#Safety and immunogenicity of a highly attenuated rVSVN4CT1-EBOVGP1 #Ebola virus #vaccine: a randomised, double-blind, placebo-controlled, phase 1 clinical trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Safety and immunogenicity of a highly attenuated rVSVN4CT1-EBOVGP1 Ebola virus vaccine: a randomised, double-blind, placebo-controlled, phase 1 clinical trial

David K Clarke, PhD, Rong Xu, PhD †, Demetrius Matassov, PhD †, Theresa E Latham, MSc, Ayuko Ota-Setlik, MSc, Cheryl S Gerardi, BSc, Amara Luckay, MSc, Susan E Witko, MSc, Luz Hermida, PhD, Terry Higgins, PhD, Marc Tremblay, BSc, Susan Sciotto-Brown, MSc, Tracy Chen, PhD, Michael A Egan, PhD, Janice M Rusnak, MD, Lucy A Ward, PhD, John H Eldridge, PhD

Published: January 14, 2020 / DOI: https://doi.org/10.1016/S1473-3099(19)30614-0

 

Summary

Background

The safety and immunogenicity of a highly attenuated recombinant vesicular stomatitis virus (rVSV) expressing HIV-1 gag (rVSVN4CT1-HIV-1gag1) was shown in previous phase 1 clinical studies. An rVSV vector expressing Ebola virus glycoprotein (EBOV-GP) in place of HIV-1 gag (rVSVN4CT1-EBOVGP1) showed single-dose protection from lethal challenge with low passage Ebola virus in non-human primates. We aimed to evaluate the safety and immunogenicity of the rVSVN4CT1-EBOVGP1 vaccine in healthy adults.

Methods

We did a randomised double-blind, placebo-controlled, phase 1 dose-escalation study at a single clinical site (Optimal Research) in Melbourne, FL, USA. Eligible participants were healthy men and non-pregnant women aged 18–60 years, with a body-mass index (BMI) of less than 40 kg/m 2, no history of filovirus infection, VSV infection, or receipt of rVSV in previous studies, and who had not visited regions where Ebola virus outbreaks have occurred. Three cohorts were enrolled to assess a low (2·5 × 10 4 plaque forming units [PFU]), intermediate (2 × 10 5 PFU), or high dose (1·8 × 10 6 PFU) of the vaccine. Participants within each cohort were randomly allocated (10:3) to receive vaccine or placebo by intramuscular injection in a homologous prime and boost regimen, with 4 weeks between doses. All syringes were masked with syringe sleeves; participants and study site staff were not blinded to dose level but were blinded to active vaccine and placebo. The primary outcomes were safety and tolerability; immunogenicity, assessed as GP-specific humoral immune response (at 2 weeks after each dose) and cellular immune response (at 1 and 2 weeks after each dose), was a secondary outcome. All randomised participants were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, NCT02718469.

Findings

Between Dec 22, 2015, and Sept 15, 2016, 39 individuals (18 [46%] men and 21 [54%] women, mean age 51 years [SD 10]) were enrolled, with ten participants receiving the vaccine and three participants receiving placebo in each of three cohorts. One participant in the intermediate dose cohort was withdrawn from the study because of a diagnosis of invasive ductal breast carcinoma 24 days after the first vaccination, which was considered unrelated to the vaccine. No severe adverse events were observed. Solicited local adverse events occurred in ten (26%) of 39 participants after the first dose and nine (24%) of 38 participants after the second dose; the events lasted 3 days or less, were predominantly injection site tenderness (17 events) and injection site pain (ten events), and were either mild (19 events) or moderate (ten events) in intensity. Systemic adverse events occurred in 13 (33%) of 39 participants after the first dose and eight (21%) of 38 participants after the second dose; the events were mild (45 events) or moderate (11 events) in severity, and the most common events were malaise or fatigue (13 events) and headache (12 events). Arthritis and maculopapular, vesicular, or purpuric rash distal to the vaccination site(s) were not reported. A GP-specific IgG response was detected in all vaccine recipients after two doses (and IgG response frequency was 100% after a single high dose), and an Ebola virus neutralising response was detected in 100% of participants in the high-dose cohort.

