Paving the way for potential treatments for Zika virus infections, Seattle scientists have become the first to demonstrate the devastating effects of the disease in a monkey, an animal that closely resembles humans.
Researchers with the University of Washington Center for Innate Immunity and Immune Disease on Monday reported the first case of Zika-caused brain damage in the fetus of a nonhuman primate: a single pigtail macaque.
It’s a key step toward understanding the impact of the mostly mosquito-borne virus that’s spreading in more than 50 countries, causing severe birth defects and other problems, said Dr. Kristina Adams Waldorf, the UW expert who was lead author on the study published in the journal Nature Medicine.
“It’s the final, definitive proof that Zika causes fetal brain injury,” said Adams Waldorf, an obstetrician who has studied infections in pregnancy for 15 years. “It removes any lingering doubt.”
She led the 32-member team behind the work, along with senior authors Lakshmi Rajagopal, an infectious-disease expert at Seattle Children’s Research Institute, and Michael Gale Jr., a UW immunologist.
Starting last March, when the horror of Zika-induced birth effects was just becoming clear, the group launched an experiment that infected a pregnant, 9-year-old macaque with the virus.
The monkey mother showed no signs of illness, but very quickly – within 10 days of infection – the fetus developed brain damage similar to that seen in human babies affected by Zika.
“When I was watching the images come up for the first fetal MRI, we didn’t know what to expect,” said Adams Waldorf. “But the moment we saw the first fetal brain lesion, we knew we were re-creating the fetal brain-disruption sequence.”
That’s the name for the constellation of severe birth defects detected in babies in Brazil and other countries since the virus began exploding across Latin America, the Caribbean – and beyond.
“I started making phone calls,” Adams Waldorf said.
Reproducing Zika effects in a monkey, even just a single animal, is a huge development, several experts familiar with the latest research said. Not only does it confirm that Zika infection causes harm, it provides a realistic model for testing possible therapies.
“I think it’s very significant,” said Carolyn Coyne, a University of Pittsburgh virus researcher who has been among scientists racing to understand the disease. “We’re at the point for Zika that we need to fully recapitulate the phenotype that we’ve seen in humans. If you’re really trying to test in a pregnant-animal model, what’s the effect of vaccination? What are the effects of these drugs?”
Damage quickly seen
The pigtail macaque is ideal. It’s known to be susceptible to flaviviruses like Zika, and its pregnancies are similar to those in people, the study noted.
Dr. David Schwartz, a clinical professor of pathology at the Medical College of Georgia, Augusta University, agreed.
“I think that from reading this one article, it appears to be one of the potential best animal models we have, not only for testing therapeutic models, but for testing vaccines,” said Schwartz, a medical epidemiologist who tracks global health crises.
The Seattle-led researchers injected Zika virus under the skin of the pregnant monkey in five sites on its forearms during the week of gestation that corresponded to 28 weeks, the start of the third trimester, in humans.
Like most infected humans, the macaque showed no signs of rash, conjunctivitis or fever, all symptoms of Zika disease.
But weekly ultrasounds and MRIs quickly revealed damage in the fetus, which showed smaller-than-normal head size, brain lesions and other signs of harm.
The fetus was delivered by C-section. The animals were killed and autopsied. Evidence of Zika, but not active infection, was found in multiple organs of both.
Researchers were careful to note the study did not confirm microcephaly, the development of much smaller-than-normal heads seen in many Zika-affected babies. That likely was because the animal was infected later in pregnancy, Adams Waldorf said.
Previous Zika research had been conducted in cells and in mice. And pregnant Rhesus macaque monkeys had been infected with Zika in a study, but no effects on the fetuses were found.
The urgency of the Zika epidemic spurred investigators to act quickly, Gale said. The strain of Zika virus used for the experiment was from Cambodia in 2010 because it was so difficult at the time to obtain strains from the Brazil outbreak early last spring.
“When we initiated the study, the Cambodian strain was the one we had the most virus produced from,” Gale said. “Because it was a pregnancy model, we couldn’t wait.”
That strain is nearly identical, a 99.9 percent match, to the current virus, he added.
The UW-led researchers were able to respond swiftly because Adams Waldorf and Rajagopal were part of a larger team already studying infections such as Group B streptococcus in pregnancy.
“I think everything went fast,” Rajagopal said. “On one side, it’s exciting. On the other side, you see how devastating this is.”
Focus on prevention
Additional experiments are continuing. Another pregnant monkey and fetus have been infected and examined, but the results weren’t available in time for publication. Eight other Zika-infected animals are currently being observed, Gale said.
The new study also shows that any therapy for Zika will have to focus on preventing infection, Adams Waldorf said. The damage to the fetus occurred so quickly after infection, within days, that there’s no window for intervention after the fact.
“It’s going to have to be a vaccine or a prophylactic,” she said.
Various efforts are under way to find drugs or vaccines to stop Zika, including a clinical trial in humans sponsored by the National Institutes of Health.
Funding, however, continues to be an obstacle. A standoff in Congress has blocked a $1.1 billion plan to fight the virus, weeks after transmission of the disease by local mosquitoes in Florida was confirmed. Last week, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told reporters he might have to halt Phase 2 of the human vaccine trial, unless the money is approved.
Funds for the UW study, which cost an estimated $200,000, were diverted from other research, investigators said.
For Adams Waldorf, who has been warning her pregnant patients about Zika for months, the experiment’s success only underscored her concerns.
“I had some insider knowledge that Zika virus can, so to speak, liquefy the fetal brain,” she said.
Local transmission of Zika has infected nearly 16,000 people in U.S. territories, including more than 1,000 pregnant women, according to the Centers for Disease Control and Prevention. Nearly 3,000 cases of Zika in the continental U.S. have been confirmed in people who traveled to areas where the virus is spreading, including 34 in Washington state. At least 671 women nationwide were pregnant. Seventeen live babies with Zika-related birth defects have been born in the U.S. Five Zika-affected pregnancies with birth defects ended.
“U.S. citizens are not getting the message,” Adams Waldorf said. “They don’t know how dangerous the epidemic is.”
