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Immune Response of Neonates Born to Mothers Infected With SARS-CoV-2

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To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What is the association of maternal SARS-CoV-2 infection with immune response in offspring in the first 2 months of life?

Findings  In this cohort study of 21 mothers who tested positive for SARS-CoV-2 at delivery and their 22 newborns, there was 1 case of potential mother-infant vertical virus transmission and 1 case of horizontal virus transmission. Infants who received breastmilk during the first 2 months of life had significantly higher spike-specific salivary IgA antibody levels compared with formula-fed infants, and IgA spike immune complexes were detected in breastmilk.

Meaning  Findings suggest that maternal protection goes beyond passive immunity, with immune complexes in breastmilk stimulating the active development of the neonatal immune system.


Importance  Although several studies have provided information on short-term clinical outcomes in children with perinatal exposure to SARS-CoV-2, data on the immune response in the first months of life among newborns exposed to the virus in utero are lacking.

Objective  To characterize systemic and mucosal antibody production during the first 2 months of life among infants who were born to mothers infected with SARS-CoV-2.

Design, Setting, and Participants  This prospective cohort study enrolled 28 pregnant women who tested positive for SARS-CoV-2 infection and who gave birth at Policlinico Umberto I in Rome, Italy, from November 2020 to May 2021, and their newborns. Maternal and neonatal systemic immune responses were investigated by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breastmilk and infant saliva 48 hours after delivery and 2 months later.

Exposures  Maternal infection with SARS-CoV-2 in late pregnancy.

Main Outcomes and Measures  The systemic immune response was evaluated by the detection of SARS-CoV-2 IgG and IgA antibodies and receptor binding domain–specific IgM antibodies in maternal and neonatal serum. The mucosal immune response was assessed by measuring spike-specific antibodies in breastmilk and in infant saliva, and the presence of antigen-antibody spike IgA immune complexes was investigated in breastmilk samples. All antibodies were detected using an enzyme-linked immunosorbent assay.

Results  In total, 28 mother-infant dyads (mean [SD] maternal age, 31.8 [6.4] years; mean [SD] gestational age, 38.1 [2.3] weeks; 18 [60%] male infants) were enrolled at delivery, and 21 dyads completed the study at 2 months’ follow-up. Because maternal infection was recent in all cases, transplacental transfer of virus spike-specific IgG antibodies occurred in only 1 infant. One case of potential vertical transmission and 1 case of horizontal infection were observed. Virus spike protein–specific salivary IgA antibodies were significantly increased (P = .01) in infants fed breastmilk (0.99 arbitrary units [AU]; IQR, 0.39-1.68 AU) vs infants fed an exclusive formula diet (0.16 AU; IQR, 0.02-0.83 AU). Maternal milk contained IgA spike immune complexes at 48 hours (0.53 AU; IQR, 0.25-0.39 AU) and at 2 months (0.09 AU; IQR, 0.03-0.17 AU) and may have functioned as specific stimuli for the infant mucosal immune response.

Conclusions and Relevance  In this cohort study, SARS-CoV-2 spike–specific IgA antibodies were detected in infant saliva, which may partly explain why newborns are resistant to SARS-CoV-2 infection. Mothers infected in the peripartum period appear to not only passively protect the newborn via breastmilk secretory IgA but also actively stimulate and train the neonatal immune system via breastmilk immune complexes.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 3, 2021.

Published: November 3, 2021. doi:10.1001/jamanetworkopen.2021.32563

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Conti MG et al. JAMA Network Open.

Corresponding Author: Rita Carsetti, MD, Diagnostic Immunology Research Unit, Multimodal Medicine Research Area, Bambino Gesù Children's Hospital, IRCCS, Viale Baldelli 38, 00146 Rome, Italy (

Author Contributions: Dr Carsetti had full access to all of the experimental data in the study, and Dr Terrin had full access to all of the clinical data in the study; Drs Carsetti and Terrin take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Conti and Terreri contributed equally to this work and are considered co–first authors. Drs Terrin and Carsetti contributed equally to this work and are considered co–last authors.

Concept and design: Conti, Terreri, Piano Mortari, Zacco, De Luca, Brunelli, Terrin, Carsetti.

Acquisition, analysis, or interpretation of data: Conti, Terreri, Albano, Natale, Boscarino, Zacco, Palomba, Cascioli, Corrente, Capponi, Mirabella, Fernandez Salinas, Marciano, De Luca, Pangallo, Quaranta, Alteri, Russo, Galoppi, Brunelli, Perno, Terrin, Carsetti.

Drafting of the manuscript: Conti, Terreri, Albano, Zacco, Corrente, Capponi, Mirabella, Marciano, De Luca, Pangallo, Quaranta, Russo, Galoppi, Terrin, Carsetti.

Critical revision of the manuscript for important intellectual content: Piano Mortari, Natale, Boscarino, Palomba, Cascioli, Fernandez Salinas, De Luca, Alteri, Russo, Brunelli, Perno, Terrin.

Statistical analysis: Terreri, Boscarino.

Obtained funding: Marciano, Russo, Galoppi, Carsetti.

Administrative, technical, or material support: Conti, Terreri, Piano Mortari, Albano, Natale, Palomba, Cascioli, Corrente, Capponi, Mirabella, Fernandez Salinas, Marciano, Pangallo, Quaranta, Russo, Galoppi, Terrin.

Supervision: Piano Mortari, Russo, Brunelli, Perno, Terrin, Carsetti.

Conflict of Interest Disclosures: None reported.

Funding/Support: Italian Ministry of Health grants RF2013-02358960 and COVID-2020-12371817 and Ricerca Corrente 2021 “5 per mille.”

Role of the Funder/Sponsor: The funders 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; or decision to submit the manuscript for publication.

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