Interpretation

The rVSVN4CT1-EBOVGP1 vaccine was well tolerated at all dose levels tested and was immunogenic despite a high degree of attenuation. The combined safety and immunogenicity profile of the rVSVN4CT1-EBOVGP1 vaccine vector support phase 1–2 clinical evaluation.

Funding

US Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense: Joint Project Manager for Chemical, Biological, Radiological and Nuclear Medical.

Keywords: Ebola; Vaccines.

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Association Between #Treatment with Oral Third-Generation #Cephalosporin #Antibiotics and #Mortality #Outcomes in #Ebola Virus Disease: A Multinational Retrospective Cohort Study (Trop Med Int Health, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Trop Med Int Health. 2020 Jan 7. doi: 10.1111/tmi.13369. [Epub ahead of print]

Association Between Treatment with Oral Third-Generation Cephalosporin Antibiotics and Mortality Outcomes in Ebola Virus Disease: A Multinational Retrospective Cohort Study.

Aluisio AR1, Perera SM2, Yam D3, Garbern S1, Peters JL4, Abel L4, Cho DK4, Woldemichael D2, Kennedy SB5, Massaquoi M5, Sahr F6, Liu T3, Levine AC1.

Author information: 1 Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, USA. 2 International Medical Corps, Washington, DC, USA. 3 Center for Statistical Sciences, Department of Biostatistics, Brown University School of Public Health, Providence, USA. 4 Warren Alpert Medical School of Brown University, Providence, USA. 5 Ministry of Health, Monrovia, Liberia. 6 College of Medicine and Allied Health Sciences, University of Sierra Leone, Sierra Leone, Freetown.

 

Abstract

OBJECTIVE:

To evaluate the association between oral third-generation cephalosporin antibiotic treatment and mortality in Ebola Virus Disease (EVD).

METHODS:

This retrospective cohort studied EVD-infected patients admitted to five Ebola Treatment Units in Sierra Leone and Liberia during 2014-15. Empiric treatment with Cefixime 400 mg once daily for five days was the clinical protocol: however, due to resource variability, only a subset of patients received treatment. Data on sociodemographics, clinical characteristics, malaria status and Ebola viral loads were collected. The primary outcome was mortality compared between cases treated with Cefixime within 48 hours of admission to those not treated within 48 hours. Propensity scores were derived using clinical covariates. Mortality between treated and untreated cases was compared using propensity-matched conditional logistic regression and bootstrapped log-linear regression analyses to calculate an odds ratio (OR) and relative risk (RR), respectively, with associated 95% confidence intervals (CI).

RESULTS:

Of 424 cases analyzed, 360 (84.9%) met the Cefixime treatment definition. The mean age was 30.5 years and 40.3% were male. Median Cefixime treatment duration was 4 days (IQR: 3, 5). Among Cefixime-treated patients, mortality was 54.7% (95% CI: 49.6-59.8%), vs. 73.4% (95% CI: 61.5-82.7%) in untreated patients. In conditional logistic regression, mortality likelihood was significantly lower among cases receiving Cefixime (OR=0.48, 95% CI: 0.32-0.71; p=0.01). In the bootstrap analysis, a non-significant risk reduction was found with Cefixime treatment (RR=0.82, 95% CI: 0.64-1.16, p=0.11).

CONCLUSION:

Early oral Cefixime may be associated with reduced mortality in EVD and warrants further investigation.

© 2020 John Wiley & Sons Ltd.

KEYWORDS: Antibiotics; Cephalosporin; Cohort Study; Ebola Virus; Viral hemorrhagic fevers

PMID: 31912627 DOI: 10.1111/tmi.13369

Keywords: Antibiotics; Cephalosporins; Cefixime; Ebola.

