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A '''human challenge study''', also called a '''challenge trial''' or '''controlled human infection model''' (CHIM), is a type of [[clinical trial]] for a [[vaccine]] or other [[drug|pharmaceutical]] involving the intentional exposure of the test subject to the condition tested.<ref name="lamb">{{Cite journal|last1=Lambkin-Williams|first1=Rob|last2=Noulin|first2=Nicolas|last3=Mann|first3=Alex|last4=Catchpole|first4=Andrew|last5=Gilbert|first5=Anthony S.|date=22 June 2018|title=The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics|journal=Respiratory Research|volume=19|issue=1|pages=123|doi=10.1186/s12931-018-0784-1|issn=1465-993X|pmc=6013893|pmid=29929556 |doi-access=free }}</ref><ref name="eyal">{{Cite journal|last1=Eyal|first1=Nir|last2=Lipsitch|first2=Marc|last3=Smith|first3=Peter G.|title=Human challenge studies to accelerate coronavirus vaccine licensure|url= |journal=The Journal of Infectious Diseases|doi=10.1093/infdis/jiaa152|date=31 March 2020|volume=221|issue=11|pages=1752–1756|pmid=32232474|pmc=7184325| name-list-style = vanc }}</ref><ref name="callaway">{{Cite journal|vauthors=Callaway E |date=April 2020|title=Should scientists infect healthy people with the coronavirus to test vaccines?|journal=Nature|volume=580|issue=7801|pages=17|doi=10.1038/d41586-020-00927-3|pmid=32218549|bibcode=2020Natur.580...17C|s2cid=256820005 |doi-access=}}</ref> Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential [[side effect]]s of the substance being tested.<ref name=eyal/><ref name=callaway/> Controlled human infection studies are also used to study viruses and immune responses.<ref name="Killingley 2022">{{cite journal |last1=Killingley |first1=Ben |last2=Mann |first2=Alex J. |last3=Kalinova |first3=Mariya |last4=Boyers |first4=Alison |last5=Goonawardane |first5=Niluka |last6=Zhou |first6=Jie |last7=Lindsell |first7=Kate |last8=Hare |first8=Samanjit S. |last9=Brown |first9=Jonathan |last10=Frise |first10=Rebecca |last11=Smith |first11=Emma |last12=Hopkins |first12=Claire |last13=Noulin |first13=Nicolas |last14=Löndt |first14=Brandon |last15=Wilkinson |first15=Tom |last16=Harden |first16=Stephen |last17=McShane |first17=Helen |last18=Baillet |first18=Mark |last19=Gilbert |first19=Anthony |last20=Jacobs |first20=Michael |last21=Charman |first21=Christine |last22=Mande |first22=Priya |last23=Nguyen-Van-Tam |first23=Jonathan S. |last24=Semple |first24=Malcolm G. |last25=Read |first25=Robert C. |last26=Ferguson |first26=Neil M. |last27=Openshaw |first27=Peter J. |last28=Rapeport |first28=Garth |last29=Barclay |first29=Wendy S. |last30=Catchpole |first30=Andrew P. |last31=Chiu |first31=Christopher |title=Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults |journal=Nature Medicine |date=May 2022 |volume=28 |issue=5 |pages=1031–1041 |doi=10.1038/s41591-022-01780-9 |pmid=35361992 |url=https://www.nature.com/articles/s41591-022-01780-9 |access-date=12 April 2024|hdl=10044/1/96278 |hdl-access=free }}</ref><ref name=":0">{{Cite journal |last1=Lindeboom |first1=Rik G. H. |last2=Worlock |first2=Kaylee B. |last3=Dratva |first3=Lisa M. |last4=Yoshida |first4=Masahiro |last5=Scobie |first5=David |last6=Wagstaffe |first6=Helen R. |last7=Richardson |first7=Laura |last8=Wilbrey-Clark |first8=Anna |last9=Barnes |first9=Josephine L. |last10=Kretschmer |first10=Lorenz |last11=Polanski |first11=Krzysztof |last12=Allen-Hyttinen |first12=Jessica |last13=Mehta |first13=Puja |last14=Sumanaweera |first14=Dinithi |last15=Boccacino |first15=Jacqueline M. |date=July 2024 |title=Human SARS-CoV-2 challenge uncovers local and systemic response dynamics |journal=Nature |language=en |volume=631 |issue=8019 |pages=189–198 |doi=10.1038/s41586-024-07575-x |issn=1476-4687 |pmc=11222146 |pmid=38898278|bibcode=2024Natur.631..189L }}</ref>
