilities in Western Rwanda and randomized (1:1) to receive the 2-dose Ebola vaccine regimen (Ad26.ZEBOV, MVA-BN-Filo (group A)) or control (unvaccinated pregnant women (group B)). The primary objectives are to (1) assess adverse maternal/fetal outcomes in randomized pregnant women up to 1.5 months after delivery and (2) assess adverse neonatal/infant outcomes in neonates/infants born to randomized women up to 3.5 months after birth. The frequency and relatedness of all serious adverse events in women and newborns from randomization or birth, respectively, until study end will be reported. The reactogenicity and unsolicited adverse events of the 2-dose Ebola vaccine regimen in all vaccinated pregnant women (group A) will be reported. We will also assess the immunogenicity of the 2-dose Ebola vaccine regimen in 150 pregnant women who are anticipated to receive both vaccine doses within the course of their pregnancy (a subset of the 1000 pregnant vaccinated women from group A) compared to 150 non-pregnant women vaccinated after delivery (a subset of group B). The persistence of maternal antibodies in 75 infants born to women from the group A subset will be assessed. Exploratory analyses include assessment of acceptability of the 2-dose Ebola vaccine regimen among group A and assessment of maternal antibodies in breast milk in 50 women from group A and 10 controls (women from group B prior to vaccination)., Discussion: This study is intended to support a label variation to relax restrictions on use in pregnant women, a vulnerable population with high medical need., Trial Registration: Clinicaltrials.gov NCT04556526 . September 21, 2020., (© 2022. The Author(s).)

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., Competing Interests: Competing interests: DWJ, BG and LSHTM are partners on two research consortia (EBOVAC1, EBOVAC3) with Janssen Vaccines and Prevention B.V. funded by the European Commission., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine., Methods: 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 10 5 to 1 × 10 8 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity., Findings: Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 10 6 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis)., Interpretation: Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines., Funding: Innovative Medicines Initiative 2 Joint Undertaking., Competing Interests: Declaration of interests TPM is an employee of NewLink Genetics Corporation. SD and ME are employees of Merck Sharp & Dohme. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa., Methods and Findings: In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc., Conclusions: The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU., Trial Registration: ClinicalTrials.gov NCT02564523., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ZA, HB, CB, LR, CL and RT report grants from IMI2-2 [Grant Agreement EBOVAC2 (No.115861) from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme] during the conduct of the study. SBS reports grants from Janssen Vaccines & Prevention B.V. during the conduct of the study. MK was a full-time employee of Janssen, Pharmaceutical Companies of Johnson & Johnson at the time of the study. GS, CR, AG, DH, VB, KL, ML and MD were full-time employees of Janssen, Pharmaceutical Companies of Johnson & Johnson at the time of the study, and may own shares in Janssen, Pharmaceutical Companies of Johnson & Johnson. All other authors have nothing to disclose.

Background: The effect of malaria infection on the immunogenicity of the recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein (GP) vaccine (rVSVΔG-ZEBOV-GP) (ERVEBO) is unknown., Methods: The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) vaccinated 7998 asymptomatic adults with rVSVΔG-ZEBOV-GP during the 2014-2016 Ebola epidemic. In STRIVE's immunogenicity substudy, participants provided blood samples at baseline and at 1, 6, and 9-12 months. Anti-GP binding and neutralizing antibodies were measured using validated assays. Baseline samples were tested for malaria parasites by polymerase chain reaction., Results: Overall, 506 participants enrolled in the immunogenicity substudy and had ≥1 postvaccination antibody titer. Of 499 participants with a result, baseline malaria parasitemia was detected in 73 (14.6%). All GP enzyme-linked immunosorbent assay (ELISA) and plaque reduction neutralization test (PRNT) geometric mean titers (GMTs) at 1, 6, and 9-12 months were above baseline, and 94.1% of participants showed seroresponse by GP-ELISA (≥2-fold rise and ≥200 ELISA units/mL), while 81.5% showed seroresponse by PRNT (≥4-fold rise) at ≥1 postvaccination assessment. In participants with baseline malaria parasitemia, the PRNT seroresponse proportion was lower, while PRNT GMTs and GP-ELISA seroresponse and GMTs showed a trend toward lower responses at 6 and 9-12 months., Conclusion: Asymptomatic adults with or without malaria parasitemia had robust immune responses to rVSVΔG-ZEBOV-GP, persisting for 9-12 months. Responses in those with malaria parasitemia were somewhat lower., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

