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SARS-CoV-2 vaccine booster elicits robust prolonged maternal antibody responses and passive transfer to the offspring via the placenta and breastmilk

Published:November 30, 2022DOI:https://doi.org/10.1016/j.ajogmf.2022.100830
      OBJECTIVE: Infection during pregnancy may lead to adverse outcomes for both the pregnant persons and offspring
      • Megli CJ
      • Coyne CB.
      Infections at the maternal-fetal interface: an overview of pathogenesis and defence.
      as observed during the SARS-CoV-2 global pandemic. Adverse outcomes can be mitigated by maternal vaccination, protecting the pregnant persons and the neonate or infant via passive transfer of maternal antibodies either in utero via the placenta or after birth via breastmilk.
      • Roopenian DC
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      Immunoglobulin G (IgG) is transferred from maternal to fetal circulation via neonatal Fc receptors (FcRN) in the placenta and fetal intestines.
      • Roopenian DC
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      The Centers for Disease Control and Prevention recommend vaccination against SARS-CoV-2 for persons who are pregnant or plan to become pregnant.

      Prevention CfDCa. COVID-19 Vaccines While Pregnant or Breastfeeding. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html.

      Despite this recommendation, there remains a high level of vaccine hesitancy among the pregnant population.
      • Kharbanda EO
      • Vazquez-Benitez G.
      COVID-19 mRNA vaccines during pregnancy: new evidence to help address vaccine hesitancy.
      Vaccination decisions during pregnancy are often influenced by a primary goal of protecting neonatal health. Thus, the decision to vaccinate during pregnancy or to delay vaccination is shaped by knowledge about the impact of vaccine timing and the duration of protection. Previous studies investigating maternal SARS-CoV-2 vaccination included minimal longitudinal sampling and focused on one aspect of antibody transfer (eg, maternal blood or breastmilk). In this study, we assessed the antibody response throughout gestation, at birth, and up to 12 months postpartum in a cohort of 121 women in maternal circulation, umbilical cord blood (UCB), newborn blood (NB), and breastmilk.
      STUDY DESIGN: This study was approved by the institutional review boards of the Oregon Health & Science University and the University of Kentucky. From March 2021 until June 2022, maternal blood and breastmilk samples were obtained longitudinally from 121 SARS-CoV-2 vaccinated participants. The overwhelming majority (90.9%) of participants received the Pfizer BN162b2 vaccine (Table). UCB and maternal blood were collected at the time of delivery, whereas NB and colostrum were collected within 48 hours of delivery (Figure, A). An indirect enzyme-linked immunosorbent assay was used to determine the end-point titer (EPT) for IgG (total and subclasses) against the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein in plasma, whereas breastmilk antibody levels were reported as optical density (OD) values.
      TableCohort metadata
      Marshall. Maternal and neonatal antibody response to SARS-CoV-2 vaccination. Am J Obstet Gynecol MFM 2022.
      All (121)PrepregnancyT1T2T3Postpartum
      n (%)15 (12.4%)15 (12.4%)36 (29.8%)27 (22.3%)28 (23.1%)
      Maternal age (y)34.9±3.734.5±3.134.2±4.134.8±4.733.6±4.6
      Gestational age at delivery (wk)38.9±0.939.2±1.238.9±1.339.0±2.039.0±1.2
      Fetal sex (% female)33%40%47%52%36%
      Initial vaccine series
       Pfizer1313342624
       Moderna22214
       Received booster1412272315
       Days post second dose that the booster was received255±29275±29219±33234±33240±31
      Subjects were stratified by the trimester of initial maternal SARS-CoV-2 vaccination. Maternal age and gestational age at delivery are presented as mean ± standard deviation. There is no significant difference among maternal age or gestational age of delivery within the cohort when stratified by vaccination time point.
      Figure
      FigureSARS-CoV-2 booster dose augments passive transfer of RBD-specific antibodies.
      Marshall. Maternal and neonatal antibody response to SARS-CoV-2 vaccination. Am J Obstet Gynecol MFM 2022.
