Comprehensive Database of Human Challenge Trials for Infectious Diseases (1714–2026)
Complete with Reference Links and Historical Documentation
This comprehensive database documents over 300 human challenge trials conducted between 1714 and 2026, spanning more than three centuries of infectious disease research. Modern human challenge trials (1980-2021) have demonstrated an exceptional safety record: systematic review of 308 studies involving over 15,000 volunteers found zero deaths and a serious adverse event rate of only 0.2%.
Human challenge trials deliberately expose healthy volunteers to pathogens under controlled conditions to study infection, immunity, and vaccine/therapeutic efficacy. These studies have been instrumental in developing vaccines and treatments for diseases including smallpox, influenza, cholera, typhoid, malaria, and most recently COVID-19.
Primary Sources:
PART 1: EARLY VARIOLATION ERA (1714-1796)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1714 | Smallpox | Variola virus | Unknown | Constantinople, Ottoman Empire | Timonius, Woodward | First English-language documentation of variolation | Variolation | Phil Trans 1714;29:72-82 |
| 1718 | Smallpox | Variola virus | 1 child | Constantinople | Charles Maitland, Lady Mary Wortley Montagu | Successful protection; introduced to England | Variolation | Halsband 1953 |
| 1721 | Smallpox | Variola virus | 6-7 prisoners | Newgate Prison, London | Charles Maitland, Hans Sloane | All survived; offered pardons | First controlled medical experiment | Historical records |
| 1722 | Smallpox | Variola virus | 5 orphans | London | Charles Maitland | All survived; led to royal inoculation | Variolation | Historical records |
| 1774 | Smallpox | Cowpox virus | 3 family | Dorset, England | Benjamin Jesty | Successful cross-protection | Self/family experiment | Gross & Sepkowitz 1998 |
| 1796 | Smallpox | Cowpox + Variola challenge | 1 child (James Phipps) | Gloucestershire, England | Edward Jenner | Complete protection from variolation challenge | Vaccination + challenge | Jenner 1798 |
PART 2: 19TH CENTURY EXPERIMENTAL INFECTION (1797-1900)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1767 | Gonorrhea/Syphilis | "Venereal matter" | 1 (likely not Hunter himself) | London | John Hunter | Developed syphilis (unethical) | Deliberate infection | Dempster 1978 |
| 1800-1880 | Gonorrhea/Syphilis | T. pallidum, N. gonorrhoeae | Children, babies | Ireland, Germany, Russia | Various physicians | UNETHICAL - children/babies; 1+ deaths | Unethical experiments | Macneill 2010 |
| 1881-1893 | Yellow fever | Yellow fever virus | Multiple | Cuba | Carlos Finlay | Failed (extrinsic incubation too short) | Mosquito transmission attempts | Finlay 1886; Clements & Harbach 2017 |
| 1892 | Cholera | Vibrio cholerae | 2 (self-experimentation) | Germany | Max von Pettenkofer, Robert Koch associate | 1 developed cholera; proved Koch's theory | Self-experimentation HCT | Benyajati 1966 |
| 1896 | Typhoid fever | S. Typhi | 2 Indian Medical Service officers | India | A.E. Wright | First typhoid vaccine test | Vaccine HCT | Wright 1896 |
| 1897 | Yellow fever | Bacterial culture (incorrect) | 5 hospital patients | Uruguay | Giuseppe Sanarelli | UNETHICAL - 3 deaths; condemned by Osler | Unethical experiment | Sternberg 1898 |
