The molecular events that affect disease transmission and human response to the Ebola and Marburg viruses are poorly understood. NIAID researchers and NIAID-supported scientists at external institutions, are studying many aspects of the Ebola and Marburg viruses and how they cause disease. This includes seeking better ways to diagnose and treat Ebola virus disease and Marburg fevers and using applied research to develop vaccines, treatments, and diagnostics.
NIAID is supporting the development of multiple Ebola vaccine candidates that are in various stages of development.
The NIAID Vaccine Research Center (VRC) developed an Ebola vaccine candidate in collaboration with the U.S. Army Medical Research Institute of Infectious Diseases and Okairos, a Swiss-Italian biotech company acquired by GlaxoSmithKline (GSK) in 2013. Known as the NIAID/GSK investigational Ebola vaccine, or cAd3-EBOZ, the candidate vaccine is based on a type of chimpanzee cold virus, called chimp adenovirus type 3 (cAd3). The adenovirus is used as a vector, or carrier, to deliver Ebola genetic material. The vector is a non-replicating viral vector, which means the vaccine delivers the Ebola virus gene inserts but does not replicate further. The gene inserts express an Ebola virus protein designed to prompt the human body to make an immune response. The investigational vaccine contains no infectious Ebola virus material.
When tested in Phase 1 clinical trials in the United States and the United Kingdom in 2014, the NIAID/GSK investigational Ebola vaccine proved to be safe and induced an immune response. The vaccine candidate began Phase 2 testing in February 2015 through the launch of the PREVAIL I trial (Partnership for Research on Ebola Virus in Liberia). The randomized, placebo-controlled clinical trial enrolled 1,500 participants. It was originally designed to advance to a Phase 3 trial among 28,000 volunteers but was scaled back because the decline in new Ebola cases made it impossible to conduct the larger study. Findings presented in February 2016 indicate the vaccine was well-tolerated and induced an immune response.
NIAID has also been involved in testing the rVSV-ZEBOV Ebola vaccine candidate. The vaccine uses a genetically engineered version of vesicular stomatitis virus, an animal virus that primarily affects cattle, to carry an Ebola virus gene insert. The investigational vaccine was developed by the Public Health Agency of Canada and licensed to NewLink Genetics Corporation. Merck & Co., Inc., is responsible for advancing the vaccine toward regulatory approval.
In Phase 1 testing conducted by NIAID and the Walter Reed Army Institute of Research, rVSV-ZEBOV proved to be safe and elicited robust antibody responses in all 40 of the healthy adults who received it. The investigational vaccine is now undergoing Phase 2 testing with the cAd3-EBOZ candidate in the PREVAIL I trial in Liberia. Findings of the Phase 2 trial presented in February 2016 indicate the vaccine was well-tolerated and induced an immune response among participants. Additional organizations are testing rVSV-ZEBOV in late-stage clinical trials in West Africa. The Centers for Disease Control and Prevention and the U.S. Department of Health and Human Services(HHS) Office of the Assistant Secretary for Preparedness and Response, in partnership with the Sierra Leone College of Medicine and Allied Health Sciences and the Sierra Leone Ministry of Health and Sanitation launched in April 2015 a combined Phase 2 and 3 trial in Sierra Leone to test the safety and efficacy of rVSV-ZEBOV.
NIAID and other funding partners supported the development and preclinical and clinical testing of an investigational vaccine regimen designed to specifically protect against the Ebola virus strains responsible for the recent outbreak in West Africa. The vaccine candidate combines the Ad26.ZEBOV vector (based on the AdVac platform developed by Crucell Holland B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson) with a modified vaccinia virus Ankara (MVA)-vectored vaccine (MVA-BN Filo) developed by Bavarian Nordic. Crucell and NIAID have supported Phase 1 trials of the vaccine in the United Kingdom and the United States, respectively. Additional Phase 1 trials are underway in Africa, and in July 2015, Crucell initiated a Phase 2 clinical trial of the investigational vaccine in the United Kingdom and France. In October 2015, Crucell launched a clinical trial in Sierra Leone to test the safety and immunogenicity of the regimen. The HHS Biomedical Advanced Research and Development Authority (BARDA) is supporting advanced development of this regimen.
