Building on decades investigating antibody treatments for infectious diseases that cause epidemics, a team at Vanderbilt University Medical Center has developed a highly effective monoclonal antibody treatment for COVID-19 that formed the basis for a new drug called AZD7442 at an unprecedented clip — only 25 days.
“Twenty-five days was unbelievably fast, and the fulfillment of a life dream,” said James Crowe, M.D., director of the Vanderbilt Vaccine Center. “We’ve been working on antibody treatments to address epidemics for 25 years, but until now the process always took too long.”
Timing Was Off, Again and Again
“With the Ebola virus outbreak, the antibody discovery process took us a year. By then the outbreak was contained,” Crowe said. With the Zika virus outbreak, it took about seven months, but that was still too slow, he explained; it was the same story with the H5N1 avian influenza and the chikungunya virus outbreaks.
“We developed amazing antibody drugs, but by the time we did, no one cared. The epidemics were over,” Crowe said.
Enter the Department of Defense
The Vanderbilt Vaccine Center research team ultimately joined the Pandemic Prevention Platform Program (P3) sponsored by the Defense Advanced Research Projects Agency (DARPA). The goal of P3 is to speed up the process of finding effective antibody treatments for new infectious diseases to within 60 days, Crowe explained.
“In 2018, we won a $29 million grant from DARPA to support us in accelerating the process,” Crowe said. The team did a practice “sprint” to develop an antibody treatment for Zika, and within 78 days identified a treatment that worked with 100 percent success in mice and non-human primate models.
“With Zika and H5N1 we developed amazing antibody drugs, but by the time we did, no one cared. The epidemics were over.”
Crowe and Colonel Matt Hepburn, M.D., a program manager with DARPA’s Biologic Technologies Office, recently appeared together on CBS 60 Minutes to discuss the many ways that rapid responses to epidemics support military readiness, domestic tranquility and global stability.
A Need for Speed
Crowe’s lab began their COVID-19 work using blood from Seattle’s Patient Zero. Obtaining this blood posed challenges, he said. Crowe had to involve the CEO of FedEx to rush the sample out on a Sunday.
“They flew the sample in with a critical shipments team, and then, since Vanderbilt is closed on Sundays, they sent a driver from the Memphis hub in a Lincoln Town Car to deliver it to my house,” Crowe said.
Within 25 days – unprecedentedly fast – the group identified two naturally occurring antibodies in the blood of people who had survived COVID-19. They were AZD8895 (tixagevimab) and AZD1061 (cilgavimab). AstraZeneca then engineered the antibodies to have a longer half-life and designated the combination AZD7442.
Improving on Nature
While the unaltered antibodies would have persisted for about three weeks, the engineered ones last for about three months, Crowe explained. “You can change the sequence slightly in the bottom half of the antibodies where they engage with the immune system, working with three different amino acids, and that extends the antibodies’ usefulness,” he said.
“Imagine everyone in a nursing home inoculated in one day. Treating a similar population via infusion would take weeks.”
AstraZeneca had used this approach with six previous antibody treatment formulations. “It was known to be safe and to work,” Crowe said.
“Data that AstraZeneca released in August showed that the combination decreased the risk of a patient developing symptomatic COVID-19 by 77 percent, compared with placebo,” Crowe said. Importantly, more than 75 percent of the trial population comprised people with comorbidities that rendered them particularly vulnerable to severe disease or death from COVID-19 — people whose immune systems are less capable of mounting a strong response to vaccination.
Crowe’s research group projects the prophylactic effects of AZD7442 to last up to 12 months. Furthermore, preliminary data suggests the combination neutralizes SARS-CoV-2 variants, including the Delta variant.
A phase 3 trial evaluating AZD7442 in hospitalized COVID-19 patients is expected to wrap up later this year, with the main measure being time from randomization to sustained recovery over a 90-day period, Crowe stated. The FDA has not yet authorized any other antibody therapy for treating COVID-19 in the hospital, he added.
Big Practical Advantages
Most current antibody treatments are given by intravenous infusion, and this has been a major limitation on their use, Crowe explained. “Until now, a patient has been diagnosed in one place and then they have had to travel elsewhere for the infusion, and the treatment process may take hours,” he said.
The main breakthrough with the new COVID-19 antibody treatment is that it’s a simple injection that takes 10 seconds and can be administered by many different healthcare professionals, he added.
“Our goal is not just to create drugs or make money, but to use the resources of foundations and governments to find practical solutions for the world’s most vulnerable people.”
This greatly broadens the potential for the preventative treatment. “Imagine everyone in a nursing home inoculated in one day,” he said. “Treating a similar population via infusion would take weeks.”
Next Challenge: Lowering Cost
“A lot of future research is going to focus on dropping the cost of antibody treatments like this one to $10 per dose,” Crowe said. Today, such biologic drugs have high price tags, around $1,000 to $2,000 per dose, he noted. This aspirational goal parallels Crowe’s longstanding focus on research to benefit people in low- and middle-income countries.
“Our goal is not just to create drugs or make money,” Crowe said, “but to use the resources of foundations and governments to find practical solutions for the world’s most vulnerable people.”