COVID-19 vaccination could potentially offer significant benefits to pregnant women, who are at an increased risk of severe illness and death from COVID-19, and to their unborn babies, who are more likely to suffer adverse outcomes than are babies who weren’t exposed to the virus in utero. There has been uncertainty around the risks and benefits of vaccinating pregnant women for COVID-19 because they were excluded from the initial clinical trials for the Moderna and Pfizer/BioNTech vaccines currently available under emergency use authorization in the US.
Clinical trials are now getting underway to address COVID-19 vaccine safety and efficacy in pregnant women. Last week (February 18), Pfizer and BioNTech announced a global Phase 2/3 trial of their COVID-19 vaccine in 4,000 healthy pregnant women. The placebo-controlled, observer-blinded study will track the safety, tolerability, and immunogenicity of two doses of vaccine 21 days apart, compared to placebo, for 7 to 10 months. The trial will also assess safety in infants of vaccinated mothers and the transfer of antibodies from mother to child for up to six months after birth.
As that trial gets off the ground, Duke University School of Medicine maternal-fetal medicine specialist Geeta Swamy is starting an observational study of COVID-19 vaccination. She and her colleagues will follow about 350 pregnant women, collecting data on any symptoms following vaccination, as well as antibody levels in the mother and in the newborn’s umbilical cord blood. The study will be open to pregnant women who receive any COVID-19 vaccine, rather than limited to a single manufacturer.
Swamy is also a coinvestigator for an ongoing Pfizer/BioNTech Phase 3 vaccine trial that does not include pregnant women and is a member of the US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) but does not participate in committee decisions for COVID-19 vaccines due to her work on the trials. She spoke with The Scientist about finally launching studies in pregnant women, an effort she says manufacturers ideally should have started months ago.
The Scientist: Why is it important to study maternal immunity and COVID-19 vaccination in pregnant women?
Geeta Swamy: We know that pregnant women are at increased risk of complications related to COVID infection, particularly with regards to increased risk of hospital admission, ICU admission, need for mechanical ventilation, and other related complications. So, it’s important to figure out not only why the infection is causing these problems, but also what we can do to prevent that and make sure we’re doing everything possible to ensure maternal health, as well as the health of the infant. And vaccines are one of the ways to do that.
TS: What is the design and goal of the COVID-19 vaccination observational study that you’re planning?
GS: At this point, given that we have had this permissive allowance of vaccinations under the emergency use authorization from the FDA, we know that actually thousands of women have gotten vaccinated already and will likely continue to get vaccinated outside of a clinical trial. What we’d like to do is collect data regarding not only the immediate safety profile with regards to side effects like fever, fatigue, and so forth, but also the impact on the overall pregnancy, such as what we consider adverse pregnancy outcomes like preterm birth and low birth weight in the infant. [We also plan to study] the immune response, meaning, how does the vaccine perform in pregnant women? Do the antibody profiles look similar to those seen in nonpregnant people as demonstrated in the clinical trials? And is there also a potential benefit to the newborn infant by transmission of maternal antibodies across the placenta?
TS: What were the obstacles to running trials in pregnant women earlier, as this is happening well after the main trials have started?
We now know somewhere upwards of 20,000-plus women who are pregnant have gotten vaccinated.
GS: In order to do clinical trials in pregnancy, our regulatory pathway . . . in the US has been that we, in addition to human studies in nonpregnant people, need information and data on how the vaccine performed in, say, a pregnant animal model, like in mice or rats or that sort of thing. Those studies have to be done before the FDA will allow an investigational product to be studied in pregnant women. So one barrier is that it takes time to get those things accomplished early on, especially in the setting of a pandemic when people are extremely focused on the first issue of finding an effective vaccine.
The other aspect, though, is that there often is significant hesitancy to enroll or to conduct investigational studies in pregnant women. A lot of that stems from the historical designation of pregnant women being a vulnerable population, with vulnerable being defined as somehow not able to make decisions for themselves or at risk for being coerced, when in actuality they are certainly a special population [with] other risks to consider, but should not be relegated to the end of the line for evaluating what needs to be done in research. Alternatively, we’re left with trying to use expert opinion instead of having done it through the controlled research setting where we could have minimized the number of people potentially exposed and get data in a more timely manner.
TS: As you know, Pfizer and BioNTech are launching a placebo-controlled Phase 2/3 study of their vaccine in 4,000 pregnant women. How is that study different from what you’re planning?
GS: The Pfizer study is planned to follow other similar trials [with] a placebo control, which means that a portion of participants get the vaccine and portion get a placebo like a saline injection. That is really a good model to follow, to have a clear comparison group to see what happens in those who get the vaccine and those who don’t. Unfortunately, it does still raise some ethical concerns at this point, given that we know pregnant women are at increased risk, as we discussed previously, from complications from COVID, and that . . . we now know somewhere upwards of 20,000-plus women who are pregnant have gotten vaccinated. It becomes a question that pregnant women want to choose to get the vaccine. Would they really want to enroll in a trial to get a placebo, weighing those risks and benefits? It isn’t in any way that it would be wrong to do a placebo-controlled trial. It may just not be that people are willing to choose that as an option. The observational study is basically anyone who is getting vaccinated per CDC guidelines and prioritization groups.
TS: Do you think there’s a chance Pfizer might not be able to meet its enrollment goals?
GS: It is an international study and planned to be across multiple countries, multiple sites. My concern is, I don’t know that they would never meet their goal, but will they be able to meet it in a timely enough fashion to give us data that is helpful during the still ongoing pandemic?
TS: Would observational data be sufficient for a full FDA approval or is a rigorous, placebo-controlled trial necessary?
GS: That is a decision that the FDA would have to weigh in on to decide if it would be adequate. Right now, there have been discussions with the FDA to consider observational data for what is called real-world evidence, or RWE. Generally speaking, in order to even consider observational data, you do need that data on many thousands of individuals. And it would have to be a planned analysis. . . . For example, take the outcomes of pregnant women prior to the pandemic, maybe in the year 2019 or even during the pandemic, before [a COVID-19] vaccine was available, to compare outcomes. That is not as easy as it sounds, because when you select control groups, there are other biases introduced. For example, how do you compare them based on the same baseline parameters and so forth? But there are ways to attempt to do that.
Editor’s note: The interview has been edited for brevity.