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

Alexander J Keeley; Fatoumata E Camara; Edwin P Armitage; Gabrielle de Crombrugghe; Jainaba Sillah; Modou Lamin Fofana; Victoria Rollinson; Elina Senghore; Musukoi Jammeh; Alana L Whitcombe; Amat Bittaye; Haddy Ceesay; Isatou Ceesay; Bunja Samateh; Muhammed Manneh; Martina Carducci; Luca Rovetini; Elena Boero; Luisa Massai; Lady Chilel Sanyang; Ousman Camara; Ebrima E Cessay; Miren Iturriza; Danilo Gomes Moriel; Adam Kucharski; Pierre R Smeesters; Anne Botteaux; Ya Jankey Jagne; Nicole J Moreland; Ed Clarke; Beate Kampmann; Michael Marks; Omar Rossi; Henrik Salje; Claire E Turner; Thushan I de Silva

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^*
, Fatoumata E Camara
, Edwin P Armitage
, Gabrielle de Crombrugghe
, Jainaba Sillah
, Modou Lamin Fofana
, Victoria Rollinson
, Elina Senghore
, Musukoi Jammeh
, Alana L Whitcombe
, Amat Bittaye
, Haddy Ceesay
, Isatou Ceesay
, Bunja Samateh
, Muhammed Manneh
, Martina Carducci
, Luca Rovetini
, Elena Boero
, Luisa Massai
, Lady Chilel Sanyang

Ousman Camara, Ebrima E Cessay, Miren Iturriza, Danilo Gomes Moriel, Adam Kucharski, Pierre R Smeesters, Anne Botteaux, Ya Jankey Jagne, Nicole J Moreland, Ed Clarke, Beate Kampmann, Michael Marks, Omar Rossi, Henrik Salje, Claire E Turner, Thushan I de Silva^*

^*Corresponding author for this work

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3360-3371
Number of pages	32
Journal	Nature Medicine
Volume	31
Issue number	10
Early online date	8 Aug 2025
DOIs	https://doi.org/10.1038/s41591-025-03868-4
Publication status	Published - 1 Oct 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Humans
Streptococcus pyogenes/immunology
Immunity, Humoral/immunology
Streptococcal Infections/immunology
Infant
Female
Immunoglobulin G/immunology
Child, Preschool
Antibodies, Bacterial/immunology
Antigens, Bacterial/immunology
Male
Gambia/epidemiology
Child
Streptococcal Vaccines/immunology
Infant, Newborn
Adult
Adolescent
Bacterial Outer Membrane Proteins/immunology
Carrier Proteins

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Keeley, A. J., 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., ... de Silva, T. I. (2025). Early-life serological profiles and the development of natural protective humoral immunity to Streptococcus pyogenes in a high-burden setting. Nature Medicine, 31(10), 3360-3371. https://doi.org/10.1038/s41591-025-03868-4

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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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author = "Keeley, \{Alexander J\} and Camara, \{Fatoumata E\} and Armitage, \{Edwin P\} and \{de Crombrugghe\}, Gabrielle and Jainaba Sillah and Fofana, \{Modou Lamin\} and Victoria Rollinson and Elina Senghore and Musukoi Jammeh and Whitcombe, \{Alana L\} and Amat Bittaye and Haddy Ceesay and Isatou Ceesay and Bunja Samateh and Muhammed Manneh and Martina Carducci and Luca Rovetini and Elena Boero and Luisa Massai and Sanyang, \{Lady Chilel\} and Ousman Camara and Cessay, \{Ebrima E\} and Miren Iturriza and Moriel, \{Danilo Gomes\} and Adam Kucharski and Smeesters, \{Pierre R\} and Anne Botteaux and Jagne, \{Ya Jankey\} and Moreland, \{Nicole J\} and Ed Clarke and Beate Kampmann and Michael Marks and Omar Rossi and Henrik Salje and Turner, \{Claire E\} and \{de Silva\}, \{Thushan I\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = oct,

day = "1",

doi = "10.1038/s41591-025-03868-4",

language = "English",

volume = "31",

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Keeley, AJ, Camara, FE, Armitage, EP, de Crombrugghe, G, Sillah, J, Fofana, ML, Rollinson, V, Senghore, E, Jammeh, M, Whitcombe, AL, Bittaye, A, Ceesay, H, Ceesay, I, Samateh, B, Manneh, M, Carducci, M, Rovetini, L, Boero, E, Massai, L, Sanyang, LC, Camara, O, Cessay, EE, Iturriza, M, Moriel, DG, Kucharski, A, Smeesters, PR, Botteaux, A, Jagne, YJ, Moreland, NJ, Clarke, E, Kampmann, B, Marks, M, Rossi, O, Salje, H, Turner, CE & de Silva, TI 2025, 'Early-life serological profiles and the development of natural protective humoral immunity to Streptococcus pyogenes in a high-burden setting', Nature Medicine, vol. 31, no. 10, pp. 3360-3371. https://doi.org/10.1038/s41591-025-03868-4

TY - JOUR

T1 - Early-life serological profiles and the development of natural protective humoral immunity to Streptococcus pyogenes in a high-burden setting

AU - Keeley, Alexander J

AU - Camara, Fatoumata E

AU - Armitage, Edwin P

AU - de Crombrugghe, Gabrielle

AU - Sillah, Jainaba

AU - Fofana, Modou Lamin

AU - Rollinson, Victoria

AU - Senghore, Elina

AU - Jammeh, Musukoi

AU - Whitcombe, Alana L

AU - Bittaye, Amat

AU - Ceesay, Haddy

AU - Ceesay, Isatou

AU - Samateh, Bunja

AU - Manneh, Muhammed

AU - Carducci, Martina

AU - Rovetini, Luca

AU - Boero, Elena

AU - Massai, Luisa

AU - Sanyang, Lady Chilel

AU - Camara, Ousman

AU - Cessay, Ebrima E

AU - Iturriza, Miren

AU - Moriel, Danilo Gomes

AU - Kucharski, Adam

AU - Smeesters, Pierre R

AU - Botteaux, Anne

AU - Jagne, Ya Jankey

AU - Moreland, Nicole J

AU - Clarke, Ed

AU - Kampmann, Beate

AU - Marks, Michael

AU - Rossi, Omar

AU - Salje, Henrik

AU - Turner, Claire E

AU - de Silva, Thushan I

PY - 2025/10/1

Y1 - 2025/10/1

N2 - 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.

AB - 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.

KW - Humans

KW - Streptococcus pyogenes/immunology

KW - Immunity, Humoral/immunology

KW - Streptococcal Infections/immunology

KW - Infant

KW - Female

KW - Immunoglobulin G/immunology

KW - Child, Preschool

KW - Antibodies, Bacterial/immunology

KW - Antigens, Bacterial/immunology

KW - Male

KW - Gambia/epidemiology

KW - Child

KW - Streptococcal Vaccines/immunology

KW - Infant, Newborn

KW - Adult

KW - Adolescent

KW - Bacterial Outer Membrane Proteins/immunology

KW - Carrier Proteins

U2 - 10.1038/s41591-025-03868-4

DO - 10.1038/s41591-025-03868-4

M3 - Article (Academic Journal)

C2 - 40781379

SN - 1078-8956

VL - 31

SP - 3360

EP - 3371

JO - Nature Medicine

JF - Nature Medicine

IS - 10

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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