During the mid 20th and 21st century, the number of human challenge studies has been increasing.<ref name="Adams-Phipps">{{cite journal |last1=Adams-Phipps |first1=Jupiter |last2=Toomey |first2=Danny |last3=Więcek |first3=Witold|last4=Schmit |first4=Virginia|last5=Wilkinson |first5=James|last6=Scholl |first6=Keller|last7=Jamrozik |first7=Joshua|last8=Roestenberg |first8=Meta|last9=Manheim |first9=David|title=A Systematic Review of Human Challenge Trials, Designs, and Safety|journal=Clinical Infectious Diseases|date=11 October 2022 |volume=76 |issue=4 |pages=609–619 |doi=10.1093/cid/ciac820 |pmid=36219704 |pmc=9938741 |doi-access=free }}</ref><ref name="cohen16">{{cite journal|url=https://www.science.org/doi/10.1126/science.352.6288.882|title=Studies that intentionally infect people with disease-causing bugs are on the rise|first=Jon|last=Cohen|journal=Science|doi=10.1126/science.aaf5726|date=18 May 2016|volume=352 |issue=6288 |pages=882–885 |url-access=subscription}}</ref> A challenge study to test promising vaccines for prevention of [[COVID-19]] was under consideration during 2020 by several vaccine developers, including the [[World Health Organization]] (WHO),<ref name="who-chall">{{Cite web|title=Key criteria for the ethical acceptability of COVID-19 human challenge studies|url=https://apps.who.int/iris/bitstream/handle/10665/331976/WHO-2019-nCoV-Ethics_criteria-2020.1-eng.pdf|publisher=World Health Organization|date=6 May 2020|access-date=18 May 2020}}</ref><ref name="cohen20">{{Cite journal|url=https://www.science.org/content/article/speed-coronavirus-vaccine-testing-deliberately-infecting-volunteers-not-so-fast-some|title=Speed coronavirus vaccine testing by deliberately infecting volunteers? Not so fast, some scientists warn|last=Cohen|first=Jon|date=31 March 2020|journal=Science|doi=10.1126/science.abc0006|s2cid=216451224|access-date=19 April 2020|url-access=subscription}}</ref> and was approved in the UK in 2021.<ref>{{Cite web|title=World's first coronavirus Human Challenge study receives ethics approval in the UK|url=https://www.gov.uk/government/news/worlds-first-coronavirus-human-challenge-study-receives-ethics-approval-in-the-uk|access-date=18 February 2021|website=GOV.UK|language=en}}</ref>
Over the second half of the 20th and the 21st centuries, vaccines for some 15 major pathogens have been fast-tracked in human challenge studies while contributing toward vaccine development to prevent [[cholera]], [[Typhoid fever|typhoid]], [[Flu season|seasonal flu]], and other infections.<ref name="mcmaster">{{Cite web|title=McMaster researcher contributes to WHO guidelines for COVID-19 vaccine testing|url=https://brighterworld.mcmaster.ca/articles/mcmaster-researcher-contributes-to-who-guidelines-for-covid-19-vaccine-testing/|author=Wade Hemsworth|publisher=McMaster University Medical School, Hamilton, Canada|date=13 May 2020|access-date=25 May 2020}}</ref> Since the 1980s, challenge trials which reported about [[Adverse event|adverse events]] have had only 0.2% of patients with serious adverse events, and no deaths.<ref name="Adams-Phipps" />
According to [[medical ethics|medical ethicists]], methods of conducting clinical trials by human challenge testing have improved over the 21st century to satisfy ethical, safety, and regulatory requirements, becoming scientifically acceptable and ethically valid as long as participants are well-informed and volunteer freely, and the trials adhere to established rigor for conducting clinical research.<ref name=eyal/><ref name=callaway/><ref name=mcmaster/>
