Studying SARS-CoV-2 and mRNA Vaccines in Mothers and Babies

Researchers at Massachusetts General Hospital are investigating the effects of SARS-CoV-2 infection and the COVID-19 mRNA vaccines on pregnant and lactating people and neonates.

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"Mothers and infants are populations that have been historically left out of scientific research or were the last to be studied," says Andrea Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology at Massachusetts General Hospital. "Pregnant people have been confronted with a lack of information specific to them and it is difficult for them to make decisions in that vacuum. We were committed to making sure these populations are studied at Mass General."

Clinical Care and Research Make a Biorepository Possible

Pregnant individuals are at significant risk of severe morbidity and mortality compared to age-matched non-pregnant individuals, according to the CDC. "We know pregnant patients are more likely to be admitted to the ICU, to receive invasive ventilation, to need ECMO, and to die," says Dr. Edlow. According to large national studies by the Maternal-Fetal Medicine Units Network, severe to critical COVID-19 in pregnant individuals is associated with an increased risk of Cesarean birth, hypertensive disorders of pregnancy, preterm birth, postpartum hemorrhage, pre-labor rupture of membranes and venous thromboembolic disease.

Early in the pandemic, Dr. Edlow and her colleagues established the Mass General Brigham COVID-19 in Pregnancy Biorepository to better understand interactions between pregnancy and SARS-CoV-2, including pregnancy-specific immune response to COVID-19, transmission of the virus and immunity to neonates, the impact maternal inflammation and immune response has on the developing fetus, and maternal immune response to the COVID-19 vaccines.

The biorepository contains samples of maternal blood, maternal nasopharyngeal swabs and saliva, umbilical cord blood, breast milk, and placental tissue from more than 1,100 women and neonates with a variety of COVID-19 vaccination statuses.

"This effort spanned across the Mass General Brigham system and included experts from multiple disciplines," notes Dr. Edlow. "We are caring for these pregnant and lactating individuals, and we can do this type of collaborative work because of the research expertise that exists at Mass General."

Maternal-Fetal Transmission of SARS-CoV-2 Infection and Antibodies in Pregnancy

Although pregnancy increases the risk of severe illness from COVID-19, placental and fetal infections are rare—research shows placental infection rates around 7%, and vertical transmission from mother to fetus ranges from 1%-3%. "The interesting question is why aren't babies and placentas getting infected," says Dr. Edlow.

To answer that question, the team studied the transplacental transfer of anti-SARS-CoV-2 antibodies and transmission of SARS-CoV-2 infection from mother to neonate. In a study published in Jama Network Open, they looked at 127 pregnant women (64 who tested positive for COVID-19 on nasopharyngeal swab and 63 uninfected). While participants had detectable viral loads in respiratory samples, the researchers found no detectable virus in maternal, placental or cord blood samples.

The team also found reduced transplacental transfer of anti-SARS-CoV-2 antibodies between mothers infected with SAR-CoV-2 and neonates compared to transfer of anti-influenza hemagglutinin A antibodies. In addition, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors—which SARS-CoV2 uses for entry into cells—were found in placental tissue from study participants, but they were physically separated and TMPRSS2 expression was low. "The combination of physical separation and low expression of TMPRSS2 in the placenta is likely also protective," says Dr. Edlow.

The protection conferred by lack of viremia and receptor distribution is good news for neonates but may point to increased risk of COVID-19 infection in older infants. To better understand SARS-CoV2 antibody transfer from mother to baby, Dr. Edlow and Galit Alter, PhD, principal investigator at the Ragon Institute of Mass General, MIT and Harvard, looked at the transfer of IgG across the placenta.

The investigators studied the humoral immune responses to influenza and pertussis vaccination, and natural infection with SARS-CoV-2 in maternal blood samples and cord blood, from matched mother-baby pairs. Influenza and pertussis antibodies were transferred from mother to neonate through the placenta with high efficiency, but SARS-CoV2 antibody transfer was much lower in comparison, and the immune function of the antibodies that were present was reduced. These phenomena were only observed in the third trimester of pregnancy.