ABSTRACT The recent impact of Ebola virus disease (EVD) on public health in Africa clearly demonstrates the need for a safe and efficacious vaccine to control outbreaks and mitigate its threat to global health. ERVEBO® is an effective recombinant Vesicular Stomatitis Virus (VSV)-vectored Ebola virus vaccine (VSV-EBOV) that was approved by the FDA and EMA in late 2019 for use in prevention of EVD. Since the parental virus VSV, which was used to construct VSV-EBOV, is pathogenic for livestock and the vaccine virus may be shed at low levels by vaccinated humans, widespread deployment of the vaccine requires investigation into its infectivity and transmissibility in VSV-susceptible livestock species. We therefore performed a comprehensive clinical analysis of the VSV-EBOV vaccine virus in swine to determine its infectivity and potential for transmission. A high dose of VSV-EBOV resulted in VSV-like clinical signs in swine, with a proportion of pigs developing ulcerative vesicular lesions at the nasal injection site and feet. Uninoculated contact control pigs co-mingled with VSV-EBOV-inoculated pigs did not become infected or display any clinical signs of disease, indicating the vaccine is not readily transmissible to naïve pigs during prolonged close contact. In contrast, virulent wild-type VSV Indiana had a shorter incubation period and was transmitted to contact control pigs. These results indicate that the VSV-EBOV vaccine causes vesicular illness in swine when administered at a high dose. Moreover, the study demonstrates the VSV-EBOV vaccine is not readily transmitted to uninfected pigs, encouraging its safe use as an effective human vaccine.

Background: We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations., Methods and Findings: In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d'Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant's last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants., Conclusions: Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age., Trial Registration: ClinicalTrials.gov NCT02564523., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: HB, CB, LR reports grants from IMI2-2 [Grant Agreement EBOVAC2 (No.115861) from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme], during the conduct of the study. SBS reports grants from Janssen Vaccines and Prevention, during the conduct of the study. GS, CR, AG, DH, VB, KL, ML and MD were full-time employees of Janssen, Pharmaceutical Companies of Johnson & Johnson at the time of the study, and declared ownership of shares in Janssen, Pharmaceutical Companies of Johnson & Johnson. All other authors have nothing to disclose.

Clinical development of Ebola virus vaccines (EVV) was accelerated by the West African Ebola virus epidemic which remains the deadliest in history. To compare and rank the EVV according to their immunogenicity and safety. A total of 21 randomized controlled trial, evaluating seven different vaccines with different doses, and 5,275 participants were analyzed. The rVSVΔG-ZEBOV-GP (2 × 10 7 ) vaccine was more immunogenic ( P -score 0.80). For pain, rVSVΔG-ZEBOV-GP (≤10 5 ) had few events ( P -score 0.90). For fatigue and headache, the DNA-EBOV (≤ 4 mg) was the best one with P -scores of 0.94 and 0.87, respectively. For myalgia, the ChAd3 (10 10 ) had a lower risk ( P -score 0.94). For fever, the Ad5.ZEBOV (≤ 8 × 10 10 ) was the best one ( P -score 0.80). The best vaccine to be used to stop future outbreak of Ebola is the rVSVDG-ZEBOV-GP vaccine at dose of 2 × 10 7 PFU.

