Neutralizing Antibodies Protect Against Enterovirus D68

By Will Boggs MD

August 05, 2020

NEW YORK (Reuters Health) - Antibodies from previously infected individuals can neutralize enterovirus D68 (EV-D68), the putative cause of acute flaccid myelitis (AFM) outbreaks, and protect against infection, researchers report.

"The antibodies we discovered are unexpectedly potent in their ability to inhibit the virus," Dr. James E. Crowe of Vanderbilt University Medical Center, in Nashville, Tennessee, told Reuters Health by email. "Thus, we have a real opportunity to use them in the clinic to prevent or treat infection."

AFM outbreaks associated with EV-D68 have been documented worldwide, but the role of antibodies in protection against EV-D68 infection and disease remains uncertain. Neutralizing antibodies for EV-D68 appear to be nearly universal in adult human sera, and AFM occurs almost exclusively in children.

Dr. Crowe and colleagues sought to characterize the different classes of antibodies made by humans in response to natural infection with EV-D68.

In 12 individuals with previous documented EV-D68 respiratory tract infections, they identified 28 monoclonal antibodies demonstrating neutralization of a B1 clade EV-D68 isolate with half maximal inhibitory concentration (IC50) below 50 mcg/mL.

Eleven of those neutralizing antibodies also neutralized a D clade isolate, with seven exhibiting at least a 10-fold decrease in potency by IC50 value for the heterologous virus.

Moreover, all antibodies with half maximal effective concentrations (EC50) of 1 mcg/mL or lower to B1 clade isolates bound to a B2 clade isolate and about half also bound to a D clade isolate.

In mouse models, prophylactic administration of the highly cross-reactive monoclonal antibody EV68-228 provided sterilizing immunity in the blood and lungs of mice challenged with EV-D68 and completely protected animals from death and neurologic disease, the researchers report in Science Immunology.

Similarly, therapeutic treatment with EV68-228 sterilized the blood within 24 hours of administration. Such treatment improved survival and neurologic disease when given as late as 48 hours after EV-D68 challenge, and, when given at 72 hours after infection, the mouse that survived improved clinically.

"An antibody prevention or treatment is well on its way in development for enterovirus D68, but the medical community will need to decide what is the best target product profile for use, either widespread use for prevention, post-exposure prophylaxis, or treatment of children with EV-D68 respiratory illness with or without mild paralysis," Dr. Crowe said.

"The lead antibody identified in these studies is being developed by IDBiologics, Inc. for clinical trial testing in humans," added Dr. Crowe, who is founder of the company. "The antibody might prevent or treat EV-D68 infection, thus preventing acute flaccid myelitis disease."

Dr. Kevin Messacar of Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, in Aurora, who studies EV-D68 and its association with AFM, told Reuters Health by email, "In the mouse model, the efficacy of anti-enterovirus D68 neutralizing antibodies in stopping disease progression was striking; the question in humans is whether we can initiate treatment within a therapeutic window to see similar efficacy. In humans, the delay from EV-D68 infection through an incubation period to onset of respiratory symptoms, then around a week later onset of neurologic symptoms of AFM, suggests the therapeutic window to halt or reverse neurologic damage may be narrow."

"Awareness and early recognition of AFM are paramount to the efficacy of any potential therapy," he said. "We really need every healthcare provider to be thinking AFM in any patient presenting with weakness, particularly in the summer-fall enterovirus season, and pursuing MRI imaging and a spinal tap to confirm a diagnosis so any potential treatments could be started as early in the course of disease as possible."

The study had no commercial funding. Vanderbilt University has applied for a patent concerning antibodies discussed in the study, with Dr. Crowe and one of his coauthors listed as inventors.

SOURCE: Science Immunology, online July 3, 2020.