Association of Gestational Age at Coronavirus Disease 2019 (COVID-19) Vaccination, History of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection, and a Vaccine Booster Dose With Maternal and Umbilical Cord Antibody Levels at Delivery : Obstetrics & Gynecology

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Contents: Original Research

Association of Gestational Age at Coronavirus Disease 2019 (COVID-19) Vaccination, History of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection, and a Vaccine Booster Dose With Maternal and Umbilical Cord Antibody Levels at Delivery

Yang, Yawei J. MD, PhD; Murphy, Elisabeth A. PhD; Singh, Sunidhi BA; Sukhu, Ashley C. BS; Wolfe, Isabel BS; Adurty, Sanjana BA; Eng, Dorothy BA, BS; Yee, Jim BS; Mohammed, Iman BA; Zhao, Zhen PhD; Riley, Laura E. MD; Prabhu, Malavika MD

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doi: 10.1097/AOG.0000000000004693
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Coronavirus disease 2019 (COVID-19) vaccination is recommended for pregnant individuals at any gestational age to decrease the risk of COVID-19 in pregnancy, because pregnancy increases the risk of severe disease.1 However, gestational age at vaccination may influence umbilical cord antibody levels at delivery. Therefore, although maternal protection is the priority for vaccination, determining the immune protection provided to neonates will help inform future infant-immunization strategies. Data drawn from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across various gestational ages in pregnancy have demonstrated that transplacental transfer of antibodies varies by gestational age of infection.5 In women vaccinated against COVID-19, transplacental immunoglobulin (Ig)G transfer occurs 4–6 weeks after maternal vaccine dose 1; some data have demonstrated that maternal and umbilical cord anti-spike antibody levels are positively correlated, whereas other data have demonstrated that neonatal anti-spike levels at birth are unrelated to timing of maternal vaccination.2,3

Previous exposure to an antibody-inducing event, such as prior infection or vaccination, may lead to differential antibody response, but the effects in pregnant women are not well understood. In nonpregnant individuals, vaccination after previous SARS-CoV-2 infection leads to a more rapid and sustained antibody response.6

We sought to describe the association of COVID-19 vaccination before and during pregnancy with maternal and umbilical cord anti-spike IgG levels at the time of delivery, as well as the association of prior SARS-CoV-2 infection and a booster dose during pregnancy with anti-spike maternal and umbilical cord IgG levels.

METHODS

We conducted a retrospective cohort study of pregnant women with a self-report in the medical record of receipt of at least one dose of an mRNA-based COVID-19 vaccine (Pfizer-BioNTech BNT162b2 [Pfizer] or Moderna mRNA-1273 [Moderna]) or one dose of a viral vector–based COVID-19 vaccine (Johnson & Johnson/Janssen JNJ-78436735 [J&J/Janssen]) before or in pregnancy, and who delivered a liveborn neonate at 34 weeks of gestation or more at a single academic medical center between March 6 and October 28, 2021. At the time of admission for delivery, all women were tested for SARS-CoV-2 infection using reverse transcription polymerase chain reaction (RT-PCR), and admission blood samples were collected for routine clinical studies. At the time of delivery, umbilical cord blood was collected for routine neonatal clinical studies. Among patients meeting inclusion criteria, leftover maternal blood samples and corresponding leftover umbilical cord blood samples were de-identified and analyzed for semi-quantitative IgG against anti-spike using a relative index value.7 The relative index value is defined as the instrument readout of the test sample antibody value divided by the instrument cutoff value (mean readout of noninfected and nonvaccinated control samples+6 SDs). We included data only if we were able to obtain at least the maternal blood sample from a dyad.