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Recurrent #Ebolavirus disease in the #DRC: #update and #challenges (AIMS Public Health, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

AIMS Public Health. 2019 Nov 20;6(4):502-513. doi: 10.3934/publichealth.2019.4.502. eCollection 2019.

Recurrent Ebolavirus disease in the Democratic Republic of Congo: update and challenges.

Inungu J1, Iheduru-Anderson K2, Odio OJ3.

Author information: 1 Master of Public Health Program, College of Health Professions, Central Michigan University, Michigan, United States. 2 Nursing Program, Central Michigan University, Michigan, United States. 3 Department of Internal Medicine, Medical School Hospital, University of Kinshasa, Kinshasa, Congo.

 

Abstract

The current Ebolavirus disease (EVD) outbreak in the provinces of North Kivu and Ituri is the tenth outbreak affecting the Democratic Republic of Congo (DRC); the first outbreak occurring in a war context, and the second most deadly Ebolavirus outbreak on record following the 2014 outbreak in West Africa. The DRC government’s response consisted of applying a package of interventions including detection and rapid isolation of cases, contact tracing, population mapping, and identification of high-risk areas to inform a coordinated effort. The coordinated effort was to screen, ring vaccinate, and conduct laboratory diagnoses using GeneXpert (Cepheid) polymerase chain reaction. The effort also included ensuring safe and dignified burials and promoting risk communication, community engagement, and social mobilization. Following the adoption of the “Monitored Emergency Use of Unregistered Products Protocol,” a randomized controlled trial of four investigational treatments (mAb114, ZMapp, and REGN-EB3 and Remdesivir) was carried out with all consenting patients with laboratory-confirmed EVD. REGN-EB3 and mAb114 showed promise as treatments for EVD. In addition, one investigational vaccine (rVSV-ZEBOV-GP) was used first, followed by a second prophylactic vaccine (Ad26.ZEBOV/MVA-BN-Filo) to reinforce the prevention. Although the provision of clinical supportive care remains the cornerstone of EVD outbreak management, the DRC response faced daunting challenges including general insecurity, violence and community resistance, appalling poverty, and entrenched distrust of authority. Ebolavirus remains a public health threat. A fully curative treatment is unlikely to be a game-changer given the settings of transmission, zoonotic nature, limits of effectiveness of any therapeutic intervention, and timing of presentation.

© 2019 the Author(s), licensee AIMS Press.

KEYWORDS: Ebola outbreak; epidemiology; hemorrhagic fever; prevention; treatment

PMID: 31909070 PMCID: PMC6940573 DOI: 10.3934/publichealth.2019.4.502

Keywords: Ebola; DRC; Public Health.

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In Vivo Activity of #Amodiaquine against #Ebola Virus #Infection (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2019 Dec 27;9(1):20199. doi: 10.1038/s41598-019-56481-0.

In Vivo Activity of Amodiaquine against Ebola Virus Infection.

DeWald LE1,2, Johnson JC1,3, Gerhardt DM1, Torzewski LM1,4, Postnikova E1, Honko AN1,5, Janosko K1, Huzella L1, Dowling WE6, Eakin AE6, Osborn BL6, Gahagen J7, Tang L7, Green CE7, Mirsalis JC7, Holbrook MR1, Jahrling PB1,8, Dyall J9, Hensley LE1.

Author information: 1 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. 2 Emergent BioSolutions Inc, Gaithersburg, MD, 20879, USA. 3 AbViro LLC, Bethesda, MD, 20814, USA. 4 Bioqual Inc, Rockville, MD, 20850, USA. 5 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. 6 Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20892, USA. 7 SRI International, Menlo Park, CA, 94025, USA. 8 Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. 9 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, 21702, USA. dyallj@niaid.nih.gov.

