Early-life serological profiles and the development of natural protective humoral immunity to Streptococcus pyogenes in a high-burden setting

Abstract

Streptococcus pyogenes leads to 500,000 deaths annually, many due to rheumatic heart disease in low-income settings. Limited understanding of natural protective immunity to S. pyogenes hinders vaccine development. Here we describe the evolution of serological profiles to conserved vaccine antigens and serotype-specific M proteins from birth and throughout the life course in The Gambia. As placentally transferred IgG waned after birth, serological evidence of new exposure was seen in 23% of infants during the first year of life. After culture-confirmed S. pyogenes events, the highest IgG increases occurred in children younger than 2 years of age after both pharyngeal and skin disease and asymptomatic carriage at both sites. Higher IgG levels against conserved vaccine antigens correlated with functional activity and were associated with protection from culture-confirmed events after adjustment for age and anti-M protein IgG levels. To our knowledge, our data provide the first evidence of protection associated with humoral immunity to conserved vaccine candidate antigens in humans.

Metadata

Item Type:	Article
Authors/Creators:	Keeley, A.J. https://orcid.org/0000-0001-9386-1157 Camara, F.E. Armitage, E.P. de Crombrugghe, G. Sillah, J. Fofana, M.L. Rollinson, V. Senghore, E. Jammeh, M. Whitcombe, A.L. Bittaye, A. Ceesay, H. Ceesay, I. Samateh, B. Manneh, M. Carducci, M. Rovetini, L. Boero, E. Massai, L. Sanyang, L.C. Camara, O. Cessay, E.E. Iturriza, M. Moriel, D.G. Kucharski, A. Smeesters, P.R. Botteaux, A. Jagne, Y.J. Moreland, N.J. Clarke, E. Kampmann, B. Marks, M. Rossi, O. Salje, H. Turner, C.E. de Silva, T.I. https://orcid.org/0000-0002-6498-9212
Copyright, Publisher and Additional Information:	© 2025 The authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Bacterial infection; Bacteriology; Translational immunology
Dates:	Submitted: 11 February 2025 Accepted: 30 June 2025 Published (online): 8 August 2025 Published: 8 August 2025
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number National Institute for Health and Care Research NIHR203321 WELLCOME TRUST (THE) UNSPECIFIED
Depositing User:	Symplectic Sheffield
Date Deposited:	14 Aug 2025 08:20
Last Modified:	14 Aug 2025 08:20
Status:	Published online
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41591-025-03868-4
Related URLs:	Dataset
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Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:230357