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VUMC-led team ‘sprints’ to develop Zika virus treatment

Apr. 11, 2019, 10:27 AM

 

by Bill Snyder

In January scientists at Vanderbilt University Medical Center and colleagues in Boston, Seattle and St. Louis were given an audacious goal to develop — in 90 days — a protective antibody-based treatment that potentially will stop the spread of the Zika virus.

They finished on April 2 — 12 days early — thanks to a combination of technology, ceaseless communication and teamwork.

“It was as if we worked in the same lab,” said Robert Carnahan, PhD, associate professor of Pediatrics at Vanderbilt University School of Medicine, who spearheaded the project. “I think that had as much to do with it as any science did.”

The successful “sprint” was part of the Pandemic Protection Platform program launched last year by the Defense Advanced Research Agency (DARPA) of the U.S. Department of Defense. The goal is to prepare and deploy protective antibody treatments to squelch dangerous viral outbreaks threatening public health and national security — anywhere.

Lab manager Rachel Nargi prepares a B-cell culture during the recent “sprint” to develop an antibody-based treatment for Zika virus infection.
Lab manager Rachel Nargi prepares a B-cell culture during the recent “sprint” to develop an antibody-based treatment for Zika virus infection. (photo by Anne Rayner)

VUMC’s piece of the program is a five-year cooperative agreement worth up to $28 million led by principal investigator James Crowe Jr., MD, Vanderbilt Vaccine Center director and Ann Scott Carell Professor in the departments of Pediatrics and Pathology, Microbiology and Immunology.

The next sprint, which may begin this fall, aims to speed production to a mere 60 days and may target another dangerous virus — perhaps Ebola. Two more sprints will follow.

While the DARPA sprint does not involve human testing, its goal ultimately is to develop ways to stop pandemics — widespread and rapidly spreading viral outbreaks — even in remote corners of the world.

One day it may be possible, Carnahan said, to deploy two specialists with portable equipment to the site of an outbreak, where they draw blood samples from survivors and spin the blood down with a centrifuge to isolate antibody-producing B-cells.

Using the latest technology, they determine the genetic sequences of the antibodies and send that information electronically to the United States, where labs then synthesize the genes, produce the antibodies, and test their anti-virus ability.

Crowe and his colleagues already have developed a monoclonal antibody that is being tested in clinical trials for its ability to protect against Zika virus infection. This mosquito-transmitted virus can cause severe birth defects in babies whose mothers were infected while pregnant.

But older methods of developing therapeutic antibodies can take months. It’s also difficult to give intravenous injections of antibodies to hundreds of people in remote areas.

Instead, the researchers are trying a new tactic: isolating the nucleic acid, the messenger RNA, that encodes the antibody protein, and giving it as a quick, intramuscular injection. Cells that take up the RNA will begin to produce the desired antibody almost immediately.

From blood samples collected from survivors of Zika infection, Crowe, Carnahan and their colleagues isolated B-cells and selected the most promising anti-Zika antibodies produced by these cells.

The lead antibodies were sent to the lab of Michael Diamond, MD, PhD, at Washington University in St. Louis, where they were further tested in vivo (in animal models) for their ability to provide protection from Zika infection.

They also were sent to the lab of Galit Alter, PhD, at the Ragon Institute of MGH, MIT and Harvard in Boston, where they were modified to enhance their virus-fighting ability.

The most-promising lead candidates were then sent to the team at the Infectious Disease Research Institute (IDRI) in Seattle led by Steve Reed, PhD and Neal Van Hoeven, PhD. Using novel approaches, IDRI researchers created RNA formulations of these antibodies carried by nanoparticles.

The RNA-delivered antibodies were tested for their potency against the Zika virus at Washington University and in the lab of Dan Barouch, MD, PhD, at Boston’s Beth Israel Deaconess Medical Center, which determined they met the challenge.

Others at VUMC who directed different parts of the project were Merissa Mayo, PMP (project management professional), senior staff scientist Pavlo Gilchuk, PhD, lab managers Rachel Nargi and Robin Bombardi, MS, Associate Pediatrics Professor Cinque Soto, PhD, and Megan Leksell.

As one might imagine, the sprint took an incredible amount of coordination. While the experience generated new scientific insights and technological innovations, just as important was the successful implementation of team science, Carnahan said.

“We spent many, many phone calls and ran lots of operational experiments,” Carnahan said. “There was a real feeling … of clarity, openness—and trust,” he added. As a colleague noted, “This was one of the most amazing experiences I’ve ever been a part of.”

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