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New method tested to block chikungunya infection

Jun. 14, 2019, 12:48 PM

by Bill Snyder

Chikungunya is the exotic-sounding name of an emergent, mosquito-borne tropical viral infection that can cause chronic and debilitating joint pain and arthritis.

It’s also the first target of an exciting new approach that injects genetic material into the bodies of infected and at-risk individuals to trigger rapid production of potent, virus-neutralizing antibodies.

A phase 1 safety trial began in humans in February. It is based on prior successful testing in animals described by researchers at Vanderbilt University Medical Center (VUMC) and their colleagues this week in the journal Science Immunology.

“This approach could revolutionize the feasibility of widespread use of human monoclonal antibody therapy and prophylaxis for infectious diseases,” the researchers concluded.

The research was supported in part by a grant from the Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense, which has as a priority the development of methods for preventing or stopping pandemics of infectious disease.

The anti-chikungunya antibody was discovered in the lab of James Crowe Jr., MD, at VUMC in the blood of a previously infected person who had developed potent immunity against the virus.

The Crowe lab has developed high-efficiency methods for isolating from the bloodstream antibody-producing white blood cells, and then transforming them into factories that can churn out large quantities of single, “monoclonal” antibodies.

However, “antibodies are quite expensive and take a long time to develop,” Crowe said, while widespread outbreaks of viral infections — called pandemics — can spread extremely rapidly. What’s needed, he said, is an approach for moving “very, very fast.”

It would be quicker if the body was coaxed to produce the antibodies on its own. But that would require a genetic trigger.

So, with colleagues at Moderna Inc., a biotechnology firm in Cambridge, Massachusetts, the researchers determined the antibody’s intermediate genetic blueprint, the messenger or mRNA, which in stepwise fashion is transcribed from the gene, the DNA, and then translated into the antibody protein.

Normally mRNA is rapidly degraded in the bloodstream. To protect it, the Moderna team encapsulated it in a lipid nanoparticle using in their proprietary technology. Once injected, cells took up the encapsulated mRNA and began producing antibody.

The injections generated antibodies that protected mice against chikungunya-induced joint disease and arthritis. Protective levels of antibodies were also observed in a monkey species that received the mRNA. On this basis, Moderna received approval from the U.S. Food and Drug Administration to conduct a safety trial in humans.

“This is the first time that an RNA has been used to encode an antibody in a human being,” said Crowe, director of the Vanderbilt Vaccine Center. “This is a major milestone in biotech development. It’s very exciting to see that an RNA can be put into people safely.”

After beginning the human trial with a low dose, Moderna recently increased the dose while continuing to determine how many antibodies are being produced.

“The idea is to start low and increase the dose slowly to a level that we think will be effective,” Crowe said. “We’ll know this year whether it’s safe and has promise.”

If so, this approach could be applied to any condition in which the immune system is involved or there’s inflammation including cancer and auto-immune diseases like rheumatoid arthritis. Antibody-based therapy also is being explored for treatment of central nervous system diseases like multiple sclerosis and Alzheimer’s disease.

Crowe is the Ann Scott Carell Professor in the Departments of Pediatrics and of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine. Vanderbilt colleagues included Nurgun Kose, Gopal Sapparapu, PhD, and Robin Bombardi.

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