The colliding #epidemics of #COVID19, #Ebola, and #measles in the #DRC (Lancet Glob Health, summary)

[Source: Lancet Global Health, full page: (LINK). Summary, edited.]

The colliding epidemics of COVID-19, Ebola, and measles in the Democratic Republic of the Congo

Jean B Nachega, Placide Mbala-Kingebeni, John Otshudiema, Alimuddin Zumla, Jean-Jacques Muyembe Tam-Fum

Open Access | Published: June 23, 2020 | DOI: https://doi.org/10.1016/S2214-109X(20)30281-3

__

The Democratic Republic of the Congo is facing major public health challenges due to a  confluence of major outbreaks of Ebola virus disease, measles, and COVID-19.1,  2,  3 ,  4 The tenth Ebola outbreak in eastern DR Congo began on Aug 1, 2018, and as of May 28,  2020, there have been 3406 Ebola virus disease cases with 2243 deaths. The Ebola virus  disease outbreak was well controlled in northeast DR Congo following a multisectoral  response, but four new confirmed Ebola cases were detected in northwest DR Congo on  June 1, 2020, and an outbreak response is underway.4  Additionally, the DR Congo has  been burdened with recurrent measles outbreaks: 13 380 2 cases in 2011, 88 381 cases in  2013, and 311 471 cases in 2019.2  The first confirmed case of COVID-19 in DR Congo was  diagnosed on March 10, 2020, and the government declared a state of emergency on  March 24, 2020. A national multisectoral response committee instituted lockdown in the  capital, Kinshasa, the epicentre of the epidemic in DR Congo, in which daily confirmed  cases now average 100. As of June 16, 2020, 4777 COVID-19 cases with 106 deaths have  been reported from the DR Congo.5

(…)

Keywords: SARS-CoV-2; COVID-19; Ebola; Measles; DRC.

——

#Characterisation of Infectious #Ebola Virus From the Ongoing #Outbreak to Guide Response Activities in the #DRC: A Phylogenetic and in Vitro Analysis (Lancet Infect Dis., abstract)

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

Lancet Infect Dis. 2019 Sep;19(9):1023-1032. doi: 10.1016/S1473-3099(19)30291-9. Epub 2019 Jul 9.

Characterisation of Infectious Ebola Virus From the Ongoing Outbreak to Guide Response Activities in the Democratic Republic of the Congo: A Phylogenetic and in Vitro Analysis

Laura K McMullan 1, Mike Flint 2, Ayan Chakrabarti 2, Lisa Guerrero 2, Michael K Lo 2, Danielle Porter 3, Stuart T Nichol 2, Christina F Spiropoulou 2, César Albariño 2

Affiliations: 1 Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: lim8@cdc.gov. 2 Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. 3 Gilead Sciences, Foster City, CA, USA.

PMID: 31300330 DOI: 10.1016/S1473-3099(19)30291-9

 

Abstract

Background:

The ongoing Ebola virus outbreak in the Ituri and North Kivu Provinces of the Democratic Republic of the Congo, which began in July, 2018, is the second largest ever recorded. Despite civil unrest, outbreak control measures and the administration of experimental therapies and a vaccine have been initiated. The aim of this study was to test the efficacy of candidate therapies and diagnostic tests with the outbreak strain Ituri Ebola virus. Lacking a virus isolate from this outbreak, a recombinant Ituri Ebola virus was compared with a similarly engineered Makona virus from the 2013-16 outbreak.

Methods:

Using Ebola virus sequences provided by organisations in DR Congo and a reverse genetics system, we generated an authentic Ebola virus from the ongoing outbreak in Ituri and North Kivu provinces. To relate this virus to other Ebola viruses in DR Congo, we did a phylogenetic analysis of representative complete Ebola virus genome sequences from previous outbreaks. We evaluated experimental therapies being tested in clinical trials in DR Congo, including remdesivir and ZMapp monoclonal antibodies, for their ability to inhibit the growth of infectious Ituri Ebola virus in cell culture. We also tested diagnostic assays for detection of the Ituri Ebola virus sequence.

