Vanderbilt University Medical Center has launched a first-in-human clinical trial to determine the safety and efficacy of an experimental monoclonal antibody against enterovirus D68 (EV-D68), which can cause severe respiratory disease and — in rare cases — a debilitating, polio-like neurologic condition.
Currently there are no approved, specific treatments in the United States for severe EV-D68 infection or for the neurological condition, called acute flaccid myelitis (AFM), which mostly affects children. Symptoms include sudden arm or leg weakness and loss of muscle tone and reflexes, which can lead to paralysis.
Sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, the clinical trial began June 26 and will be conducted in 36 healthy volunteers — ages 18 to 49, at VUMC and the University of Maryland — through the Infectious Diseases Clinical Research Consortium (IDCRC).
The antibody, EV68-228-N, was isolated at VUMC from people who had EV-D68 respiratory infections, and it has been produced for the study through a partnership of two biotechnology companies — KBio, which is based in Owensboro, Kentucky, and San Diego-based ZabBio, Inc.
“This study highlights VUMC’s remarkable ability to connect clinical research and basic discovery,” said the study’s principal investigator, C. Buddy Creech, MD, MPH, director of the Vanderbilt Vaccine Research Program and Edie Carell Johnson Professor of Pediatrics.
In this case, patient-oriented research led to the discovery of a potent neutralizing antibody, which led back to the clinic, and an NIH-funded, first-in-human clinical trial, Creech said.
One of more than 100 non-polio enteroviruses, EV-D68 was first identified in California in 1962. The virus is likely spread from person to person when an infected person coughs, sneezes or touches a surface that is then touched by others.
Because of its association with AFM, and the increase in infections during the past decade, the virus is considered a public health threat, and efforts are underway to prevent its spread.
Following a large outbreak of EV-D68 infections in the summer of 2014, during which 120 AFM cases were reported in 34 states, James Crowe Jr., MD, and his colleagues in the Vanderbilt Vaccine Center isolated antibodies from the blood of several adolescents who had been infected by the virus.
Crowe, the Ann Scott Carell Professor, professor of Pediatrics and Pathology, Microbiology & Immunology and director of the Vanderbilt Vaccine Center, and his colleagues have pioneered the development of monoclonal antibody therapies against a host of viral infections, including COVID-19.
One of the potently neutralizing antibodies against EV-D68 they isolated, EV68-228, protected mice from respiratory and neurologic disease when it was given either before or after infection, the researchers reported in the journal Science Immunology in 2020.
The paper’s first author, Matthew Vogt, MD, PhD, then a postdoctoral fellow in Pediatric Infectious Diseases at VUMC, developed the screening technology used to isolate EV68-228 while in the Crowe laboratory.
Researchers across the country are continuing preclinical studies of the antibody. Vogt, now assistant professor of Pediatrics and Microbiology & Immunology at the University of North Carolina, Chapel Hill, also is investigating how EV-D68 causes AFM in a mouse model of infection.
“This study highlights VUMC’s remarkable ability to connect clinical research and basic discovery.”
C. Buddy Creech, MD, MPH, the study’s principal investigator and director of the Vanderbilt Vaccine Research Program
In 2019 ZabBio approached the Food and Drug Administration (FDA) to discuss EV68-228 as a potential treatment for EV-D68 AFM.
Shortly afterward, ZabBio orchestrated a collaboration between VUMC researchers and KBio, which uses a unique plant-based platform to rapidly produce biologic and vaccine drug candidates, to produce large amounts of EV68-228-N needed for preclinical and clinical studies.
With support from NIAID/IDCRC, the group secured FDA’s approval of the Phase 1 study application for EV68-228-N in 2024.
In the upcoming clinical trial, six of the volunteers will receive an inactive placebo and serve as the control group. The remaining 30, in groups of 10, will receive a single dose of EV68-228-N intravenously in one of three dose levels.
Participants will be followed closely over four months to evaluate the safety of the monoclonal antibody, how long it lasts in the body, and what dose will be most appropriate to advance in clinical trials.
Investigators expect the antibody to be well tolerated, as are other monoclonal antibodies, and they will use the data to determine how long a single dose may be effective in the bloodstream.
Since 2014, 750 confirmed cases of AFM have been reported nationwide, typically occurring in outbreaks that emerge every two years. As of May 2, seven cases had been confirmed this year, in California, Illinois, Iowa, New York and Texas, according to the CDC.
About the Infectious Disease Clinical Research Consortium (IDCRC)
The IDCRC, consisting of the Vaccine Treatment and Evaluation Units and the IDCRC Leadership Group (UM1AI148684), was formed in 2019 to support the planning and implementation of infectious diseases clinical research that efficiently addresses the scientific priorities of NIAID. The consortium includes infectious diseases leaders and clinical researchers from Emory University, University of Maryland School of Medicine, Baylor College of Medicine, Cincinnati Children’s Medical Center and University of Cincinnati, Fred Hutchinson Cancer Research Center, Johns Hopkins University, Kaiser Permanente Washington Health Research Institute, New York University, Saint Louis University, Vanderbilt University Medical Center, University of Alabama at Birmingham, University of Rochester, University of Washington, and NIAID.
This project is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under UM1AI148452.