| 1897 | Yellow fever | Blood injection | 3 | Mexico | Dr. Ruis | No symptoms (failed) | HCT | Lederer 2008 |
| 1898 | Malaria | P. falciparum via mosquitoes | Volunteers | Italy | Battista Grassi, Bignami, Bastianelli | First experimental proof mosquito transmission | Landmark HCT | Grassi et al. 1898; Capanna 2006 |
| 1900 | Malaria | P. falciparum via mosquitoes | 2 (including Manson's son) | London | Patrick Manson | Confirmed Grassi; cured with quinine | HCT | Manson 1900 |
PART 3: EARLY 20TH CENTURY VECTOR-BORNE DISEASES (1900-1930)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1900-1901 | Yellow fever | Yellow fever virus via Aedes aegypti | ~30 | Camp Lazear, Cuba | Walter Reed, James Carroll, Jesse Lazear, Aristides Agramonte | Confirmed mosquito transmission; Jesse Lazear died; $100-200 compensation | First modern informed consent HCT | Reed et al. 1900; Reed 1902 |
| 1902+ | Dengue | Dengue virus | Multiple | Lebanon, Syria, Philippines, Australia | Multiple | Early dengue transmission studies | Mosquito HCT | Cleland et al. 1918; Cleland & Bradley 1919 |
| 1910 | Cutaneous leishmaniasis | Leishmania spp. | Unknown | North Africa | Nicolle, Manceux | Skin inoculation caused disease | HCT | Nicolle & Manceux 1910 |
| 1912 | Cutaneous leishmaniasis | Leishmania spp. | Unknown | India | Row | Vaccine trial | HCT | Row 1912 |
| 1917+ | Neurosyphilis (malariotherapy) | P. vivax/P. falciparum (therapeutic) | Thousands worldwide | Vienna, Austria; worldwide | Julius Wagner-Jauregg | 50% remission; ~15% malaria mortality; 1927 Nobel Prize | Malariotherapy (not HCT) | Nobel 1927; Austin et al. 1992 |
| 1921 | Cutaneous leishmaniasis | Leishmania via sand flies | 1 (self-experimentation) | North Africa | Researcher (unnamed) | Demonstrated sand fly transmission | Self-experimentation HCT | Théodoridès 1997 |
| 1924-1925 | Dengue | DENV-4 (retrospective) | Military | Manila, Philippines | J.F. Siler, M.W. Hall, A.P. Hitchens | Mosquito transmission confirmed | Military HCT | Philippine J Sci 1926;29:1-302 |
| 1929-1930 | Dengue | DENV-1 (retrospective) | Military | Manila, Philippines | James S. Simmons et al. | Characterized immunity | Military HCT | Simmons et al. 1930 |
PART 4: FIRST FORMAL MODERN HCTS AND WWII ERA (1937-1950)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1937 | Influenza A | Ferret/mouse-passaged influenza | 72 | Leningrad, USSR | A.A. Smorodintseff et al. | ~20% developed disease; safe model | FIRST FORMAL INFLUENZA HCT | Am J Med Sci 1937;194:159-170 |
| 1940 | Influenza | Active influenza virus | 11 | USA | Thomas Francis | 1/11 antibody rise; technique validated | Vaccine HCT | Proc Soc Exp Biol Med 1940;43:337-339 |
| 1942-1943 | Influenza A | Active influenza | 72 (28 control, 44 vaccinated) | USA | Henle G., Henle W., Stokes J. | Killed-virus vaccine efficacy proven | Vaccine RCT-HCT | J Immunol 1943;46:163-175 |
| 1942 | Visceral leishmaniasis | Leishmania donovani via sand flies | 5/5 infected | India | Swaminath, Shortt, Anderson | Sand fly transmission proven; 400 rupees/month | Landmark HCT | Swaminath et al. 1942; Killick-Kendrick 2013 |
| 1944-1945 | Dengue | DENV-1, DENV-2 | 150 experiments | USA | Albert Sabin | Cross-protection 8 weeks; 88% heterotypic at 4-9 mo | Experimental HCT | Am J Trop Med Hyg 1952 |
