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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
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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.

Abstract

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 (rita.carsetti@opbg.net).

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.

References
1.
World Health Organization. Definition and categorization of the timing of mother-to-child transmission of SARS-CoV-2. Published online February 7, 2021. Accessed September 21, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-mother-to-child-transmission-2021.1
2.
Vella  F , Senia  P , Ceccarelli  M ,  et al.  Transmission mode associated with coronavirus disease 2019: a review.   Eur Rev Med Pharmacol Sci. 2020;24(14):7889-7904. doi:10.26355/eurrev_202007_22296PubMedGoogle Scholar
3.
Groß  R , Conzelmann  C , Müller  JA ,  et al.  Detection of SARS-CoV-2 in human breastmilk.   Lancet. 2020;395(10239):1757-1758. doi:10.1016/S0140-6736(20)31181-8PubMedGoogle ScholarCrossref
4.
Chambers  C , Krogstad  P , Bertrand  K ,  et al.  Evaluation for SARS-CoV-2 in breast milk from 18 infected women.   JAMA. 2020;324(13):1347-1348. doi:10.1001/jama.2020.15580PubMedGoogle ScholarCrossref
5.
World Health Organization. Breastfeeding and COVID-19. Published online June 23, 2020. Accessed September 21, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci_Brief-Breastfeeding-2020.1
6.
Dumitriu  D , Emeruwa  UN , Hanft  E ,  et al.  Outcomes of neonates born to mothers with severe acute respiratory syndrome coronavirus 2 infection at a large medical center in New York City.   JAMA Pediatr. 2021;175(2):157-167. doi:10.1001/jamapediatrics.2020.4298PubMedGoogle ScholarCrossref
7.
Dowling  DJ , Levy  O .  Ontogeny of early life immunity.   Trends Immunol. 2014;35(7):299-310. doi:10.1016/j.it.2014.04.007PubMedGoogle ScholarCrossref
8.
Cinicola  B , Conti  MG , Terrin  G ,  et al.  The protective role of maternal immunization in early life.   Front Pediatr. 2021;9:638871. doi:10.3389/fped.2021.638871PubMedGoogle Scholar
9.
Brandtzaeg  P .  Mucosal immunity: integration between mother and the breast-fed infant.   Vaccine. 2003;21(24):3382-3388. doi:10.1016/S0264-410X(03)00338-4PubMedGoogle ScholarCrossref
10.
Egerup  P , Fich Olsen  L , Christiansen  AH ,  et al.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies at delivery in women, partners, and newborns.   Obstet Gynecol. 2021;137(1):49-55. doi:10.1097/AOG.0000000000004199PubMedGoogle ScholarCrossref
11.
Flannery  DD , Gouma  S , Dhudasia  MB ,  et al.  Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios.   JAMA Pediatr. 2021;175(6):594-600. doi:10.1001/jamapediatrics.2021.0038PubMedGoogle ScholarCrossref
12.
Pace  RM , Williams  JE , Järvinen  KM ,  et al.  Characterization of SARS-CoV-2 RNA, antibodies, and neutralizing capacity in milk produced by women with COVID-19.   mBio. 2021;12(1):e03192-20. doi:10.1128/mBio.03192-20PubMedGoogle Scholar
13.
Perl  SH , Uzan-Yulzari  A , Klainer  H ,  et al.  SARS-CoV-2-specific antibodies in breast milk after COVID-19 vaccination of breastfeeding women.   JAMA. 2021;325(19):2013-2014. doi:10.1001/jama.2021.5782PubMedGoogle ScholarCrossref
14.
Aranburu  A , Piano Mortari  E , Baban  A ,  et al.  Human B-cell memory is shaped by age- and tissue-specific T-independent and GC-dependent events.   Eur J Immunol. 2017;47(2):327-344. doi:10.1002/eji.201646642PubMedGoogle ScholarCrossref
15.
Brandtzaeg  P , Nilssen  DE , Rognum  TO , Thrane  PS .  Ontogeny of the mucosal immune system and IgA deficiency.   Gastroenterol Clin North Am. 1991;20(3):397-439. doi:10.1016/S0889-8553(21)00564-1PubMedGoogle ScholarCrossref
16.
Miles  DJC , Gadama  L , Gumbi  A , Nyalo  F , Makanani  B , Heyderman  RS .  Human immunodeficiency virus (HIV) infection during pregnancy induces CD4 T-cell differentiation and modulates responses to bacille Calmette-Guérin (BCG) vaccine in HIV-uninfected infants.   Immunology. 2010;129(3):446-454. doi:10.1111/j.1365-2567.2009.03186.xPubMedGoogle ScholarCrossref
17.
