{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:24:25Z","timestamp":1785306265820,"version":"3.55.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"1Day Sooner"},{"name":"Center for Effective Altruism\u2019s Long Term Future Fund"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded \u201csevere\u201d were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciac820","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T14:18:13Z","timestamp":1665497893000},"page":"609-619","source":"Crossref","is-referenced-by-count":45,"title":["A Systematic Review of Human Challenge Trials, Designs, and Safety"],"prefix":"10.1093","volume":"76","author":[{"given":"Jupiter","family":"Adams-Phipps","sequence":"first","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Toomey","sequence":"additional","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"},{"name":"Warren Alpert Medical School of Brown University , Providence, Rhode Island , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witold","family":"Wi\u0119cek","sequence":"additional","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Schmit","sequence":"additional","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keller","family":"Scholl","sequence":"additional","affiliation":[{"name":"RAND Corporation, Pardee RAND Graduate School , Santa Monica, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euzebiusz","family":"Jamrozik","sequence":"additional","affiliation":[{"name":"The Ethox Centre & Wellcome Centre for Ethics and the Humanities, Nuffield Department of Population Health, University of Oxford , Oxford , United Kingdom"},{"name":"Monash Bioethics Centre, Monash University , Clayton, VIC , Australia"},{"name":"Royal Melbourne Hospital Department of Medicine, University of Melbourne , Parkville, VIC , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Osowicki","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute , Parkville, VIC , Australia"},{"name":"Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne , Parkville, VIC , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meta","family":"Roestenberg","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Leiden University Medical Centre , Leiden , The Netherlands"},{"name":"Department of Infectious Diseases, Leiden University Medical Center , Leiden, ZA The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-8380","authenticated-orcid":false,"given":"David","family":"Manheim","sequence":"additional","affiliation":[{"name":"1Day Sooner Research Team , Lewes, Delaware , USA"},{"name":"Technion, Israel Institute of Technology , Haifa , Israel"},{"name":"ALTER, Association for Long Term Existence and Resilience , Rehovot , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"70","DOI":"10.12688\/wellcomeopenres.12256.1","article-title":"A framework for Controlled Human Infection Model (CHIM) studies in Malawi: report of a Wellcome Trust workshop on CHIM in low income countries held in Blantyre, Malawi","volume":"2","author":"Gordon","year":"2017","journal-title":"Wellcome Open Res"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"e312\u201322","DOI":"10.1016\/S1473-3099(18)30177-4","article-title":"Experimental infection of human volunteers","volume":"18","author":"Roestenberg","year":"2018","journal-title":"Lancet Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1086\/513990","article-title":"Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge","volume":"175","author":"Church","year":"1997","journal-title":"J Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1086\/518510","article-title":"Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update","volume":"196","author":"Epstein","year":"2007","journal-title":"J Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ijid.2016.05.013","article-title":"Randomized controlled trials for influenza drugs and vaccines: a review of controlled human infection studies","volume":"49","author":"Balasingam","year":"2016","journal-title":"Int J Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fcimb.2019.00107","article-title":"The future of flu: a review of the human challenge model and systems biology for advancement of influenza vaccinology","volume":"9","author":"Sherman","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"key":"2023021818293450300_","first-page":"638","article-title":"Vaxchora: the first FDA-approved cholera vaccination in the United States","volume":"42","author":"Mosley","year":"2017","journal-title":"Pharm Ther"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1186\/s13063-019-3843-0","article-title":"When could human challenge trials be deployed to combat emerging infectious diseases? Lessons from the case of a Zika virus human challenge trial","volume":"20","author":"Palacios","year":"2019","journal-title":"Trials"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1093\/cid\/ciaa935","article-title":"Evaluating use cases for human challenge trials in accelerating SARS-CoV-2 vaccine development","volume":"72","author":"Nguyen","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"e00417","DOI":"10.1128\/mBio.00417-16","article-title":"Evaluation of antihemagglutinin and antineuraminidase antibodies as correlates of protection in an influenza A\/H1N1 virus healthy human challenge