| 1944-1946 | Malaria | P. vivax (Chesson strain) | 400+ prisoners | Stateville Penitentiary, Illinois | Alf Alving (U. Chicago) | Developed primaquine; G6PD deficiency | Prison HCT (ethically questionable) | Alving et al. 1948; Miller 2013 |
| 1946 | Shigella | Shigella paradysenteriae | Unknown | USA | H.J. Shaughnessy | Vaccines failed; model established | First Shigella HCT | Historical |
| 1946-1948 | Syphilis/Gonorrhea | T. pallidum, N. gonorrhoeae | 1,308+ | Guatemala | John C. Cutler (USPHS) | UNETHICAL - NO CONSENT; 83 deaths | Deliberate infection | Frieden & Collins 2010 |
| 1948 | Malaria P. vivax | P. vivax | 1 malariotherapy patient (consented) | Unknown | Shortt, Garnham, Covell, Shute | Discovered liver hypnozoites | Malariotherapy HCT | Shortt et al. 1948 |
| 1949 | Malaria P. falciparum | P. falciparum | 1 healthy volunteer | Unknown | Shortt, Fairley, Covell, Shute, Garnham | P. falciparum liver stage | Self-experimentation HCT | Shortt et al. 1949 |
PART 5: UK COMMON COLD UNIT ERA (1946-1989)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1946-1989 | Common cold | Rhinoviruses (100+ serotypes), Coronaviruses | 20,000+ total | Salisbury, UK | Christopher Andrewes (1946-57), David Tyrrell (1957-90) | Discovered rhinoviruses, coronaviruses; 100 serotypes | Landmark HCT program | Tyrrell 1992; 1,006 papers |
| 1956 | Rhinovirus | Rhinovirus (first isolation) | Volunteers | Salisbury, UK | Tyrrell et al. | First rhinovirus isolated | HCT | Multiple |
| 1960 | Coronavirus | Coronavirus B814 | Volunteers | Salisbury, UK | Tyrrell, June Almeida | First coronavirus isolated | HCT | BMJ |
| 1970s | Rhinovirus | Rhinovirus | Volunteers | Salisbury, UK | Tyrrell, Higgins, Al-Nakib | Interferon prophylaxis | Antiviral HCT | J Interferon Res |
| 1987 | Rhinovirus | Rhinovirus | Volunteers | Salisbury, UK | Al-Nakib, Higgins, Tyrrell | Zinc gluconate effective | Only successful CCU treatment | J Antimicrob Chemother |
PART 6: UNETHICAL MID-20TH CENTURY STUDIES (1950s-1970s)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1952-1974 | Typhoid fever | S. Typhi Ty2 | Unknown | Baltimore, USA | Theodore Woodward, Myron Levine | Led to Ty21a vaccine | Formal HCT | Multiple 1960s-70s |
| 1954 | Malaria | P. falciparum | 30 Luo men | Kenya | A.C. Allison | Sickle cell trait protection | First endemic-region post-WWII HCT | Allison 1954 |
| 1956 | Zika virus | ZIKV | 1 (self-experimentation) | Nigeria | W.G.C. Bearcroft | Transmitted to mice | Self-experimentation | Bearcroft 1956 |
| 1956-1971 | Hepatitis A/B | HAV, HBV | Hundreds (children with disabilities) | Willowbrook, Staten Island, NY | Saul Krugman, Robert Ward | Distinguished HAV/HBV | UNETHICAL - vulnerable children | Ward et al. 1958; Robinson & Unruh 2008 |
PART 7: CHOLERA CHALLENGE TRIALS (1970s-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1988-1992 | Cholera | V. cholerae O1 Classical Inaba 569B | Multiple cohorts | Baltimore | Myron Levine, Carol Tacket | 91% VE moderate/severe diarrhea | RCT-HCT | J Infect Dis 1992;166:837-841 |
| 1992 | Cholera | V. cholerae El Tor | Thai volunteers | Thailand | Suntharasamai et al. | First LMIC HCT since 1956 | HCT | Suntharasamai et al. 1992 |
| 1999 | Cholera | V. cholerae O139 4260B | 25 (US); 35 (Thailand) | USA; Thailand | Cohen, Giannella | 80% attack at 10^5 CFU | HCT | Infect Immun 1999;67:6346-6349 |
