. 2022 Oct;3(10):e735-e743.

doi: 10.1016/S2666-5247(22)00158-6. Epub 2022 Aug 16.

Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study

Stephanie W Lo¹, Kate Mellor², Robert Cohen³, Alba Redin Alonso⁴, Sophie Belman², Narender Kumar², Paulina A Hawkins⁵, Rebecca A Gladstone⁶, Anne von Gottberg⁷, Balaji Veeraraghavan⁸, K L Ravikumar⁹, Rama Kandasamy¹⁰, Sir Andrew J Pollard¹¹, Samir K Saha¹², Godfrey Bigogo¹³, Martin Antonio¹⁴, Brenda Kwambana-Adams¹⁵, Shaper Mirza¹⁶, Sadia Shakoor¹⁷, Imran Nisar¹⁷, Jennifer E Cornick¹⁸, Deborah Lehmann¹⁹, Rebecca L Ford²⁰, Betuel Sigauque²¹, Paul Turner²², Jennifer Moïsi²³, Stephen K Obaro²⁴, Ron Dagan²⁵, Idrissa Diawara²⁶, Anna Skoczyńska²⁷, Hui Wang²⁸, Philip E Carter²⁹, Keith P Klugman⁵, Gail Rodgers³⁰, Robert F Breiman³¹, Lesley McGee³², Stephen D Bentley², Carmen Muñoz-Almagro⁴, Emmanuelle Varon³³; Global Pneumococcal Sequencing Consortium

Collaborators, Affiliations

Collaborators

Global Pneumococcal Sequencing Consortium:
Abdullah Brooks, Alejandra Corso, Alexander Davydov, Alison Maguire, Anmol Kiran, Benild Moiane, Bernard Beall, Chunjiang Zhao, David Aanensen, Dean Everett, Diego Faccone, Ebenezer Foster-Nyarko, Ebrima Bojang, Ekaterina Egorova, Elena Voropaeva, Eric Sampane-Donkor, Ewa Sadowy, Geetha Nagaraj, Helio Mucavele, Houria Belabbès, Naima Elmdaghri, Jennifer Verani, Jeremy Keenan, John Lees, Jyothish N Nair Thulasee Bhai, Kedibone Ndlangisa, Khalid Zerouali, Leon Bentley, Leonid Titov, Linda De Gouveia, Maaike Alaerts, Margaret Ip, Maria Cristina de Cunto Brandileone, Md Hasanuzzaman, Metka Paragi, Michele Nurse-Lucas, Mignon du Plessis, Mushal Ali, Nicholas Croucher, Nicole Wolter, Noga Givon-Lavi, Nurit Porat, Özgen Köseoglu Eser, Pak-Leung Ho, Patrick Eberechi Akpaka, Paula Gagetti, Peggy-Estelle Tientcheu, Pierra Law, Rachel Benisty, Rafal Mostowy, Roly Malaker, Samanta Cristine Grassi Almeida, Sanjay Doiphode, Shabir Madhi, Shamala Devi Sekaran, Stuart Clarke, Somporn Srifuengfung, Susan Nzenze, Tamara Kastrin, Theresa Ochoa, Waleria Hryniewicz, Yulia Urban