Findings:

The phylogenetic analysis of whole-genome sequences from each Ebola virus outbreak suggests there are at least two Ebola virus strains in DR Congo, which have independently crossed into the human population. The Ituri Ebola strain initially grew slower than the Makona strain, yet reached similar mean yields of 3 × 107 50% tissue culture infectious dose by 72 h infection in Huh-7 cells. Ituri Ebola virus was similar to Makona in its susceptibility to inhibition by remdesivir and to neutralisation by monoclonal antibodies from ZMapp and other monoclonal antibodies. Remdesivir inhibited Ituri Ebola virus at a 50% effective concentration (EC50) of 12nM (with a selectivity index of 303) and Makona Ebola virus at 13nM (with a selectivity index of 279). The Zmapp monoclonal antibodies 2G4 and 4G7 neutralised Ituri Ebola virus with a mean EC50 of 0·24 μg/mL and 0·48 μg/mL, and Makona Ebola virus with a mean EC50 of 0·45 μg/mL and 0·2 μg/mL. The Xpert Ebola and US Centers for Disease Control and Prevention real-time RT-qPCR diagnostic assays detected Ituri and Makona Ebola virus sequences with similar sensitivities and efficiencies, despite primer site binding mismatches in the Ituri Ebola virus.

Interpretation:

Our findings provide a rationale for the continued testing of investigational therapies, confirm the effectiveness of the diagnostic assays used in the region, and establish a paradigm for the use of reverse genetics to inform response activities in an outbreak.

Funding: US Centers for Disease Control and Prevention.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Keywords: Ebola; Ebola-Makona; Ebola-Ituri; DRC; Antivirals; Remdesivir; Monoclonal antibodies; ZMapp; Diagnostic tests.

—–

#Fragment #screening targeting #Ebola virus #nucleoprotein C-terminal domain identifies lead candidates (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 21 May 2020, 104822 | In Press, Journal Pre-proof | Short Communication

Fragment screening targeting Ebola virus nucleoprotein C-terminal domain identifies lead candidates

David J. Aceti a, Hamza Ahmed b, William M. Westler a, Chao Wu b, Hesam Dashti a,c, Marco Tonelli a, Hamid Eghbalnia a, Gaya K. Amarasinghe b, John L. Markley a

a Biochemistry Department and National Magnetic Resonance Facility at Madison, University of Wisconsin-Madison, Madison, WI 53706, USA; b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; c Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA

Received 10 January 2020, Revised 8 May 2020, Accepted 15 May 2020, Available online 21 May 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104822

 

Highlights

  • Performed a high throughput screen (HTS) to identify binders of Ebola NP.
  • Identified several binders that target Ebola NP C-terminal domain.
  • Validated binding and propose structure-activity relationships.
  • Highlight the utility of Ebola NP C-terminus as a potential therapeutic target.

 

Abstract

The Ebola Virus is a causative agent of viral hemorrhagic fever outbreaks and a potential global health risk. The outbreak in West Africa (2013-2016) led to 11,000+ deaths and 30,000+ Ebola infected individuals. The current outbreak in the Democratic Republic of Congo (DRC) with 3,000+ confirmed cases and 2,000+ deaths attributed to Ebola virus infections provides a reminder that innovative countermeasures are still needed. Ebola virus encodes 7 open reading frames (ORFs). Of these, the nucleocapsid protein (eNP) encoded by the first ORF plays many significant roles, including a role in viral RNA synthesis. Here we describe efforts to target the C-terminal domain of eNP (eNP-CTD) that contains highly conserved residues 641‒739 as a pan-Ebola antiviral target. Interactions of eNP-CTD with Ebola Viral Protein 30 (eVP30) and Viral Protein 40 (eVP40) have been shown to be crucial for viral RNA synthesis, virion formation, and virion transport. We used nuclear magnetic response (NMR)-based methods to screened the eNP-CTD against a fragment library. Perturbations of 1D 1H NMR spectra identified of 48 of the 439 compounds screened as potential eNP CTD interactors. Subsequent analysis of these compounds to measure chemical shift perturbations in 2D 1H,15N NMR spectra of 15N-labeled protein identified six with low millimolar affinities. All six perturbed an area consisting mainly of residues at or near the extreme C-terminus that we named “Site 1” while three other sites were perturbed by other compounds. Our findings here demonstrate the potential utility of eNP as a target, several fragment hits, and provide an experimental pipeline to validate viral-viral interactions as potential panfiloviral inhibitor targets.

Keywords: Filovirus; Ebola; Antivirals.