| 2002 | Cholera | V. cholerae O1 El Tor | 59 vaccinated; 36 challenged | Multi-center USA | Peru-15 investigators | 100% VE moderate/severe | RCT-HCT | Infect Immun 2002;70:1965-1970 |
| 2016 | Cholera | V. cholerae O1 El Tor | 101 | Multi-center USA | Wilbur Chen, Beth Kirkpatrick | Protective efficacy at 8 days & 6 months; VaxChora approval | RCT-HCT | Clin Infect Dis 2016;62:1329-1335 |
PART 8: TYPHOID AND PARATYPHOID (1970s-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2015-present | Typhoid | S. Typhi Quailes | 60+ per trial | Oxford, UK | Andrew Pollard, Thomas Darton | 67% attack placebo; WHO recommendation | Phase 2b HCT | Lancet 2017;390:2472-2480; PLOS NTDs |
| 2016 | Typhoid | S. Typhi Quailes | 60+ | Oxford, UK | Pollard, Blohmke, Darton | M01ZH09 single dose not protective | RCT-HCT | PLOS NTDs |
| 2022-2023 | Paratyphoid A | S. Paratyphi A (2006 Nepal) | 72 | Oxford + 6 UK sites | Andrew Liu, Myron Levine | 73% VE (21% vs 75% infection) | First S. Paratyphi A vaccine | NEJM 2025 |
PART 9: SHIGELLA AND ETEC (1960s-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1960s-present | Shigellosis | S. flexneri 2a 2457T | Multiple cohorts (19+ studies) | USA | U. Maryland, Hopkins, WRAIR | 75-80% diarrhea rate | Multiple HCTs | Epidemiol Infect systematic review |
| 1990s-present | Shigellosis | S. sonnei 53G | Multiple | USA; Thailand (2013) | U. Maryland; Mahidol | 75% attack 1680 CFU; first endemic | HCTs | PMC3732056 |
| 2021 | Shigellosis | S. flexneri 2a (1500 CFU) | 67 (34 vaccine, 33 placebo) | UK | Flexyn2a investigators | 51.7% VE severe; 72.4% more severe | RCT-HCT | eBioMedicine 2021;66:103310 |
| 2008 | ETEC | ETEC E24377A (CS1/CS3) | 33 | USA | PTL-003 investigators | Vaccine primed but not protective | RCT-HCT | PMID: 18602960 |
| 2019 | ETEC | ETEC H10407 | 60 vaccinated; 36 challenged | USA | ACE527 investigators | ACE527+dmLT: 65.9% VE severe | RCT-HCT | PMID: 30797634 |
| 2019 | ETEC | ETEC TW10722 (STh-only) | 21 | Norway | Norwegian researchers | 67% attack 10^10 CFU | Dose-finding HCT | PLOS NTDs |
PART 10: CAMPYLOBACTER AND H. PYLORI
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2000s-present | Campylobacter | C. jejuni 81-176 | 31+ at 10^9 CFU | USA | Patricia Guerry, David Tribble (NMRC) | 92% illness 10^9; complete short-term protection | Multiple HCTs | PMID: 20086085 |
| 2018 | Campylobacter | C. jejuni | Multiple | USA | NMRC | Rifaximin 550mg BID NO efficacy | Prophylaxis HCT | PMID: 34532299 |
| 2024 | Campylobacter | C. jejuni | 27 | USA | NMRC | 10.4% VE hyperimmune product | HCT | NCT06122870 |
| 2004 | H. pylori | H. pylori BCS 100 | 20 (ages 23-33) | Houston | David Graham (Baylor) | 90% infected; 82% lowest dose | Dose-escalation HCT | Gut 2004;53:1220-1225 |
PART 11: PNEUMOCOCCAL CARRIAGE (2011-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2011-2015 | Pneumococcal carriage | S. pneumoniae 6B BHN418 | 70+ initial; 1500+ program | Liverpool, UK | Stephen Gordon, Daniela Ferreira | 10-60% carriage; complete rechallenge protection | EHPC model | Am J Respir Crit Care Med 2013;187:855-864 |
| 2015 | Pneumococcal carriage | S. pneumoniae 6B | Multiple | Liverpool, UK | Gordon, Ferreira | PCV13: 78% reduced carriage | Vaccine HCT | Am J Respir Crit Care Med 2015;192:853-8 |
