FLC | Primate scientists work to identify best COVID-19 research model

Primate scientists work to identify best COVID-19 research model

May 12, 2020

Within weeks of the arrival of SARS-CoV-2 samples at the Tulane National Primate Research Center, two of the lab’s African green monkeys had contracted severe lung disease.

Skip Bohm, the chief veterinarian at the research center, says these are the first documented cases they’ve seen of severe illness from the new coronavirus in nonhuman primates.

“It's an initial study, a few animals. But if it can be reproduced, it would be a very important model for looking at very severe disease in people,” Bohm says. “Before we can study any treatments or vaccines or even just the disease itself, we have to establish that we have an animal model that exhibits the same type of diseases as it occurs in humans.”

An animal model is a proxy that scientists find—or create using gene editing—that experiences a particular disease the way humans do. Studying animals, though controversial, is highly convenient for infectious disease research. It's illegal to deliberately infect human volunteers, but laboratory animals are easy to isolate and observe, and they can be subjected to invasive procedures and tissue sampling.

In addition, without an animal model that closely replicates what goes on in humans, there’s potential for harm in a fast-moving pandemic response like the one mobilizing now, warns Jay Rappaport, the director of Tulane National Primate Research Center. There’s also potential for vaccines to trigger immune enhancement, meaning people who have been vaccinated actually get sicker when exposed to the disease, which has been an obstacle in trying to create vaccines for other viral illnesses, including dengue fever.

“These studies really need to be done first in a model that closely resembles what happens in humans,” Rappaport said.

Yet choosing among our evolutionary cousins to model the human experience of a disease is an exercise in approximation and compromise. It may seem like monkeys would always be the best choice to replicate human illnesses, but primate species aren't susceptible to all the same viruses.

“It's not always going to be monkeys,” says Dave O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin. He works with the Wisconsin National Primate Research Center, which, like Tulane, is part of a network of primate research centers jointly supported by the NIH and university hosts around the country. The centers are now diverting most of their focus to coronavirus research.

As the pandemic became increasingly serious, O’Connor’s team took the sequence of the receptor the virus uses to latch on to human cells, and compared that sequence across a variety of lab animals, including macaques and African green monkeys. They found both of these species and humans have identical sequences at the key place where the virus binds, a reason to believe SARS-CoV-2 might be able to infect nonhuman primates. But this didn’t take into account restriction factors, specialized built-in immune responses—usually proteins—which are released in cells to prevent the replication of different viruses. These can vary widely among species.

By the time the virus samples arrived at Tulane, a study in China had shown rhesus macaques could be infected, but there was no guarantee the team would be able to replicate their results or successfully infect the African green monkeys. But it was important to try: Testing treatments and vaccines in monkeys can say more about their safety and efficacy than tests in other animals might.

Their first coronavirus experiment tested two species of monkey, African greens and Rhesus macaques, and two routes of exposure: aerosol exposure (breathing the virus in from the air) and direct contact (the virus was swabbed in the animals’ eyes, noses, and tracheas). Within days after initial exposure, all the monkeys were shedding the virus from everywhere the scientists sampled: eyes, nose, mouth, rectum, and vagina. But none of the animals had noticeable symptoms.

Then, suddenly, the day after an examination in which she had appeared normal, one of the African green monkeys from the direct contact group showed signs of very severe pneumonia. CT scans showed her right lung was full of fluid, and she was so severely ill she met the study's criteria for early euthanasia. Two weeks later, a second African green female, this time from the aerosol group, developed the exact same symptoms in the same abrupt manner. She was also euthanized early, and scans again revealed severe edema in her right lung.

Bohm is quick to point out that these results are very preliminary, and need to be repeated to see if more African greens come down with severe illness. The national primate centers are working in unusually close collaboration to try and fit this puzzle together more quickly—a group at one of the other centers is also studying the disease in African greens. So far, they have observed illness but not of the same severity as observed at Tulane.

Many scientists argue primate research is irreplaceable, at least for now, and that it has been essential to some of the most important advances in modern medicine, including tuberculosis vaccines and many of the best treatments for HIV. Bohm, whose chief role is as the veterinarian to the monkeys at Tulane, has spent a lot of time weighing this calculation.

“Anybody who’s in research understands that there are sacrifices that the animals make,” Bohm said.

He takes this seriously, especially in the case of intelligent animals like nonhuman primates. If scientists conclude the only way to move forward on a particular problem is by studying animals, he says, their next step is to design the experiment to reduce, to the greatest extent possible, the number of animals involved, and the pain and distress they have to endure. In the end, he feels, the benefits to humans justify this kind of work.

“I have a daughter who’s got type 1 diabetes, and she wouldn’t be alive today if it weren’t for advances in animal research,” Bohm said.

For now, his team at Tulane is poring over the tissue samples and other results from their first trial. They are planning to replicate their study with additional African greens. Then, within a few months, they will begin running trials of vaccines and drugs from various external groups.

“There are a lot of different products coming up through the pipeline, including different treatments,” Bohm said. “[We’re] on the phone almost every day with either biotech groups, Big Pharma, or NIH talking about studies they want to get going.”