NIAID is also supporting the development of multivalent filovirus vaccine regimens combining non-replicating human adenovirus vectors Ad26 with non-replicating Ad35 (both in development at Crucell Holland B.V.), or Ad26 vectors with Bavarian Nordic’s MVA-BN Filo.
Additionally, NIAID is funding Profectus Biosciences, Inc., to develop additional recombinant vesicular stomatitis virus (VSV)-vectored vaccines against Ebola and Marburg viruses. NIAID is supporting the preclinical studies for the trivalent vaccine against Marburg and the Zaire and Sudan strains of Ebola. The U.S. Department of Defense plans to support an upcoming Phase 1 clinical trial of the monovalent vaccine against the Zaire strain of Ebola. NIAID also is supporting testing of a candidate nanoparticle Ebola vaccine developed by Novavax. When combined with an adjuvant manufactured by Novavax, the investigational vaccine showed promise in nonhuman primates. Initial results from a Phase 1 trial found the vaccine candidate to be well-tolerated and elicited an immune response.
NIAID also is partnering with the University of Texas Medical Branch at Galveston to advance a human parainfluenza virus type 3-vectored Ebola vaccine developed by NIAID scientists. The parainfluenza virus is used as a weakened, replicating viral vector, or carrier, to deliver Ebola genetic material designed to stimulate a protective immune response against Ebola virus. The vaccine candidate is designed to be delivered to the respiratory tract as an aerosol or liquid and induced a robust immune response in monkeys and protected monkeys exposed to Zaire Ebolavirus. NIAID initiated a Phase 1 clinical trial to test the safety and efficacy of the aerosolized version in September 2015.
NIAID is supporting and conducting research to produce a vaccine candidate based on an existing rabies vaccine that would protect against Ebola, Marburg, and rabies viruses. NIAID intramural scientists are working with Thomas Jefferson University investigators to pursue a version of the vaccine for human and veterinary use, as well as a version for African wildlife. The National Institutes of Health (NIH)licensed the candidate rabies/Ebola vaccines to Exxell BIO, which aims to advance the products through clinical testing and potential commercialization.
NIAID is advancing research on several investigational Ebola treatments in different stages of development.
ZMapp, an investigational Ebola treatment developed by Mapp Biopharmaceutical Inc., is a “cocktail” of three different proteins, called monoclonal antibodies. The antibodies are produced in tobacco plants specifically bioengineered to produce large quantities of the proteins. When tested in nonhuman primates, ZMapp demonstrated strong antiviral activity and protected the animals from death as late as five days after infection with Zaire Ebola virus. The NIAID Division of Microbiology and Infectious Diseases supported the earlier development and preclinical testing of ZMapp. BARDA is supporting accelerated development and manufacturing activities.
ZMapp was administered under emergency use authorization to Ebola-infected patients in Africa, the United States, and Western Europe. The NIH-led PREVAIL II clinical trial examining the safety and efficacy of ZMapp launched in March 2015 in the United States, Liberia, Sierra Leone, and Guinea. Investigators originally aimed to enroll 200 participants but closed enrollment at the end of January 2016 with 72 participants total as the West Africa Ebola outbreak ended. Results presented in February 2016 indicate the antibody cocktail was well-tolerated and showed promise, but there was insufficient data to determine definitively whether it is a better treatment for Ebola virus disease than supportive care alone.
Additionally, through the NIAID Centers of Excellence for Translational Research program, Erica Ollmann Saphire, Ph.D., of Scripps Research Institute, leads a consortium to study immunotherapeutics against viral hemorrhagic fevers, which identified ZMapp’s structure and how it binds to Ebola virus. Dr. Saphire is using this knowledge to test next-generation antibodies for better binding and efficacy.
BCX4430, developed by BioCryst Pharmaceuticals with support from NIAID, is an investigational small molecule drug with broad spectrum antiviral activity, including against Ebola. BCX4430 has protected animals against infection with Ebola and Marburg viruses. BioCryst and NIAID launched a Phase 1 clinical study in healthy volunteers in December 2014 to examine the product’s safety and determine a treatment dosage.