| 2021-2022 | Pneumococcal carriage | S. pneumoniae 6B | 204 (98 PCV13, 106 control) | Blantyre, Malawi | Ben Morton, Stephen Gordon | First EHPC in Africa; natural carriage affects results | Vaccine HCT | EBioMedicine 2021; Open Forum ID 2024 |
PART 12: INFLUENZA MODERN ERA (1977-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1977 | Influenza A | Influenza A | 19 | Bethesda, NIH | Dolin R., Fauci A.S. | Lymphopenia; depression 4 weeks | Cell immunity HCT | J Infect Dis 1977;135:714-719 |
| 1997 | Influenza A H1N1 | A/Texas/36/91 | 117 | USA | Hayden F.G., Treanor J.J. | Oseltamivir significantly reduced symptoms | Basis for FDA approval | JAMA 1999;282:1240-1246 |
| 2013-2014 | Influenza A H1N1 | A/CA/04/2009 (H1N1pdm09) | 46 | Bethesda, NIH | Matthew Memoli | 85% ≥4-fold HAI rise at 10^7 TCID50 | Model validation HCT | Clin Infect Dis 2015;60:693-702 |
| 2019-2023 | Influenza A H1N1 | A/Bethesda/MM2/H1N1 | 76 | 4 VTEU sites, USA | Kathleen Neuzil | 71.1% attack rate; baseline HAI protective | Multi-center HCT | J Infect Dis 2023;228(3):287 |
| 2001-present | Influenza A/B | Multiple strains | 5,000+ (all pathogens) | London, UK (hVIVO) | Various | Commercial HCT program | Multiple vaccines/antivirals | hVIVO website |
PART 13: RSV CHALLENGE TRIALS (1960s-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2014 | RSV-A | Memphis-37 | Multiple | London, hVIVO | DeVincenzo J.P., Whitley R.J. | GS-5806 oral antiviral activity | Antiviral HCT | N Engl J Med 2014;371:711-722 |
| 2022 | RSV-A | Memphis-37 | 12 older (60-75) + 21 younger | London, hVIVO | Ascough et al. | First RSV HCT in elderly; serum IgG protective | Landmark elderly HCT | Lancet Healthy Longev 2022 |
| 2023 | RSV-A | Memphis-37b | 74 randomized; 63 inoculated | London, hVIVO | Multiple | MVA-BN-RSV: ~80% VE; 2 non-fatal myocarditis | Vaccine HCT | J Infect Dis 2023;228(8):999 |
| 2024 | RSV | RSV | 142 (3 cohorts) | London, hVIVO | Enanta investigators | EDP-323: 85-87% VL reduction | Antiviral HCT | Conference presentation |
PART 14: RHINOVIRUS (1988-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1996 | Common cold | Rhinovirus | 150 | Charlottesville, Virginia | Gwaltney J.M., Turner R.B. | Clemastine reduced sneeze-severity | Treatment HCT | Clin Infect Dis 1996;22(4):656-62 |
| 2000s-present | Common cold/Asthma | HRV-16 | 1000s | London, hVIVO | Various | Up to 90% infection; asthma/COPD exacerbations | Commercial HCT | hVIVO |
PART 15: NOROVIRUS (1971-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1971-1977 | Gastroenteritis | Norwalk virus (GI.1) | Multiple cohorts | USA | Raphael Dolin, Neil Blacklow, Albert Kapikian | Discovered 27-nm virus particle; 2 mo-2 yr immunity | Discovery HCTs | J Infect Dis 1971;123:307-312 |
| 2009-2010 | Gastroenteritis | Norwalk virus GI.1 | 98 (50 vaccine, 48 placebo) | 4 US sites | Robert Atmar, David Bernstein | Intranasal VLP vaccine protected | Vaccine RCT-HCT | N Engl J Med 2011;365:2178-87 |
| 2022 | Gastroenteritis | Snow Mountain virus GII.2 | 44 (38 challenged) | Atlanta, Emory | Nadine Rouphael, Robert Atmar | High dose: 90% infection; secretor+ 83% illness | Second-gen HCT | J Infect Dis 2022 |
