Zika is a disease whose burden falls most heavily on pregnant women. In most people who come down with it, the virus is symptomless, and passes through the body with the person none the wiser. When symptoms do bloom, they are unpleasant, but not particularly dangerous to most. If someone who’s pregnant gets Zika, however, the consequences for the fetus can be devastating. The virus causes underdevelopment of the head and brain, known as microcephaly, and a hodgepodge of other symptoms, like eye damage and clubfoot, which are loosely categorized as Congenital Zika Syndrome.
For this reason, a working group made up of bioethicists, OB/GYNs, vaccinologists and others recently released ethics guidelines for Zika vaccine development, in which they recommend that pregnant women should be included in clinical trials for Zika vaccines.
Pregnant women are very rarely included in medical research. They are seen as too complicated, given all the physiological changes of pregnancy, and too risky; researchers and companies that sponsor research may be worried about possible harm to the fetus, and the legal liability that could follow. The Department of Health and Human Services’ regulations classify pregnant women as a “vulnerable population” that needs special protection when participating in research. This doesn’t mean they can’t be included—the regulations lay out 10 conditions that must be met when enrolling pregnant women in a research study. A 1994 Institute of Medicine report also recommended that pregnant women should be considered eligible for studies, and only be excluded if there is no benefit to them or if there’s a clear danger to the fetus. But they tend to still be excluded from most research anyway.
This means that evidence on how well a drug or vaccine works in pregnant women, and how safe it is for pregnant women to use, mostly comes after the fact. Data is slowly collected from pregnant women who use the drug once it is already out, and compiled into observational studies. One study found that of all the drugs approved by the Food and Drug Administration between 2000 and 2010, 98 percent of them had an “undetermined” risk of birth defects. And for drugs approved between 1980 and 2000, it took an average of 27 years for after-the-fact data gathering to yield enough results for the “undetermined” status to be changed to something more specific.
So there are consequences, generally, of the exclusion of pregnant women from medical research. “And with Zika—because pregnant women [are] really at the heart of the concerns around the Zika epidemic, it was something that really couldn’t be overlooked,” says Carleigh Krubiner, a member of the ethics working group that put out the guidance, and a research scholar in bioethics at Johns Hopkins University.
The group, which was funded by the Wellcome Trust, did around 60 consultations with experts, Krubiner said, including speaking to people at the National Institutes of Health, which is currently testing several Zika vaccines that are in various stages of development. Ultimately, the group settled on three broad recommendations. First, researchers “should pursue and prioritize development of ZIKV vaccines that will be acceptable for use by pregnant women in the context of an outbreak.”
Second, even for vaccines that aren’t necessarily intended for use by pregnant people, there is always the chance that someone enrolled in the trial might be pregnant without knowing, or might become pregnant shortly after getting the vaccine. The group wants researchers to be sure to collect data on these people, so that we can learn as much as possible about how any vaccine might affect someone who’s pregnant.
And finally, they say, pregnant women “should have fair access to participating in ZIKV vaccine trials that carry the prospect of direct benefit.” For pregnant women in Brazil, or Puerto Rico, or other areas where Zika is endemic, participating in a vaccine trial could offer a chance to protect themselves and their fetuses that they wouldn’t otherwise have, since no vaccines are currently on the market.
“What are they owed, out of respect and out of a duty of justice, to ensure that they aren’t excluded from the potential benefits that could be associated with participating in a trial?” Krubiner says.
None of the Zika vaccines that are currently in clinical trials have reached the stage where they could conceivably include pregnant women. That probably wouldn’t happen until a Phase Three trial, Krubiner says. Phases One and Two are still establishing the basic safety of the vaccine.
“There’s no question that we’ll need to target women of reproductive age who are pregnant or might be pregnant,” Peter Hotez, the dean of the National School of Tropical Medicine at Baylor College of Medicine, told me in an email. “So sooner or later we’ll need to include such populations in safety trials. I think once we get an initial safety signal in healthy adult non-pregnant volunteers that Zika vaccines do not produce Guillain-Barré Syndrome [an autoimmune nervous disorder that Zika can trigger in rare cases] or produce other serious adverse events, I think it is possible to proceed with enrolling women of reproductive age and ultimately pregnant women.”
The NIH vaccine that is the farthest along is currently in Phase Two. It’s a vaccine based on the DNA of the Zika virus, which is a novel approach to making vaccines—there aren’t currently any DNA vaccines approved for use in humans. That could also put a wrench in the works; researchers may decide it’s too risky to include pregnant women in a trial of a totally new genre of vaccine. Krubiner thinks the best candidates for use in pregnant people would be vaccines that use killed versions of the virus, which is a much more established method.
They wanted to get this guidance out now, Krubiner says, to give researchers time to incorporate it before any Phase Three trials actually begin. Since “the epidemic has waned a little bit,” she says, that also gives the scientific community room to be more methodical in developing these vaccines. Often in an outbreak situation, there’s a rush to just get a vaccine as fast as possible. Of course, the flip side to that coin, Hotez points, out is that since Zika transmission is down, “it may not be possible to assess this year whether or not any experimental Zika vaccine actually protects against infection or can interrupt transmission.”
“Our hope as we move forward is to develop a much broader framework for different types of pathogens, different types of epidemic threats,” Krubiner says, “and to ensure that for all these different threats that come out that pregnant women aren’t forgotten and left behind.”