key: cord-0687052-bfcrgcjg
authors: Rottenstreich, Amihai; Zarbiv, Gila; Oiknine-Djian, Esther; Vorontsov, Olesya; Zigron, Roy; Kleinstern, Geffen; Wolf, Dana G.; Porat, Shay
title: Timing of SARS-CoV-2 vaccination during the third trimester of pregnancy and transplacental antibody transfer: a prospective cohort study
date: 2021-11-03
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.10.003
sha: b67fb5a37d40f143770aa8a6954b65d4a41d83e2
doc_id: 687052
cord_uid: bfcrgcjg

OBJECTIVE: We aimed to assess the impact of early versus late third-trimester maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on transplacental transfer and neonatal levels of SARS-CoV-2 antibodies. METHODS: Maternal and cord blood sera were collected following term delivery after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination, with the first vaccine dose administered between 27 and 36 weeks of gestation. SARS-CoV-2 spike protein (S) and receptor-binding domain (RBD) -specific, IgG levels and neutralizing potency were evaluated in maternal and cord blood samples. RESULTS: The study cohort consisted of 171 parturients—median age 31 years (interquartile range (IQR) 27–35 years); median gestational age 39(+5) weeks (IQR 38(+5)–40(+4) weeks)–83 (48.5%) were immunized in early thrird-trimester (first dose at 27–31 weeks) and 88 (51.5%) were immunized in late third trimester (first dose at 32–36 weeks). All mother–infant paired sera were positive for anti S- and anti-RBD-specific IgG. Anti-RBD-specific IgG concentrations in neonatal sera were higher following early versus late third-trimester vaccination (median 9620 AU/mL (IQR 5131–15332 AU/mL) versus 6697 AU/mL (IQR 3157–14731 AU/mL), p 0.02), and were positively correlated with increasing time since vaccination (r = 0.26; p 0.001). Median antibody placental transfer ratios were increased following early versus late third-trimester immunization (anti-S ratio: 1.3 (IQR 1.1–1.6) versus 0.9 (IQR 0.6–1.1); anti-RBD-specific ratio: 2.3 (IQR 1.7–3.0) versus 0.7 (IQR 0.5–1.2), p <0.001). Neutralizing antibodies placental transfer ratio was greater following early versus late third-trimester immunization (median 1.9 (IQR 1.7–2.5) versus 0.8 (IQR 0.5–1.1), p <0.001), and was positively associated with longer duration from vaccination (r = 0.77; p <0.001). CONCLUSIONS: Early compared with late third-trimester maternal SARS-CoV-2 immunization enhanced transplacental antibody transfer and increased neonatal neutralizing antibody levels. Our findings highlight that vaccination of pregnant women early in the third trimester may enhance neonatal seroprotection.

Pregnant women and their infants, particularly neonates, are at a higher risk for severe disease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Pregnant women who contract coronavirus disease 2019 are more likely to be admitted to an intensive care unit and require invasive ventilation because of COVID-19 compared with non-pregnant women [1] [2] [3] [4] . Furthermore, maternal SARS-CoV-2 infection has been associated with adverse perinatal outcomes including preterm delivery and stillbirth [1] [2] [3] [4] . Although children have been shown to be more mildly affected by COVID-19 compared with adults, infants are at significantly higher risk for severe disease course compared with older children [5, 6] .

The two SARS-CoV-2 mRNA vaccines of Pfizer and Moderna were shown to elicit a robust immune response among pregnant women [7] , coupled with data supporting their safety throughout gestation [8] . In addition to their suggested role in preventing maternal illness, recent studies have demonstrated that antenatal vaccination may lead to transplacental transfer of maternally derived anti-SARS-CoV-2 antibodies [7, [9] [10] [11] . As children, including young infants, are currently not eligible for SARS-CoV-2 vaccination, offering neonatal J o u r n a l P r e -p r o o f seroprotection in the early, vulnerable stages of life through maternal immunization is of paramount importance. This principle is well-established for the prevention of other potentially life-threatening respiratory infections such pertussis and influenza [12] [13] [14] [15] [16] . In Israel, a nationwide mass vaccination campaign against COVID-19 using the BNT162b2 (Pfizer/BioNTech) mRNA vaccine was started in December 2020.