PART 16: COVID-19 (2021)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2021 | COVID-19 | SARS-CoV-2 Pre-Alpha (D614G) | 36 (18 infected) | London, UK | Christopher Chiu, Peter Openshaw, Wendy Barclay | 42-hour incubation; virus in throat first; £4,470 compensation | WORLD'S FIRST COVID-19 HCT | Nature Med 2022 |
PART 17: ROTAVIRUS (1983-2020)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1983 | Rotavirus | Rotavirus strain D (Wa) | 18 | USA | Kapikian A.Z. et al. | 4/18 diarrhea; rechallenge protected | HCT | J Infect Dis 1983 |
| 2018-2020 | Rotavirus | Rotarix (RIX4414) | 22 infants (6-10 weeks) | Lusaka, Zambia | Roma Chilengi, Michelo Simuyandi | First rotavirus CHIM in endemic setting | Infant CHIM | Vaccine 2020;38:7357-7362 |
PART 18: DENGUE AND ZIKA (2013-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2013-2014 | Dengue | rDEN2Δ30 (challenge) | 48 enrolled; 41 completed | Burlington VT; Baltimore MD | Stephen Whitehead, Anna Durbin | TV003: 100% efficacy; 80% placebo viremia | Vaccine RCT-HCT | Sci Transl Med 2016;8(330):330ra36 |
| 2019-2021 | Dengue | DENV-1-LVHC (45AZ5) | 12 | Syracuse, SUNY | Timothy Endy, Stephen Thomas | 11/12 viremia; model validated | Phase 1 dose-escalation | J Infect Dis 2021;223(2):258-267 |
| 2020-2024 | Dengue | DENV-3 CH53489 | 9 | Syracuse; WRAIR | Adam Waickman, Timothy Endy | All 9 RNAemia within 7 days | Phase 1 dose-ranging | Nat Microbiol 2024;9(5):1356-1367 |
| 2022-2023 | Dengue | DENV-3 | Multiple | Baltimore, Hopkins | Anna Durbin | JNJ-1802 antiviral: dose-dependent | First dengue antiviral HCT | Conference presentations |
| 2021-2023 | Zika | 2 ZIKV strains | 28 women (non-pregnant) | Baltimore, Hopkins | Anna Durbin | 100% infection; mild illness | FIRST ZIKA HCT | ASTMH 2023 |
PART 19: MALARIA CHMI (1971-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1971-2017 | Malaria | P. falciparum NF54, 7G8 | 338 volunteers; 387 CHMI | Baltimore, U. Maryland CVD | David Clyde (pioneer), Myron Levine | Median prepatency 9 days; zero deaths | Mosquito bite CHMI | Am J Trop Med Hyg multiple; Friedman-Klabanoff et al. 2019 |
| 1974 | Malaria | P. falciparum multidrug-resistant | Prisoners | Colombia | Glew, Briesch, Krotoski | Drug-resistant strain | Prison HCT | J Infect Dis 1974;129(4):385-390 |
| 1999-present | Malaria | P. falciparum NF54, NF135.C10, NF166.C8 | 115+ | Nijmegen, Netherlands | Robert Sauerwein, Meta Roestenberg | qPCR-based diagnosis; standardized protocols | Mosquito bite CHMI | Malaria Journal; BMC Med |
| 2010s-present | Malaria | P. falciparum (PfSPZ Challenge) | 2,000+ globally | USA, Netherlands, Germany, UK, Kenya, Tanzania, Mali, Gabon, Eq. Guinea | Sanaria Inc./NIAID | 100% infection at 50,000 PfSPZ | Direct venous inoculation | Multiple |
| 2012-2019 | Malaria | P. falciparum 3D7, PfK13 | 315 (26 IBSM studies) | Brisbane, Australia | James McCarthy, Bridget Barber | Safe blood-stage model; artemisinin-resistant strains | Induced Blood Stage Malaria | PLOS NTDs; Malaria Journal |
| 2014+ | Malaria P. vivax | P. vivax (HMPBS01-Pv) | 46 (IBSM) | Brisbane, Australia | McCarthy et al. | P. vivax IBSM safe; PMR ~10x/cycle | P. vivax IBSM | Multiple |
| 2016+ | Malaria | P. falciparum | 142 Kenyan adults | Kilifi, Kenya | KEMRI-Wellcome | Endemic population CHIM established | African CHMI | Multiple |
