The exclusion of pregnant and lactating women from an effort to vaccinate people exposed to the Ebola virus in the current outbreak is wrong, indefensible, and should be reversed, three public health experts wrote Monday in an opinion article published in STAT.
The Johns Hopkins University experts argued it is unfair to deny pregnant and lactating women the experimental vaccine if they wish to take it, given the great risk Ebola poses to them. The fatality rate is 80 percent or higher for pregnant women who contract Ebola, and nearly all survivors miscarry.
The decision was made by the Democratic Republic of the Congo’s health ministry, based on the advice of two expert panels that advise it on use of experimental Ebola therapies and vaccines. But the DRC’s position echoes the recommendations of the World Health Organization on how to use Merck’s still-unlicensed Ebola vaccine.
“The … vaccine will give pregnant women, and the children they are carrying, a chance to live. Without it, most of the pregnant women infected with Ebola, and almost all of their infants, will die,” wrote Ruth Faden, Ruth Karron, and Carleigh Krubiner in their commentary.
The current outbreak in northeastern DRC is of grave concern to the WHO and other agencies mounting a response, set as it is in a part of the country engulfed in a long-running conflict. More than 100 armed groups operate in the area, and traveling among affected communities requires military escort.
A total of 111 cases have been recorded since the outbreak was declared on Aug. 1, and 72 of those people have died.
A ring vaccination program has been mounted to try to halt spread of the virus. In this program — like the one undertaken in another outbreak in the country earlier this year — the Merck vaccine is being offered to contacts of known cases and the contacts of contacts. Anyone over the age of 1 can be vaccinated. Anyone, that is, except pregnant and lactating women.
The exclusion is based on safety concerns due to the fact that the vaccine is made with live viruses. It’s not Ebola, but rather a livestock virus called vesicular stomatitis virus that doesn’t cause disease in people. The VSV virus has been modified to contain a protein from Ebola viruses that teaches the immune system to recognize and fight Ebola.
Those vaccine viruses cannot infect a recipient with the deadly disease. But live virus vaccines are typically more reactogenic, meaning they are more likely than killed-virus vaccines to make a recipient feel achy, or run a fever, or experience soreness at the injection site. There is also at least theoretical concern that the viruses in the vaccine could pass through the placenta to the fetus, Karron told STAT in a joint interview with her co-authors, but she added there is little evidence that live virus vaccines are harmful in pregnancy.
Still, in general there is wariness about giving pregnant and lactating women any drug or vaccine that hasn’t been tested in this population. But researchers and companies are also leery about testing drugs or vaccines in pregnant and lactating women — and women in this demographic were excluded from the clinical trials that studied the Merck vaccine.
There is a vicious cycle at play here, said Faden, former director of the Johns Hopkins Berman Institute of Bioethics.
“People will say, ‘Well, where’s the evidence this vaccine is safe in pregnancy?’ Well, how can we know if we’ve never tested it in pregnancy? ‘Well, we couldn’t test it in pregnancy because it’s not safe to test it in pregnancy,’” she said. “And if you can’t get off that … little spinning wheel, pregnant women and their babies are going to be left out indefinitely.”
The three experts — Karron is a pediatrician and professor at Hopkins’s public health school, and Krubiner is a policy fellow at the Center for Global Development in Washington, D.C. — are part of a project called PREVENT. The acronym stands for Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies.
They wrote the commentary on their own, but say their position on the unfairness of the current Ebola vaccination policy is shared by the other members of the group.
The PREVENT initiative stems from work to advocate for more research in women. For years, drugs in development were mostly tested in men, a practice that failed to recognize that women are biologically different and that results found in men might not extrapolate faithfully to women.
While progress has been made on that front, Faden said, pregnant women are still largely absent from clinical trials, resulting in a paucity of information about whether new drugs and vaccines are safe for them. The goal may be to protect these women and the fetuses they carry, but that impulse to protect harms them as a consequence, she and her colleagues argued.
Karron noted that women are more likely to be caregivers, meaning if there is Ebola in a community, they may be at greatest risk of contracting it. And in some countries where Ebola is transmitted, women have more children, spending many years either pregnant or breastfeeding.
According to the CIA World Factbook, the mean age at which women have their first child in DRC is just under 20 years old and, on average, women have 4.4 children each. In the United States, the comparable figures are 26.4 years old and 1.9 children apiece.
“It further disadvantages a much larger population,” Karron said of the policy not to offer this vaccine to pregnant and lactating women.