Introduction: This article describes the protocol of an Ebola vaccine clinical trial which investigates the safety and immunogenicity of a two-dose prophylactic Ebola vaccine regimen comprised of two Ebola vaccines (Ad26.ZEBOV and MVA-BN-Filo) administered 56 days apart, followed by a booster vaccination with Ad26.ZEBOV offered at either 1 year or 2 years (randomisation 1:1) after the first dose. This clinical trial is part of the EBOVAC3 project (an Innovative Medicines Initiative 2 Joint Undertaking), and is the first to evaluate the safety and immunogenicity of two different booster vaccination arms in a large cohort of adults., Methods and Analysis: This study is an open-label, monocentric, phase 2, randomised vaccine trial. A total of 700 healthcare providers and frontliners are planned to be recruited from the Tshuapa province in the Democratic Republic of the Congo (DRC). The primary and secondary objectives of the study assess the immunogenicity of the first (Ad26.ZEBOV), second (MVA-BN-Filo) and booster (Ad26.ZEBOV) dose. Immunogenicity is assessed through the evaluation of EBOV glycoprotein binding antibody responses after vaccination. Safety is assessed through the collection of serious adverse events from the first dose until 6 months post booster vaccination and the collection of solicited and unsolicited adverse events for 1 week after the booster dose., Ethics and Dissemination: The protocol was approved by the National Ethics Committee of the Ministry of Health of the DRC (n°121/CNES/BN/PMMF/2019). The clinical trial was registered on 4 December 2019 on ClinicalTrials.gov. Trial activities are planned to finish in October 2022. All participants are required to provide written informed consent and no study-related procedures will be performed until consent is obtained. The results of the trial will be added on ClinicalTrials.gov, published in peer-reviewed journals and presented at international conferences., Trial Registration Number: NCT04186000; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ebola virus (EBOV) of the genus Ebolavirus belongs to the family Filoviridae, which cause disease in both humans and non-human primates. Zaire Ebola virus accounts for the highest fatality rate, reaching 90%. Considering that EBOV has a high infection and fatality rate, the development of a highly effective vaccine has become a top public health priority. Glycoprotein (GP) plays a critical role during infection and protective immune responses. Herein, we developed an EBOV GP recombinant DNA vaccine that targets the major histocompatibility complex (MHC) class II compartment by fusing with lysosomal-associated membrane protein 1 (LAMP1). Through lysosome trafficking and antigen presentation transferring, the LAMP1 targeting strategy successfully improved both humoral and cellular EBOV-GP-specific immune responses. After three consecutive immunizations, the serum antibody titers, especially the neutralizing activity of mice immunized with the pVAX-LAMP/GP EBO vaccine were significantly higher than those of the other groups. Antigen-specific T cells showed positive activity against three dominant peptides, EAAVSHLTTLATIST, IGEWAFWETKKNLTR, and ELRTFSILNRKAIDF, with high affinity for MHC class II molecules predicted by IEDB-recommended. Preliminary safety observation denied histological alterations. DNA vaccine candidate pVAX-LAMP/GP EBO shows promise against Ebola epidemic and further evaluation is guaranteed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Implementing an Ebola vaccine trial in a remote area in the Democratic Republic of the Congo (DRC), and being confronted with a dysfunctional health care system and acute unmet health needs of participants, ethical considerations were made regarding the ancillary care obligations of the sponsor and researchers. Spurred by the occurrence of non-related (serious) adverse events (NR-SAEs), the Universities of Antwerp and Kinshasa jointly developed an algorithm, accompanied by an algorithm policy. The algorithm consists of a set of consecutive questions with binary response options, leading to structured, non-arbitrary and consistent support and management for each NR-SAE. It is the result of dialogue and collaboration between the sponsor (University of Antwerp) and the principal investigator (University of Kinshasa), consultation of literature, and input of research ethics and social sciences experts. The characteristics of the project and its budgetary framework were taken into account, as well as the local socioeconomic and healthcare situation. The algorithm and related policy have been approved by the relevant ethics committee (EC), so field implementation will begin when the study activities resume in November 2021. Lessons learnt will be shared with the relevant stakeholders within and outside DRC.If NR-SAEs are not covered by a functioning social welfare system, sponsors and researchers should develop a feasible, standardised and transparent approach to the provision of ancillary care. National legislation and contextualised requirements are therefore needed, particularly in low/middle-income countries, to guide researchers and sponsors in this process. Protocols, particularly of clinical trials conducted in areas with 'access to care' constraints, should include adequate ancillary care arrangements. Furthermore, it is essential that local ECs systematically require ancillary care provisions to enhance the well-being and protection of the rights of research participants. This project was funded by the European Union's Horizon 2020 research and innovation programme, European Federation of Pharmaceutical Industries and Associations, and the Coalition for Epidemic Preparedness Innovations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replication-deficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus., Methods: This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18-65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I-III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov, NCT02416453, and EudraCT, 2015-000596-27., Findings: Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I-III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99·5%) participants received at least one dose of vaccine or placebo. The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and per-protocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoprotein-binding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649-5867) in the 28-day interval group, 10 131 EU/mL (8554-11 999) in the 56-day interval group, and 11 312 mL (9072-14106) in the 84-day interval group, with antibody concentrations persisting at 1149-1205 EU/mL up to day 365., Interpretation: The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen., Funding: Innovative Medicines Initiative and Janssen Vaccines & Prevention BV., Translation: For the French translation of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The 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., Methods: This 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., Results: From 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., Discussion: The 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 Registration: ClinicalTrials.gov NCT02876328 . Registered on 23 August 2016.