Affiliations

¹ Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, UK. Electronic address: stephanie.lo@sanger.ac.uk.
² Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, UK.
³ ACTIV, Association Clinique et Thérapeutique Infantile du Val-de-Marne, Saint Maur-des-Fossés, France; GPIP, Groupe de Pathologie Infectieuse Pédiatrique, Paris, France; AFPA, Association Française de Pédiatrie Ambulatoire, Saint-Germain-en-Laye, France; Université Paris Est, IMRB-GRC GEMINI, Créteil, France; Clinical Research Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France; Unité Court Séjour, Petits nourrissons, Service de Néonatalogie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
⁴ Department of RDI Microbiology, Institut de Recerca Sant Joan de Deu, Hospital Sant Joan de Deu, Barcelona, Spain; School of Medicine, Universitat Internacional de Catalunya, Barcelona, Spain; Spanish Network of Epidemiology and Public Health, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain.
⁵ Rollins School Public Health, Emory University, Atlanta, GA, USA.
⁶ Department of Biostatistics, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁷ Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Johannesburg, South Africa.
⁸ Department of Clinical Microbiology, Christian Medical College, Vellore, India.
⁹ Central Research Laboratory, Kempegowda Institute of Medical Sciences, Bangalore, India.
¹⁰ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Churchill Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK; School of Women and Children's Health, University of New South Wales, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
¹¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Churchill Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
¹² Child Health Research Foundation, Dhaka, Bangladesh.
¹³ Kenya Medical Research Institute, Kisumu, Kenya.
¹⁴ WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Fajara, The Gambia.
¹⁵ WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Fajara, The Gambia; NIHR Global Health Research Unit on Mucosal Pathogens, Division of Infection and Immunity, University College London, London, UK.
¹⁶ Microbiology and Immunology Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.
¹⁷ Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
¹⁸ Malawi-Liverpool-Wellcome-Trust, Blantyre, Malawi; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
¹⁹ Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
²⁰ Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
²¹ Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
²² Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²³ Agence de Médecine Préventive, Abidjan, Côte d'Ivoire.
²⁴ Division of Pediatric Infectious Disease, University of Nebraska Medical Center Omaha, Omaha, NE, USA; International Foundation against Infectious Diseases in Nigeria, Abuja, Nigeria.
²⁵ Ben-Gurion University of the Negev, Beer-Sheva, Israel.
²⁶ Department of Microbiology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco; National Reference Laboratory, Mohammed VI University of Health Sciences, Casablanca, Morocco.
²⁷ Department of Epidemiology and Clinical Microbiology, National Medicines Institute, Warsaw, Poland.
²⁸ Peking University People 's Hospital, Beijing, China.
²⁹ Institute of Environmental Science and Research Limited, Kenepuru Science Centre, Porirua, New Zealand.
³⁰ Pneumonia Program, Bill & Melinda Gates Foundation, Seattle, WA, USA.
³¹ Rollins School Public Health, Emory University, Atlanta, GA, USA; Emory Global Health Institute, Emory University, Atlanta, GA, USA.
³² Centers for Disease Control and Prevention, Atlanta, GA, USA.
³³ National Reference Center for Pneumococci, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

PMID: 35985351
PMCID: PMC9519462
DOI: 10.1016/S2666-5247(22)00158-6

Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study

Stephanie W Lo et al. Lancet Microbe. 2022 Oct.

. 2022 Oct;3(10):e735-e743.

doi: 10.1016/S2666-5247(22)00158-6. Epub 2022 Aug 16.

Authors

Collaborators

Global Pneumococcal Sequencing Consortium:
Abdullah Brooks, Alejandra Corso, Alexander Davydov, Alison Maguire, Anmol Kiran, Benild Moiane, Bernard Beall, Chunjiang Zhao, David Aanensen, Dean Everett, Diego Faccone, Ebenezer Foster-Nyarko, Ebrima Bojang, Ekaterina Egorova, Elena Voropaeva, Eric Sampane-Donkor, Ewa Sadowy, Geetha Nagaraj, Helio Mucavele, Houria Belabbès, Naima Elmdaghri, Jennifer Verani, Jeremy Keenan, John Lees, Jyothish N Nair Thulasee Bhai, Kedibone Ndlangisa, Khalid Zerouali, Leon Bentley, Leonid Titov, Linda De Gouveia, Maaike Alaerts, Margaret Ip, Maria Cristina de Cunto Brandileone, Md Hasanuzzaman, Metka Paragi, Michele Nurse-Lucas, Mignon du Plessis, Mushal Ali, Nicholas Croucher, Nicole Wolter, Noga Givon-Lavi, Nurit Porat, Özgen Köseoglu Eser, Pak-Leung Ho, Patrick Eberechi Akpaka, Paula Gagetti, Peggy-Estelle Tientcheu, Pierra Law, Rachel Benisty, Rafal Mostowy, Roly Malaker, Samanta Cristine Grassi Almeida, Sanjay Doiphode, Shabir Madhi, Shamala Devi Sekaran, Stuart Clarke, Somporn Srifuengfung, Susan Nzenze, Tamara Kastrin, Theresa Ochoa, Waleria Hryniewicz, Yulia Urban

