{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:22:30Z","timestamp":1791872550965,"version":"4.3.4"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T00:00:00Z","timestamp":1683158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive <jats:italic>Streptococcus pneumoniae<\/jats:italic> serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>A single-centre review of all EHPC studies performed 2011\u20132021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In 1416 individuals (median age 21, IQR 20\u201325), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96\/658, non-colonised = 86\/1005, OR 1.81 (95% CI 1.28\u20132.56, <jats:italic>P<\/jats:italic> = &lt;0.001). The majority were mild (pneumococcal group = 72.7% [120\/165 reported symptoms], non-pneumococcal = 86.7% [124\/143 reported symptoms]). 1.6% (23\/1416) required antibiotics for safety.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0284399","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T17:53:28Z","timestamp":1683222808000},"page":"e0284399","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comprehensive review of safety in Experimental Human Pneumococcal Challenge"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0871-4780","authenticated-orcid":true,"given":"Ryan 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(Accessed 15\/08\/22)."},{"key":"pone.0284399.ref003","volume-title":"Good Clinical Practice Guide","author":"Medicines and Healthcare products Regulatory Agency","year":"2012"},{"issue":"S2","key":"pone.0284399.ref004","doi-asserted-by":"crossref","DOI":"10.1186\/s13063-019-3844-z","article-title":"Typhoidal Salmonella human challenge studies: ethical and practical challenges and considerations for low-resource settings","volume":"20","author":"M Raymond","year":"2019","journal-title":"Trials"},{"issue":"3","key":"pone.0284399.ref005","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1084\/jem.20011576","article-title":"The immune response to pneumococcal proteins during experimental human carriage","volume":"195","author":"TL McCool","year":"2002","journal-title":"J Exp Med"},{"issue":"10","key":"pone.0284399.ref006","doi-asserted-by":"crossref","first-page":"5724","DOI":"10.1128\/IAI.71.10.5724-5732.2003","article-title":"Serum Immunoglobulin G Response to Candidate Vaccine Antigens during Experimental Human Pneumococcal Colonization","volume":"71","author":"TL McCool","year":"2003","journal-title":"Infect Immun"},{"issue":"9","key":"pone.0284399.ref007","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tim.2011.06.003","article-title":"Experimental human pneumococcal carriage models for vaccine research","volume":"19","author":"DM Ferreira","year":"2011","journal-title":"Trends Microbiol"},{"issue":"7","key":"pone.0284399.ref008","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1164\/rccm.201503-0542OC","article-title":"First human challenge testing of a pneumococcal vaccine. 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Robinson","year":"2022","journal-title":"American journal of respiratory and critical care medicine"},{"key":"pone.0284399.ref012","unstructured":"Zaidi SR, Jochems SP, Rein\u00e9 J, et al. Mechanisms and kinetics of bacterial clearance after experimental colonisation in adults with asthma. Available at https:\/\/www.medrxiv.org\/content\/10.1101\/2020.08.19.20177790v1. (Accessed 11\/08\/22)."},{"issue":"5","key":"pone.0284399.ref013","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1164\/rccm.202004-1483OC","article-title":"Experimental human pneumococcal colonization in older adults is feasible and safe, not immunogenic","volume":"203","author":"H Adler","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"pone.0284399.ref014","doi-asserted-by":"crossref","first-page":"1800599","DOI":"10.1183\/13993003.00599-2018","article-title":"Hands are vehicles for transmission of Streptococcus pneumoniae in novel controlled human infection study","volume":"52","author":"V Connor","year":"2018","journal-title":"Eur Respir J"},{"issue":"9","key":"pone.0284399.ref015","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1164\/rccm.201811-2081LE","article-title":"Two Randomized Trials of the Effect of Live Attenuated Influenza Vaccine on Pneumococcal Colonization","volume":"199","author":"J Rylance","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"issue":"10","key":"pone.0284399.ref016","doi-asserted-by":"crossref","first-page":"4523","DOI":"10.1172\/JCI128865","article-title":"Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization","volume":"129","author":"SP Jochems","year":"2019","journal-title":"J Clin Invest"},{"issue":"8","key":"pone.0284399.ref017","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1164\/rccm.201212-2277OC","article-title":"Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults","volume":"187","author":"DM Ferreira","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"pone.0284399.ref018","unstructured":"UK Health Security Agency. Pneumococcal disease guidance, data and analysis. Available at. https:\/\/www.gov.uk\/government\/collections\/pneumococcal-disease-guidance-data-and-analysis (Accessed 15\/08\/22)."},{"key":"pone.0284399.ref019","unstructured":"US Food and Drug Administration. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Available at https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical. (Accessed 10\/08\/22)."},{"key":"pone.0284399.ref020","unstructured":"Safety, Tolerability, and Efficacy Study of Prophylactic S. Pneumoniae Vaccine Following Challenge With S. Pneumoniae. Available at https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02116998 (Accessed 11\/08\/22)."},{"issue":"7","key":"pone.0284399.ref021","doi-asserted-by":"crossref","first-page":"e291","DOI":"10.1016\/S2666-5247(20)30240-8","article-title":"A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study","volume":"2","author":"J Osowicki","year":"2021","journal-title":"Lancet Microbe"},{"issue":"1","key":"pone.0284399.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-29119-w","article-title":"Impact of viral upper respiratory tract infection on the concentration of nasopharyngeal pneumococcal carriage among Kenyan children","volume":"8","author":"SC Morpeth","year":"2018","journal-title":"Sci Rep"},{"issue":"11","key":"pone.0284399.ref023","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.3201\/eid2211.160902","article-title":"Nasopharyngeal pneumococcal density and evolution of acute respiratory illnesses in young children, Peru, 2009\u20132011","volume":"22","author":"RR Fan","year":"2016","journal-title":"Emerg Infect Dis"},{"key":"pone.0284399.ref024","doi-asserted-by":"crossref","DOI":"10.12688\/wellcomeopenres.15689.1","article-title":"A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi\u2013A feasibility study","volume":"5","author":"B Morton","year":"2020","journal-title":"Wellcome Open Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T17:54:05Z","timestamp":1683222845000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284399"}},"subtitle":[],"editor":[{"given":"Luis Felipe","family":"Reyes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,5,4]]},"references-count":24,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0284399","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,4]]}}}