Background: During the large 2013-16 Ebola virus outbreak caused by the Zaire Ebola virus, about 20% of cases were reported in children. This study is the first, to our knowledge, to evaluate an Ebola vaccine in children younger than 6 years. We aimed to evaluate the safety, reactogenicity, and immunogenicity of a monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in a paediatric population., Methods: This phase 2, randomised, observer-blind, controlled trial was done in a vaccine centre in Mali and a university hospital centre in Senegal. Healthy children were randomly assigned through a web-based system (1:1; stratified by age group, gender, and centre) to receive ChAd3-EBO-Z (day 0) and meningococcal serogroups A,C,W-135,Y tetanus toxoid conjugate vaccine (MenACWY-TT; month 6), or MenACWY-TT (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind from study start until interim day 30 analysis and became single-blind as of interim analysis. Primary outcomes assessed were serious adverse events (up to study end, month 12), solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). As secondary endpoints, we evaluated anti-glycoprotein Zaire Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02548078., Findings: From Nov 11, 2015, to May 9, 2016, of 776 children screened for eligibility, 600 were randomly assigned (200 [33%] in each age strata: 1-5, 6-12, 13-17 years), 300 (50%) to the ChAd3-EBO-Z/MenACWY-TT group and 300 (50%) to the MenACWY-TT/ChAd3-EBO-Z group; all were included in the total vaccinated cohort. Post-day 0 vaccination, the most common solicited injection site symptom was pain (127 [42%] of 300 in the ChAd3-EBO-Z/MenACWY-TT group vs 60 [20%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group); the most common solicited general adverse event was fever (95 [32%] of 300 in the ChAd3-EBO-Z/MenACWY-TT group vs 28 [9%] of 300 in the MenACWY-TT/ChAd3-EBO-Z group). Unsolicited adverse events post-day 0 vaccination were reported by 41 (14%) of 300 participants in the ChAd3-EBO-Z/MenACWY-TT group and 24 (8%) of 300 MenACWY-TT/ChAd3-EBO-Z recipients. Serious adverse events were reported for two (1%) of 300 children in each group; none were considered vaccination related. No clinical symptoms of thrombocytopenia were reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentrations (GMC) in the ChAd3-EBO-Z/MenACWY-TT group were 1564 (95% CI 1340-1826) for those aged 13-17 years, 1395 (1175-1655) for 6-12 years, and 2406 (1942-2979) for 1-5 years. Anti-glycoprotein Ebola virus IgG antibody responses persisted up to 12 months post-vaccination, with a GMC of 716 (95% CI 619-828) for those aged 13-17 years, 752 (645-876) for 6-12 years, and 1424 (1119-1814) for 1-5 years., Interpretation: ChAd3-EBO-Z was immunogenic and well tolerated in children aged 1-17 years. This study provides the first ChAd3-EBO-Z data in a paediatric population. Further development should focus on multivalent approaches including Sudan and Marburg strains, and heterologous prime-boost strategies, for instance using modified vaccinia Ankara-based vaccine to boost the immune response., Funding: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The 2014 Zaire Ebola virus disease epidemic accelerated vaccine development for the virus. We aimed to assess the safety, reactogenicity, and immunogenicity of one dose of monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in adults., Methods: This phase 2, randomised, observer-blind, controlled trial was done in study centres in Cameroon, Mali, Nigeria, and Senegal. Healthy adults (≥18 years) were randomly assigned with a web-based system (1:1; minimisation procedure accounting for age, gender, centre) to receive ChAd3-EBO-Z (day 0), or saline placebo (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind until planned interim day 30 analysis, single-blind until month 6, and open-label after month 6 vaccination. Primary outcomes assessed in the total vaccinated cohort, which comprised all participants with at least one study dose administration documented, were serious adverse events (up to study end, month 12); and for a subcohort were solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). Secondary endpoints (subcohort; per-protocol cohort) evaluated anti-glycoprotein Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02485301., Findings: Between July 22, 2015, and Dec 10, 2015, 3030 adults were randomly assigned; 3013 were included in the total vaccinated cohort (1509 [50·1%] in the ChAd3-EBO-Z group and 1504 [49·9%] in the placebo/ChAd3-EBO-Z group), 17 were excluded because no vaccine was administered. The most common solicited injection site symptom was pain (356 [48%] of 748 in the ChAd3-EBO-Z group vs 57 [8%] of 751 in the placebo/ChAd3-EBO-Z group); the most common solicited general adverse event was headache (345 [46%] in the ChAd3-EBO-Z group vs 136 [18%] in the placebo/ChAd3-EBO-Z group). Unsolicited adverse events were reported by 123 (16%) of 749 in the ChAd3-EBO-Z group and 119 (16%) of 751 in the placebo/ChAd3-EBO-Z group. Serious adverse events were reported for 11 (1%) of 1509 adults in the ChAd3-EBO-Z group, and 18 (1%) of 1504 in the placebo/ChAd3-EBO-Z group; none were considered vaccination-related. No clinically meaningful thrombocytopenia was reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentration was 900 (95% CI 824-983) in the ChAd3-EBO-Z group. There were no treatment-related deaths., Interpretation: ChAd3-EBO-Z was immunogenic and well tolerated in adults. Our findings provide a strong basis for future development steps, which should concentrate on multivalent approaches (including Sudan and Marburg strains). Additionally, prime-boost approaches should be a focus with a ChAd3-based vaccine for priming and boosted by a modified vaccinia Ankara-based vaccine., Funding: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Little information exists regarding Ebola vaccine rVSVΔG-ZEBOV-GP and pregnancy. The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) randomized participants without blinding to immediate or deferred (18-24 weeks postenrollment) vaccination. Pregnancy was an exclusion criterion, but 84 women were inadvertently vaccinated in early pregnancy or became pregnant <60 days after vaccination or enrollment. Among immediate vaccinated women, 45% (14/31) reported pregnancy loss, compared with 33% (11/33) of unvaccinated women with contemporaneous pregnancies (relative risk 1.35, 95% CI 0.73-2.52). Pregnancy loss was similar among women with higher risk for vaccine viremia (conception before or <14 days after vaccination) (44% [4/9]) and women with lower risk (conception >15 days after vaccination) (45% [10/22]). No congenital anomalies were detected among 44 live-born infants examined. These data highlight the need for Ebola vaccination decisions to balance the possible risk for an adverse pregnancy outcome with the risk for Ebola exposure.