 

Abstract

During the Ebola virus disease (EVD) epidemic in Western Africa (2013‒2016), antimalarial treatment was administered to EVD patients due to the high coexisting malaria burden in accordance with World Health Organization guidelines. In an Ebola treatment center in Liberia, EVD patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. As artemether and artesunate are derivatives of artemisinin, the beneficial anti-Ebola virus (EBOV) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. Amodiaquine is a widely used antimalarial in the countries that experience outbreaks of EVD and, therefore, holds promise as an approved drug that could be repurposed for treating EBOV infections. We investigated the potential anti-EBOV effect of amodiaquine in a well-characterized nonhuman primate model of EVD. Using a similar 3-day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. However, the treatment regimen did not result in a survival benefit or decrease of disease signs in EBOV-infected animals. While amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral.

PMID: 31882748 DOI: 10.1038/s41598-019-56481-0

Keywords: Antivirals; Ebola; Amodiaquine; Animal models.

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#Ebola virus disease in #children in #Conakry and Coyah #ETCs and #risk #factors associated with death (Med Mal Infect., abstract)

[Source: US National Library of Medicine, full page: (LINKLINK). Abstract, edited.]

Med Mal Infect. 2019 Dec 21. pii: S0399-077X(19)31077-7. doi: 10.1016/j.medmal.2019.12.001. [Epub ahead of print]

Ebola virus disease in children in Conakry and Coyah Ebola treatment centers and risk factors associated with death.

Sow MS1, Sow DC2, Diallo ML3, Kassé D3, Sylla K2, Camara A4, Djiro SD5, Diallo MOS2, Bah EI2, Bah I2, Diallo MP3.

Author information: 1 Service des maladies infectieuses et tropicales de l’hôpital National de Donka. Electronic address: smsaliou@gmail.com. 2 Service des maladies infectieuses et tropicales de l’hôpital National de Donka. 3 Service de pédiatrie de l’hôpital National de Donka. 4 Chaire de santé publique. 5 Registre des cancers de Guinée, Guinea.

 

Abstract

OBJECTIVE:

To study Ebola virus disease (EVD) in children aged 15 years and below, and to identify risk factors associated with death.

PATIENTS AND METHODS:

Retrospective, multicenter, descriptive, and analytical study of files of children aged 15 years and below in Ebola treatment centers (ETC) of Donka from March 2014 to May 2015. We included all files of children aged 15 years and below hospitalized for EVD in the two ETCs.

RESULTS:

A total of 739 patients hospitalized in both ETCs, 146 children aged 15 years and below (20%) were registered during the study period. The mean age of children was 6.73±4.26 years. Most children were aged above five years (65.8%) and the mean time to consultation was 4.34±3.21 days. The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%), vomiting (41.8%), abdominal pain (29.5%), and diarrhea (28.8%). The case fatality was 48%, including 54.3% in Coyah and 45% in Conakry. Older age (aOR=0.83, 95% CI [0.76-0.95]), fever (aOR=3.28, 95% CI [1.22-8.87]), diarrhea (aOR=2.98, 95% CI [1.19-4.48]), and hemorrhage (aOR=3.13, 95% CI [1.00-10.38]) were independently associated with death due to EVD.

CONCLUSION:

EVD remains serious especially in children, with high case fatality. Risk factors independently associated with death were young age, diarrhea, hemorrhage, and fever. Particular attention to these risk factors and vaccination will contribute to improving the prognosis of EVD in children.

Copyright © 2019 Elsevier Masson SAS. All rights reserved.

KEYWORDS: Children; Ebola; Ebola treatment center

PMID: 31874716 DOI: 10.1016/j.medmal.2019.12.001

Keywords: Ebola; Guinea; Pediatrics.

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#Ebola #Patient Virus Cycle Threshold and #Risk of #Household #Transmission of Ebola Virus (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Ebola Patient Virus Cycle Threshold and Risk of Household Transmission of Ebola Virus

Mary R Reichler, Dana Bruden, Harold Thomas, Bobbie Rae Erickson, Barbara Knust, Nadia Duffy, John Klena, Thomas Hennessy, the Household Transmission Investigative Team

The Journal of Infectious Diseases, jiz511, https://doi.org/10.1093/infdis/jiz511

Published: 19 December 2019

 

Abstract

Background

Identifying risk factors for household transmission of Ebola virus (EBOV) is important to guide preventive measures during Ebola outbreaks.