Clinical data and vaccination data were abstracted from the electronic medical record. Data on race and ethnicity were included to describe the population of women vaccinated against COVID-19 who were included in this study. The Pfizer and Moderna vaccinations follow a two-dose vaccination course; women who received the Pfizer or Moderna vaccines were categorized at delivery as having received one dose of the vaccine, two doses of vaccine (but less than 14 days after dose 2), or fully vaccinated (14 days or more after dose 2). The J&J/Janssen vaccination follows a one-dose vaccination course; women who received the J&J/Janssen vaccine were categorized at the time of delivery as having received one dose of the vaccine (less than 14 days after the single dose) or fully vaccinated (14 days or more after the single dose). Women were also categorized as having a prior SARS-CoV-2 infection if they had a history of positive RT-PCR or serology test results or positive anti-nucleocapsid antibodies (which are produced only in the setting of infection). Women who received an additional dose of an mRNA COVID-19 vaccine after completing the initial course of vaccination as above were categorized as having received a booster dose (initial course Pfizer or Moderna, received three total vaccine doses; initial course J&J/Janssen, received two total vaccine doses). No woman who received a booster dose had a history of being immunocompromised. Clinical data were de-identified and linked with the de-identified samples for analyses.

We evaluated the relationship between maternal anti-spike IgG levels at delivery and time of initiation of vaccination before or throughout pregnancy among women not receiving a booster dose, using a Wilcoxon rank sum test. We conducted a similar analysis for umbilical cord anti-spike IgG levels compared with time of maternal vaccination. Among dyads with both a maternal and umbilical cord blood sample, we calculated the placental transfer ratio (umbilical cord IgG/maternal IgG). We also compared the maternal and umbilical cord anti-spike IgG levels by timing of maternal vaccination initiation, stratified by prior history of SARS-CoV-2 infection, using a Wilcoxon rank sum test. Finally, we studied the maternal and umbilical cord anti-spike IgG levels of women who received a booster dose by trimester of maternal vaccination initiation, using a Wilcoxon rank sum test. All analyses were performed using the geometric means of anti-spike IgG levels.

Statistical analysis was performed using R 3.6.3, RStudio 1.1.463. The study was approved by the Weill Cornell Medicine Institutional Review Board. This work was supported in part by the Weill Cornell Medicine COVID-19 Research Grant and The Bender Foundation, Inc.

RESULTS

We included 1,359 women who delivered 1,374 neonates (15 sets of twins) in this study (Table 1). From this cohort, we captured samples from 1,359 pregnant women and 1,362 neonates. All women had negative RT-PCR test results for SARS-CoV-2 during the delivery admission. Women received vaccine dose 1 between December 16, 2020, and September 1, 2021, vaccine dose 2 between January 5, 2021, and September 22, 2021, and a vaccine booster dose between August 27, 2021, and October 14, 2021. Women were vaccinated between 6 weeks before pregnancy and 41 weeks of gestation (Table 1).

T1
Table 1.:
Demographic, Clinical, and Vaccine Characteristics of the Cohort

Maternal anti-spike IgG levels were detectable at delivery regardless of gestational age at vaccination among fully vaccinated women. Levels of maternal anti-spike IgG at delivery increased with greater gestational age at vaccination until vaccine initiation at 34 weeks of gestation, at which point anti-spike IgG levels were lower (these women were often not fully vaccinated before delivery, Fig. 1A). We noted a similar trend in umbilical cord anti-spike IgG levels based on timing of maternal vaccination, with lower anti-spike IgG levels at delivery noted with maternal vaccine initiation after 32 weeks of gestation (Fig. 1B). The median placental transfer ratio ranged between 1 and 2 for much of the time period of maternal vaccination initiation but dropped below 1 with vaccination initiation after 32 weeks of gestation (Fig. 1C).