To evaluate the risk-benefits balance of the rVSV-ΔG-ZEBOV-GP vaccine. We performed a systematic review to summarize data on safety, immunogenicity and efficacy. About 17,600 adults and 234 children received 11 different doses of the V920 vaccine ranging from 3000 to 100 million and 20 million plaque-forming units, respectively, during Phase I-III clinical trials. Cases of severe but transient arthritis were reported in about six and 0.08% of vaccinees in high-income countries (HICs) and low-middle-income countries (LMICs), respectively. The 20 million plaque-forming units dose yielded GP-specific antibody titres which peaked at day 28 with a pooled geometric mean titres of 2557.7 (95% CI: 1665.5-3934.2) versus 1156.9 (95% CI: 832.5-1649.2) but with similar seroconversion rates at 96% (95% CI: 87-100) versus 100% (95% CI: 90-100) for HICs and LMICs, respectively. Data from stringent Phase I-II clinical trials in LMICs and HICs and from the ring efficacy trials yielded a good risk-benefit balance of the V920 vaccine in adults, but also in children and pregnant and lactating women and HIV-infected people.

Introduction : Ebolaviruses are non-segmented negative-strand RNA viruses in the Filoviridae family that cause a neglected infectious disease designated as Ebola virus disease (EVD). The most prominent member is the Ebola virus (EBOV), representing the Zaire ebolavirus species that has been responsible for the largest reported EVD outbreaks including the West African epidemic and the current outbreak in the Democratic Republic of the Congo. Today, the most advanced EVD vaccine approaches target EBOV and multiple phase 1-4 human trials have been performed over the past few years. The most advanced platforms include vectored vaccines based on vesicular stomatitis virus (VSV-EBOV), distinct human (Ad5 and Ad26) and chimpanzee (ChAd3) adenoviruses and modified vaccinia Ankara (MVA) as well as DNA-based vaccines administered as a prime-only or homologous or combined prime-boost immunization. Areas covered : Here, we review and discuss human trials with a focus on vaccine safety and immunogenicity. Expert opinion : Despite obvious progress and promising success in EBOV vaccine development, many shortcomings and challenges remain to be tackled in the future.