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The intent of a challenge study is to fast-track the timeline for providing evidence of safety and efficacy of a [[prescription drug|therapeutic drug]] or vaccine, especially by compressing (to a few months) the usually lengthy duration of [[Phases of clinical research|Phase{{nbsp}}II–III trials]] (typically, many years).<ref name=eyal/><ref name=callaway/><ref name="boodman">{{Cite web|url=https://www.statnews.com/2020/03/11/researchers-rush-to-start-moderna-coronavirus-vaccine-trial-without-usual-animal-testing/|title=Coronavirus vaccine clinical trial starting without usual animal data|publisher=STAT|author=Eric Boodman|date=13 March 2020|access-date=19 April 2020}}</ref> Following preliminary proof of safety and efficacy of a candidate drug or vaccine in laboratory animals and healthy humans, controlled "challenge" studies may be implemented to bypass typical Phase{{nbsp}}III research, providing an accelerated path to regulatory approval of the test compound for widespread prevention against an [[infectious disease]], such as COVID-19.<ref name=eyal/><ref name=cohen20/>
The design of a challenge study involves first
==Ethics==
Two commonly discussed general thresholds for risk to research participant are minimizing all risk after the infection and avoiding serious injury.<ref name="Binik 2020">{{cite journal |last1=Binik |first1=Ariella |title=What risks should be permissible in controlled human infection model studies? |journal=Bioethics |date=May 2020 |volume=34 |issue=4 |pages=420–430 |doi=10.1111/bioe.12736|pmid=32115747 |s2cid=211727412 }}</ref> Researchers typically customize other thresholds for each clinical trial.<ref name="Binik 2020"/>
Common reasons for participating in human challenge studies include altruism and wishing to contribute to medical progress.<ref name="Eberts 2023">{{cite journal |last1=Eberts |first1=Jake D |last2=Zimmer-Harwood |first2=Paul |last3=Elsey |first3=James W B |last4=Fraser-Urquhart |first4=Alastair |last5=Smiley |first5=Thomas |title=Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model |journal=Clinical Infectious Diseases |date=14 August 2023 |volume=77 |issue=Supplement_3 |pages=S224–S230 |doi=10.1093/cid/ciad350 |pmid=37579204 |pmc=10425139 |url=https://academic.oup.com/cid/article/77/Supplement_3/S224/7242430 |access-date=1 May 2024}}</ref><ref name="Marsh 2022" /> People who participate in these studies might be more altruistic in general than others, including possibly more likely to contribute to their communities in other ways, such as donating blood.<ref name="Marsh 2022">{{cite journal |last1=Marsh |first1=Abigail A. |last2=Magalhaes |first2=Monica |last3=Peeler |first3=Matthew |last4=Rose |first4=Sophie M. |last5=Darton |first5=Thomas C. |last6=Eyal |first6=Nir |last7=Morrison |first7=Josh |last8=Shah |first8=Seema K. |last9=Schmit |first9=Virginia |title=Characterizing altruistic motivation in potential volunteers for SARS-CoV-2 challenge trials |journal=PLOS ONE |date=2 November 2022 |volume=17 |issue=11 |pages=e0275823 |doi=10.1371/journal.pone.0275823 |doi-access=free |pmid=36322529 |bibcode=2022PLoSO..1775823M |pmc=9629635 }}</ref>
==Vaccines for infections==
Challenge studies have been used to expedite evaluation of vaccines for several diseases,<ref name="callaway" /> such as cholera,<ref>{{Cite journal|title=Oral vaccines for preventing cholera|last1=D|first1=Sinclair|last2=K|first2=Abba|date=16 March 2011|journal=The Cochrane Database of Systematic Reviews|doi=10.1002/14651858.CD008603.pub2|pmc=6532691|pmid=21412922|last3=K|first3=Zaman|last4=F|first4=Qadri|last5=PM|first5=Graves|volume=2011|issue=3|pages=CD008603}}</ref> typhoid fever,<ref>{{Cite journal|last1=Waddington|first1=Claire S.|last2=Darton|first2=Thomas C.|last3=Woodward|first3=William E.|last4=Angus|first4=Brian|last5=Levine|first5=Myron M.|last6=Pollard|first6=Andrew J.