scholarly journals Emergence of Ebola Virus Escape Variants in Infected Nonhuman Primates Treated with the MB-003 Antibody Cocktail

Cell Reports ◽  
2015 ◽  
Vol 12 (12) ◽  
pp. 2111-2120 ◽  
Author(s):  
Jeffrey R. Kugelman ◽  
Johanny Kugelman-Tonos ◽  
Jason T. Ladner ◽  
James Pettit ◽  
Carolyn M. Keeton ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Escape ◽  
Antibody Cocktail

scholarly journals Two-antibody pan-ebolavirus cocktail confers broad therapeutic protection in ferrets and nonhuman primates

2018 ◽  
Author(s):  
Zachary A. Bornholdt ◽  
Andrew S. Herbert ◽  
Chad E. Mire ◽  
Shihua He ◽  
Robert W. Cross ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ebola Virus ◽  
Democratic Republic ◽  
Democratic Republic Of Congo ◽  
Rapid Development ◽  
Emerging Infectious Diseases ◽  
Disease Outbreaks ◽  
Research Model ◽  
Class Antibody ◽  
Antibody Cocktail

All available experimental vaccines and immunotherapeutics1,2 against Ebola virus (EBOV), including rVSV-ZEBOV3 and ZMappTM4, lack activity against other ebolaviruses associated with human disease outbreaks. This year, two separate outbreaks of EBOV in the Democratic Republic of Congo underscored the unpredictable nature of ebolavirus reemergence in a region that has historically experienced outbreaks of the divergent ebolaviruses Sudan virus (SUDV) and Bundibugyo virus (BDBV)5. Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs)6,7(see companion manuscript, Wec et al.) could protect against lethal EBOV, SUDV, and BDBV infection in ferrets and nonhuman primates (NHPs). MBP134AF not only not only establishes a viable therapeutic countermeasure to outbreaks caused by antigenically diverse ebolaviruses but also affords unprecedented effectiveness and potency—a single 25-mg/kg dose was fully protective in NHPs. This best-in-class antibody cocktail is the culmination of an intensive collaboration spanning academia, industry and government in response to the 2013-2016 EBOV epidemic6,7 and provides a translational research model for the rapid development of immunotherapeutics targeting emerging infectious diseases.

scholarly journals Evaluation in Nonhuman Primates of Vaccines against Ebola Virus

2002 ◽  
Vol 8 (5) ◽  
pp. 503-507 ◽  
Author(s):  
Thomas W. Geisbert ◽  
Peter Pushko ◽  
Kevin Anderson ◽  
Jonathan Smith ◽  
Kelly J. Davis ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ebola Virus

scholarly journals Equine-Origin Immunoglobulin Fragments Protect Nonhuman Primates from Ebola Virus Disease

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Hualei Wang ◽  
Gary Wong ◽  
Wenjun Zhu ◽  
Shihua He ◽  
Yongkun Zhao ◽  
...  
Keyword(s):  
Large Scale ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
West African ◽  
Clinical Testing ◽  
The Past ◽  
Over 40 Years

ABSTRACT Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans, with fatality rates reaching 90% and with no licensed specific therapeutics to treat ill patients. Advances over the past 5 years have firmly established monoclonal antibody (MAb)-based products as the most promising therapeutics for treating EBOV infections, but production is costly and quantities are limited; therefore, MAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal F(ab′)2 fragments from horses hyperimmunized with an EBOV vaccine. The F(ab′)2 was found to potently neutralize West African and Central African EBOV in vitro. Treatment of nonhuman primates (NHPs) with seven doses of 100 mg/kg F(ab′)2 beginning 3 or 5 days postinfection (dpi) resulted in a 100% survival rate. Notably, NHPs for which treatment was initiated at 5 dpi were already highly viremic, with observable signs of EBOV disease, which demonstrated that F(ab′)2 was still effective as a therapeutic agent even in symptomatic subjects. These results show that F(ab′)2 should be advanced for clinical testing in preparation for future EBOV outbreaks and epidemics. IMPORTANCE EBOV is one of the deadliest viruses to humans. It has been over 40 years since EBOV was first reported, but no cure is available. Research breakthroughs over the past 5 years have shown that MAbs constitute an effective therapy for EBOV infections. However, MAbs are expensive and difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since EBOV is endemic in several third world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antiserum F(ab′)2 fragments from horses vaccinated with an EBOV vaccine, and we tested the protectiveness in monkeys. We showed that F(ab′)2 was effective in 100% of monkeys even after the animals were visibly ill with EBOV disease. Thus, F(ab′)2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

scholarly journals Previremic Identification of Ebola or Marburg Virus Infection Using Integrated Host-Transcriptome and Viral Genome Detection

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Emily Speranza ◽  
Ignacio Caballero ◽  
Anna N. Honko ◽  
Joshua C. Johnson ◽  
J. Kyle Bohannon ◽  
...  
Keyword(s):  
Host Response ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Clinical Symptoms ◽  
Infectious Agent ◽  
Marburg Virus ◽  
Viral Rna ◽  
Molecular Tests ◽  
Early Replication ◽  
Host Infection