In work published in Cell, Drs. Alter, Edlow and their colleagues found that this impaired antibody transfer is driven by changes in IgG glycosylation. "We found that antibodies in COVID had fucose sugar groups attached to them. That pattern of glycosylation is unfavorable to transfer to the neonate given the pattern of receptors that are expressed in the placenta," says Dr. Edlow.

Despite the unfavorable glycosylation profiles, researchers observed some compensatory mechanisms: Antibodies in cord blood were afucosylated; the lack of fucose was associated with enhanced natural killer cell activity and help neonates fight infection. In addition, COVID-positive mothers had patterns of placental receptor expression that suggested the placenta was trying to compensate for the relatively low transfer of anti-COVID antibodies to the fetus. Dr. Edlow stresses that this understanding may contribute to more targeted vaccine design and timing for pregnant women and newborns.

SARS-CoV2 Antibody Transfer via Breastmilk in Infected Mothers

Another way mothers can transfer immunity to the neonate is through breastfeeding. In a study published in Cell Reports, Dr. Alter and Dr. Edlow's team found that maternal COVID-19 infection produces SARS-CoV2- specific IgA and IgM antibodies in breastmilk, but those antibodies are functionally attenuated compared to serum antibodies. IgA, the dominant antibody isotype, persisted in breastmilk for five months after infection (the duration of the study), and IgG and IgM were present in smaller amounts.

"We saw that breastmilk antibodies were much less inflammatory and had less overall functionality than serum antibodies. That makes sense: you don't want to feed newborns highly inflammatory antibodies," says Dr. Edlow.

Immune Response in Pregnant and Lactating Individuals After COVID-19 mRNA Vaccination

In a study of 84 pregnant, 31 lactating, and 16 non-pregnant women of reproductive age published in the American Journal of Obstetrics and Gynecology, Dr. Edlow along with Dr. Alter and Kathryn Gray, MD, PhD, assistant professor of obstetrics, gynecology and reproductive biology at Harvard Medical School, observed that pregnant and lactating individuals had a robust antibody response after two doses of the COVID-19 mRNA vaccines, similar to non-pregnant women of reproductive age. "Even though pregnant women were excluded from the vaccine trials, this study shows that the vaccine works as expected in pregnant women," says Dr. Edlow.

But in vaccinated mothers, the distribution of antibody isotypes in breastmilk was different than in mothers who had been infected with SARS-COV-2. After one vaccine dose, breastmilk showed robust levels of IgG, IgA and IgM. After a second mRNA dose, IgG levels rose significantly. "When mothers are vaccinated, IgG makes up a much more dominant part of breastmilk than with natural infection," says Dr. Edlow. "We thought this might be due to the way the vaccine is administered—intramuscularly—might stimulate more of an IgG response."

The robust maternal immune response to mRNA vaccination also has benefits for neonates: Spike protein (S)- and receptor-binding domain (RBD)-specific IgG were found in the cord blood of all 10 babies born during the study period. The levels of S-specific IgG in particular rose with longer time between maternal vaccination and delivery, suggesting that timing of vaccination in pregnant women may be important with regard to passing immunity on to neonates.

Motivated by frequent patient questions regarding how long maternal antibodies from COVID vaccination might provide infant protection, Dr. Edlow again collaborated with Dr. Alter to examine the durability of anti-Spike antibodies in 77 infants after maternal vaccination. In a paper published in JAMA, they demonstrated that 98% of infants born to vaccinated mothers had detectable antibodies at 2 months of age, and 57% at 6 months of age.