Background: As part of the ring vaccination trial in Guinea, Front Line Workers were invited to participate in a sub-study to provide additional information on the immunogenicity and safety of rVSVΔG/ZEBOV-GP. Here we summarize the information on the safety follow-up., Methods: An open-label, non-randomized, immunogenicity evaluation of one dose of rVSVΔG/ZEBOV-GP was conducted in Conakry, Guinea between March 2015 and July 2016. Front-line workers refusing vaccination were invited to participate as a control group. Participants were followed for 3 months with a subset followed-up for 6 months after vaccination. Women becoming pregnant during the follow-up were followed until pregnancy outcome. Solicited and unsolicited adverse events were monitored at each contact with participants using standardized study forms., Results: 2016 vaccinated participants and 99 controls were included in the safety cohort. On the 3 days post-vaccination visit adverse events were very common, with over 70% of participants reporting at least one adverse event. The most frequently reported symptoms were headache, fatigue, arthralgia, subjective fever and myalgia. Among participants that completed fever diaries (n = 887), post-vaccination fever was reported by 15.22%. Comparing to the unvaccinated group, local reaction, fatigue, headache, arthralgia, myalgia and subjective fever occurring within the first 3 days post-vaccination were statistically significantly different in the vaccinated group compared to the unvaccinated. A total of 8 Serious Adverse Events were identified during follow-up. 2 SAEs were related to pregnancy., Conclusions: Results confirm that adverse events 3 days after vaccination with the rVSV candidate vaccine are common. The occurrence of fever is of particular concern in the context of ongoing Ebola transmission. Additional studies should address important data gaps regarding the use of the vaccine in pregnancy and other vulnerable populations., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Alongside the clinical aspects of the immunogenicity and safety trial of an Ebola vaccine deployed among front-line workers, a qualitative study was conducted to describe motivations behind individuals' decisions to participate - or not to participate - in the study., Methods: In July and August 2015, focus group discussions and semi-structured individual interviews were conducted in Conakry, Guinea. Individuals were eligible for the qualitative study if they met the inclusion criteria of the immunogenicity and safety study irrespective of their participation. Surveys were also conducted among several institution and department heads of staff included in the study as well as vaccine trial staff members. Discussion and interview transcripts were analyzed using content thematic analysis., Results: Interviews and focus groups were conducted among 110 persons, of whom about two-thirds (67%) participated in the vaccine trial. There was at least one group interview conducted at each participating trial site, along with numerous formal and informal interviews and conversations through the enrollment period. Participants were often motivated by a desire to save and protect themselves and others, contribute to scientific progress, or lead by example. Non-participants expressed concerns regarding the risk and costs of participation, particularly the fear of unknown side effects following vaccination, and distrust or fear of stigmatization., Conclusions: Despite the unique nature of the 2014-2015 Ebola outbreak, front-line workers employed much of the same logic when choosing to participate as in other clinical trials in similar settings. Special consideration should be given to addressing perceived inequity, misunderstanding, and mistrust among the target populations in future trials. Clinical trial registry number: This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.

