{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:50Z","timestamp":1772169170481,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.19811.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000}}],"reference-count":25,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome","award":["211433"],"award-info":[{"award-number":["211433"]}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    Tuberculosis (TB) caused 1.5 million deaths in 2020, making it the leading infectious killer after COVID-19. Bacille Calmette-Guerin (BCG) is the only licensed vaccine against TB but has sub-optimal efficacy against pulmonary TB and reduced effectiveness in regions close to the equator with high burden. Efforts to find novel vaccines are hampered due to the need for large-scale, prolonged, and costly clinical trials. Controlled human infection models (CHIMs) for TB may be used to accelerate vaccine development by ensuring only the most promising vaccine candidates are selected for phase 3 trials, but it is not currently possible to give participants\n                    <ns4:italic>Mycobacterium tuberculosis<\/ns4:italic>\n                    as a challenge agent. This study aims to replicate and refine an established BCG CHIM at the Liverpool School of Tropical Medicine. Participants will receive an intradermal injection with licensed BCG vaccine (Statens Serum Institut strain). In phase A, participants will undergo punch biopsy two weeks after administration, paired with minimally invasive methods of skin sampling (skin swab, microbiopsy, skin scrape). BCG detection by classical culture and molecular methods will be compared between these techniques and gold standard punch biopsy. Techniques meeting our pre-defined sensitivity and specificity criteria will be applied in Phase B to longitudinally assess intradermal BCG growth two, seven and fourteen days after administration. We will also measure compartmental immune responses in skin, blood and respiratory mucosa in Phase B. This feasibility study will transfer and refine an existing and safe model of BCG controlled human infection. Longitudinal BCG quantification has the potential to increase model sensitivity to detect vaccine and therapeutic responses. If successful, we aim to transfer the model to Malawi in future studies, a setting with endemic TB disease, to accelerate development of vaccines and therapeutics relevant for underserved populations who stand to benefit the most.\n                    <ns4:bold>Registration:<\/ns4:bold>\n                    ISRCTN: ISRCTN94098600 and ClinicalTrials.gov: NCT05820594\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.19811.2","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T08:51:26Z","timestamp":1717577486000},"page":"424","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A feasibility study of controlled human infection with intradermal Bacillus Calmette\u2013Gu\u00e9rin (BCG) injection: Pilot BCG controlled human infection model"],"prefix":"10.12688","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9698-4299","authenticated-orcid":false,"given":"Emma","family":"Carter","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9698-4299","authenticated-orcid":false,"given":"Ben","family":"Morton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6852-3682","authenticated-orcid":false,"given":"Dima","family":"ElSafadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3195-2210","authenticated-orcid":false,"given":"Kondwani","family":"Jambo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tinashe","family":"Kenny-Nyazika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Hyder-Wright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5771-0981","authenticated-orcid":false,"given":"Gift","family":"Chiwala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-3618","authenticated-orcid":false,"given":"Tarsizio","family":"Chikaonda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony E.","family":"Chirwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7170-8052","authenticated-orcid":false,"given":"Jonathan","family":"Gonzalez Sanchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Yip","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Biagini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7160-6275","authenticated-orcid":false,"given":"Shaun H.","family":"Pennington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Saunderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madlen","family":"Farrar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Myerscough","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea M.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-1116","authenticated-orcid":false,"given":"Stephen B.","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0594-0902","authenticated-orcid":false,"given":"Daniela M.","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref-1","article-title":"Global tuberculosis report 2021","year":"2021"},{"key":"ref-2","article-title":"The End TB strategy","year":"2015"},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"698-702","DOI":"10.1001\/jama.1994.03510330076038","article-title":"Efficacy of BCG vaccine in the prevention of Tuberculosis. Meta-analysis of the published literature.","volume":"271","author":"G Colditz","year":"1994","journal-title":"JAMA."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"1154-8","DOI":"10.1093\/ije\/22.6.1154","article-title":"Protective effect of BCG against Tuberculous meningitis and miliary Tuberculosis: a meta-analysis.","volume":"22","author":"L Rodrigues","year":"1993","journal-title":"Int J Epidemiol."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"1173-80","DOI":"10.1016\/S0140-6736(06)68507-3","article-title":"Effect of BCG vaccination on childhood Tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness.","volume":"367","author":"B Trunz","year":"2006","journal-title":"Lancet."