In June 2015, NIAID and the Ministry of Health of Liberia launched the PREVAIL III study to evaluate people in Liberia who have survived Ebola virus disease (EVD) within the past two years. Investigators hope to better understand the long-term health consequences of Ebola virus infection, determine if survivors develop immunity that will protect them from future Ebola virus infection, and assess whether previously EVD-infected individuals can transmit the virus to close contacts and sexual partners. The five-year study is expected to enroll approximately 7,500 people, including 1,500 people of any age who survived EVD and 6,000 of their close contacts.
Preliminary findings from the study presented in February 2016 indicate that both Ebola survivors and their close contacts have a high burden of illness. However, the prevalence of eye, musculoskeletal, and neurological complications was greater among the individuals who survived EVD. Thirty-eight percent of the 97 male survivors who provided one or more semen samples for analysis had Ebola detected in their semen at least once. In one case, Ebola was detected in participant’s semen sample 18 months after he had EVD symptoms. In a subset of 126 contacts who reported sexual activity with a survivor, only four percent reported regular condom use, raising concerns about potential sexual transmission of EVD. However, no cases of sexual transmission have been detected in this study thus far.
NIAID is also supporting the development of improved diagnostics to detect Ebola virus infection, including those that can provide rapid identification and can be deployed at the point of care where Ebola virus outbreaks occur. For example, since 2005 NIAID has supported BioFire Diagnostics in developing FilmArray, a multiplex polymerase chain reaction (PCR) system. Initial NIAID support focused on the development of FilmArray’s Respiratory Panel, which can simultaneously detect 20 respiratory viruses from patient samples in one hour. Efforts were expanded to include a Blood Culture Identification Panel and a Gastrointestinal Panel. NIAID provided partial support to develop an Ebola diagnostic for the FilmArray instrument, which was granted emergency use authorization by the Food and Drug Administration (FDA) in October 2014.
Additionally, with NIAID support, Corgenix Medical Corporation’s rapid immunodiagnostic for Ebola viruses—the ReEBOV Antigen Rapid Test Kit—became eligible for World Health Organization procurement and FDA emergency use authorization in February 2015. The diagnostic can provide results within 15 minutes and is based on direct detection of an Ebola protein, rather than amplification of nucleic acids. NIAID also is advancing development of other types of diagnostics, including those using novel technologies, such as microfluidics, optofluidics, and nanophotonics, which are capable of detecting an array of viruses, including Ebola viruses.
Through the NIAID-funded Broad Institute Genomic Center for Infectious Diseases, NIAID is supporting the sequencing and comparative genomic analysis of Ebola virus isolated from patients infected in the 2014–2015 Ebola outbreak in West Africa. Led by the Broad Institute's Dr. Pardis Sabeti, researchers have sequenced Ebola viral genomes of more than 660 human clinical samples. This work has provided critical information about the genetic composition and variation of Ebola viruses circulating in West Africa. NIAID made this data rapidly available to the scientific community by submitting it to the National Center for Biotechnology public database GenBank. NIAID is also supporting the access and analysis of this data through its ViPR Bioinformatics Resource Center, which provides easy access to publicly available Ebola virus genomic sequences, clinical data associated with the samples, and data analysis tools.
Additionally, NIAID provides preclinical services, such as drug screening and animal testing, to researchers in academia and industry to advance vaccine and treatment product development. NIAID established and conducted a responsive vaccine screening capability that provided essential early proof-of-concept efficacy data in nonhuman primates that was instrumental in rapidly advancing some vaccine candidates into clinical testing.
More than 30 different filovirus vaccine formulations have been evaluated through NIAID preclinical services since 2011 using animal models and assays that NIAID developed over many years. Several of these candidates qualified for further testing, and a number are currently in the product development pipeline. NIAID has also screened licensed drugs for anti-filovirus activity to gauge their potential as Ebola treatments.
Last Updated February 26, 2016