scholarly journals A Single Phosphorodiamidate Morpholino Oligomer Targeting VP24 Protects Rhesus Monkeys against Lethal Ebola Virus Infection

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Travis K. Warren ◽  
Chris A. Whitehouse ◽  
Jay Wells ◽  
Lisa Welch ◽  
Alison E. Heald ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Ebola Virus ◽  
Severe Disease ◽  
The United States ◽  
African Countries ◽  
Primate Model ◽  
Promising Target ◽  
Significant Survival ◽  
Ebov Infection ◽  
Phosphorodiamidate Morpholino Oligomers

ABSTRACT Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures. IMPORTANCE Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval.

scholarly journals A bibliometric analysis of research on Ebola in Science Citation Index Expanded

2016 ◽  
Vol Volume 112 (Number 3/4) ◽  
Author(s):  
Anastassios Pouris ◽  
Yuh-Shan Ho ◽  
◽  
Keyword(s):  
Infectious Diseases ◽  
Ebola Virus ◽  
Emerging Infectious Diseases ◽  
The United States ◽  
World Health ◽  
Global Public Health ◽  
African Countries ◽  
Citation Pattern ◽  
Global Trends ◽  
Experimental Drugs

Abstract An unprecedented outbreak of the Ebola virus in 2014 claimed more than 1000 lives in West Africa and the World Health Organization declared a global public health emergency. This outbreak will undoubtedly promote additional research related to the Ebola virus and will create debate related to experimental drugs. This article identified the quantum of research in the field since 1991; the scientific disciplines that contributed to the field; the countries, organisations and authors that supported such research and the most cited articles. An increasing trend in annual production during 1991–2013 was observed. Journal of Virology, Journal of Infectious Diseases, and Virology were the three most productive journals in the field. Similarly, the field of virology dominated the 73 categories in which the Ebola research was classified. A total of 63 countries contributed to Ebola-related research, led by the USA. The most productive institutions were the United States Army Medical Research Institute of Infectious Diseases, the Centers for Disease Control and Prevention, and the National Institute of Allergy and Infectious Diseases. African countries were more likely to be involved in international collaboration than independent research. The most influential article exhibited a notable citation pattern and presented global trends in emerging infectious diseases.

scholarly journals Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

2017 ◽  
Vol 91 (11) ◽  
Author(s):  
Judith Olejnik ◽  
Adriana Forero ◽  
Laure R. Deflubé ◽  
Adam J. Hume ◽  
Whitney A. Manhart ◽  
...  
Keyword(s):  
Host Response ◽  
Ebola Virus ◽  
Severe Disease ◽  
Health Concern ◽  
Type I ◽  
Proinflammatory Response ◽  
Tlr4 Signaling ◽  
Human Macrophages ◽  
Ebov Infection ◽  
Reston Virus

ABSTRACT Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease. IMPORTANCE Emerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV- and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.

scholarly journals Remdesivir is efficacious in rhesus monkeys exposed to aerosolized Ebola virus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Travis K. Warren ◽  
Christopher D. Kane ◽  
Jay Wells ◽  
Kelly S. Stuthman ◽  
Sean A. Van Tongeren ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Ebola Virus ◽  
Virus Disease ◽  
Clinical Pathology ◽  
Ebola Virus Disease ◽  
Lymphoid Tissues ◽  
Virus Infections ◽  
Significant Survival ◽  
Blinded Study ◽  
Vehicle Treatment

AbstractEfficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.

scholarly journals Recombinant Protein Filovirus Vaccines Protect Cynomolgus Macaques From Ebola, Sudan, and Marburg Viruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Axel T. Lehrer ◽  
Eleanore Chuang ◽  
Madhuri Namekar ◽  
Caitlin A. Williams ◽  
Teri Ann S. Wong ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Democratic Republic Of Congo ◽  
Virus Disease ◽  
Clinical Chemistry ◽  
The Other ◽  
Vaccine Platform ◽  
African Countries ◽  
Cynomolgus Macaques ◽  
Ebov Infection ◽  
Limited Scale

