When the U.S. Food and Drug Administration approved the most recent respiratory syncytial virus (RSV) vaccine on August 21, it became the first vaccine that had been developed specifically to be given during pregnancy to protect the baby after birth to receive the go-ahead. But it’s not the first vaccine that the Centers for Disease Control and Prevention has recommended during pregnancy. It joins shots for influenza, Tdap (tetanus, diphtheria and pertussis) and COVID—and is part of a strategy of immunizing people during pregnancy that has gained steam and accumulated supporting evidence in the past two decades.
Expectant people will have a choice of how to protect their newborn against RSV. They can opt to get the new parental RSV vaccine between 32 and 36 weeks of pregnancy—which will prompt their immune system to develop antibodies against RSV that will cross the placenta to the fetus and thereby protect the newborn through passive immunity for at least six months. Or they can wait until after their baby is born and give them nirsevimab, a monoclonal antibody that was approved by the FDA in July, which also provides passive immunity ahead of RSV season.
But the option of a pregnancy vaccine for RSV may be more convenient if one is already getting vaccinated against flu, COVID and pertussis during prenatal visits. And the new vaccine further solidifies the growing acceptance of using immunization during pregnancy to protect newborns against diseases at an age when their immune system is not mature enough to mount its own defense.
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“The neonatal immune system is comparatively immature, and it takes time to develop immunity to pathogens, either through vaccination—because multiple doses are needed to achieve protection—or through natural exposure,” says Catherine Mary Healy, an associate professor of pediatrics at Baylor College of Medicine and Texas Children’s Hospital. “And sometimes the infection can strike before [childhood] vaccination.”
Many infections happen right around the time of birth, before most vaccines are given, says Kathryn Edwards, a professor of pediatrics and scientific director of Vanderbilt University’s Vaccine Research Program. “But when you immunize the mother, you protect the mother from a disease that she could present to the baby, and you protect the baby against disease. So it’s a twofer—one shot but with the protection of two.”
A History of Extra Caution
It took a rocky half-century of research to bring the RSV vaccine to fruition, but it’s taken more than twice as long for pregnancy vaccines to become widely accepted by the public and by researchers and clinicians.
“As far back as the 1800s, it was realized that mothers who survived vaccinia infection gave birth to infants who were less likely to become infected,” says Healy, referring to the virus used in the smallpox vaccine. A couple of small trials in the 1930s and 1940s showed that vaccinating pregnant people against pertussis prevented their infants from getting it for the first several months after birth, and a 1961 trial found that vaccination during pregnancy protected newborns from neonatal tetanus.
“For a long time, we were scared to vaccinate pregnant people, and more importantly, we were scared to do trials in pregnant people because we see them as a protected class of individuals who are vulnerable,” says Kawsar Talaat, an associate professor of international health at Johns Hopkins University. But that attitude has been changing as more research has shown the danger of certain infections during pregnancy and the safety and effectiveness of vaccination. “There’s been a big shift, maybe in the last 15 years, in vaccinating pregnant people—not just for their safety but also for the safety of their fetuses and subsequent newborns,” Talaat says.
Neonatal tetanus, for example, killed an estimated 787,000 newborns globally in 1988. While improving hygienic practices during delivery can reduce a portion of those deaths, only tetanus vaccination during pregnancy eliminates the risk, so the World Health Organization made tetanus vaccination during pregnancy a top priority in 1989.
Health experts have known since at least the 1918 flu pandemic that outcomes from flu are worse during pregnancy, both for pregnant people and for their risk of miscarriage and preterm birth. In the 1957 flu pandemic, influenza was the leading cause of death during pregnancy. But although the U.S. Surgeon General first recommended flu vaccination during pregnancy in 1960, the push to vaccinate pregnant people against flu didn’t really take off until the threat became particularly apparent—especially to the general public—during the 2009–2010 H1N1 swine flu pandemic.
“What we’ve learned over time is that if you’re a pregnant person and you contract influenza, you are roughly two to three times more likely to be hospitalized and die than a person of the same age who is not pregnant,” says Paul Offit, an infectious disease physician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. “So as those data became clearer, it became much more compelling to give an influenza vaccine during pregnancy.” Growing evidence has shown that flu vaccination during pregnancy also decreases the risk of miscarriage and preterm birth while protecting newborns until they can get their own flu vaccine at six months old.