Defining the optimal timing for maternal SARS-CoV-2 immunization is crucial to maximize maternofetal antibody transfer and infant protection. Given the high clinical relevance, we aimed to determine the impact of maternal SARS-CoV-2 immunization timing on the efficacy of transplacental antibody transfer.

A prospective study following women admitted for delivery was performed during February-April 2021 at Hadassah Medical Centre, a tertiary-care university-affiliated hospital in Jerusalem, Israel with over 10 000 deliveries annually. Women who received the SARS-CoV-2 BNT162b2 mRNA vaccine during pregnancy were consecutively approached following their admission to the delivery room and offered participation. The institutional review board of the Hadassah Medical Centre approved this study (HMO-0064-21). Those who agreed to participate and provided written informed consent were eligible for this study.

The final study cohort included those who received the first vaccine dose at 27-36 weeks of gestation. Parturients who delivered prematurely (before 37 weeks of gestation), who had multifetal gestations and who did not complete the two-dose vaccine series before delivery were excluded. The decision to include only those vaccinated between 27 and 36 weeks of gestation was pre-defined based on data showing that maternal Tdap (tetanus, diphtheria and pertussis) vaccination, during this time period was most protective in terms of pertussis J o u r n a l P r e -p r o o f disease prevention among infants [13] . The final cohort was sub-divided into those vaccinated in early third trimester (27-31 weeks) versus late third trimester (32-36 weeks), as early third-trimester Tdap vaccination was previously found to associate with higher neonatal antibody levels and avidity [12, 14] and improved clinical effectiveness [13] . The primary outcomes were neonatal SARS-CoV-2 antibody levels and placental transfer ratios.

Demographic and clinical data were collected at the time of enrolment.

Maternal and cord blood sera were collected following delivery. Spike protein (S) (Liaison SARS-CoV-2 S1/S2 IgG; DiaSorin, Saluggia, Italy) and receptor-binding domain (RBD)specific (Architect SARS-CoV-2 IgG II Quant assay; Abbott Diagnostics, Chicago, IL, USA) IgG levels were evaluated in maternal and cord blood sera. Maternal and cord blood sera were also tested for SARS-CoV-2 RBD IgM (Liaison, DiaSorin, Saluggia, Italy). For a subset of mother-newborn dyads (arbitrarily selected), neutralizing antibody titres against SARS-CoV-2 were defined using a wild-type SARS-CoV-2 virus microneutralization assay as previously described [17] , with minor modifications. Briefly, serial two-fold dilutions of heat-inactivated serum samples (starting from 1:10; diluted in Dulbecco's modified Eagle's medium in a total volume of 50 μL) were incubated with an equal volume of viral solution, containing 100 median tissue culture infectious doses (TCID 50 ) of SARS-CoV-2 isolate USA-WA1/2020 (NR-52281; obtained from BEI Resources, Manassas, VA, USA), for 1 hour in a 96-well plate (at 37°C in humidified atmosphere with 5% CO 2 ). The serum-virus mixtures (100 µL; eight replicates of each serum dilution) were then added to a 96-well plate containing a semi-confluent VERO E6 cell monolayer (ATCC CRL-1586; maintained as described previously [18] ). Following 3 days of incubation (at 37°C in a humidified atmosphere with 5% CO 2 ), the cells in each well were scored for viral cytopathic effect. The median neutralization titre (NT 50 ) was defined as the reciprocal of the highest J o u r n a l P r e -p r o o f serum dilution that protected 50% of culture wells from cytopathic effect. Positive and negative serum controls, cell control and a viral back-titration control were included in each assay. 

During the study period, samples were collected from 207 parturients who had received the SARS-CoV-2 BNT162b2 mRNA during gestation and agreed to participate. Of them, 36 (17.4%) were excluded-first vaccine dose before 27 weeks (n = 26), first vaccine dose after 36 weeks (n = 3), preterm delivery (n = 5), did not complete the two-dose vaccine series before delivery (n = 1), twin gestation (n = 1). As a result, the final study cohort comprised 171 women including 83 (48.5%) who received the first vaccine dose at early third trimester 

This study investigated transplacental antibody transfer in 171 mother-newborn dyads, following antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. Early compared with late third-trimester maternal immunization was associated with higher neonatal anti-SARS-CoV-2 antibody levels and serum neutralizing activity. The current study findings may support the role of vaccination early at the third trimester to enhance maternofetal antibody transfer and neonatal seroprotection.