Ebola (EBOV), Marburg (MARV) and Sudan (SUDV) viruses are the three filoviruses which have caused the most fatalities in humans. Transmission from animals into the human population typically causes outbreaks of limited scale in endemic regions. In contrast, the 2013-16 outbreak in several West African countries claimed more than 11,000 lives revealing the true epidemic potential of filoviruses. This is further emphasized by the difficulty seen with controlling the 2018-2020 outbreak of EBOV in the Democratic Republic of Congo (DRC), despite the availability of two emergency use-approved vaccines and several experimental therapeutics targeting EBOV. Moreover, there are currently no vaccine options to protect against the other epidemic filoviruses. Protection of a monovalent EBOV vaccine against other filoviruses has never been demonstrated in primate challenge studies substantiating a significant void in capability should a MARV or SUDV outbreak of similar magnitude occur. Herein we show progress on developing vaccines based on recombinant filovirus glycoproteins (GP) from EBOV, MARV and SUDV produced using the Drosophila S2 platform. The highly purified recombinant subunit vaccines formulated with CoVaccine HT™ adjuvant have not caused any safety concerns (no adverse reactions or clinical chemistry abnormalities) in preclinical testing. Candidate formulations elicit potent immune responses in mice, guinea pigs and non-human primates (NHPs) and consistently produce high antigen-specific IgG titers. Three doses of an EBOV candidate vaccine elicit full protection against lethal EBOV infection in the cynomolgus challenge model while one of four animals infected after only two doses showed delayed onset of Ebola Virus Disease (EVD) and eventually succumbed to infection while the other three animals survived challenge. The monovalent MARV or SUDV vaccine candidates completely protected cynomolgus macaques from infection with lethal doses of MARV or SUDV. It was further demonstrated that combinations of MARV or SUDV with the EBOV vaccine can be formulated yielding bivalent vaccines retaining full efficacy. The recombinant subunit vaccine platform should therefore allow the development of a safe and efficacious multivalent vaccine candidate for protection against Ebola, Marburg and Sudan Virus Disease.

Introduction

2016 ◽  
Author(s):  
Sara E. Gorman ◽  
Jack M. Gorman
Keyword(s):  
United States ◽  
New York ◽  
Public Transportation ◽  
Ebola Virus ◽  
The United States ◽  
African Countries ◽  
First Case ◽  
Control And Prevention ◽  
Media Reports ◽  
The Moment

On October 8, 2014, Thomas Eric Duncan died in a Dallas hospital from Ebola virus infection. From the moment he was diagnosed with Ebola newspapers all over the country blared the news that the first case of Ebola in the United States had oc¬curred. Blame for his death was immediately assigned to the hospital that cared for him and to the U.S. Centers for Disease Control and Prevention (CDC). By the end of the month a total of four cases had developed in the United States: two in people— including Duncan— who acquired it in African countries where the disease was epidemic and two in nurses who cared for Duncan. Headlines about Ebola continued to dominate the pages of American newspapers throughout the month, warning of the risk we now faced of this deadly disease. These media reports were frightening and caused some people to wonder if it was safe to send their children to school or ride on public transportation— even if they lived miles from any of the four cases. “There are reports of kids being pulled out of schools and even some school closings,” reported Dean Baker in the Huffington Post. “People in many areas are not going to work and others are driving cars rather than taking mass transit because they fear catching Ebola from fellow passengers. There are also reports of people staying away from stores, restaurants, and other public places.” An elementary school in Maine suspended a teacher because she stayed in a hotel in Dallas that is 9.5 miles away from the hospital where two nurses contracted the virus. As Charles Blow put it in his New York Times column, “We aren’t battling a virus in this country as much as a mania, one whipped up by reactionary politicians and irresponsible media.” It turns out that Thomas Duncan was not the only person who died in the United States on October 8, 2014. If we extrapolate from national annual figures, we can say that on that day almost 7,000 people died in the United States.

Ultrasensitive point-of-care immunoassay for secreted glycoprotein detects Ebola infection earlier than PCR

2021 ◽  
Vol 13 (588) ◽  
pp. eabd9696
Author(s):  
Cassio M. Fontes ◽  
Barbara D. Lipes ◽  
Jason Liu ◽  
Krystle N. Agans ◽  
Aiwei Yan ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Early Stage ◽  
Point Of Care ◽  
Hemorrhagic Fever ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Disease Outcomes ◽  
Health Care Infrastructure ◽  
Ebov Infection ◽  
Polymerase Chain

Ebola virus (EBOV) hemorrhagic fever outbreaks have been challenging to deter due to the lack of health care infrastructure in disease-endemic countries and a corresponding inability to diagnose and contain the disease at an early stage. EBOV vaccines and therapies have improved disease outcomes, but the advent of an affordable, easily accessed, mass-produced rapid diagnostic test (RDT) that matches the performance of more resource-intensive polymerase chain reaction (PCR) assays would be invaluable in containing future outbreaks. Here, we developed and demonstrated the performance of a new ultrasensitive point-of-care immunoassay, the EBOV D4 assay, which targets the secreted glycoprotein of EBOV. The EBOV D4 assay is 1000-fold more sensitive than the U.S. Food and Drug Administration–approved RDTs and detected EBOV infection earlier than PCR in a standard nonhuman primate model. The EBOV D4 assay is suitable for low-resource settings and may facilitate earlier detection, containment, and treatment during outbreaks of the disease.