Examining antibody responses in depth using Dr. Galit Alter's Systems Serology platform revealed subtle differences between the antibody response in pregnant, non-pregnant, and lactating individuals. In a paper published in Science Translational Medicine, Drs. Edlow and Alter's teams demonstrated that Fc-receptor binding and antibody effector functions were induced with delayed kinetics (more slowly) in pregnant compared to non-pregnant and lactating individuals. This emphasizes the need to stick strictly to the recommended schedule for the first and second dose of the mRNA vaccines in pregnancy. In addition, these analyses demonstrated a distinct immune profile after vaccination during lactation, with enhanced natural killer cell-activating antibodies in lactating individuals.

Differences in SARS-CoV2 Immune Response by Fetal Sex

Males are more likely to be infected with COVID-19 and to have severe disease than females, but the mechanisms that regulate these differences are not well understood. In a study of 38 women infected with COVID-19 during pregnancy published in Science Translational Medicine, Dr. Edlow's team found that mothers who had male fetuses had significantly lower anti-SARS-CoV-2 antibody titers than those with female fetuses. These same mothers also transferred fewer SARS-CoV-2 antibodies to their fetuses. The placentas of male fetuses also demonstrated increased levels of immune response genes and proteins when mothers were infected with SARS-CoV-2.

Studying the Effects of COVID-19 and Other Maternal Exposures on the Fetal Brain

Stress and infection during pregnancy can cause maternal immune activation. Researchers hypothesize that this maternal immune activation is responsible for certain neurological disorders that present in children, including autism spectrum disorder, schizophrenia and cerebral palsy. In the case of maternal SARS-CoV-2 infection, maternal immune activation may impact fetal brain development. In fact, examination of health outcomes of more than 7700 maternal-child dyads delivering at Massachusetts General and affiliated hospitals during the first wave of the COVID pandemic found that maternal SARS-CoV-2 infection was associated with an increased risk of any offspring neurodevelopmental diagnosis at age 1.

Immune cells in the brain, called microglia, play a vital role in fetal brain development. When a mother's immune response is activated, it is thought that the fetus' microglia can be primed toward a pro-inflammatory phenotype. "Maternal immune activation and inflammation during pregnancy can have a long-lasting imprint on the developing fetus. I was interested in seeing what those long-term impacts are if they might be mediated," says Dr. Edlow.

To investigate the impact SARS-CoV-2 has on microglia, Dr. Edlow's laboratory worked with Mass General researchers including Roy Perlis, MD, MSc to create a new cellular model (described in Translational Psychiatry) of fetal microglial-like cells using umbilical cord blood immune cells. Dr. Perlis and Dr. Edlow hope this model will facilitate future insights into the effects of a range of maternal exposures (including SAR-CoV-2) in utero and their impact on fetal brain development.

Association of Delta Variant COVID-19 and Fetal Distress or Demise

In August of 2021, investigators also studied a series of cases of intrauterine fetal demise and severe fetal distress in mothers who tested positive for the Delta variant (B.1.617.2) of SARS-CoV-2 (published in The Journal of Infectious Diseases). The fetal demise or distress occurred within two weeks of diagnosis.

Through maternal samples and placental pathology, researchers found:

• Maternal viremia with Delta variant SARS-CoV-2
• High nasopharyngeal viral load
• Evidence of placental infection with Delta-variant SARS-CoV-2
• Evidence of SARS-CoV-2 placentitis

"All of these patients had mild illness and were unvaccinated," notes Dr. Edlow. "These findings complement data from the CDC that show a four-fold relative risk for stillbirth in the era of Delta compared to pre-pandemic."

Dr. Edlow says that this body of work highlights the importance of including pregnant and lactating people, and children, in research about infectious diseases, novel therapeutics and vaccines. And it shows the willingness of these people to participate.

"In reality, we don't need to protect these populations from research, especially in a deadly pandemic. We can best protect pregnant and lactating individuals and children by including them in research, and advancing knowledge about these unique groups."

Learn more about the Vincent Center for Reproductive Biology

Refer a patient to the Department of Obstetrics & Gynecology