{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:46:28Z","timestamp":1792122388457,"version":"4.4.0"},"posted":{"date-parts":[[2026,3,4]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":23,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The emergence of vaccine covered serotypes causing invasive pneumococcal disease (IPD) is a serious concern worldwide. We investigated the unexpected rise of serotype 4 causing IPD primarily in non-vaccinated young adults after the COVID-19 pandemic that further spread to adults \u2265 65 years in recent years. For this purpose, we conducted a retrospective study of serotype 4 IPD cases (n=827) reported in Spain between 2009 and 2024. Whole-genome sequencing was performed to assess clonal lineages and phylogenetic relationships. Clinical and epidemiological data were compared between serotype 4 and all other serotypes causing IPD. Epidemiological and genomic analysis confirmed that the rise started as an abrupt cluster of IPD cases in Seville (Andalusia) in the year 2022 due to the ST15063 within GPSC12 lineage. This outbreak initially caused pneumonia episodes that required hospitalization in young individuals associated with high rates of tobacco smoking, alcohol, and inhaled drugs such as cannabis and cocaine, followed by a general distribution pattern throughout the country in the following years, affecting the elderly population. Experimental studies to evaluate potential underlying mechanisms confirmed that ST15063 serotype 4 strains displayed enhanced infection rates of human lung cells that significantly increased in the presence of cigarette smoke exposure and by influenza H3N2 virus coinfection, but not with H1N1. These findings highlight the need for targeted vaccination strategies not only against pneumococcus but also against respiratory viruses such as influenza, RSV and COVID-19 and demonstrate the importance of molecular surveillance to establish effective interventions in high-risk populations.<\/jats:p>","DOI":"10.64898\/2026.02.27.26346872","type":"posted-content","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:50:13Z","timestamp":1772643013000},"source":"Crossref","is-referenced-by-count":1,"title":["Outburst of serotype 4 IPD after COVID-19 is driven by ST15063\/GPSC162 lineage associated with high-risk behaviors and greater virulence linked to influenza H3N2 virus coinfection and cigarette smoke"],"prefix":"10.64898","author":[{"given":"Covadonga","family":"P\u00e9rez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Spanish Pneumococcal Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Llorente","sequence":"additional","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Parasitology. Hospital Universitario Virgen del Roc\u00edo, Seville, Spain"},{"name":"Doctoral Program in Biomedical Sciences and Public Health. Spanish University of Distance Education (UNED), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Aguirre Alastuey","sequence":"additional","affiliation":[{"name":"Internal medicine service. Hospital Universitario Virgen del Balme, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirella","family":"Llamos\u00ed","sequence":"additional","affiliation":[{"name":"Spanish Pneumococcal Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Medical Specialties and Public Health, University Rey Juan Carlos, Alcorc\u00f3n, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Laghlali","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"El-Ayache","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schotsaert","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Marc and Jennifer Lipschultz Institute for Precision Immunology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"del Diego","sequence":"additional","affiliation":[{"name":"Health and Consumption Department, General Directorate of Public Health and Pharmaceutical Management of Andalusia, Seville, Spain"},{"name":"Spanish Ministry of Health, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Miguel","family":"Cisneros","sequence":"additional","affiliation":[{"name":"Clinical Unit of Infectious Diseases, Microbiology and Parasitology. Hospital Universitario Virgen del Roc\u00edo, Seville, Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garc\u00eda-Sastre","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, USA"},{"name":"The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirian","family":"Domenech","sequence":"additional","affiliation":[{"name":"Spanish Pneumococcal Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Sempere","sequence":"additional","affiliation":[{"name":"Spanish Pneumococcal Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Yuste","sequence":"additional","affiliation":[{"name":"Spanish Pneumococcal Reference Laboratory, National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"42","key":"2026030702001118000_2026.02.27.26346872v1.1","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1016\/j.vaccine.2015.08.009","article-title":"Secular trends (1990-2013) in serotypes and associated non-susceptibility of S. pneumoniae isolates causing invasive disease in the pre-\/post-era of pneumococcal conjugate vaccines in Spanish regions without universal paediatric pneumococcal vaccination","volume":"33","year":"2015","journal-title":"Vaccine"},{"issue":"11","key":"2026030702001118000_2026.02.27.26346872v1.2","doi-asserted-by":"crossref","first-page":"e3778","DOI":"10.1093\/cid\/ciaa1483","article-title":"Nationwide Trends of Invasive Pneumococcal Disease in Spain From 2009 Through 2019 in Children and Adults During the Pneumococcal Conjugate Vaccine Era","volume":"73","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"10","key":"2026030702001118000_2026.02.27.26346872v1.3","doi-asserted-by":"crossref","first-page":"e744","DOI":"10.1016\/S2666-5247(22)00127-6","article-title":"Effect of pneumococcal conjugate vaccines and SARS-CoV-2 on antimicrobial resistance and the emergence of Streptococcus pneumoniae serotypes with reduced susceptibility in Spain, 2004-20: a national surveillance study","volume":"3","year":"2022","journal-title":"The Lancet Microbe"},{"key":"2026030702001118000_2026.02.27.26346872v1.4","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Garc\u00eda C , Sempere J , de Miguel S , et al. 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