Affiliations

¹ Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, UK. Electronic address: stephanie.lo@sanger.ac.uk.
² Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, UK.
³ ACTIV, Association Clinique et Thérapeutique Infantile du Val-de-Marne, Saint Maur-des-Fossés, France; GPIP, Groupe de Pathologie Infectieuse Pédiatrique, Paris, France; AFPA, Association Française de Pédiatrie Ambulatoire, Saint-Germain-en-Laye, France; Université Paris Est, IMRB-GRC GEMINI, Créteil, France; Clinical Research Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France; Unité Court Séjour, Petits nourrissons, Service de Néonatalogie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
⁴ Department of RDI Microbiology, Institut de Recerca Sant Joan de Deu, Hospital Sant Joan de Deu, Barcelona, Spain; School of Medicine, Universitat Internacional de Catalunya, Barcelona, Spain; Spanish Network of Epidemiology and Public Health, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain.
⁵ Rollins School Public Health, Emory University, Atlanta, GA, USA.
⁶ Department of Biostatistics, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁷ Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Johannesburg, South Africa.
⁸ Department of Clinical Microbiology, Christian Medical College, Vellore, India.
⁹ Central Research Laboratory, Kempegowda Institute of Medical Sciences, Bangalore, India.
¹⁰ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Churchill Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK; School of Women and Children's Health, University of New South Wales, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
¹¹ Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Churchill Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
¹² Child Health Research Foundation, Dhaka, Bangladesh.
¹³ Kenya Medical Research Institute, Kisumu, Kenya.
¹⁴ WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Fajara, The Gambia.
¹⁵ WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Fajara, The Gambia; NIHR Global Health Research Unit on Mucosal Pathogens, Division of Infection and Immunity, University College London, London, UK.
¹⁶ Microbiology and Immunology Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.
¹⁷ Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
¹⁸ Malawi-Liverpool-Wellcome-Trust, Blantyre, Malawi; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
¹⁹ Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
²⁰ Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea.
²¹ Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique.
²² Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²³ Agence de Médecine Préventive, Abidjan, Côte d'Ivoire.
²⁴ Division of Pediatric Infectious Disease, University of Nebraska Medical Center Omaha, Omaha, NE, USA; International Foundation against Infectious Diseases in Nigeria, Abuja, Nigeria.
²⁵ Ben-Gurion University of the Negev, Beer-Sheva, Israel.
²⁶ Department of Microbiology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco; National Reference Laboratory, Mohammed VI University of Health Sciences, Casablanca, Morocco.
²⁷ Department of Epidemiology and Clinical Microbiology, National Medicines Institute, Warsaw, Poland.
²⁸ Peking University People 's Hospital, Beijing, China.
²⁹ Institute of Environmental Science and Research Limited, Kenepuru Science Centre, Porirua, New Zealand.
³⁰ Pneumonia Program, Bill & Melinda Gates Foundation, Seattle, WA, USA.
³¹ Rollins School Public Health, Emory University, Atlanta, GA, USA; Emory Global Health Institute, Emory University, Atlanta, GA, USA.
³² Centers for Disease Control and Prevention, Atlanta, GA, USA.
³³ National Reference Center for Pneumococci, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

PMID: 35985351
PMCID: PMC9519462
DOI: 10.1016/S2666-5247(22)00158-6

Abstract

Background: Serotype 24F is one of the emerging pneumococcal serotypes after the introduction of pneumococcal conjugate vaccine (PCV). We aimed to identify lineages driving the increase of serotype 24F in France and place these findings into a global context.