A Belgian gynecologist who works with Doctors without Borders supported the call to change the policy. Dr. Séverine Caluwaerts volunteered with MSF — the group is known by the acronym for its name in French — during the West Africa outbreak of 2014 through 2016.
After it ended, Caluwaerts published a heartrending account of a seven-months-pregnant woman who was brought to an Ebola treatment center in Forécariah province, Guinea. The woman, 25, was a known contact of a case, but had been denied access to the ring vaccination trial because she was pregnant.
Severely ill when she entered the treatment center, the woman went into early labor, giving birth to a little girl named Nubia who, miraculously, survived. The mother died.
(Caluwaerts said the child is now 2 1/2 years old; her former caregivers follow her progress, thinking of her as “a miracle child.”)
“We absolutely don’t agree with the decision of WHO and the Congolese government not to administer the vaccine to pregnant women,” Caluwaerts said. “We would at least give them the choice.”
“The risk-benefit is so much in favor of giving the vaccine.’’
The final decision on whom to vaccinate rests with the DRC government, not the WHO, said Dr. Peter Salama, the global health agency’s deputy director-general of emergency preparedness and response.
“I’m not trying to absolve WHO of responsibility here,” Salama said on Friday. “But ultimately it is up to the country’s research and ethical review bodies to weigh up what is simply not a black-and-white decision.”
But those expert panels were likely guided in their deliberations by the WHO’s recommendation against using the vaccine in pregnant and lactating women.
Interestingly, until recently the WHO also recommended against giving the vaccine to children under the age of 6, because of a lack of data to show it is safe and effective in children younger than 6. But that guidance was amended to include children ages 1 and older, if they are contacts of Ebola cases, or contacts of contacts. That is the approach that was used in the earlier Ebola outbreak in western DRC.
Salama conceded that decision was made without evidence to guide it. “It’s a good point. We don’t have a lot of data for the 1- to 6-year-old group. But we do have for slightly older children some data at least,” he said.
The agency also has a little data on the safety of the vaccine in pregnant women, though it has never published what it knows in the scientific literature. In the initial ring vaccination trial that showed the Merck vaccine is protective, roughly 20 pregnant women were inadvertently vaccinated. That can happen in clinical trials because in the early weeks of pregnancy, women often are not aware of their status.
In fact, the evidence gained from inadvertent vaccinations is likely why the WHO advises that in yellow fever outbreaks, pregnant women should be vaccinated — even though the yellow fever vaccine is made with live viruses. The vaccine has been in use for decades.
Faden and her colleagues argue it makes no sense to recommend use of the yellow fever vaccine in pregnant women, but withhold vaccine to protect against Ebola, a more deadly pathogen. Salama, though, said the analogy is not a good one; the yellow fever vaccines in use have been licensed.
“These [Ebola vaccines] are investigational products of which we have very limited data even to use in non-pregnant populations,” Salama said.
Caluwaerts’s report on Nubia’s mother mentioned the women who had been inadvertently vaccinated with the Ebola vaccine. It may be their only reference in the scientific literature. She’d learned about the data from the lead author of the initial ring vaccination trial, the WHO’s Ana Maria Henao-Restrepo.
“She hasn’t published her data yet on the 20 women who were accidentally vaccinated,” said Caluwaerts. “She just said orally at a conference that they are fine and that the babies are fine, but we haven’t seen it in writing. MSF would love to be able to see this in writing, also to be able to advocate more for the vaccine for pregnant women.’’
STAT reached out to Henao-Restrepo, but she did not reply.
Salama acknowledged there are data on these cases, but suggested there isn’t enough there to know that it’s safe to give this vaccine to pregnant women. “So far we don’t have any evidence — again, it’s very preliminary — to suggest major adverse outcomes related to vaccination,” he said. “But that’s based on an extremely small sample size.”
Still, Faden, Karron, and Krubiner argue that in the face of plenty of evidence that Ebola infection is generally deadly for pregnant women and their fetuses, the greater risk lies in not vaccinating pregnant women exposed to Ebola in this outbreak.
“It’s just unfair,” Faden said. “You’ve got other segments of the population who are at the same, or probably in some cases, less risk than pregnant women, and they’re being provided vaccine. Pregnant women are not being provided vaccine without adequate justification.”
Correction: An earlier version of this story incorrectly described Ruth Faden’s title and the Center for Global Development.