Placental Transfer of SARS-CoV-2 Antibodies Is Compromised

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Vertical transmission of SARS-CoV-2 is a rare event, as Massachusetts General Hospital researchers recently reported. However, in that study transplacental transfer of antibodies to SARS-CoV-2 was inefficient, implying that neonates and infants are vulnerable to infection subsequently.

For protection against other pathogens, neonates rely on the transfer of maternal immunoglobulin G (IgG) across the placenta. In Cell, Mass General researchers, led by Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology, and Galit Alter, PhD, principal investigator at the Ragon Institute of Mass General, MIT and Harvard, describe research that found that transfer of IgG across the placenta of SARS-CoV-2–infected pregnant women is impaired by alterations in antibody glycosylation—but that compensatory mechanisms exist to protect the neonate. These findings have implications for designing vaccines against SARS-CoV-2 for pregnant women and infants.

Study Methods

The researchers profiled humoral immune responses to influenza and pertussis vaccination and to natural infection with SARS-CoV-2 in maternal blood samples and cord blood from:

• 22 women who tested positive for SARS-CoV-2 infection in the third trimester of pregnancy and their neonates (although no neonates became infected, these dyads were designated COVID+)
• 34 contemporaneously enrolled mother–neonate dyads who tested negative (COVID–)

Antibody Transfer

As expected, influenza- and pertussis-specific IgG was higher in cord blood than in maternal blood in the COVID– dyads. The same was observed in the COVID+ dyads, showing that the placentas of COVID+ women were able to transfer antibodies.

Surprisingly, though, in the COVID+ dyads, titers of antibodies to SARS-CoV-2 were lower in cord blood than in maternal samples. The immune function of the antibodies in cord blood was also reduced. Interestingly, this defect was exclusive to the third trimester; efficient SARS-CoV-2 antibody transfer was observed in women infected during the second trimester.

Mechanism of the Alteration

The most significant contributor to poor placental antibody transfer were changes in IgG glycosylation, which may be altered in the setting of acute infection compared to vaccination-generated antibodies. They found:

• Many maternal antibodies specific to the spike protein of SARS-CoV-2 exhibited enhanced galactosylation
• In contrast, SARS-CoV-2 antibodies that transferred best to cord blood tended to be agalactosylated
• However, antibodies in cord blood also tended to be afucosylated—they lacked fucose, which interferes with natural killer cell activity—and would make neonates better able to fight infection if exposed to SARS-CoV-2

Compensatory Mechanisms

Elevated IgG levels were observed in COVID+ women and were associated with the enhanced placental transfer of all antibodies, especially agalactosylated/afucosylated antibodies.

Receptors that facilitate placental antibody transfer were co-localized in placentas of COVID+ mothers, and expression of one of these receptor types was elevated. Like higher IgG levels, these changes might promote the transfer of the afucosylated antibodies that can drive enhanced natural killer cell activity in neonates.

Implications for Protecting Infants

These data suggest a delicate, previously unappreciated balance during third-trimester pregnancy. SARS-CoV-2 infection results in:

• Changes in antibodies that protect the mother but reduce the transfer of antibodies to the neonate
• Compensatory placental changes to try to optimize transfer of the most effective antibodies to the neonate

These findings may be relevant to developing vaccines and planning the timing of vaccination for pregnant women and their newborns. Vaccines that drive high levels of afucosylated and galactosylated antibodies may optimize placental transfer and protection from infection.

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