—–

#Ebola-Specific #CD8+ and #CD4+ T Cell Responses in Sierra Leonean Ebola Virus #Survivors with and without Post Viral #Sequelae (J Infect Dis., abstract)

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

Ebola-Specific CD8+ and CD4+ T Cell Responses in Sierra Leonean Ebola Virus Survivors with and without Post Viral Sequelae

Stephanie M LaVergne, Saori Sakabe, Lansana Kanneh, Mambu Momoh, Foday Al-Hassan, Mohamed Yilah, Augustine Goba, John Demby Sandi, Michael Gbakie, Beatrice Cubitt, Matthew Boisen, Jessica M Mayeux, Ashley Smira, Kayla Shore, Iris Bica, K Michael Pollard, Juan Carlos de la Torre, Luis M Branco, Robert F Garry, Donald S Grant, John S Schieffelin, Michael B A Oldstone, Brian M Sullivan

The Journal of Infectious Diseases, jiaa268, https://doi.org/10.1093/infdis/jiaa268

Published: 21 May 2020

 

Abstract

Background

Ebola virus disease has killed thousands of West and Central Africans over the past several decades. Many who survive the acute disease later suffer from post Ebola syndrome (PES), a constellation of symptoms whose causative pathogenesis is unclear.

Methods

We investigated Ebola virus (EBOV)-specific CD8+ and CD4+ T cell responses in 37 Sierra Leonean EBOV disease survivors with (N=19) and without sequelae (N=18) of arthralgia and ocular symptoms. Peripheral blood mononuclear cells were infected with recombinant vesicular stomatitis virus encoding EBOV antigens. We also studied the presence of EBOV-specific IgG, antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, rheumatoid factor, complement levels, and cytokine levels in these two groups.

Results

Survivors with sequelae had a significantly higher EBOV-specific CD8+ and CD4+ T cell response. No differences in EBOV-specific IgG, antinuclear antibody, or anti-cyclic citrullinated peptide antibody levels were found. Survivors with sequelae showed significantly higher rheumatoid factor levels.

Conclusion

EEBOV-specific CD8+ and CD4+ T cell responses were significantly higher in Ebola survivors with PES. These findings suggest that pathogenesis may occur as an immune mediated disease via virus-specific T cell immune response or that persistent antigen exposure leads to increased and sustained T cell responses.

Ebola virus, post Ebola sequelae, T cell response

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Ebola; Immunopathology.

——

A Multi – #Filovirus #Vaccine Candidate: Co-Expression of #Ebola, #Sudan, and #Marburg #Antigens in a Single #Vector (Vaccines, abstract)

[Source: Vaccines, full page: (LINK). Abstract, edited.]

A Multi-Filovirus Vaccine Candidate: Co-Expression of Ebola, Sudan, and Marburg Antigens in a Single Vector

by  Sarah Sebastian 1,2,†, Amy Flaxman 1,† , Kuan M. Cha 1, Marta Ulaszewska 1, Ciaran Gilbride 1, Hannah Sharpe 1 , Edward Wright 3 , Alexandra J. Spencer 1, Stuart Dowall 4, Roger Hewson 4, Sarah Gilbert 1  and Teresa Lambe 1,*

1 Nuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; 2 Current address: Vaccitech Ltd., Oxford Science Park, Oxford OX4 4GE, UK; 3 School of Life Sciences, University of Sussex, Falmer BN1 9QG, UK; 4 Public Health England, Porton Down, Salisbury, Wiltshire SP4 0JG, UK

*Author to whom correspondence should be addressed.

†These authors contributed equally to this work.

Vaccines 2020, 8(2), 241; https://doi.org/10.3390/vaccines8020241 (registering DOI)

Received: 6 April 2020 / Revised: 18 May 2020 / Accepted: 19 May 2020 / Published: 21 May 2020

(This article belongs to the Special Issue Vaccines for Ebola Virus and Related Diseases)

 

Abstract

In the infectious diseases field, protective immunity against individual virus species or strains does not always confer cross-reactive immunity to closely related viruses, leaving individuals susceptible to disease after exposure to related virus species. This is a significant hurdle in the field of vaccine development, in which broadly protective vaccines represent an unmet need. This is particularly evident for filoviruses, as there are multiple family members that can cause lethal haemorrhagic fever, including Zaire ebolavirus, Sudan ebolavirus, and Marburg virus. In an attempt to address this need, both pre-clinical and clinical studies previously used mixed or co-administered monovalent vaccines to prevent filovirus mediated disease. However, these multi-vaccine and multi-dose vaccination regimens do not represent a practical immunisation scheme when considering the target endemic areas. We describe here the development of a single multi-pathogen filovirus vaccine candidate based on a replication-deficient simian adenoviral vector. Our vaccine candidate encodes three different filovirus glycoproteins in one vector and induces strong cellular and humoral immunity to all three viral glycoproteins after a single vaccination. Crucially, it was found to be protective in a stringent Zaire ebolavirus challenge in guinea pigs in a one-shot vaccination regimen. This trivalent filovirus vaccine offers a tenable vaccine product that could be rapidly translated to the clinic to prevent filovirus-mediated viral haemorrhagic fever.

