For those still skeptical that the Zika virus is causing brain defects in babies infected in the womb, a new study provides some pretty strong evidence.

Researchers from the University of Washington reported Monday that they infected a pregnant pigtail macaque monkey, then monitored the development of her fetus.

Within three weeks of infection, there were already signs that the fetus’s brain had sustained damage. The white matter stopped developing, as did the size of the head.

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“We have incontrovertible, irrefutable evidence … that Zika causes fetal brain injury,” lead author Dr. Kristina Adams Waldorf said in an interview with STAT.

“It does it, and it does it fast.”

Adams Waldorf is an obstetrician-gynecologist who researches the impact of infections on pregnancy. While she normally works on bacterial infections, she rapidly shifted gears early this year, gathering a large team of fellow researchers to see if they could study Zika’s effect on developing fetal brains in pigtail macaques — the animal model with which she normally works.

The study, published in the journal Nature Medicine, is unusual, reporting on infection in a single animal. While studies in primates are generally small, it would be more common to have data on three or four infected animals and an equal number of healthy animals for comparison purposes.

Adams Waldorf explained that at the time the group started the trial, they had a single pregnant macaque. So that’s what they studied.

Risks even in late pregnancy

The female was already well-along in her pregnancy, at the equivalent of 28 weeks or the beginning of the third trimester in a human pregnancy. The fetus’s development was monitored by weekly ultrasounds, and it was delivered by Cesarean section at the equivalent of 38 weeks.

In humans, Zika infection in the first trimester seems to lead to the worst damage in affected fetuses. But experts have warned for some time that it’s likely that other problems — hearing loss, vision loss, developmental delays — may arise when infection occurs later in pregnancy.

That’s what this work mirrored, Adams Waldorf said.

The rapidity of fetal brain damage suggests that preventing Zika infection in pregnant women has to be the goal, Adams Waldorf said; developing a treatment to be given after a woman develops symptoms would be a waste of time.

Animal proof?

Adams Waldorf said the work proves Zika infection in the womb causes brain birth defects — fulfilling a test known as Koch’s postulates. Laid out in 1884, Koch’s postulates are criteria that must be met to prove a pathogen causes a disease. A key proof is that the pathogen causes the disease when it is inoculated into a healthy laboratory animal.

Other researchers, though, said one cannot make this claim based on the study of a single animal.

“I think that given what we know about human Zika infection, it’s really tempting to say ‘Aha! This is really showing the same thing in a macaque,’’’ said Dave O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison.

“But with [a single animal] and without appropriate controls that were imaged the exact same way at the exact same time points, I would just be a little bit more cautious than that.”

O’Connor has also been working on Zika infection in rhesus macaques, taking the unusual step of sharing his data online in real time. His lab infected four pregnant macaques, but did not see brain damage in the fetuses.

They injected their monkeys with a much lower dose of Zika virus than Adams Waldorf’s team used — another detail that O’Connor and others point to in cautioning how much one can conclude from this experiment.

The monkeys in O’Connor’s lab got one injection of the virus. Adams Waldorf’s team used five injections, each containing 1,000 times more virus than O’Connor used, he noted.

“At best, mosquitoes can deliver a fraction of that,” agreed Nikos Vasilakis, a pathology professor at the University of Texas Medical Branch in Galveston who is also studying Zika infections in macaques.

Adams Waldorf explained that Aedes mosquitoes make a series of small bites when they feed, injecting virus each time if they are infected. That was the rationale for using multiple doses and the amount of virus given to the pregnant animal.

Those issues aside, both O’Connor and Vasilakis praised the work, saying it shows pigtail macaques could be a useful animal model for human Zika infection. Animal models are critical in research, especially in the development of vaccines and drugs.

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