|date=1 May 2014|title=Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies|url=https://www.journalofinfection.com/article/S0163-4453(14)00012-7/abstract|journal=Journal of Infection|language=en|volume=68|issue=5|pages=405–418|doi=10.1016/j.jinf.2014.01.006|issn=0163-4453|pmid=24491597|url-access=subscription}}</ref> malaria,<ref name="tuju">{{Cite journal|title=Vaccine candidate discovery for the next generation of malaria vaccines|last1=J|first1=Tuju|last2=G|first2=Kamuyu|date=1 October 2017|journal=Immunology|doi=10.1111/imm.12780|pmc=5588761|pmid=28646586|last3=Lm|first3=Murungi|last4=Fha|first4=Osier|volume=152|issue=2|pages=195–206}}</ref> influenza,<ref name=lamb/> [[streptococcal pharyngitis]],<ref>{{cite journal |last1=Osowicki |first1=Joshua |last2=Azzopardi |first2=Kristy I. |last3=McIntyre |first3=Liam |last4=Rivera-Hernandez |first4=Tania |last5=Ong |first5=Cheryl-lynn Y. |last6=Baker |first6=Ciara |last7=Gillen |first7=Christine M. |last8=Walker |first8=Mark J. |last9=Smeesters |first9=Pierre R. |last10=Davies |first10=Mark R. |last11=Steer |first11=Andrew C. |title=A Controlled Human Infection Model of Group A Streptococcus Pharyngitis: Which Strain and Why? |journal=mSphere |date=13 February 2019 |volume=4 |issue=1 |pages=e00647–18, /msphere/4/1/mSphere647–18.atom |doi=10.1128/mSphere.00647-18|pmid=30760615 |pmc=6374595 }}</ref> [[tuberculosis]],<ref>{{cite journal |last1=McShane |first1=Helen |title=Controlled Human Infection Models: Is it Really Feasible to Give People Tuberculosis? |journal=American Journal of Respiratory and Critical Care Medicine |date=15 May 2020 |volume=201 |issue=10 |pages=1180–1181 |doi=10.1164/rccm.201912-2408ED|pmid=31904993 |pmc=7233336 |s2cid=210041310 }}</ref> [[shigella]],<ref>{{cite journal |last1=MacLennan |first1=Calman A |last2=Aguilar |first2=Anastazia Older |last3=Steele |first3=A Duncan |title=Consensus Report on Shigella Controlled Human Infection Model: Introduction and Overview |journal=Clinical Infectious Diseases |date=9 December 2019 |volume=69 |issue=Supplement_8 |pages=S577–S579 |doi=10.1093/cid/ciz886|pmid=31816066 |pmc=6901124 }}</ref> [[pertussis]],<ref>{{cite journal |last1=Merkel |first1=Tod J |title=Toward a Controlled Human Infection Model of Pertussis |journal=Clinical Infectious Diseases |date=11 July 2020 |volume=71 |issue=2 |pages=412–414 |doi=10.1093/cid/ciz842|pmid=31552410 |pmc=7353834 }}</ref> and [[dengue fever]].<ref>{{cite journal |last1=Rose |first1=Anuradha |last2=Sekhar |first2=Amrita |title=Bioethics of establishing a CHIM model for dengue vaccine development |journal=International Journal of Infectious Diseases |date=July 2019 |volume=84 |pages=S74–S79 |doi=10.1016/j.ijid.2019.01.013|pmid=30641207 |doi-access=free }}</ref>
Other than expediting clinical evaluation of vaccine properties, advantages of using challenge studies for vaccine candidates include minimizing bias which is inherently part of traditional [[Cohort study|cohort studies]], as both the exposure (timing of infection, virus challenge dose) and outcome (assessment of blood [[biomarker]]s) are standardized.<ref name=tuju/> Disadvantages include high cost of conducting the trial at multiple locations and the complex management of infrastructure for a challenge trial, especially for obtaining national regulatory approval, organizing participants and trial personnel, and implementing laboratories with [[Good Clinical Laboratory Practice]] qualifications.<ref name=tuju/> Before beginning a challenge study, a vaccine sponsor must have demonstrated [[Good Manufacturing Practice]] standards for approval to use the candidate vaccine in humans, including expensive [[toxicology]] and [[immunogenicity]] testing.<ref name=tuju/><ref name="plotkin">{{cite journal|pmc=7167540|pmid=32331807|title=Extraordinary diseases require extraordinary solutions|first1=Stanley A.|last1=Plotkin|first2=Arthur|last2=Caplan|journal=Vaccine|volume=38|issue=24|pages=3987–8|date=20 April 2020|doi=10.1016/j.vaccine.2020.04.039}}</ref> The vaccine sponsor may have required proof of safety and efficacy of [[adjuvant]]s for delivering the vaccine, demonstrated what the effective vaccination schedule may be, and coordinated with international regulatory agencies and bioethicists for approval and eventual distribution, all requiring coordinated financing and planning.<ref name=tuju/>