model","volume":"7","author":"Memoli","year":"2016","journal-title":"mBio"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1001\/jama.282.13.1240","article-title":"Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment","volume":"282","author":"Hayden","year":"1999","journal-title":"JAMA"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1016\/S0140-6736(17)32149-9","article-title":"Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella typhi: a randomised controlled, phase 2b trial","volume":"390","author":"Jin","year":"2017","journal-title":"Lancet"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/infdis\/jiw237","article-title":"Fractional third and fourth dose of RTS, S\/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite infection and immunogenicity study","volume":"214","author":"Regules","year":"2016","journal-title":"J Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.4161\/hv.29375","article-title":"Evaluation of the immune response to RTS, S\/AS01 and RTS, S\/AS02 adjuvanted vaccines: randomized, double-blind study in malaria-na\u00efve adults","volume":"10","author":"Leroux-Roels","year":"2014","journal-title":"Hum Vaccin Immunother"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1136\/jme.2003.004440","article-title":"Challenge studies of human volunteers: ethical issues","volume":"30","author":"Hope","year":"2004","journal-title":"J Med Ethics"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1136\/medethics-2020-106438","article-title":"Payment in challenge studies: ethics, attitudes and a new payment for risk model","volume":"46","author":"Grimwade","year":"2020","journal-title":"J Med Ethics"},{"key":"2023021818293450300_"},{"key":"2023021818293450300_"},{"key":"2023021818293450300_","author":"Manheim"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1007\/978-3-030-41480-1","volume-title":"Human challenge studies in endemic settings: ethical and regulatory issues","author":"Jamrozik","year":"2021"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.biologicals.2020.04.004","article-title":"Third human challenge trial conference, Oxford, United Kingdom, 6\u20137 February 2020, a meeting report","volume":"66","author":"Pollard","year":"2020","journal-title":"Biologicals"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2217\/fmb.12.15","article-title":"Human challenge studies: a review of adequacy of reporting methods and results","volume":"7","author":"Kalil","year":"2012","journal-title":"Future Microbiol"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1093\/infdis\/jit620","article-title":"Determination of the 50% human infectious dose for Norwalk virus","volume":"209","author":"Atmar","year":"2014","journal-title":"J Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.3201\/eid1410.080117","article-title":"Norwalk virus shedding after experimental human infection","volume":"14","author":"Atmar","year":"2008","journal-title":"Emerg Infect Dis"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1008704","article-title":"Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment","volume":"16","author":"Nguyen-Van-Tam","year":"2020","journal-title":"PLoS Pathog"},{"key":"2023021818293450300_","doi-asserted-by":"publisher","author":"Wilkinson","DOI":"10.5281\/zenodo.6711717"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s12936-016-1435-y","article-title":"Mosquito bite immunization with radiation-attenuated Plasmodium falciparum sporozoites: safety, tolerability, protective efficacy and humoral immunogenicity","volume":"15","author":"Hickey","year":"2016","journal-title":"Malar J"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1093\/cid\/ciw145","article-title":"Single-dose live oral cholera vaccine CVD 103-HgR protects against human experimental infection with Vibrio cholerae O1 El Tor","volume":"62","author":"Chen","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2023021818293450300_"},{"key":"2023021818293450300_","article-title":"A fresh take on the adverse event landscape","author":"Neuer","journal-title":"Clin Res"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"e41174","DOI":"10.1371\/journal.pone.0041174","article-title":"Challenges in coding adverse events in clinical trials: a systematic review","volume":"7","author":"Schroll","year":"2012","journal-title":"PLoS One"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"e291\u20139","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":"Osowicki","year":"2021","journal-title":"Lancet Microbe"},{"key":"2023021818293450300_","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/1475-2875-8-277","article-title":"Cardiac complication after experimental human malaria infection: a case report","volume":"8","author":"Nieman","year":"2009","journal-title":"Malar J"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciac820\/46781585\/ciac820.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/4\/609\/49255886\/ciac820.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/4\/609\/49255886\/ciac820.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T13:38:12Z","timestamp":1678196292000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/76\/4\/609\/6758436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,10,11]]},"published-print":{"date-parts":[[2023,2,18]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciac820","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.03.20.22272658","asserted-by":"object"}]},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,15]]},"published":{"date-parts":[[2022,10,11]]}}}