ABSTRACT Outbreaks of filoviruses, such as those caused by the Ebola (EBOV) and Marburg (MARV) virus, are difficult to detect and control. The initial clinical symptoms of these diseases are nonspecific and can mimic other endemic pathogens. This makes confident diagnosis based on clinical symptoms alone impossible. Molecular diagnostics for these diseases that rely on the detection of viral RNA in the blood are only effective after significant disease progression. As an approach to identify these infections earlier in the disease course, we tested the effectiveness of viral RNA detection combined with an assessment of sentinel host mRNAs that are upregulated following filovirus infection. RNAseq analysis of EBOV-infected nonhuman primates identified host RNAs that are upregulated at early stages of infection. NanoString probes that recognized these host-response RNAs were combined with probes that recognized viral RNA and were used to classify viral infection both prior to viremia and postviremia. This approach was highly successful at identifying samples from nonhuman primate subjects and correctly distinguished the causative agent in a previremic stage in 10 EBOV and 5 MARV samples. This work suggests that unified host response/viral fingerprint assays can enable diagnosis of disease earlier than testing for viral nucleic acid alone, which could decrease transmission events and increase therapeutic effectiveness. IMPORTANCE Current molecular tests that identify infection with high-consequence viruses such as Ebola virus and Marburg virus are based on the detection of virus material in the blood. These viruses do not undergo significant early replication in the blood and, instead, replicate in organs such as the liver and spleen. Thus, virus begins to accumulate in the blood only after significant replication has already occurred in those organs, making viremia an indicator of infection only after initial stages have become established. Here, we show that a multianalyte assay can correctly identify the infectious agent in nonhuman primates (NHPs) prior to viremia through tracking host infection response transcripts. This illustrates that a single-tube, sample-to-answer format assay could be used to advance the time at which the type of infection can be determined and thereby improve outcomes.

scholarly journals Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Science ◽  
2020 ◽  
Vol 369 (6506) ◽  
pp. 1010-1014 ◽  
Author(s):  
Johanna Hansen ◽  
Alina Baum ◽  
Kristen E. Pascal ◽  
Vincenzo Russo ◽  
Stephanie Giordano ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Selective Pressure ◽  
Three Dimensional ◽  
Spike Protein ◽  
Humanized Mice ◽  
Dimensional Structure ◽  
Antibody Treatment ◽  
Virus Escape ◽  
Escape Mutants ◽  
Antibody Cocktail

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola—one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

scholarly journals Quantitative serology assays for determination of antibody responses to Ebola virus glycoprotein and matrix protein in nonhuman primates and humans

2016 ◽  
Vol 126 ◽  
pp. 55-61 ◽  
Author(s):  
Hong Vu ◽  
Sergey Shulenin ◽  
Allen Grolla ◽  
Jonathan Audet ◽  
Shihua He ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Antibody Responses ◽  
Virus Glycoprotein

scholarly journals Clinical Laboratory Values as Early Indicators of Ebola Virus Infection in Nonhuman Primates

2017 ◽  
Vol 23 (8) ◽  
pp. 1316-1324 ◽  
Author(s):  
Ronald B. Reisler ◽  
Chenggang Yu ◽  
Michael J. Donofrio ◽  
Travis K. Warren ◽  
Jay B. Wells ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Clinical Laboratory ◽  
Laboratory Values ◽  
Ebola Virus Infection ◽  
Early Indicators

scholarly journals Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

2015 ◽  
Vol 90 (1) ◽  
pp. 279-291 ◽  
Author(s):  
Zhen-Yong Keck ◽  
Sven G. Enterlein ◽  
Katie A. Howell ◽  
Hong Vu ◽  
Sergey Shulenin ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
Human Pathogens ◽  
Content Type ◽  
The Core

ABSTRACTFiloviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members ofFiloviridaesuch as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.IMPORTANCEFiloviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species ofEbolavirusand several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

scholarly journals An Adenovirus Vaccine Expressing Ebola Virus Variant Makona Glycoprotein Is Efficacious in Guinea Pigs and Nonhuman Primates

2016 ◽  
Vol 214 (suppl 3) ◽  
pp. S326-S332 ◽  
Author(s):  
Shipo Wu ◽  
Andrea Kroeker ◽  
Gary Wong ◽  
Shihua He ◽  
Lihua Hou ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Variant ◽  
Adenovirus Vaccine

scholarly journals Immune Parameters Correlate with Protection Against Ebola Virus Infection in Rodents and Nonhuman Primates

2012 ◽  
Vol 4 (158) ◽  
pp. 158ra146-158ra146 ◽  
Author(s):  
G. Wong ◽  
J. S. Richardson ◽  
S. Pillet ◽  
A. Patel ◽  
X. Qiu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Immune Parameters ◽  
Ebola Virus Infection
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