Abstract

All circulating immunoglobulin G (IgG) antibodies in human newborns are of maternal origin1 and transferred across the placenta to provide passive immunity until newborn IgG production takes over 15 weeks after birth2. However, maternal IgG can also negatively interfere with newborn vaccine responses3. The concentration of IgG increases sharply during the third trimester of gestation and children delivered extremely preterm are believed to largely lack this passive immunity1,2,4. Antibodies to individual viruses have been reported5,6,7,8,9,10,11,12, but the global repertoire of maternal IgG, its variation in children, and the epitopes targeted are poorly understood. Here, we assess antibodies against 93,904 epitopes from 206 viruses in 32 preterm and 46 term mother–child dyads. We find that extremely preterm children receive comparable repertoires of IgG as term children, albeit at lower absolute concentrations and consequent shorter half-life. Neutralization of the clinically important respiratory syncytial virus (RS-virus) was also comparable until three months of age. These findings have implications for understanding infectious disease susceptibility, vaccine development, and vaccine scheduling in newborn children.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Code availability

The pipeline for processing the VirScan data has been published previously; the script for all other analyses described in the paper is available from https://github.com/Brodinlab/maternal_abs.

Data availability

All VirScan sequencing data (Figs. 1 and 2) is deposited at the NCBI Sequence Read Archive database (PRJNA516865). The ELISA (Fig. 3) and virus neutralization raw data (Fig. 4) are readily available upon request.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Hobbs, J. R. & Davis, J. A. Serum γG-globulin levels and gestational age in premature babies. Lancet 289, 757–759 (1967).

  2. 2.

    Conway, S. P., Dear, P. R. & Smith, I. Immunoglobulin profile of the preterm baby. Arch. Dis. Child. 60, 208–212 (1985).

  3. 3.

    Siegrist, C.-A. & Aspinall, R. B-cell responses to vaccination at the extremes of age. Nat. Rev. Immunol. 9, 185–194 (2009).

  4. 4.

    Salimonu, L. S., Ladipo, O. A., Adeniran, S. O. & Osukoya, B. O. Serum immunoglobulin levels in normal, premature and postmature newborns and their mothers. Int. J. Gynaecol. Obstet. 16, 119–123 (1978).

  5. 5.

    Leuridan, E., Hens, N., Hutse, V., Aerts, M. & Van Damme, P. Kinetics of maternal antibodies against rubella and varicella in infants. Vaccine 29, 2222–2226 (2011).

  6. 6.

    van der Zwet, W. C., Vandenbroucke-Grauls, C. M. J. E., van Elburg, R. M., Cranendonk, A. & Zaaijer, H. L. Neonatal antibody titers against varicella-zoster virus in relation to gestational age, birth weight, and maternal titer. Pediatrics 109, 79–85 (2002).

  7. 7.

    Ochola, R. et al. The level and duration of RSV-Specific maternal IgG in infants in Kilifi Kenya. PLoS ONE 4, e8088 (2009).

  8. 8.

    Francis, J. P. et al. Maternal antibodies to pneumolysin but not to pneumococcal surface protein A delay early pneumococcal carriage in high-risk Papua New Guinean infants. Clin. Vaccine Immunol. 16, 1633–1638 (2009).

  9. 9.

    Leuridan, E. et al. Early waning of maternal measles antibodies in era of measles elimination: longitudinal study. BMJ 340, c1626 (2010).

  10. 10.

    Watanaveeradej, V. et al. Transplacentally transferred maternal-infant antibodies to dengue virus. Am. J. Trop. Med. Hyg. 69, 123–128 (2003).

  11. 11.

    Jiang, Y. et al. Maternal antiviral immunoglobulin accumulates in neural tissue of neonates to prevent HSV neurological disease. MBio 8, e00678-17 (2017).

  12. 12.

    Aizawa, Y. et al. Role of maternal antibodies in infants with severe diseases related to human parechovirus type 31. Emerg. Infect. Dis. 21, 1966–1972 (2015).

  13. 13.

    Winkelstein, J. A. et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore) 85, 193–202 (2006).

  14. 14.

    Hernandez-Trujillo, V. P. et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J. Clin. Immunol. 34, 627–632 (2014).

  15. 15.

    Jennewein, M. F., Abu-Raya, B., Jiang, Y., Alter, G. & Marchant, A. Transfer of maternal immunity and programming of the newborn immune system. Semin. Immunopathol. 39, 605–613 (2017).

  16. 16.

    Xu, G. J. et al. Comprehensive serological profiling of human populations using a synthetic human virome. Science 348, aaa0698 (2015).

  17. 17.

    Olin, A. et al. Stereotypic immune system development in newborn children. Cell 174, 1277–1292.e14 (2018).

  18. 18.