F1
Fig. 1.:
Maternal and umbilical cord blood anti-spike immunoglobulin (Ig)G levels at delivery in response to coronavirus disease 2019 (COVID-19) vaccination. A. All vaccinated women at delivery. Maternal anti-spike IgG levels at time of delivery binned by gestational age or prepregnancy weeks at dose 1 of vaccination. Blue circles depict women fully vaccinated by delivery; red circles indicate women not fully vaccinated by delivery. Moderna vaccine (n=299), Pfizer-BioNTech (Pfizer) vaccine (n=1,007), and Johnson & Johnson/Janssen (J&J/Janssen) vaccine (n=33). B. Neonates born to all vaccinated women. Umbilical cord anti-spike IgG levels categorized by maternal gestational age or prepregnancy weeks at dose 1 of vaccination. Blue circles depict cord blood samples from neonates of women fully vaccinated by delivery; red circles indicate cord blood samples from neonates of women not fully vaccinated by delivery. Moderna vaccine (n=301), Pfizer vaccine (n=1,008), and J&J/Janssen (n=34). C. Vaccinated dyads. Placental transfer ratio (umbilical cord anti-spike IgG/maternal anti-spike IgG levels). Blue circles depict dyads with fully vaccinated women, and red circles depict dyads with not fully vaccinated women. Moderna vaccine (n=295), Pfizer vaccine (n=994), and J&J/Janssen vaccine (n=30). Women at least 14 days postvaccination course are denoted as fully vaccinated. All positive serology cutoffs were 1 (horizontal dashed line). Vertical dash ed lines indicate separation of pregnancy trimesters. Women who received a booster dose are not included.Yang. COVID-19 Vaccination and Antibody Levels. Obstet Gynecol 2022.

Maternal anti-spike IgG levels at delivery were lowest after first-trimester mRNA vaccination and highest after third-trimester mRNA vaccination for all women and for fully vaccinated women (Table 2 and Fig. 2A). Among women who received the J&J/Janssen vaccine, there was no statistically significant difference in anti-spike IgG levels by trimester of vaccination (Table 2).

T2
Table 2.:
Maternal Anti-Spike Immunoglobulin G Levels at Delivery by Trimester of Vaccine Initiation and Vaccine Type, Excluding Women Who Received a Booster Dose

Among women without a prior history of SARS-CoV-2 infection (Fig. 2A, left), fully vaccinated women demonstrated the lowest levels of anti-spike IgG at delivery with prepregnancy or first-trimester initiation of vaccination, with statistically significantly higher levels with second-trimester initiation of vaccination and statistically significantly even higher antibody levels at delivery if fully vaccinated in the third trimester. A similar statistically significant response was noted in umbilical cord anti-spike IgG levels by trimester of maternal vaccination (Fig. 2B, left). Being fully vaccinated in the first trimester was associated with statistically significantly higher maternal and umbilical cord IgG levels than receiving only one dose of vaccine in the third trimester (Fig. 2A and B, left). In contrast, among women with a prior history of SARS-CoV-2 infection, the maternal and umbilical cord blood antibody response achieved among women both fully vaccinated and not fully vaccinated in pregnancy was not statistically significantly different and was comparable with third-trimester vaccination in women without a prior history of SARS-CoV-2 infection, with the exception of statistically higher maternal anti-spike IgG levels after third-trimester vaccination in women with a prior history of SARS-CoV-2 infection (Fig. 2A and B, middle).

F2
Fig. 2.:
Maternal and umbilical cord blood anti-spike immunoglobulin (Ig)G levels in response to coronavirus disease 2019 (COVID-19) vaccination, stratified by previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal vaccination status, prepregnancy or trimester of vaccination, and receipt of booster dose. A. All women at delivery, including women who received a booster dose. Maternal anti-spike IgG levels stratified by prior history of SARS-CoV-2 infection (blue represents no prior history, and yellow represents prior history) and vaccination status at delivery (dark grey represents fully vaccinated, and red represents not fully vaccinated). Anti-spike IgG levels were grouped by timing of vaccine initiation: prepregnancy or first, second, or third trimester. Women who received a booster dose are represented in green. B. Neonates born to all vaccinated women, including women who received a booster dose. Umbilical cord anti-spike IgG levels are stratified similarly to part A, based on maternal history of SARS-CoV-2 infection, maternal vaccination status, timing of maternal vaccination, and maternal booster dose status. Women at least 14 days postvaccination course are denoted as fully vaccinated. *P<.05; P<.005; NS, not significant.Yang. COVID-19 Vaccination and Antibody Levels. Obstet Gynecol 2022.

