How does the maternal immune response balance SARS-CoV-2 antiviral responses with transplacental transfer of protection to the fetus?

In a recent study posted to medRxiv*, researchers found that in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) maternal infection, the balance between antiviral response and transplacental transfer of humoral and cellular protection relies on maternal interleukin (IL)-6 and IL10.

Background

Maternal immune responses confer protection to the fetus by eliminating the pathogen, preventing vertical transmission, and through the transplacental transfer of immune mediators to the fetus. Maternal immunoglobulin G (IgG) antibodies are transferred across the placenta from the thirteenth gestational week.

Evidence suggests that SARS-CoV-2-neutralizing antibodies (nAbs) are not only of the IgG isotype but also IgA and IgM isotypes. This raises important questions about how immune alterations in pregnancy impact the breadth of nAb isotypes, given that IgM and IgA are not transferred to the fetus due to large molecular size and the absence of corresponding transport receptors.

Besides antibodies, cytokines and immune cells play crucial roles in resolving SARS-CoV-2 infection. Natural killer (NK) cells are critical to eliminating SARS-CoV-2-infected cells. Pregnancy results in a decrease in the frequency of cluster of differentiation 4 (CD4⁺) T cells and NK cells. However, increased frequency of NK cells has been observed in neonates born to women with ongoing SARS-CoV-2 infection.

The study and findings

The present study evaluated immune responses to SARS-CoV-2 in infected women during pregnancy. Seventy-two pregnant women were enrolled between May 2020 and February 2022; all were non-vaccinated for SARS-CoV-2, and 60 were SARS-CoV-2-positive.

Nine individuals tested positive in the second trimester (recovered in the second trimester, 2R cohort), 11 tested positive between 20 to 154 days before delivery (recovered in the third trimester, 3R), and 40 tested positive within 11 days of delivery (ongoing infection, 3O). The symptomatic disease developed in 50% of the infected women.

Four were hospitalized and three required non-invasive oxygen support. Among the SARS-CoV-2-positive women, 50 mother-umbilical cord matched samples were collected at birth. Nasopharyngeal swabs were collected from neonates in 82% of the deliveries. Three newborns were SARS-CoV-2-positive but asymptomatic; one SARS-CoV-2-negative neonate was admitted to a neonatal intensive care unit (NICU).

Additionally, nine pregnant women were enrolled from July 2021 to February 2022 who were vaccinated with the BNT162b2 vaccine. The presence of IgM or IgA in cord blood indicates fetal infection. Of the 50 matched samples or dyads, anti-spike IgM and IgA antibodies were present in the cord blood of only one case.

Anti-spike IgG was present in all mothers and neonates of SARS-CoV-2-positive mothers in the 2R and 3R cohorts. The transfer ratio of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies was approximately 1 in the 2R and 3R cohorts and around 0.5 in the 3O cohort. The transfer of antibodies was more efficient with an increase in the duration between SARS-CoV-2 infection and delivery.

Following SARS-CoV-2 infection, nAbs were detected in 58.6% of mothers and 10% of neonates. The frequency of nAbs decreased as the time between SARS-CoV-2 infection and delivery increased. nAbs were detected in five neonates of the 50 tested dyads. In contrast, nAbs were detected in all neonates of the vaccinated women. Notably, the transfer ratio of nAbs did not increase with the time since infection.

The presence of symptoms did not affect maternal levels of anti-RBD antibodies or nAbs. Notably, the transfer of anti-RBD antibodies plummeted by approximately 40% in those from the 3O cohort. Anti-spike IgA and IgM have been implicated in the neutralization of SARS-CoV-2, which suggests that the poor neutralizing response in neonates might occur from a maternal neutralizing response mediated by IgA or IgM, which are non-transferable to the fetus.

To this end, the authors assessed the correlation of maternal IgM, IgA, and IgG antibodies with neutralizing titers in the ongoing infection (3O) and recovered (2R and 3R) groups. In the 3O cohort, neutralizing titers correlated well with the three antibody isotypes, and anti-spike IgG correlated stronger with IgA than IgM. Interestingly, in 2R and 3R cohorts, neutralizing titers correlated with anti-spike IgA and IgM but not with IgG.

Contrastingly, neutralization in vaccinated women was associated with anti-spike IgG levels. Next, the team studied the cellular responses of mothers and neonates between asymptomatic and symptomatic cases of the 3O cohort. They found that an ongoing infection led to a higher frequency of NK cells in maternal circulation and the cord blood. Moreover, anti-spike IgM antibodies were higher in an ongoing asymptomatic infection.

Further investigations suggested that an early immune response characterized by anti-spike IgM and NK cells was associated with asymptomatic SARS-CoV-2 infection. Furthermore, the researchers found increased IL6 and IL18 in infected mothers relative to vaccinated mothers, which have been implicated in pregnancy complications and preterm delivery.

An inverse correlation was observed between anti-RBD IgG transplacental transfer and IL6. The frequency of NK cells was inversely correlated with IL10. Overall, these data indicated that IL6 and IL10 mediate a tug of war between asymptomatic SARS-CoV-2 clearance and the transfer of anti-RBD IgG to the neonates.

Conclusions

In summary, the present study found that the decision between mounting an antiviral response in infected mothers and transferring immune protection to the fetus relied on the balance between SARS-CoV-2 infection-induced IL6 and IL10. In 2R/3R cohorts, neutralizing activity correlated with IgM and IgA.

In contrast, neutralization was associated only with IgG in the vaccinated cohort, explaining the efficient transfer of nAbs across the placenta upon vaccination. Overall, the findings suggested an evolutionary trade-off benefiting the newborns by skewing the maternal immune response to rapid SARS-CoV-2 clearance.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.