Human challenge study: Difference between revisions

Revision as of 16:36, 18 April 2021

Revision as of 05:52, 6 May 2021

Line 2:

A '''human challenge study''', also called a '''controlled human infection trial''', 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=2018-06-22|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}}</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?|url=https://www.nature.com/articles/d41586-020-00927-3|journal=Nature|volume=580|issue=7801|pages=17|doi=10.1038/d41586-020-00927-3|pmid=32218549|bibcode=2020Natur.580...17C|doi-access=free}}</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 [[21st century]], the number of human challenge studies has been increasing.<ref>{{cite journal |last1=Balasingam |first1=S |last2=Horby |first2=P |last3=Wilder-Smith |first3=A |title=The potential for a controlled human infection platform in Singapore. |journal=Singapore Medical Journal |date=September 2014 |volume=55 |issue=9 |pages=456–61 |doi=10.11622/smedj.2014114 |pmid=25273928|pmc=4293939 }}</ref><ref name="cohen16">{{cite journal|url=https://www.sciencemag.org/news/2016/05/studies-intentionally-infect-people-disease-causing-bugs-are-rise|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=2016-05-18}}</ref> A challenge study to test promising vaccines for prevention of [[Coronavirus disease 2019|COVID-19 disease]] 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=2020-05-06|access-date=2020-05-18}}</ref><ref name="cohen20">{{Cite journal|url=https://www.sciencemag.org/news/2020/03/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|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=2021-02-18|website=GOV.UK|language=en}}</ref>

Over the [[20th century|20th]] and 21st centuries, vaccines for some 15 major pathogens have been fast-tracked in human challenge studies &ndash;– involving about 30,000 participants who had no serious [[adverse effect]]s &ndash;– 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=2020-05-13|access-date=2020-05-25}}</ref> 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/>

==Design==

Line 17:

==Vaccines for viral infections==

Challenge studies have been used to expedite evaluation of vaccines for several pandemic viral diseases,<ref name="callaway">{{Cite journal|vauthors=Callaway E |date=April 2020|title=Should scientists infect healthy people with the coronavirus to test vaccines?|url=https://www.nature.com/articles/d41586-020-00927-3|journal=Nature|volume=580|issue=7801|pages=17|doi=10.1038/d41586-020-00927-3|pmid=32218549|bibcode=2020Natur.580...17C|doi-access=free}}</ref> such as cholera,<ref>{{Cite journal|title=Oral vaccines for preventing cholera|last1=D|first1=Sinclair|last2=K|first2=Abba|date=2011-03-16|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|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=2014-05-01|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=2017-10-01|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> [[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> and [[coronavirus disease 2019]].<ref>{{cite journal |last1=Gbesemete |first1=D. |last2=Barker |first2=M. |last3=Lawrence |first3=W. T. |last4=Watson |first4=D. |last5=de Graaf |first5=H. |last6=Read |first6=R. C. |title=Exploring the acceptability of controlled human infection with SARSCoV2—a public consultation |journal=BMC Medicine |date=December 2020 |volume=18 |issue=1 |pages=209 |doi=10.1186/s12916-020-01670-2|pmid=32635912 |pmc=7339437 }}</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=April 20, 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/>