COVID-19 mRNA-Vaccines During Pregnancy Are Safe Based on Postpartum Placental Immune Profiles in Both Maternal and Fetal Compartments

To the Editor: To reduce potential adverse pregnancy outcomes, mRNA vaccines could lower the chance of severe coronavirus disease-2019 infections by triggering a systemic immune response resulting in the production of effective antibodies. In general, mRNA vaccines were proven safe and effective to lower the risk of infection and decrease transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 However, since pregnant women were excluded from the initial mRNA trials on SARS-CoV-2 vaccines,1 the introduction of these new vaccines in pregnancy was approached with caution due to lack of data and safety concerns. According to the current guidelines, SARS-CoV-2 mRNA vaccines (Pfizer/BioNTech, New York, USA and Moderna, Cambridge, Massachusetts, USA) vaccines are now advised during pregnancy to prevent adverse maternal and fetal events. Importantly, mRNA vaccination also reduces the risk of fetal demise due to infections of the placenta.2 SARS-CoV-2 infection during pregnancy is known to cause fetal demise in confirmed viral placental transmission, resulting in a local, devastating infection with acute inflammation and necrosis of the placental parenchyma.3 In general, the fetal-maternal interface of the placenta is an anatomic and immunologic barrier that can prevent vertical transmission of infections,4 including placental infection. These protective placental properties necessitate investigation of potential effects of mRNA vaccination and its products received during pregnancy on developing and functional placental tissue and local placental immune response. To investigate the placental immune profile after mRNA vaccination during pregnancy, we used spatial immune profiling (GeoMx Digital Spatial Profiler, Seattle, Washington, USA). Nine placentas of women who received 1 or 2 SARS-CoV-2 mRNA vaccinations [Pfizer/BioNTech, New York, USA (BNT162b2) (n=6) or Moderna, Cambridge, Massachusetts, USA (mRNA-1273) (n=3)] during pregnancy (n=9) and control placentas of uncomplicated-term pregnancies matched by gestational age without SARS-CoV-2 vaccination (n=9) were analyzed. Vaccinations were administered during the second or third trimester of pregnancy (range: 16 to 36 wk). First, after formalin-fixing and paraffin-embedding, macroscopic and microscopic evaluation of pathology preparation of all 18 placentas (9 controls and 9 cases) were assessed using the Amsterdam Consensus Criteria previously described by Khong et al.5 The weight and measurements were within normal limits (between the 10th and 90th percentiles). The parenchyma showed a normal maturation without any significant abnormalities, as assessed using the Amsterdam Consensus Criteria previously described by Khong et al.5 These criteria integrate both macroscopic and microscopic pathologic placental abnormalities based on comparable pathophysiology and include maternal and fetal acute and chronic inflammatory responses, maternal vascular malperfusion, and fetal vascular malperfusion. Second, innovative approaches allow for next-level, in-depth analyses of protein expression profiles from specific selected tissue compartments within these formalin-fixing and paraffin-embedding tissues. By use of a spatial biology platform, local immunologic effects of mRNA vaccination on the placental immune infiltrate within 3 well-defined, specific placental tissue regions of interest were evaluated: decidua, intervillous space (both maternal compartments), and villi (fetal tissue). All fetal and maternal compartments of the cases (with maternal mRNA vaccination) and controls (uncomplicated pregnancy) showed no significant differences in any of the 53 evaluated proteins. Four proteins were found to be elevated; after statistical adjustment, they did not reach significance: fibronectin (stroma, P=0.098), granzyme A (T-cell activation, P=0.412), PD-L1 (myeloid activation, P=0.41), SMA (stroma, P=0.4740). Particularly, specific immune proteins associated with SARS-CoV-2 infection of the placenta, including CD68, CD45, CD3, CD4, CD8, CD163, CD40, CD11c, HLA-DR, and B2-microglobulin, did not show significant upregulation or downregulation. In summary, maternal mRNA vaccination against SARS-CoV-2 during pregnancy does not result in differences in altered molecular placental immune profiles of the different maternal as well as fetal placental compartments in this pilot project when compared with control placentas of women with an uncomplicated-term pregnancy who did not receive mRNA vaccination against SARS-CoV-2 during pregnancy. These results indicate and contribute to the data supporting the safety of mRNA vaccination against coronavirus disease-2019 during pregnancy.