COVID-19 vaccination in pregnancy generates functional anti-spike (anti-S) IgG antibodies in maternal circulation that are detectable in umbilical cord blood at birth and can protect newborns and infants from COVID-19.1-4 Anti-S IgG titers in the umbilical cord are correlated with maternal titers and are highest after late second and early third trimester vaccination.2-4 We characterized the persistence of vaccine-induced maternal anti-S IgG in infant blood and compared persistence of infant anti-S IgG after maternal vaccination vs natural infection.
The study included individuals who had received an mRNA COVID-19 vaccine in pregnancy or were infected with SARS-CoV-2 at 20 to 32 weeks’ gestation, had enrolled in a prospective study at 2 academic medical centers in Boston, and had enrolled their infants in this follow-up study conducted from July 21, 2021, to October 22, 2021. Individuals vaccinated or infected at 20 to 32 weeks’ gestation were enrolled because previous studies have demonstrated superior transplacental transfer of antibodies during this window compared with vaccination closer to delivery.4,5 Those infected before vaccination were excluded. Matched maternal and umbilical cord serum samples were collected at birth. Infant capillary serum samples were collected via microneedle device at 2 months after birth for infants of vaccinated mothers and at 6 months for infants of mothers who were vaccinated and mothers who had been infected with SARS-CoV-2. Antibody titers against the SARS-CoV-2 spike protein were quantified using an enzyme-linked immunosorbent assay (eMethods in the Supplement). Differences in titers between vaccinated and infected groups at delivery and 6-month infant age were assessed by the Mann-Whitney U test. Differences in proportions of infants with detectable antibodies at 6 months were assessed by the Fisher exact test. Correlation between delivery titers and infant antibody was assessed via the Spearman rank test. Analyses were conducted using Prism version 9.0. Significance was defined as a 2-sided P < .05. The study was approved by the Mass General Brigham institutional review board, and all participants provided written informed consent.
Seventy-seven vaccinated pregnant mothers and 12 with symptomatic SARS-CoV-2 infection in pregnancy were included (Table). At 2 months, capillary serum samples were collected from 49 infants of vaccinated mothers; at 6 months, serum samples were collected from 28 infants of vaccinated mothers (mean, 170 days after birth) and 12 infants of infected mothers (mean, 207 days after birth).
Vaccinated mothers had significantly higher titers at delivery, with a mean of 2.03 (SD, 0.47) optical density (OD450-570), compared with mothers after infection, with a mean of 0.65 (SD, 0.76) OD450-570 (P < .001). Similarly, the respective mean cord titers were higher after vaccination vs natural infection: 2.17 (SD, 0.50) OD450-570 vs 1.00 (SD, 0.83) OD450-570 (P < .001) (Figure). Among infants of vaccinated mothers at 2 months, 98% (48 of 49) had detectable anti-S IgG. The mean titer at 2 months was 1.29 (SD, 0.53) OD450-570, which was correlated with both maternal (r = 0.55; P < .001) and cord titers (r = 0.43; P = .01) at delivery.
Vaccination resulted in significantly greater antibody persistence in infants than infection. At 6 months, 57% (16 of 28) of infants born to vaccinated mothers had detectable antibodies (Table) compared with 8% (1 of 12) of infants born to infected mothers (P = .005). Titers were a mean of 0.33 (SD, 0.46) OD450-570 among infants of vaccinated mothers and 0 (SD, 0.01) OD450-570 among infants of infected mothers (P = .004) (Figure). Neither maternal (P = .23) nor cord (P = .05) titers were significantly correlated with infant anti-S titers at 6 months, largely because 43% of infants had no detectable titer at that time.
This study found that the majority of infants born to COVID-vaccinated mothers had persistent anti-S antibodies at 6 months compared with infants born to mothers with SARS-CoV-2 infection. Understanding the persistence of maternal antibody levels in infants is important because COVID-19 infections in this age group account for a disproportionate burden of pediatric SARS-CoV-2–associated morbidity6 and because COVID-19 vaccines are not currently planned for administration to infants younger than 6 months. Study limitations include the small number of infants, the longer mean time to follow-up in the infected group (due to pragmatic constraints related to timing of COVID-19 surges in Boston and the availability of participants for timely follow-up), and the reporting of antibody titers rather than clinical outcomes. Although the antibody titer known to be protective against COVID-19 in infants is unknown, these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination.
Accepted for Publication: January 21, 2022.
Published Online: February 7, 2022. doi:10.1001/jama.2022.1206
Corresponding Author: Andrea G. Edlow, MD, MSc, Department of Obstetrics & Gynecology, Massachusetts General Hospital, 55 Fruit St, Their Bldg, Floor 9, Boston, MA 02114 (firstname.lastname@example.org).
Author Contributions: Drs Alter and Edlow had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Shook and Ms Atyeo contributed equally to this work. Drs Alter and Edlow contributed equally to this work.
Concept and design: Yonker, Fasano, Alter, Edlow.
Acquisition, analysis, or interpretation of data: Shook, Atyeo, Yonker, Gray, Alter, Edlow.
Drafting of the manuscript: Shook, Atyeo, Yonker, Alter, Edlow.
Critical revision of the manuscript for important intellectual content: Shook, Atyeo, Yonker, Fasano, Gray, Alter.
Statistical analysis: Shook, Atyeo, Alter, Edlow.
Obtained funding: Fasano, Alter, Edlow.
Administrative, technical, or material support: Yonker, Gray, Alter, Edlow.
Supervision: Yonker, Fasano, Gray, Alter, Edlow.
Conflict of Interest Disclosures: Dr Fasano reported being a cofounder and stockholder of Alba Therapeutics; serving on the scientific advisory board of Viome; and receiving personal fees from Milky Way and Mead Johnson Nutrition. Dr Gray reported receiving nonfinancial support from Illumina, Aetion, and BillionToOne. Dr Alter reported being the founder of and consultant to Systems Seromyx; receiving grants from Sanofi, GlaxoSmithKline, BioNTech, and Medicago; and being a consultant to Leyden Labs. No other disclosures were reported.
Funding/Support: This study was supported by grants 1R01HD100022-01 and 3R01HD100022-02S2 (Dr Edlow) and 1K12HD103096 (Dr Shook) from the National Institute of Child Health and Human Development; grant 6-FY20-223 from the March of Dimes (Dr Edlow); grants K08HL1469630-03 and 3K08HL146963-02S1 (Dr Gray) and 5K08HL143183 (Dr Yonker) from the National Heart, Lung, and Blood Institute; the Ragon Institute of MGH, MIT, and Harvard and the MGH ECOR Scholars award (Dr Alter); the Nancy Zimmerman, Samana Kay MGH Research Scholars award (Dr Alter); grants 3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, 1U01CA260476-01, and CIVIC5N93019C00052 from the National Institute of Allergy and Infectious Diseases (Dr Alter); and grants OPP1146996 and INV-001650 from the Gates Foundation Global Health Vaccine Accelerator Platform (Dr Alter). The TAPII blood collection devices for infant blood draw were provided at reduced cost by YourBio Health.
Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Madeleine Burns, BS, MS, of the Massachusetts General Hospital Department of Pediatrics, for her contributions to participant recruitment and sample collection. She was not compensated for this work beyond her salary as a clinical research coordinator.
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