17:35- 17:45 Diminished humoral and cellular immune response in pregnant women upon vaccination against SARS-CoV-2 infection

During gestation, the maternal immune system mounts an immune tolerant microenvironment to prevent rejection of the semiallogenic fetus. These pregnancy-associated immune adaptations compromise an antipathogen response, as seen in the context of virus exposures, i.e., influenza A or SARS-CoV-2. Thus, in order to reduce the heightened risk for severe infection-induced morbidity or even mortality of mother and unborn child, vaccination of pregnant women is highly recommended, e.g., by the World Health Organization. However, very little is known about the efficacy of vaccinations in pregnant women. This is especially relevant in the context of vaccination against SARS-CoV-2, where novel mRNA-based vaccination technologies are used. Therefore, insights on vaccination-induced immunity in the unique setting of pregnancy require in-depth investigations. We conducted a prospective, longitudinal cohort study enrolling 31 pregnant women with singleton pregnancies during the second or third trimester. Age-matched non-pregnant women (n=29) served as controls. All study participants were vaccinated with the BioNTech/Pfizer mRNA-based BNT162b2 COVID-19 vaccine (Comirnaty®, 30µg per dose), following a two-dose vaccination protocol with an interval of 6 weeks. Blood specimens were acquired two to six weeks after the second vaccination in both groups. A prior SARSCoV-2 infection was excluded by assessment of the medical history and serology testing for nucleocapsidspecific antibodies. Additionally, cord blood and an additional maternal blood sample were collected at birth. Levels of SARS-CoV-2 neutralizing IgG antibodies were determined using the DiaSorin LIAISON® (anti-S trimer) immunoassay. Deep immune phenotyping of isolated peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry. SARS-CoV-2-specific cell-mediated immunity was assessed by stimulating T cells with the SARS-CoV-2 immunodominant domains of the spike protein (Prot_S; Miltenyi Biotec), IFN-ɣ release was subsequently measured using a chemiluminescence immunoassay (LIAISON® QuantiFERON®). Anti-SARS-CoV-2 IgG antibody levels were significantly lower in pregnant vaccinees compared to non-pregnant vaccinees (3.33 ± 0.06. vs. 3.54 ± 0.05., p = 0.002). Moreover, maternal IgG antibody titers waned rapidly in pregnant vaccinees until delivery. Cord blood IgG levels reached a 2.9-fold increase of levels detected in the maternal blood, which is surprisingly high compared to e.g., influenza-specific IgG levels in cord blood described elsewhere as a 1.5-fold increase of maternal IgG levels. Flow cytometry analysis revealed a reduction of overall T and B cell frequencies in PBMCs of pregnant vaccinees. Additionally, we observed a decreased IFN-γ response upon stimulation of T cells with the SARS-CoV-2 spike protein in pregnant vaccinees, compared to non-pregnant vaccinees. We here identified a diminished humoral and cellular immune response in pregnant women upon mRNA-based SARS-CoV-2 vaccination. These findings highlight the need to carefully reconsider vaccination schemes and dosages used to immunize pregnant women. Furthermore, our data underpin that maternal vaccination during pregnancy provides the neonate with neutralizing IgG antibodies, hereby reducing the risk for early-life infections with COVID-19 in these highly vulnerable individuals. Additional investigations, e.g., single-cell RNA sequencing, hold the potential to reveal the biological mechanisms underlying the observed blunted vaccination response in pregnant women, which opens avenues for adjustments of vaccine application strategies during pregnancy.