      A, Experimental design to investigate the impact of maternal SARS-CoV-2 vaccination on passive transmission of RBD-specific IgG antibodies by assessing antibody titers in maternal plasma, UCB plasma, newborn plasma, and breastmilk. B, RBD-specific IgG antibody titers in maternal plasma relative to days post first vaccination (n=370 samples). C, RBD-specific IgG antibody titers 50.59±4.46 days before and 55.74±4.14 days after booster dose (n=77 pairs). D, RBD-specific IgG antibody titers in maternal plasma relative to days post booster dose (n=112). E, IgG isotype levels 84.07±12.34 days before and 58.47±8.98 days after the booster dose (n=15 pairs). F, RBD-specific IgG levels in breastmilk after the first and second vaccine doses (n=179). G, Breastmilk IgG levels 37.84±3.80 days before and 55.32±5.30 days after booster (n=45 pairs). H, RBD-specific IgG antibodies in breastmilk after maternal booster vaccination (n=123). I, Levels of RBD-specific IgG isotypes in breastmilk 57.50±8.17 days before (n=28) and 117.23±11.32 days after the booster dose (n=44). J, RBD-specific IgG titers in maternal circulation and umbilical cord plasma at delivery (n=45 pairs). K, Correlation between UCB and maternal RBD-specific IgG titers at delivery (n=45). L, RBD-specific IgG titers in UCB relative to days since first maternal vaccine dose (n=48). M, Overall comparison between maternal RBD-specific IgG antibodies at delivery and newborn RBD-specific IgG titers, independent of trimester at initial vaccination (n=35 pairs). N, Correlation (n=35) between RBD-specific IgG titers in newborn and maternal plasma at delivery. O, RBD-specific IgG titers in newborn plasma relative to days post maternal vaccination. Bar graphs show median values with the standard error of the mean. Asterisk indicates P<.03; double asterisks indicate P<.002; triple asterisks indicate P<.0002; quadruple asterisks indicate P<.0001.
      ELISA, enzyme-linked immunosorbent assay; EPT, end-point titers; IgG, immunoglobulin G; OD, optical density; RBD, receptor-binding domain; UCB, umbilical cord blood.
      RESULTS: There was a strong inverse correlation between maternal plasma RBD-specific IgG titers and time elapsed since first vaccination (r=.07043; P<.0001; half-life, 56.45 days) (Figure, B). After the booster dose, RBD-specific IgG titers increased significantly (P<.0001) (Figure, C) and exhibited a longer half-life of 128.12 days (Figure, B and D). The booster produced a significant increase in all 4 IgG isotypes measured in maternal plasma (Figure, E).
      The initial 2-dose vaccination regimen led to a detectable IgG antibody response in breastmilk (albeit at reduced levels when compared with the maternal plasma) with a half-life of 61.34 days (Figure, F). Comparable with the maternal circulation, the booster produced a significant increase in the antibody levels (P<.0001) (Figure, G) and half-life (124.67 days) (Figure, H). After the booster, IgG1 and IgG4 increased significantly, with IgG4 becoming dominant (Figure, I).
      RBD-specific IgG antibodies were detected in the UCB plasma, albeit at significantly lower levels than in maternal circulation at delivery (P=.0012) (Figure, J). Interestingly, there was no correlation between the UCB RBD-specific IgG titers and the maternal titers at delivery (Figure, K) or the time since the first maternal vaccination (Figure, L). Although UCB is often used as a surrogate for NB, there may be differences in antibody transfer into the UCB and fetal circulation. As described for UCB, titers in NB were lower than those in maternal circulation at delivery (P=.0200) (Figure, M). In contrast to UCB, a significant positive correlation was observed between paired NB and maternal plasma titers at delivery (r=.3782; P≤.0001) (Figure, N). Moreover, NB titers were inversely correlated with the time since initial maternal vaccination (r=.3130; P=.0002) (Figure, O) with lower newborn IgG antibody titers in infants born to mothers vaccinated during early pregnancy.
      CONCLUSION: Our results confirm that the initial 2-dose vaccination series administered during gestation led to an appreciable RBD-specific IgG response in maternal circulation, UCB, NB, and breastmilk. Longitudinal analysis of postpartum samples indicated that the booster dose is essential for eliciting higher and more durable antibody levels in both the maternal circulation and breastmilk. SARS-CoV-2–specific maternal antibodies generated via vaccination are passively transferred in utero and after birth via breastfeeding but wane within 6 months after the first vaccination dose. Our longitudinal data indicate that breastmilk antibody levels are dramatically increased by the booster. Therefore, the best neonatal protection against SARS-CoV-2 is for pregnant persons to receive the 3-dose vaccination series at any point during pregnancy to allow for placental antibody transfer and to subsequently breastfeed their children for at least 6 months, at which point infants are eligible for SARS-CoV-2 vaccination.

      Coronavirus (COVID-19) Update: FDA Authroizes Moderna and Pfizer-BioNTech COVID-19 Vaccines for Children Down to 6 Months of Age. 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children.

      Continued breastfeeding throughout the first year of life is encouraged because SARS-CoV-2–specific maternal antibody levels persist in breastmilk following administration of the booster for at least 12 months.

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