The Tdap vaccine was next to join the roster of recommended shots during pregnancy. Pertussis rates began climbing in the 2000s as evidence revealed that protection from an updated pertussis vaccine given during early childhood wore off sooner than expected. So in 2012 the CDC began recommending that pregnant people get a Tdap vaccine between 27 and 36 weeks of gestation so that their antibodies would transfer to the fetus and protect the newborn.
Then in late 2019 a new virus arrived that threatens both pregnant people and their fetuses. “With COVID, we saw again that pregnancy was a significant risk and that people who were pregnant were much more likely to end up in the hospital and [die], with increased risk of fetal loss and miscarriage,” Talaat says. Again, though, companies were hesitant to conduct COVID vaccine trials with pregnant volunteers, which left pregnant people vulnerable to infection, she says.
“When the COVID vaccines were released in December of 2020, the CDC basically said that a pregnant person could reasonably choose to get this vaccine because they knew that you were more likely to be hospitalized and die [from the disease],” Offit says. Then the V-safe program and Vaccine Safety Datalink—two vaccine safety surveillance programs used to look for adverse events from COVID vaccines—revealed no major risks to vaccinating pregnant people, “and it became an urgent recommendation,” he says.
Despite today’s greater acceptance of pregnancy vaccines, conducting clinical trials with pregnant volunteers remains fraught. “When people consider whether to immunize themselves during pregnancy, what they have top of mind is, ‘Could this possibly hurt my baby?’ It’s a reasonable concern,” Offit says.
In an era of vaccine hesitancy and increased litigation, pharmaceutical companies may feel the need to be extra cautious about even the appearance of a safety issue. GSK stopped its own trial of an RSV vaccine for pregnant people in February 2022 because infants born in the vaccine group were more likely to be born preterm. Among 5,235 babies born to participants during the GSK trial, 6.8 percent in the vaccine group were preterm, which is a statistically significant difference compared with nearly 5.0 percent of babies born prematurely in the placebo group.
Yet the increased risk of prematurity occurred only in low- and middle-income countries, and the finding was only significant when compared with infants born to mothers who did not receive the flu or COVID vaccines. It’s plausible that the RSV vaccine did not increase the risk of prematurity but rather that the flu and COVID vaccines decreased that risk, Offit says. Those calculations were never done because GSK scrapped the trial, however.
More Vaccines on the Horizon
Researchers are forging ahead with other potential pregnancy vaccine candidates. “I do see this new wave of interest in parental vaccines following on the heels of the RSV vaccine success and the pertussis vaccine success,” says Sallie Permar, chair of pediatrics at Weill Cornell Medical College. But it’s more than just seeing the effectiveness of those vaccines, she adds.
“Honestly, I think it’s also from more women getting into leadership positions in places like [pharmaceutical companies] that are tipping the scales and also that as each pandemic comes out, it almost invariably has more severe effects on pregnant people and fetuses,” Permar says. “Other parts of the population are starting to realize that vaccines are highly needed for that population, so there’s a greater willingness to do trials during pregnancy,” she says.
Permar has been working to develop a vaccine against cytomegalovirus (CMV), the leading infectious cause of birth defects. A CMV infection during pregnancy, even in someone who has already had CMV, can cause serious problems for the fetus. These include developmental delays, seizures and vision or hearing loss.
Perhaps the biggest next contender for a pregnancy vaccine is one against group B Streptococcus, a type of bacteria that can pass to the fetus during labor and childbirth and cause life-threatening infection, including meningitis, pneumonia or sepsis. Giving a pregnant person antibiotics during labor can prevent infection during a newborn’s first week of life—but it can’t protect against late-onset infections, which can occur between one week and one month after birth.
“We seem to have come as far as we can in preventing [early-onset disease], and the needle hasn’t moved at all in terms of late-onset disease,” Healy says. Vaccination during pregnancy seems like the most obvious way to extend that protection, she adds. One promising GBS vaccine candidate is currently in phase 2 trials.
Of course, vaccines only work when people get them. Although both the flu and pertussis vaccines have been recommended during pregnancy for more than a decade, only around half of pregnant people in the U.S. actually get either vaccine. Studies suggest between 60 and 70 percent of pregnant people got the COVID vaccine last year.
Whether pregnant people will choose to get the RSV vaccine remains to be seen. “It may be that the bad RSV season we experienced last year helps move the needle towards acceptance,” Healy says. “Studies show that a strong provider recommendation is the most important factor in influencing a person’s vaccination decision, even if vaccine-hesitant.”