Mosconi  E , Rekima  A , Seitz-Polski  B ,  et al.  Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.   Mucosal Immunol. 2010;3(5):461-474. doi:10.1038/mi.2010.23PubMedGoogle ScholarCrossref
18.
Ohsaki  A , Venturelli  N , Buccigrosso  TM ,  et al.  Maternal IgG immune complexes induce food allergen-specific tolerance in offspring.   J Exp Med. 2018;215(1):91-113. doi:10.1084/jem.20171163PubMedGoogle ScholarCrossref
19.
Devito  C , Hinkula  J , Kaul  R ,  et al.  Mucosal and plasma IgA from HIV-exposed seronegative individuals neutralize a primary HIV-1 isolate.   AIDS. 2000;14(13):1917-1920. doi:10.1097/00002030-200009080-00006PubMedGoogle ScholarCrossref
20.
Planque  S , Salas  M , Mitsuda  Y ,  et al.  Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection.   AIDS. 2010;24(6):875-884. doi:10.1097/QAD.0b013e3283376e88PubMedGoogle ScholarCrossref
21.
Sterlin  D , Mathian  A , Miyara  M ,  et al.  IgA dominates the early neutralizing antibody response to SARS-CoV-2.   Sci Transl Med. 2021;13(577):eabd2223. doi:10.1126/scitranslmed.abd2223PubMedGoogle Scholar
22.
Tosif  S , Neeland  MR , Sutton  P ,  et al.  Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19.   Nat Commun. 2020;11(1):5703. doi:10.1038/s41467-020-19545-8PubMedGoogle ScholarCrossref
23.
Diociaiuti  A , Giancristoforo  S , Terreri  S ,  et al.  Are SARS-CoV-2 IgA antibodies in paediatric patients with chilblain-like lesions indicative of COVID-19 asymptomatic or paucisymptomatic infection?   J Eur Acad Dermatol Venereol. 2021;35(1):e10-e13. doi:10.1111/jdv.16934PubMedGoogle ScholarCrossref
24.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053Google ScholarCrossref
25.
Conti  MG , Natale  F , Stolfi  I ,  et al.  Consequences of early separation of maternal-newborn dyad in neonates born to SARS-CoV-2 positive mothers: an observational study.   Int J Environ Res Public Health. 2021;18(11):5899. doi:10.3390/ijerph18115899PubMedGoogle ScholarCrossref
26.
Fenizia  C , Biasin  M , Cetin  I ,  et al.  Analysis of SARS-CoV-2 vertical transmission during pregnancy.   Nat Commun. 2020;11(1):5128. doi:10.1038/s41467-020-18933-4PubMedGoogle ScholarCrossref
27.
Carsetti  R , Zaffina  S , Piano Mortari  E ,  et al.  Different innate and adaptive immune responses to SARS-CoV-2 infection of asymptomatic, mild, and severe cases.   Front Immunol. 2020;11:610300. doi:10.3389/fimmu.2020.610300PubMedGoogle Scholar
28.
Alteri  C , Cento  V , Antonello  M ,  et al. Detection and quantification of SARS-CoV-2 by droplet digital PCR in real-time PCR negative nasopharyngeal swabs from suspected COVID-19 patients.  PLoS ONE. 2020;15(9):e0236311. doi:10.1371/journal.pone.0236311PubMed
29.
Wölfel  R , Corman  VM , Guggemos  W ,  et al.  Virological assessment of hospitalized patients with COVID-2019.   Nature. 2020;581(7809):465-469. doi:10.1038/s41586-020-2196-xPubMedGoogle ScholarCrossref
30.
Brandtzaeg  P .  Secretory immunity with special reference to the oral cavity.   J Oral Microbiol. 2013;5. doi:10.3402/jom.v5i0.20401PubMedGoogle Scholar
31.
Wang  XY , Wang  B , Wen  YM .  From therapeutic antibodies to immune complex vaccines.   NPJ Vaccines. 2019;4:2. doi:10.1038/s41541-018-0095-zPubMedGoogle ScholarCrossref
32.
Niewiesk  S .  Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies.   Front Immunol. 2014;5:446. doi:10.3389/fimmu.2014.00446PubMedGoogle ScholarCrossref
33.
Carsetti  R , Quintarelli  C , Quinti  I ,  et al.  The immune system of children: the key to understanding SARS-CoV-2 susceptibility?   Lancet Child Adolesc Health. 2020;4(6):414-416. doi:10.1016/S2352-4642(20)30135-8PubMedGoogle ScholarCrossref
34.
Jones  CE , Hesseling  AC , Tena-Coki  NG ,  et al.  The impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination.   AIDS. 2015;29(2):155-165. doi:10.1097/QAD.0000000000000536PubMedGoogle ScholarCrossref
35.
Wilcox  CR , Jones  CE .  Beyond passive immunity: is there priming of the fetal immune system following vaccination in pregnancy and what are the potential clinical implications?   Front Immunol. 2018;9:1548. doi:10.3389/fimmu.2018.01548PubMedGoogle ScholarCrossref
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