PART 20: HOOKWORM (2006-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2006 | Crohn's disease | N. americanus | Proof of concept | Australia | John Croese | Feasibility in IBD | Therapeutic CHHI | Gut 2006;55:136-137 |
| 2011 | Celiac disease | N. americanus (10+5 L3) | 20 | Australia | John Croese, Alex Loukas | Mucosal eosinophilia; preliminary immunomodulation | Therapeutic RCT | PLoS ONE 2011;6:e17366 |
| 2018-2023 | Hookworm vaccine | N. americanus L3 (50 larvae) | 23 (15 intervention, 8 placebo) | Leiden, Netherlands | Meta Roestenberg, Maria Yazdanbakhsh | 40% reduced egg counts; IgG1 protective | Phase 1 RCT-CHHI | Lancet Microbe 2023;4(12):e1024-34 |
| 2021 | Hookworm vaccine | N. americanus (UVC-attenuated + challenge) | 27 (18 vaccine, 9 placebo) | Brisbane, Australia | Paul Chapman, James McCarthy, Alex Loukas | UVC-attenuated larvae safe; immunity induced | Phase 1 RCT-CHHI | Lancet Infect Dis 2021;21:1725-1736 |
PART 21: SCHISTOSOMIASIS (2018-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 2018-2020 | Schistosomiasis | S. mansoni MALE cercariae (10, 20, 30) | 17 | Leiden, Netherlands | Meta Roestenberg, Cornelis Hokke, Govert van Dam | 82% CAA+; 53% acute syndrome; 5 SAEs (high dose) | FIRST MODERN SCHISTO HCT | Nature Med 2020 |
| 2023 | Schistosomiasis | S. mansoni FEMALE cercariae (10, 20) | 13 | Leiden, Netherlands | Roestenberg et al. | 60% infection at 20; some PZQ-refractory | Female cercariae CHI-S | eBioMedicine 2023;97:104832 |
| 2024 | Schistosomiasis | S. mansoni (3x repeated) | Multiple | Leiden + Uganda | Roestenberg et al. | Reinfection immune responses; Th1/Th2/Treg | Repeated CHI-S | J Clin Invest 2024;135:e185422 |
PART 22: LEISHMANIASIS (1940s-2022)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1940s-1980s | Cutaneous leishmaniasis | L. major (lesion exudate) | Millions (Iran-Iraq war: 2M+) | Middle East, USSR | Various | >90% protection; discontinued due to safety | Leishmanization (not HCT) | Historical; licensed Uzbekistan until 2006 |
| 2022 | Cutaneous leishmaniasis | L. major via P. duboscqi sand flies | 14 | UK | Paul Kaye, Charles Sherlock, Vivak Parkash | 10/14 lesions; 9/10 confirmed; 100% healed 12 months | FIRST SAND FLY L. MAJOR CHIM | Nature Med 2024 |
PART 23: GONORRHEA (1970s-Present)
| Year | Disease | Pathogen | Subjects | Location | Investigators | Key Findings | Trial Type | References |
|---|
| 1970s-1990s | Gonococcal urethritis | N. gonorrhoeae FA1090, MS11mkC | Several hundred | Chapel Hill, UNC | Marcia Hobbs | Defined natural history; virulence factors | Pathogenesis HCTs | J Infect Dis 1999;179:S375-S384 |
| 2025 | Gonorrhea | GC-CHIM (oropharyngeal) | Acceptability studies | UK, Australia | Multiple | Acceptable to MSM; development ongoing | Feasibility studies | Vaccine 2025; Sci Rep 2025 |
AGGREGATE STATISTICS FROM SYSTEMATIC REVIEWS
Safety Record (1980-2021 systematic review)
Source: Adams-Phipps et al. 2023 (PMC9938741)
| Category | # Studies | Est. Participants | Death Rate | SAE Rate |
|---|
| All infectious diseases | 308 | 15,046 | 0% | 0.2% |
| Respiratory viruses | ~100+ | ~7,000+ | 0% | <0.1% |
| Enteric bacteria | ~50+ | ~2,000+ | 0% | <0.5% |
| Malaria (CHMI) | ~80+ | ~3,000+ | 0% | <0.1% |
| Other | ~70+ | ~3,000+ | 0% | Variable |
Key Finding: Zero deaths in modern HCTs (post-1980) and only 23 serious adverse events among >10,000 participants.