Background: This double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP)., Methods: Healthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed., Results: ZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination., Conclusions: Immune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development., Clinical Trials Registration: NCT02503202., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Nonlive vaccine approaches that are simple to deliver and stable at room temperature or 2-8°C could be advantageous in controlling future Ebola virus (EBOV) outbreaks. Using an immunopotent DNA vaccine that generates protection from lethal EBOV challenge in small animals and nonhuman primates, we performed a clinical study to evaluate both intramuscular (IM) and novel intradermal (ID) DNA delivery., Methods: Two DNA vaccine candidates (INO-4201 and INO-4202) targeting the EBOV glycoprotein (GP) were evaluated for safety, tolerability, and immunogenicity in a phase 1 clinical trial. The candidates were evaluated alone, together, or in combination with plasmid-encoded human cytokine interleukin-12 followed by in vivo electroporation using either the CELLECTRA® IM or ID delivery devices., Results: The safety profile of all 5 regimens was shown to be benign, with the ID route being better tolerated. Antibodies to EBOV GP were generated by all 5 regimens with the fastest and steepest rise observed in the ID group. Cellular immune responses were generated with every regimen., Conclusions: ID delivery of INO-4201 was well tolerated and resulted in 100% seroreactivity after 2 doses and elicited interferon-γ T-cell responses in over 70% of subjects, providing a new approach for EBOV prevention in diverse populations. Clinical Trials Registration. NCT02464670., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: During the 2014 West African Ebola outbreak, Ebola vaccine development was accelerated. The phase 1 VAC52150EBL1003 study was performed to investigate 2-dose heterologous vaccination with Ad26.ZEBOV and MVA-BN-Filo in an African population located in a high-altitude setting in Nairobi, Kenya., Methods: Healthy adult volunteers were randomized to receive one of four 2-dose vaccination schedules. The first vaccination was administered at baseline (Ad26.ZEBOV or MVA-BN-Filo), followed by the second vaccination with the alternate vaccine after either 28 or 56 days. Each schedule had a placebo comparator group. The primary objective was to assess the safety and tolerability of these regimens., Results: Seventy-two volunteers were randomized into 4 groups of 18 (15 received vaccine, and 3 received placebo). The most frequent solicited systemic adverse event was headache (frequency, 50%, 61%, and 42% per dose for MVA-BN-Filo, Ad26.ZEBOV, and placebo, respectively). The most frequent solicited local AE was injection site pain (frequency, 78%, 63%, and 33% per dose for MVA-BN-Filo, Ad26.ZEBOV, and placebo, respectively). No differences in adverse events were observed among the different vaccine regimens. High levels of binding and neutralizing anti-Ebola virus glycoprotein antibodies were induced by all regimens and sustained to day 360 after the first dose., Conclusions: Two-dose heterologous vaccination with Ad26.ZEBOV and MVA-BN-Filo was well tolerated and highly immunogenic against Ebola virus glycoprotein., Clinical Trials Registration: NCT02376426., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Ebola vaccine development was accelerated in response to the 2014 Ebola virus infection outbreak. This phase 1 study (VAC52150EBL1004) assessed safety, tolerability, and immunogenicity of heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimens in the Lake Victoria Basin of Tanzania and Uganda in mid-level altitude, malaria-endemic settings., Methods: Healthy volunteers aged 18-50 years from Tanzania (n = 25) and Uganda (n = 47) were randomized to receive placebo or active vaccination with Ad26.ZEBOV or MVA-BN-Filo (first vaccination), followed by MVA-BN-Filo or Ad26.ZEBOV (second vaccination) dose 2, respectively, with intervals of 28 or 56 days., Results: Seventy-two adults were randomized to receive vaccine (n = 60) or placebo (n = 12). No vaccine-related serious adverse events were reported. The most frequent solicited local and systemic adverse events were injection site pain (frequency, 70%, 66%, and 42% per dose for MVA-BN-Filo, Ad26.ZEBOV, and placebo, respectively) and headache (57%, 56%, and 46%, respectively). Adverse event patterns were similar among regimens. Twenty-one days after dose 2, 100% of volunteers demonstrated binding antibody responses against Ebola virus glycoprotein, and 87%-100% demonstrated neutralizing antibody responses. Ad26.ZEBOV dose 1 vaccination induced more-robust initial binding antibody and cellular responses than MVA-BN-Filo dose 1 vaccination., Conclusions: Heterologous 2-dose vaccination with Ad26.ZEBOV and MVA-BN-Filo against Ebola virus is well tolerated and immunogenic in healthy volunteers., Clinical Trials Registration: NCT02376400., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: In November 2015, a 15-year-old boy received a diagnosis of Ebola virus disease (EVD) at the John F. Kennedy Medical Center in Monrovia, Liberia. Two additional family members received a diagnosis of EVD. The protocol for a phase 2 placebo-controlled trial of 2 Ebola vaccines was amended and approved; in 4 days, a single-arm cluster vaccination trial using the Merck rVSVΔG-ZEBOV-GP vaccine was initiated. Here, we evaluate the safety and immunogenicity of the vaccine and discuss challenges for its implementation in a small Ebola outbreak., Method: We conducted a ring vaccination study among contacts and contacts of close contacts of EVD cases a in Monrovia. Participants were evaluated 1 and 6 months after vaccination., Results: Among 650 close contacts and contacts of close contacts of EVD cases, 210 (32%) consented and were vaccinated with rVSVΔG-ZEBOV-GP. Of those vaccinated, 189 (90%) attended the month 1 follow-up visit; 166 (79%) attended the month 6 visit. No serious adverse events were reported. Among 88 participants without an elevated antibody level at baseline, 77.3% (95% confidence interval, 68.5-86.1) had an antibody response at 1 month., Conclusions: The Merck rVSVΔG-ZEBOV-GP vaccine appeared to be safe and immunogenic among the vaccinated individuals. However, fewer than one third of eligible individuals consented to vaccination. These data may help guide implementation decisions for of cluster vaccination programs in an Ebola cluster outbreak response situation., (Published by Oxford University Press for the Infectious Diseases Society of America 2018.)

