Human challenge study: Difference between revisions

Revision as of 00:44, 19 August 2023

Revision as of 13:34, 16 September 2023

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{{Use dmy dates|date=August 2021}}

{{short description|Intentional exposure of test subjects to a pathogen to test a vaccine or drug}}

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/>

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}}</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}}</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 – involving about 30,000 participants – 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.<ref name="Adams-Phipps" />

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==Ethics==

Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse.<ref>{{Cite journal|last1=Metzger|first1=W. G.|last2=Ehni|first2=H.-J.|last3=Kremsner|first3=P. G.|last4=Mordmüller|first4=B. G.|date=2019|title=Experimental infections in humans—historical and ethical reflections|journal=Tropical Medicine & International Health|language=en|volume=24|issue=12|pages=1384–1390|doi=10.1111/tmi.13320|pmid=31654450|issn=1365-3156|doi-access=free}}</ref> Special ethical issues can arise when a wealthy country finances and organizes these clinical trials in a less wealthy country.<ref>{{cite journal |last1=Gordon |first1=SB |last2=Rylance |first2=J |last3=Luck |first3=A |last4=Jambo |first4=K |last5=Ferreira |first5=DM |last6=Manda-Taylor |first6=L |last7=Bejon |first7=P |last8=Ngwira |first8=B |last9=Littler |first9=K |last10=Seager |first10=Z |last11=Gibani |first11=M |last12=Gmeiner |first12=M |last13=Roestenberg |first13=M |last14=Mlombe |first14=Y |last15=Wellcome Trust CHIM workshop |first15=participants. |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. |journal=Wellcome Open Research |date=2017 |volume=2 |pages=70 |doi=10.12688/wellcomeopenres.12256.1 |pmid=29018841|pmc=5627502 |doi-access=free }}</ref>

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"/>

==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}}</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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==External links==

* {{cite journal |last1=Callaway |first1=Ewen |title=Hundreds of people volunteer to be infected with coronavirus |journal=Nature |date=22 April 2020 |doi=10.1038/d41586-020-01179-x |pmid=32322034 |s2cid=216082569 |doi-access=}}

* [https://www.theatlantic.com/ideas/archive/2020/04/challenge-trial-ethical-imperative/610309/ Let volunteers take the COVID challenge: Young, healthy, informed people should be allowed to participate in vaccine trials.] Conor Friedersdorf, ''The Atlantic'', 21 April 2020

* [https://1daysooner.org/ 1 Day Sooner], US-UK advocacy organization for human challenge studies of candidate COVID-19 vaccines (25,104 volunteers from 102 countries, as of late May 2020)