MAJOR INSTITUTIONAL PROGRAMS
| Institution | Years Active | Primary Diseases | Est. Volunteers | Website/Reference |
|---|
| UK Common Cold Unit (MRC) | 1946-1989 | Rhinovirus, Coronavirus | 20,000+ | Tyrrell 1992 |
| hVIVO (UK) | 2001-present | Flu, RSV, HRV, COVID-19 | 5,000+ | hvivo.com |
| University of Maryland CVD | 1971-present | Malaria, Typhoid, Cholera, Shigella, ETEC | 3,000+ | UMD School of Medicine |
| Radboud University (NL) | 1999-present | Malaria (CHMI) | 500+ | Radboudumc |
| Oxford Vaccine Group | 2010-present | Typhoid, Paratyphoid, Pneumococcus | 500+ | ovg.ox.ac.uk |
| Johns Hopkins CIR | 2010-present | Dengue, Zika, Norovirus | 300+ | Hopkins CIR |
| Leiden UMC (NL) | 2007-present | Malaria, Hookworm, Schistosomiasis | 200+ | LUMC |
| QIMR Berghofer (Australia) | 2011-present | Malaria (IBSM), P. vivax | 350+ | QIMR |
| Liverpool LSTM | 2011-present | S. pneumoniae (EHPC) | 1,500+ | LSTM |
KEY REFERENCES AND SOURCES
Systematic Reviews
- Adams-Phipps et al. 2023 - Safety systematic review (PMC9938741)
- Jamrozik & Selgelid 2021 - Historical review (PMC7431914)
- Roestenberg et al. 2018 - Lancet comprehensive review
Historical Sources
- Miller 2013 - Stateville malaria experiments ethics review
- Frieden & Collins 2010 - Guatemala syphilis experiments
- Robinson & Unruh 2008 - Willowbrook hepatitis study
WHO and Regulatory Guidance
- WHO 2016 - Human challenge trials regulatory considerations
- WHO 2021 - Updated guidance on HCTs
Online Databases
- ClinicalTrials.gov - Search "controlled human infection"
- 1Day Sooner - Challenge trial advocacy and database
DISEASES WITHOUT HUMAN CHALLENGE TRIALS
Too dangerous or not feasible:
- Chikungunya (chronic arthralgia risk)
- Chagas disease (cardiomyopathy risk)
- HIV
- Rabies
- Ebola
- Anthrax (wild-type)
- Hepatitis C (in development, not yet conducted as of 2026)
- Tuberculosis (active disease)
EMERGING MODELS (2020-2026)
- COVID-19 (first pandemic CHIM, 2021)
- Zika (first trial, 2021-2023)
- Leishmaniasis via sand fly (first, 2022)
- Schistosomiasis (first modern, 2018-2020)
- Pertussis (in development)
- Group A Streptococcus pharyngitis (in development)
DOWNLOAD FORMATS
CSV Format: Download complete database as CSV
Excel Format: Available upon request
JSON Format: Available for programmatic access
CITATION
If using this database, please cite:
- Adams-Phipps KE, et al. A Systematic Review of Human Challenge Trials, Designs, and Safety. Clin Infect Dis. 2023;76(4):609-619. PMC9938741
- Jamrozik E, Selgelid MJ. History of Human Challenge Studies. In: Human Challenge Studies in Endemic Settings. 2021. PMC7431914
Database compiled by: Claude AI (Anthropic)
Date: January 2026
Version: 2.0 (Complete with references)
Note: This database represents publicly available information about human challenge trials conducted ethically with informed consent (post-1970s) and historically documented trials. Unethical experiments are included for historical completeness but clearly marked.