Background: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine., Methods: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events., Results: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb., Conclusions: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control., Clinical Trials Registration: NCT02451891; NCT02485912., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

The West African Ebola virus (EBOV) epidemic has fast-tracked countermeasures for this rare, emerging zoonotic pathogen. Until 2013-2014, most EBOV vaccine candidates were stalled between the preclinical and clinical milestones on the path to licensure, because of funding problems, lack of interest from pharmaceutical companies, and competing priorities in public health. The unprecedented and devastating epidemic propelled vaccine candidates toward clinical trials that were initiated near the end of the active response to the outbreak. Those trials did not have a major impact on the epidemic but provided invaluable data on vaccine safety, immunogenicity, and, to a limited degree, even efficacy in humans. There are plenty of lessons to learn from these trials, some of which are addressed in this review. Better preparation is essential to executing an effective response to EBOV in the future; yet, the first indications of waning interest are already noticeable.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE), a phase 2/3 trial of investigational rVSV∆G-ZEBOV-GP vaccine, was conducted during an unprecedented Ebola epidemic. More than 8600 eligible healthcare and frontline response workers were individually randomized to immediate (within 7 days) or deferred (within 18-24 weeks) vaccination and followed for 6 months after vaccination for serious adverse events and Ebola virus infection. Key challenges included limited infrastructure to support trial activities, unreliable electricity, and staff with limited clinical trial experience. Study staff made substantial infrastructure investments, including renovation of enrollment sites, laboratories, and government cold chain facilities, and imported equipment to store and transport vaccine at ≤-60oC. STRIVE built capacity by providing didactic and practical research training to >350 staff, which was reinforced with daily review and feedback meetings. The operational challenges of safety follow-up were addressed by issuing mobile telephones to participants, making home visits, and establishing a nurse triage hotline. Before the Ebola outbreak, Sierra Leone had limited infrastructure and staff to conduct clinical trials. Without interfering with the outbreak response, STRIVE responded to an urgent need and helped build this capacity., Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

Animal models have played a pivotal role in all stages of vaccine development. Their predictive value for vaccine effectiveness depends on the pathogen, the robustness of the animal challenge model, and the correlates of protection (if known). This article will cover key questions regarding bridging animal studies to efficacy trials in humans. Examples include human papillomavirus (HPV) vaccine in which animal protection after vaccination with heterologous prototype virus-like particles (VLPs) predicted successful efficacy trials in humans, and a recent approval of anthrax vaccine in accordance with the "Animal Rule." The establishment of animal models predictive of vaccine effectiveness in humans has been fraught with difficulties with low success rate to date. Challenges facing the use of animal models for vaccine development against Ebola and HIV will be discussed., (Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.)

Introduction: In 2014-2016, an Ebola epidemic devastated Guinea; more than 3800 cases and 2500 deaths were reported to the World Health Organization. In August 2015, as the epidemic waned and clinical trials of an experimental, Ebola vaccine continued in Guinea and neighboring Sierra Leone, we conducted a national household survey about Ebola-related knowledge, attitudes, and practices (KAP) and opinions about "hypothetical" Ebola vaccines., Methods: Using cluster-randomized sampling, we selected participants aged 15+ years old in Guinea's 8 administrative regions, which had varied cumulative case counts. The questionnaire assessed socio-demographic characteristics, experiences during the epidemic, Ebola-related KAP, and Ebola vaccine attitudes. To assess the potential for Ebola vaccine introduction in Guinea, we examined the association between vaccine attitudes and participants' characteristics using categorical and multivariable analyses., Results: Of 6699 persons invited to participate, 94% responded to at least 1 Ebola vaccine question. Most agreed that vaccines were needed to fight the epidemic (85.8%) and that their family would accept safe, effective Ebola vaccines if they became available in Guinea (84.2%). These measures of interest and acceptability were significantly more common among participants who were male, wealthier, more educated, and lived with young children who had received routine vaccines. Interest and acceptability were also significantly higher among participants who understood Ebola transmission modes, had witnessed Ebola response teams, knew Ebola-affected persons, believed Ebola was not always fatal, and would access Ebola treatment centers. In multivariable analyses of the majority of participants living with young children, interest and acceptability were significantly higher among those living with vaccinated children than among those living with unvaccinated children., Discussion: The high acceptability of hypothetical vaccines indicates strong potential for introducing Ebola vaccines across Guinea. Strategies to build public confidence in use of Ebola vaccines should highlight any similarities with safe, effective vaccines routinely used in Guinea., (Published by Elsevier Ltd.)

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., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)