Methods: Whole-genome sequencing was performed on a collection of serotype 24F pneumococci from asymptomatic colonisation (n=229) and invasive disease (n=190) isolates among individuals younger than 18 years in France, from 2003 to 2018. To provide a global context, we included an additional collection of 24F isolates in the Global Pneumococcal Sequencing (GPS) project database for analysis. A Global Pneumococcal Sequence Cluster (GPSC) and a clonal complex (CC) were assigned to each genome. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted using the same 24F collection and supplemented with a global collection of genomes belonging to the lineage of interest from the GPS project database (n=25 590).

Findings: Serotype 24F was identified in numerous countries mainly due to the clonal spread of three lineages: GPSC10 (CC230), GPSC16 (CC156), and GPSC206 (CC7701). GPSC10 was the only multidrug-resistant lineage. GPSC10 drove the increase in 24F in France and had high invasive disease potential. The international dataset of GPSC10 (n=888) revealed that this lineage expressed 16 other serotypes, with only six included in 13-valent PCV (PCV13). All serotype 24F isolates were clustered in a single clade within the GPSC10 phylogeny and long-range transmissions were detected from Europe to other continents. Spatiotemporal analysis showed GPSC10-24F took 3-5 years to spread across France and a rapid change of serotype composition from PCV13 serotype 19A to 24F during the introduction of PCV13 was observed in neighbouring country Spain.

Interpretation: Our work reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases.

Funding: Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests AvG reports grants from the US Centers for Disease Control and Prevention and Sanofi; travel fees from Pfizer, Sanofi, and Merck; and is the chairperson of South Africa National Advisory Group on Immunisation, outside of the submitted work. AJP reports grants from Gavi, WHO, and AstraZeneca, and is a member of the Joint Committee on Vaccination and Immunisation and WHO Strategic Advisory Group of Experts on Immunization, outside of the submitted work. IN reports grants from BMGF and travel fees from the International Symposium on Pneumococci and Pneumococcal Diseases, outside of the submitted work. JM is an employee of Pharma Vaccines, outside of the submitted work. RD reports grants from Pfizer, MSD, and MedImmune–AstraZeneca, consulting and speaker fees from Pfizer and MSD, outside of the submitted work. SDB reports personal fees from Pfizer and Merck, outside the submitted work. CMA reports grants from Pfizer, outside of the submitted work. EV report grants from Santé Publique France, Pfizer, and MSD, outside of the submitted work. All other authors declare no competing interests.

Figures

**Figure 1**
Proportion of serotype 24F pneumococcal lineages from France between 2003 and 2018 (A–C) and predominant antibiotic resistance profiles of each lineage (D) GPSC=global pneumococcal sequence cluster. PCV=pneumococcal conjugate vaccine.

**Figure 2**
Prevalence of pneumococcal lineages by clinical manifestations and odds ratio for causing overall invasive diseases (A) and meningitis by reference to carriage (B) The odds ratio and 95% CI were calculated using Fisher's Exact test. *Indicates statistical significance. GPSC=global pneumococcal sequence cluster.

**Figure 3**
Global phylogeny of GPSC10 (A) and time-resolved phylogeny of a cluster of GPSC10-24F *Streptococcus pneumoniae* (B) All but one serotype 24F isolates were clustered together, regardless of their country of origin, indicating a clonal spread of GPSC10-24F across the world. The GPSC10 global phylogeny and time-resolved phylogeny can be interactively visualised in Microreact. GPSC=global pneumococcal sequence cluster.

**Figure 4**
Bayesian skyline plots of estimated median effective population size of EU-clade-I and EU-clade II of GPSC10-24F *Streptococcus pneumoniae* over time (A, C) and observed prevalence of GPSC10-24F *S pneumoniae* from overall invasive disease and carriage in France over the collection year (B, D) The figure shows three exponential increases in effective population size in the EU-clade-I and one exponential increase in the EU-clade-II. The most recent increase in EU-clade-I coincided with the observed prevalence increase of GPSC10-24F in both overall disease and carriage isolates in France. GPSC=global pneumococcal sequence cluster.

See this image and copyright information in PMC

References

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Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study

Collaborators

Affiliations

Emergence of a multidrug-resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13: an international whole-genome sequencing study

Authors

Collaborators

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Abstract

Conflict of interest statement

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Medical