    Lozano, N. A. et al. Expression of FcRn receptor in placental tissue and its relationship with IgG levels in term and preterm newborns. Am. J. Reprod. Immunol. 80, e12972 (2018).

  19. 19.

    Scheltema, N. M. et al. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob. Health 5, e984–e991 (2017).

  20. 20.

    Feldman, S. A., Audet, S. & Beeler, J. A. The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulfate. J. Virol. 74, 6442–6447 (2000).

  21. 21.

    Wilcox, C. R., Holder, B. & Jones, C. E. Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy. Front. Immunol. 8, 1294 (2017).

  22. 22.

    Jennewein, M. F. & Alter, G. The immunoregulatory roles of antibody glycosylation. Trends Immunol. 38, 358–372 (2017).

  23. 23.

    Resch, B., Kurath, S. & Manzoni, P. Epidemiology of respiratory syncytial virus infection in preterm infants. Open Microbiol. J. 5, 135–143 (2011).

  24. 24.

    van den Hof, S., Wallinga, J., Widdowson, M. A. & Conyn-van Spaendonck, M. A. Protecting the vaccinating population in the face of a measles epidemic: assessing the impact of adjusted vaccination schedules. Epidemiol. Infect. 128, 47–57 (2002).

Download references

Acknowledgements

We are grateful to all the families taking part in this study, all colleagues at the Karolinska University Hospital neonatology and delivery wards. We are also indebted to S. Elledge and T. Kula at Harvard University for sharing the VirScan bacteriophage library and their assistance. The study was funded by a European Research Council starting grant (no. ERC-StG-677559), Wallenberg Clinical Fellow grant (no. MMW 2017.0127), Karolinska Institutet (KI Research Assistant 2015 grant), and the Swedish Research council (grant no. 2015–03028) to P.B.

Author information

Author notes

  1. These authors contributed equally: Christian Pou, Dieudonné Nkulikiyimfura.

Affiliations

  1. Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

    • Christian Pou
    • , Dieudonné Nkulikiyimfura
    • , Axel Olin
    • , Tadepally Lakshmikanth
    • , Jaromir Mikes
    • , Jun Wang
    • , Yang Chen
    • , Anna Karin Bernhardsson
    •  & Petter Brodin
  2. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

    • Ewa Henckel
    • , Anna Gustafsson
    •  & Kajsa Bohlin
  3. Department of Newborn Medicine, Karolinska University Hospital, Stockholm, Sweden

    • Ewa Henckel
    • , Anna Karin Bernhardsson
    • , Anna Gustafsson
    • , Kajsa Bohlin
    •  & Petter Brodin

Authors

  1. Search for Christian Pou in:

  2. Search for Dieudonné Nkulikiyimfura in:

  3. Search for Ewa Henckel in:

  4. Search for Axel Olin in:

  5. Search for Tadepally Lakshmikanth in:

  6. Search for Jaromir Mikes in:

  7. Search for Jun Wang in:

  8. Search for Yang Chen in:

  9. Search for Anna Karin Bernhardsson in:

  10. Search for Anna Gustafsson in:

  11. Search for Kajsa Bohlin in:

  12. Search for Petter Brodin in:

Contributions

C.P. established the VirScan method and performed all the experimental analyses using VirScan and ELISA. D.N. and P.B. performed the computational analyses. E.H., A.K.B., P.B., A.G., and K.B. enrolled the children and collected the samples. A.O., T.L., J.M., and J.W. assisted with sample organization, processing, and metadata analysis. Y.C. developed the data analysis infrastructure and database. P.B., E.H., and K.B. designed the study. P.B., D.N., and C.P. created the figures and wrote the manuscript with input from all coauthors.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Petter Brodin.

Extended data

  1. Extended Data Fig. 1 Parental repertoires of antiviral antibodies.

    a, Viruses targeted by antibodies in fathers. b, Viruses targeted by antibodies in mothers.

  2. Extended Data Fig. 2 Preterm/term repertoires of antiviral antibodies.

    Principal component analysis based of global antiviral repertoires (species level). Each dot represents a unique individual child (n = 102); the first sample available at birth or first days of life is used as in Fig. 1d and the dots are colored by gestational age at birth for each child.

  3. Extended Data Fig. 3 Antibodies to immunodominant epitopes in preterm and term children.

    The frequencies of maternal IgG to 70 immunodominant epitopes (mean frequency > 50% of seropositive children) in term (x axis) and preterm (y axis) children. The point size represents the mean frequencies in all children.

  4. Extended Data Fig. 4 Neutralizing capacity of anti-influenza A antibodies in preterm and term children.

    Dilution curve and percentage neutralizing capacity of maternal antibodies in cord blood (preterm n = 13, term n = 10). The points indicate the mean values and the error bars define the minimum and maximum values of viral neutralization.

Supplementary information

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41591-019-0392-8