Methods

We enrolled all confirmed persons with EBOV disease who were the first case patient in a household from December 2014 to April 2015 in Freetown, Sierra Leone, and their household contacts. Index patients and contacts were interviewed, and contacts were followed up for 21 days to identify secondary cases. Epidemiologic data were linked to EBOV real-time reverse-transcription polymerase chain reaction cycle threshold (Ct) data from initial diagnostic specimens obtained from enrolled index case patients.

Results

Ct data were available for 106 (71%) of 150 enrolled index patients. Of the Ct results, 85 (80%) were from blood specimens from live patients and 21 (20%) from oral swab specimens from deceased patients. The median Ct values for blood and swab specimens were 21.0 and 24.0, respectively (P = .007). In multivariable analysis, a Ct value from blood specimens in the lowest quintile was an independent predictor of both increased risk of household transmission (P = .009) and higher secondary attack rate among household contacts (P = .03), after adjustment for epidemiologic factors.

Conclusions

Our findings suggest the potential to use Ct values from acute EBOV diagnostic specimens for index patients as an early predictor of high-risk households and high-risk groups of contacts to help prioritize EBOV disease investigation and control efforts.

Ebola, Ebola virus, transmission, household contact, cycle threshold, epidemiology, risk factors, preventive factors, Sierra Leone

Keywords: Ebola; Diagnostic tests.

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A Novel #Bacterium-Like #Particle-Based #Vaccine Displaying the #SUDV Glycoprotein Induces Potent Humoral and Cellular Immune Responses in Mice (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Dec 11;11(12). pii: E1149. doi: 10.3390/v11121149.

A Novel Bacterium-Like Particle-Based Vaccine Displaying the SUDV Glycoprotein Induces Potent Humoral and Cellular Immune Responses in Mice.

Xu S1,2, Jiao C2, Jin H2,3, Li W2,3, Li E2,4, Cao Z2,3, Shi Z1,2, Yan F2, Zhang S2,5, He H6, Chi H2,7, Feng N2,7, Zhao Y2,7, Gao Y2,7, Yang S2,7, Wang J1, Wang H2,3,7, Xia X2,7.

Author information: 1 College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China. 2 Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Military Veterinary Research Institute, Academy of Military Medical Sciences, Changchun 130122, China. 3 Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. 4 College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. 5 College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China. 6 Key Laboratory of Animal Resistant Biology of Shandong, Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250014, China. 7 Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225000, China.

 

Abstract

Sudan virus (SUDV) causes severe lethal hemorrhagic fever in humans and nonhuman primates. The most effective and economical way to protect against Sudan ebolavirus disease is prophylactic vaccination. However, there are no licensed vaccines to prevent SUDV infections. In this study, a bacterium-like particle (BLP)-based vaccine displaying the extracellular domain of the SUDV glycoprotein (eGP) was developed based on a gram-positive enhancer matrix-protein anchor (GEM-PA) surface display system. Expression of the recombinant GEM-displayed eGP (eGP-PA-GEM) was verified by Western blotting and immunofluorescence assays. The SUDV BLPs (SBLPs), which were mixed with Montanide ISA 201VG plus Poly (I:C) combined adjuvant, could induce high SUDV GP-specific IgG titers of up to 1:40,960 and robust virus-neutralizing antibody titers reached 1:460. The SBLP also elicited T-helper 1 (Th1) and T-helper 2 (Th2) cell-mediated immunity. These data indicate that the SBLP subunit vaccine has the potential to be developed into a promising candidate vaccine against SUDV infections.

KEYWORDS: SUDV; bacterium-like particles; eGP; immune response; subunit vaccine

PMID: 31835785 DOI: 10.3390/v11121149

Keywords: Ebola; Sudan virus; Vaccines; Animal models.

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