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===COVID-19===
{{See also|COVID-19 vaccine clinical research#Trial and authorization status}}
Human challenge studies
In May 2020, a guidance document was issued by the WHO on criteria for conducting challenge clinical trials and providing clinical care for the participants.<ref name=who-chall/> Following the challenge infection with or without the candidate vaccine, volunteers would be monitored closely in hospitals or clinics managed by physicians treating people with COVID-19 disease and with life-saving resources, if needed.<ref name=eyal/><ref name=callaway/><ref name=who-chall/> Volunteering for a vaccine challenge study during the COVID-19 pandemic is likened to the emergency service of healthcare personnel for COVID-19-infected people, [[firefighter]]s, or [[organ donation|organ donors]].<ref name=eyal/><ref name=callaway/>
Human SARS-CoV-2 challenge studies have also been conducted to investigate the viral infection and immune response kinetics in COVID-19.<ref name="Killingley 2022" /><ref name=":0" /> Unlike patient-based studies, challenge studies provide a unique opportunity to examine the immune system before viral exposure, immediately after exposure, and in individuals who do not become infected upon exposure. These studies have enabled scientists to identify a biomarker for protection and discover that various distinct immune responses precede symptom onset, including some that are also present in individuals who do not become infected upon exposure.<ref name=":0" />
In March 2024, funding for a five-year international consortium to develop and run human challenge studies for mucosal (transmission-blocking) Covid vaccines was announced on behalf of the [[European Union]]’s Horizon Europe Programme and the [[Coalition for Epidemic Preparedness Innovations]] (CEPI).<ref name="CEPI March 2024">{{cite web |title=Global consortium plans coordinated human challenge studies in hunt for transmission-blocking coronavirus vaccines {{!}} CEPI |url=https://cepi.net/global-consortium-plans-coordinated-human-challenge-studies-hunt-transmission-blocking-coronavirus |website=cepi.net |access-date=1 May 2024}}</ref> Called Mucosal Immunity in human Coronavirus Challenge (MusiCC) and led by [[Imperial College London]], trials are planned to take place in the UK, Europe, Singapore, and the United States.<ref name="CEPI March 2024" /> Representatives of the consortium and its Scientific Advisory Board met in April 2024 to start the project.<ref name="Imperial News Apr 2024">{{cite web |title=Imperial-led global human challenge consortium kick off ambitious 5-year project {{!}} Imperial News {{!}} Imperial College London |url=https://www.imperial.ac.uk/news/252855/imperial-led-global-human-challenge-consortium-kick/ |website=Imperial News |access-date=1 May 2024 |language=en |date=24 April 2024}}</ref> At that meeting, a speaker from CEPI said that human challenge studies were a part of the goal of achieving vaccines for new pandemic diseases in 100 days.<ref name="Imperial News Apr 2024" /> Two trials to test doses of strains of SARS-CoV-2 for challenge studies were begun in 2024, in London and Singapore.<ref name="London 2024 trial">{{cite web |title=An Exploratory Study to Establish the Dose, Safety and Pathogenicity of a SARS-CoV-2 Omicron Challenge Strain (BA.5) in Healthy Participants 18 to 40 Years of Age |url=https://clinicaltrials.gov/study/NCT06492564 |website=clinicaltrials.gov |publisher=NIH |access-date=21 June 2025 |date=28 January 2025}}</ref><ref name="Singapore 2024 trial">{{cite web |last1=Young |first1=Barnaby |title=The Singapore Platform for Controlled Human Infections With SARS-CoV-2 |url=https://clinicaltrials.gov/study/NCT06654973 |website=clinicaltrials.gov |publisher=NIH |access-date=21 June 2025 |date=22 October 2024}}</ref>
==References==
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