Personalized stratification of back to work risk amidst COVID-19: A machine learning approach (Preprint)

2020 ◽  
Author(s):  
Carson Lam ◽  
Jacob Calvert ◽  
Gina Barnes ◽  
Emily Pellegrini ◽  
Anna Lynn-Palevsky ◽  
...  
Keyword(s):  
Machine Learning ◽  
High Risk ◽  
Learning Algorithm ◽  
Severe Disease ◽  
High Specificity ◽  
Population Level ◽  
The United States ◽  
Health Condition ◽  
Available P ◽  
Severe Illness

BACKGROUND In the wake of COVID-19, the United States has developed a three stage plan to outline the parameters to determine when states may reopen businesses and ease travel restrictions. The guidelines also identify subpopulations of Americans that should continue to stay at home due to being at high risk for severe disease should they contract COVID-19. These guidelines were based on population level demographics, rather than individual-level risk factors. As such, they may misidentify individuals at high risk for severe illness and who should therefore not return to work until vaccination or widespread serological testing is available. OBJECTIVE This study evaluated a machine learning algorithm for the prediction of serious illness due to COVID-19 using inpatient data collected from electronic health records. METHODS The algorithm was trained to identify patients for whom a diagnosis of COVID-19 was likely to result in hospitalization, and compared against four U.S policy-based criteria: age over 65, having a serious underlying health condition, age over 65 or having a serious underlying health condition, and age over 65 and having a serious underlying health condition. RESULTS This algorithm identified 80% of patients at risk for hospitalization due to COVID-19, versus at most 62% that are identified by government guidelines. The algorithm also achieved a high specificity of 95%, outperforming government guidelines. CONCLUSIONS This algorithm may help to enable a broad reopening of the American economy while ensuring that patients at high risk for serious disease remain home until vaccination and testing become available.

scholarly journals Combination therapy protects macaques against advanced Marburg virus disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Robert W. Cross ◽  
Zachary A. Bornholdt ◽  
Abhishek N. Prasad ◽  
Viktoriya Borisevich ◽  
Krystle N. Agans ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Rhesus Monkeys ◽  
Viral Infections ◽  
Virus Disease ◽  
Marburg Virus ◽  
Therapeutic Window ◽  
Post Inoculation ◽  
Primate Model ◽  
Lethal Infection ◽  
Human Primate

AbstractMonoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.

The Normalization of Sino-French Diplomatic Relations in 1964 and the Formation of the “One-China” Principle: Negotiations over Breaking French Diplomatic Relations with the Republic of China Government and the Recognition of the People’s Republic of China as the Sole Legitimate Government

2012 ◽  
Vol 8 (1) ◽  
pp. 252-271
Author(s):  
Madoka Fukuda
Keyword(s):  
The United States ◽  
People’S Republic Of China ◽  
Diplomatic Relations ◽  
People's Republic Of China ◽  
African Countries ◽  
Republic Of China ◽  
The Republic Of China ◽  
The Republic ◽  
The Government ◽  
The One

AbstractThis article examines the substance and modification of the “One-China” principle, which the government of the People’s Republic of China (PRC) pursued in the mid 1960s. Under this principle, a country wishing to establish diplomatic relations with the PRC was required first to break off such relations with the Republic of China (ROC). In 1964 the PRC established diplomatic relations with France. This was its first ambassadorial exchange with a Western government. The PRC, in the negotiations over the establishment of diplomatic relations, attempted to achieve some consensus with France on the matter of “One-China”. The PRC, nevertheless, had to abandon these attempts, even though it demanded fewer conditions of France than of the United States (USA), Japan and other Western countries in the 1970s. The PRC had demanded adherence to the “One-China” principle since 1949. France, however, refused to accept this condition. Nevertheless, the PRC established diplomatic relations with France before the latter broke off relations with the ROC. Subsequently, the PRC abandoned the same condition in negotiations with the African governments of the Republic of Congo, Central Africa, Dahomey and Mauritania. After the negotiations with France, the PRC began to insist that the joint communiqué on the establishment of diplomatic relations should clearly state that “the Government of the People’s Republic of China is the sole legal government of China”. However, France refused to insert these words into the communiqué. Afterwards, the PRC nevertheless insisted on putting such a statement into the joint communiqués or exchanges of notes on the establishment of diplomatic relations with the African countries mentioned above. This was done in order to set precedents for making countries accede to the “One-China” principle. The “One-China” principle was, thus, gradually formed in the process of the negotiation and bargaining between the PRC and other governments.

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