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

Alexander J Keeley^{1

2

3

4}, Fatoumata E Camara⁵, Edwin P Armitage^{5

6

7}, Gabrielle de Crombrugghe^{5

8

9}, Jainaba Sillah⁵, Modou Lamin Fofana⁵, Victoria Rollinson⁵, Elina Senghore⁵, Musukoi Jammeh⁵, Alana L Whitcombe¹⁰, Amat Bittaye⁵, Haddy Ceesay⁵, Isatou Ceesay⁵, Bunja Samateh⁵, Muhammed Manneh⁵, Martina Carducci¹¹, Luca Rovetini¹¹, Elena Boero¹¹, Luisa Massai¹¹, Lady Chilel Sanyang⁵, Ousman Camara⁵, Ebrima E Cessay⁵, Miren Iturriza¹¹, Danilo Gomes Moriel¹¹, Adam Kucharski¹², Pierre R Smeesters^{8

9}, Anne Botteaux⁸, Ya Jankey Jagne⁵, Nicole J Moreland¹⁰, Ed Clarke⁵, Beate Kampmann^{5

6

13}, Michael Marks^{6

14

15}, Omar Rossi¹¹, Henrik Salje¹⁶, Claire E Turner^{17

18}, Thushan I de Silva^{19

20

21}

Affiliations

¹ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia. alexander.keeley@lshtm.ac.uk.
² Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK. alexander.keeley@lshtm.ac.uk.
³ The Florey Institute of Infection, University of Sheffield, Sheffield, UK. alexander.keeley@lshtm.ac.uk.
⁴ Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK. alexander.keeley@lshtm.ac.uk.
⁵ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
⁶ Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.
⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ Molecular Bacteriology Laboratory, European Plotkin Institute for Vaccinology, Université Libre de Bruxelles, Brussels, Belgium.
⁹ Department of Paediatrics, Brussels University Hospital, Academic Children Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
¹⁰ Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
¹¹ GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.
¹² Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.
¹³ Charité Centre for Global Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Hospital for Tropical Diseases, University College London Hospital, London, UK.
¹⁵ Division of Infection and Immunity, University College London, London, UK.
¹⁶ Department of Genetics, University of Cambridge, Cambridge, UK.
¹⁷ The Florey Institute of Infection, University of Sheffield, Sheffield, UK.
¹⁸ School of Biosciences, University of Sheffield, Sheffield, UK.
¹⁹ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia. t.desilva@sheffield.ac.uk.
²⁰ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK. t.desilva@sheffield.ac.uk.
²¹ The Florey Institute of Infection, University of Sheffield, Sheffield, UK. t.desilva@sheffield.ac.uk.

PMID: 40781379
DOI: 10.1038/s41591-025-03868-4

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

Alexander J Keeley et al. Nat Med. 2025.

. 2025 Aug 8.

doi: 10.1038/s41591-025-03868-4. Online ahead of print.

Authors

Affiliations

¹ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia. alexander.keeley@lshtm.ac.uk.
² Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK. alexander.keeley@lshtm.ac.uk.
³ The Florey Institute of Infection, University of Sheffield, Sheffield, UK. alexander.keeley@lshtm.ac.uk.
⁴ Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK. alexander.keeley@lshtm.ac.uk.
⁵ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
⁶ Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.
⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ Molecular Bacteriology Laboratory, European Plotkin Institute for Vaccinology, Université Libre de Bruxelles, Brussels, Belgium.
⁹ Department of Paediatrics, Brussels University Hospital, Academic Children Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
¹⁰ Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
¹¹ GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.
¹² Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.
¹³ Charité Centre for Global Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Hospital for Tropical Diseases, University College London Hospital, London, UK.
¹⁵ Division of Infection and Immunity, University College London, London, UK.
¹⁶ Department of Genetics, University of Cambridge, Cambridge, UK.
¹⁷ The Florey Institute of Infection, University of Sheffield, Sheffield, UK.
¹⁸ School of Biosciences, University of Sheffield, Sheffield, UK.
¹⁹ Vaccines and Immunity Theme, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia. t.desilva@sheffield.ac.uk.
²⁰ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK. t.desilva@sheffield.ac.uk.
²¹ The Florey Institute of Infection, University of Sheffield, Sheffield, UK. t.desilva@sheffield.ac.uk.

PMID: 40781379
DOI: 10.1038/s41591-025-03868-4

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.

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Conflict of interest statement

Competing interests: A.J.K. received training in immunoassay development and delivery from the GSK Vaccines Institute for Global Health, an affiliate of GlaxoSmithKline (GSK). GSK had no role in overall study design, data analysis or data interpretation for this study. O.R., M.C., E.B., L.R., L.M., M.I. and D.G.M. are employees of the GSK Vaccines Institute for Global Health. A.B. and P.R.S. are inventors on a submitted patent related to Streptococcus pyogenes vaccines. The other authors declare no competing interests.

References

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

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

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