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Sebastian, S.; Flaxman, A.; Cha, K.M.; Ulaszewska, M.; Gilbride, C.; Sharpe, H.; Wright, E.; Spencer, A.J.; Dowall, S.; Hewson, R.; Gilbert, S.; Lambe, T. A Multi-Filovirus Vaccine Candidate: Co-Expression of Ebola, Sudan, and Marburg Antigens in a Single Vector. Vaccines 2020, 8, 241.

Keywords: Ebola; Marburg virus; Sudan virus; Filovirus; Vaccines.

——

Identification of Novel #Adjuvants for #Ebola #VLP #Vaccine (Vaccines, abstract)

[Source: Vaccines, full page: (LINK). Abstract, edited.]

Identification of Novel Adjuvants for Ebola Virus-Like Particle Vaccine

by  Huapeng Feng 1, Sumiho Nakatsu 1, Tiago Jose da Silva Lopes 2, Masaki Imai 1, Seiya Yamayoshi 1, Makoto Yamashita 1, Tokiko Watanabe 1,3,* and Yoshihiro Kawaoka 1,2,4,*

1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA; 3 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; 4 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

*Authors to whom correspondence should be addressed.

Vaccines 2020, 8(2), 215; https://doi.org/10.3390/vaccines8020215 (registering DOI)

Received: 17 April 2020 / Revised: 3 May 2020 / Accepted: 5 May 2020 / Published: 10 May 2020

(This article belongs to the Section Vaccines against (re)emerging and Tropical Infections Diseases)

 

Abstract

Ebola virus disease is a severe disease, often fatal, with a mortality rate of up to 90%. Presently, effective treatment and safe prevention options for Ebola virus disease are not available. Therefore, there is an urgent need to develop control measures to prevent or limit future Ebola virus outbreaks. Ebola virus protein-based virus-like particle (VLP) and inactivated whole virion vaccines have demonstrated efficacy in animal models, and the addition of appropriate adjuvants may provide additional benefits to these vaccines, including enhanced immune responses. In this study, we screened 24 compounds from injectable excipients approved for human use in Japan and identified six compounds that significantly enhanced the humoral response to Ebola VLP vaccine in a murine model. Our novel adjuvant candidates for Ebola VLP vaccine have already been demonstrated to be safe when administered intramuscularly or subcutaneously, and therefore, they are closer to clinical trials than adjuvants whose safety profiles are unknown.

Keywords: Ebola vaccine; virus-like particle; adjuvants

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Feng, H.; Nakatsu, S.; Lopes, T.J.S.; Imai, M.; Yamayoshi, S.; Yamashita, M.; Watanabe, T.; Kawaoka, Y. Identification of Novel Adjuvants for Ebola Virus-Like Particle Vaccine. Vaccines 2020, 8, 215.

Keywords: Ebola; Vaccines.

——

#Pharmacokinetics of #TKM-130803 in #SierraLeone: an patients with Ebola virus disease:  plasma concentrations exceed target levels, with drug accumulation in the most severe patients (EbioMedicine, abstract)

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

EBioMedicine. 2020 Jan 13:102601. doi: 10.1016/j.ebiom.2019.102601. [Epub ahead of print]

Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease:  plasma concentrations exceed target levels, with drug accumulation in the most severe patients.

Scott JT1, Sharma R2, Meredith LW3, Dunning J4, Moore CE5, Sahr F6, Ward S2, Goodfellow I3, Horby P5; RAPIDE-TKM trial team5.

Author information: 1 MRC-University of Glasgow Centre for Virus Research, G61 1QH, UK; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK. Electronic address: janet.scott@glasgow.ac.uk. 2 Liverpool School of Tropical Medicine, Liverpool, UK. 3 Department of Pathology, Division of Virology, University of Cambridge, Cambridge CB2 1QP, UK; Department of Public Health, University of Makeni, Makeni, Sierra Leone. 4 National Infection Service, Public Health England, London, UK; Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 5 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 6 Republic Sierra Leone Armed Forces, Military Hosp 34, Freetown, Sierra Leone.

 

Abstract

BACKGROUND:

TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored.

METHODS:

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04-0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL).

FINDINGS:

Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs).

INTERPRETATION:

TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations.

FUNDING:

This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU.

TRIAL REGISTRATION:

Pan African Clinical Trials Registry PACTR201501000997429.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Ebola; Pharmacokinetics; TKM; Tekmira

PMID: 31953031 DOI: 10.1016/j.ebiom.2019.102601

Keywords: Antivirals; Ebola; Sierra Leone.

——

#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.

——-

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.

——

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.

——