Comprehensive serologic profile and specificity of maternal and neonatal cord blood SARS-CoV-2 antibodies

Abstract

Background: Initial studies on COVID-19 in pregnancy have demonstrated a range of neutralizing activity, but little has been published on the full profile of SARS CoV-2 related antibodies in maternal and cordblood.

Objective: This study aimed to describe the profile and specificity of maternal and neonatal cord blood antibody profiles in response to SARS-CoV-2 virus exposure.

Study design: This was a prospective cohort study of delivering patients at Thomas Jefferson University Hospital from April 2020 to February 2021. The primary objective was to describe unique maternal and fetal antibody epitope titers and specificity in patients with COVID-19 history. Serologic profile was assessed with a multiplex platform. Antigens used were hemagglutinin trimer influenza A (Hong Kong H3); spike trimers for SARS-CoV-2, SARS-CoV-1, Middle East respiratory syndrome coronavirus, and betacoronaviruses HKU-1 and OC43; and spike N-terminal domain, spike receptor-binding domain, and nucleocapsid protein (full length) for SARS-CoV-2.

Results: Here, 112 maternal samples and 101 maternal and cord blood pairs were analyzed. Of note, 37 patients had a known history of COVID-19 (positive polymerase chain reaction test) during pregnancy. Of 36 patients, 16 (44%) were diagnosed with COVID-19 within 7 days of delivery. Moreover, 15 of the remaining 76 patients (20%) without a known diagnosis had positive maternal serology. For those with a history of COVID-19, we identified robust immunoglobulin G response in maternal blood to CoV-2 nucleocapsid, spike (full length), and spike (receptor-binding domain) antigens with more modest responses to the spike (N-terminal domain) antigen. In contrast, the maternal blood immunoglobulin M response seemed more specific to spike (full length) epitopes than nucleocapsid, spike (receptor-binding domain), or spike (N-terminal domain) epitopes. There were significantly higher maternal and cord blood immunoglobulin G responses not only to CoV-2 spike (127.1-fold; standard deviation, 2.0; P<.00001) but also to CoV-1 spike (21.1-fold higher; standard deviation, 1.8; P<.00001) and Middle East respiratory syndrome spike (6.9-fold higher; standard deviation, 2.5; P<.00001). In contrast, maternal immunoglobulin M responses were more specific to CoV-2 spike (15.8-fold; standard deviation, 2.1; P<.00001) but less specific to CoV-1 (2.5-fold higher; standard deviation, 0.71; P<.00001) and no significant difference for Middle East respiratory syndrome. Maternal and cord blood immunoglobulin G antibodies were highly correlated for both spike and nucleocapsid (R²=0.96 and 0.94, respectively).

Conclusion: Placental transfer was efficient, with robust nucleocapsid and spike responses. Both nucleocapsid and spike antibody responses should be studied for a better understanding of COVID-19 immunity. Immunoglobulin G antibodies were cross-reactive with related CoV-1 and Middle East respiratory syndrome spike epitopes, whereas immunoglobulin M antibodies, which cannot cross the placenta to provide neonatal passive immunity, were more SARS-CoV-2 specific. Neonatal cord blood may have significantly different fine specificity than maternal blood, despite the high efficiency of immunoglobulin G transfer.

Keywords: COVID-19; immunity; passive immunity; pregnancy; serology.

Figure 1

Maternal and cordblood SARS CoV-2 serological profile at delivery Maternal and cord blood COVID-19 refers to samples from patients with known COVID-19 history (polymerase chain reaction confirmed) or positive maternal serology. Data are reported as natural log-transformed luminescence signal. A, CoV-specific IgM responses (top) and CoV-specific IgG responses (bottom) in maternal sera and cord blood samples to the spike proteins of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HKU-1, and OC43. Participants with previous COVID-19 history had significantly higher responses not only to CoV-2 spike (P<10⁻¹⁸) but also to CoV-1 spike (P<10⁻⁹) and MERS spike (P<10⁻⁸). In contrast, for IgM responses in maternal blood, participants with previous COVID-19 history showed a significantly higher response to CoV-2 (P<10⁻¹⁹) but a lesser response to CoV-1 (P<10⁻⁵) and no significant difference to MERS. B, Fine specificity of SARS-CoV-2–specific IgM (top) and IgG (bottom) responses in maternal sera and cord blood samples to SARS-CoV-2 epitopes, that is, N protein, the full-length S protein, and its functional subdomains, that is, RBD and NTD. Participants with previous COVID-19 had robust IgG response in maternal blood to CoV-2 N, S (full length), and S (RBD) antigens that were approximately 40-fold, 130-fold, and 15-fold higher, respectively, than what was found in participants without previous COVID-19, with more modest responses to the S (NTD) antigen. In contrast, maternal blood IgM response to S (full length) was approximately 15-fold higher in participants with COVID-19 than in participants with no previous COVID-19 history but only 2- to 2-fold higher for N or S (RBD). IgG, immunoglobulin G; IgM, immunoglobulin M; MERS, Middle East respiratory syndrome; N, nucleocapsid; NTD, N-terminal domain; RBD, receptor-binding domain; S, spike.

Figure 2

Principal component analysis of antibody responses IgM and IgG responses to CoV-2 antigens N protein, spike, and RBD distinguish between previous COVID-19 cases from maternal and cord blood. IgG, immunoglobulin G; IgM, immunoglobulin M; N, nucleocapsid; NTD, N-terminal domain; RBD, receptor-binding domain

Figure 3

Correlation between maternal and cord blood antibody titers Correlation between maternal and cord blood IgG and IgM antibodies to full-length spike and N epitopes. A linear fit between maternal and cord blood IgG responses showed a slope of 1.01 for both CoV-2 spike and CoV-2 N protein antigens. IgG, immunoglobulin G; IgM, immunoglobulin M; N, nucleocapsid.

Figure 4

Maternal SARS CoV-2 titers at delivery and latency from infection Data were taken from 36 documented COVID-19 cases. Data are reported as natural log-transformed luminescence signal. IgG, immunoglobulin G.

Figure 5

Maternal SARS CoV-2 antibody titers and placental pathology Data were taken from 22 patients with maternal vascular malperfusion documented on placental histopathology and 30 patients with no evidence of maternal vascular malperfusion. Data are reported as natural log-transformed luminescence signal. Mean maternal nucleoprotein (N)-IgM and spike (S)-IgM were significantly higher in patients with maternal vascular malperfusion (10.3±1.5 vs 9.6±0.8 [P=.03] and 10.0±2.0 vs 8.8±1.9 [P=.02], respectively), as were N-IgG and S-IgG (10.6±2.7 vs 9.1 ±2.0 [P=.02] and 10.4±2.9 vs 8.3±2.4 [P=.01], respectively). CI, confidence interval; IgG, immunoglobulin G; IgM, immunoglobulin M.