Finally, women receiving a booster dose demonstrated maternal anti-spike IgG levels that were statistically significantly greater than third-trimester vaccination among fully vaccinated women in women both with and without a history of SARS-CoV-2 infection (Fig. 2A, right). Umbilical cord anti-spike IgG levels after receipt of a booster dose were not statistically significantly different from levels generated in vaccinated women with a history of SARS-CoV-2 infection but were statistically significantly higher than levels elicited among those without a history of SARS-CoV-2 infection who were fully vaccinated in the third trimester (Fig. 2B, right).

DISCUSSION

Maternal immunization against COVID-19 is paramount to minimizing the risks of COVID-19 in pregnancy; thus, vaccination is recommended irrespective of gestational age.1,8,9 In this large cohort, we demonstrate that immunization at any point in pregnancy, or before pregnancy, is associated with detectable maternal anti-spike antibody levels at delivery. Although the highest maternal, and consequently umbilical cord blood, antibody levels occur with early third-trimester vaccination, our data should not be interpreted to suggest that women should defer vaccination until the third trimester. Rather, our data support the importance of early completion of a full vaccination series. First, women cannot predict whether they may deliver prematurely, and these data reflect findings only from deliveries after 34 weeks of gestation. Second, maternal protection throughout pregnancy through vaccination is best for the fetus, by minimizing risks of severe COVID-19. Moreover, we demonstrate that neonates born to fully vaccinated women, even those vaccinated early in the first trimester, had similar or higher umbilical cord anti-spike IgG levels than neonates born to women who initiated vaccination in the third trimester but were not fully vaccinated before delivery. Thus, the risks of waiting until the third trimester to initiate vaccination in the hopes of optimizing neonatal antibody level at delivery do not benefit either the pregnant woman or the fetus.

We also observed an association between a prior history of SARS-CoV-2 infection and a higher and more sustained immune response among women after vaccination in pregnancy. Although the data regarding a booster dose are limited in this study, women without a history of SARS-CoV-2 infection who received a booster dose in the third trimester but were vaccinated before pregnancy or in the first trimester demonstrate the highest anti-spike IgG levels in maternal and umbilical cord blood. Whether the response to a booster dose is associated with a sustained immune response is unknown at this time. However, it is possible that the sustained response noted with vaccination after SARS-CoV-2 infection may illustrate what we can expect with receipt of a booster dose across trimesters in pregnancy. If this is the case, the discussion on optimal timing of COVID-19 vaccination may be moot, because primary vaccination series followed by a booster dose when eligible is associated with the highest anti-spike IgG antibody levels in both pregnant women and neonates. This is the currently recommended strategy for protection against COVID-19 but may evolve as more data define immune correlates of protection for adults and neonates.

We note some limitations to our study. First, the cohort of women included in this study does not reflect every vaccinated woman who delivered at 34 weeks of gestation or more during the study period. Some women were not included owing to either lack of leftover clinical sample or lack of documentation in the medical record regarding vaccination status. However, we do not believe this omission introduces bias into the study, because this loss of patients is random. In addition, we are unable to comment on the associations between maternal antibody levels and clinical characteristics such as immunosuppressing conditions or medication use or other comorbidities. It is also possible that women may have had a distant history of SARS-CoV-2 infection with both lack of documentation and waning levels of anti-nucleocapsid antibodies below the limit of detection. These women would thus have been miscategorized as not having a prior history of SARS-CoV-2 infection. Finally, our findings on the effect of a booster dose are limited by the small sample size and reflect a booster dose only in the third trimester. However, we were able to confirm that all women who received a booster dose were not immunosuppressed or using immunosuppressing medications; thus, none received an additional mRNA vaccine as a “third dose.” Other categories of maternal and corresponding umbilical cord samples also had small sample sizes, and thus comparisons may not be powered to detect small differences.

In summary, COVID-19 vaccination before and throughout pregnancy is associated with detectable maternal anti-spike IgG levels at delivery. Fully vaccinated women, regardless of timing of vaccine initiation, transmit higher levels of antibodies to neonates at the time of delivery. A third-trimester booster dose is associated with the highest maternal and umbilical cord antibody levels. Because immune correlates of protection are not well established at this time, following the recommended vaccination strategy is the optimal approach to protecting pregnant women and their fetuses from COVID-19.

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