Pregnant women were excluded from the initial trials evaluating the different SARS-CoV-2 vaccines [19, 20] . Nevertheless, although universal recommendations have not yet emerged, given the risk for severe disease course and the accumulating reassuring data for their use in the setting of pregnancy [7, 8] , the World Health Organization, the US Centers for Disease

CoV-2 vaccine following shared decision-making [21] [22] [23] [24] . Antenatal SARS-CoV-2 immunization is primarily aimed at preventing maternal illness, considering the low rate of severe disease in the paediatric age group [25] . Nevertheless, the optimal antenatal vaccination regimen to maintain maternal immunity throughout gestation is still unclear.

Furthermore, severe COVID-19, while rare, can still occur in infants [25] . Hence, the farreaching potential to confer neonatal protection against COVID-19 and potentially decrease community transmission through maternal immunization raises critical questions concerning the optimal timing of antenatal vaccination. Physiologically, transplacental antibody transfer is a dynamic process starting in the second trimester; however, it is most efficient in the third trimester [26, 27] . For maternal pertussis and influenza vaccination this issue has been extensively studied [12] [13] [14] [15] [16] , as most women have been previously exposed or immunized J o u r n a l P r e -p r o o f against these pathogens, but the findings may not apply for the different SARS-CoV-2 vaccines, which prime a de novo immune response.

In this study, we evaluated pregnant women immunized with the SARS-CoV-2 BNT162b2 mRNA vaccine, with the first dose given between 27 and 36 weeks of gestation. We demonstrated that maternal immunization during the early third trimester (27- showing augmented transplacental transfer and neonatal antibody levels along with improved clinical outcomes, following early third-trimester vaccination [12] [13] [14] [15] [16] . This is in contrast to two other studies evaluating parturients who delivered following antenatal SARS CoV-2 mRNA vaccination, which did not demonstrate a correlation between the transplacental placental of anti-RBD-specific IgG and neutralizing antibodies [7, 28] . The sample size in those studies was limited, including women who received either the Pfizer or Moderna vaccine, and placental antibody transfer was not evaluated according to gestational age at the time of immunization [7, 28] . Although the results of the current study are encouraging, future studies should evaluate the kinetics and durability of these passively acquired antibodies in The major strength of our study is its relatively large cohort size, which allowed for a robust analysis of the superiority of early third-trimester immunization. Nevertheless, this study has several limitations. First, the observational single-centre design of the study may limit the generalizability of our findings. Second, the effects of maternal immunization at an earlier gestational age as well as of the impact of other SARS-CoV-2 vaccines on transplacental antibody transfer dynamics remain to be determined. Earlier immunization could provide maternal protection against COVID-19 through the longer course of pregnancy and may benefit preterm infants. Finally, vaccine-induced maternally derived antibodies might blunt the infant humoral immune response to future SARS-CoV-2 vaccination; although the clinical significance of this interference effect is largely unknown [27] , it should be acknowledged and further explored.

The current study results indicate that early third-trimester immunization has the potential to maximize maternofetal transplacental antibody transfer, thereby affording adequate seroprotection during early infancy. As the strategy of maternal SARS-CoV-2 immunization is gaining support, there is a critical need for further scientific evidence to inform the ideal timing for vaccination during pregnancy that would provide mothers and neonates with the highest clinical protection against COVID-19. As the extent of SARS-CoV-2 community spread declines in several parts of the globe, optimizing neonatal immunity may be more heavily weighted by immunization policy-makers.

AR and DGW had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. SP, AR and DGW were respoinsible for the concept and design; all authors contributed to acquisition, analysis, or interpretation of data. The manuscript was drafted by AR, GZ, sP, GK, EOD and DGW.

Laboratory analyses were by EOD, OV and DGW. Statistical analysis was by AR and GK.

All authors read and approved the final manuscript.

Additional supporting information may be found online in the supporting information tab for this article. 

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We thank Dr Doron Kabiri, Dr Shlomi Yahalomi, Prof. Yosef Ezra and Dr Roy Alter for their assistance in patient enrolment. We also thank Rimma Barsuk and Yulia Yachnin for their technical assistance.

The authors declare that they have no conflicts of interest.

Individual-level data will not be made publicly available with this article. Requests for sharing of de-identified individual-level participant data for scientific research can be directed to the corresponding author. All proposals will be subject to scientific review and institutional review board approval at Hadassah Medical Centre.

No external funding was used for this study.