},{"key":"ref-6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103993","article-title":"Tuberculosis vaccines in the era of COVID-19 - what is taking us so long?","volume":"79","author":"H Dockrell","year":"2022","journal-title":"EBioMedicine."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"757-770","DOI":"10.1016\/S2213-2600(19)30251-6","article-title":"Live-attenuated Mycobacterium Tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial.","volume":"7","author":"M Tameris","year":"2019","journal-title":"Lancet Respir Med."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"1021-8","DOI":"10.1016\/S0140-6736(13)60177-4","article-title":"Safety and efficacy of MVA85A, a new Tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial.","volume":"381","author":"M Tameris","year":"2013","journal-title":"Lancet."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"e00479-17","DOI":"10.1128\/IAI.00479-17","article-title":"Controlled Human Malaria Infection: applications, advances, and challenges.","volume":"86","author":"D Stanisic","year":"2018","journal-title":"Infect Immun."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"1104-15","DOI":"10.1056\/NEJMoa2035916","article-title":"Safety and efficacy of a Typhoid Conjugate Vaccine in Malawian children.","volume":"385","author":"P Patel","year":"2021","journal-title":"N Engl J Med."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.12688\/wellcomeopenres.18767.2","article-title":"Practical considerations for a TB Controlled Human Infection Model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi [version 2; peer review: 2 approved, 1 approved with reservations].","volume":"8","author":"S Gordon","year":"2023","journal-title":"Wellcome Open Res."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"2380-1","DOI":"10.1128\/JCM.00648-11","article-title":"Sensitivity to isoniazid of Mycobacterium bovis BCG strains and BCG 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T05:35:33Z","timestamp":1724909733000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":25,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.19811.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.19811.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.23582.r85854","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.23582.r97056","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.23582.r85854","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.21943.r68106, Valerie Koeken, Todia Setiabudiawan, Radboud University Medical Center, Nijmegen, 23 Oct 2023, version 1, 3 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v1#referee-response-68106","order":0,"name":"referee-response-68106","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Emma Carter<\/b>; \n<i>Posted: 29 Apr 2024<\/i>; Responses to reviewer 1 comments-  (I) \n<b>Reviewer Concern:<\/b> Using BCG-CHIM for vaccine or therapeutic testing could primarily indicate immune protection against BCG rather than Mtb. BCG lacks crucial Mtb elements like the RD1 region which consist ESAT6\/CFP10 and another antigen such as Ag85B, which BCG does produce but not secrete. Why not consider MTBVAC, a potentially more accurate challenge agent for Mtb? Lastly, for clarity and future applicability, could you elaborate on how the study might adapt to incorporate alternative TB challenge agents as they become available?  \n<b>Author Response:&nbsp;<\/b>Thank you for these suggestions. We have made the choice to select BCG as our initial challenge agent to optimise the TB CHIM for several reasons, although we acknowledge the limitations of this as a challenge model for pulmonary tuberculosis. A workshop discussion taking place in Liverpool and Malawi agreed that BCG was currently the preferred agent to optimise a TB CHIM as it is licensed in both countries, has a long-established safety profile, has been used as control agent in novel vaccine studies, and has been reliably recovered from previous challenge models(1).&nbsp;  When alternative challenge agents are considered, including genetically modified \n<i>Mycobacterium tuberculosis, <\/i>a detailed assessment of transmission risk and government regulatory approval would be required as well as dose optimisation for optimal mycobacterial recovery. These considerations require significant investment and time, and whilst these are underway, we have made a decision to commence with BCG as a pilot agent. Regarding the use of MTBVac as a human challenge agent, we agree that this may have potential as a future challenge agent but would also require regulatory approval for use. When incorporating new challenge agents into the model, we plan to use techniques we have optimised for microsampling, mycobacterial recovery including culture and PCR techniques as well as single cell analysis and spatial transcriptomics of the immune response specific to mycobacteria\n<i>. <\/i>The BCG CHIM allows us to safely develop these.\n<i> <\/i>In terms of specific alternative challenge agents, BCG strains are under development that involve fluorophore insertion which would allow in vivo serial monitoring of BCG growth without the need for tissue sampling (2).  Incorporation of this into a CHIM would require comparison of the fluorescent signal with serial tissue sampling used in our current model to ensure concordance with mycobacterial growth ex vivo. Conditionally replicating suicide strains of M.tb have been developed and are undergoing further testing in animals to ensure safety (3).  They would would then need first-in-to-human studies to assure suicide on removal of the conditioning agent prior to incorporation into CHIMs.Further explanation of the rationale for selection of BCG as a challenge agent has been added to the introduction and discussion. Additional information has been added to the discussion in to elaborate on how future challenge agents may be incorporated into the model. 1b. Phase A is as a safety pilot for high-dose (4x) adult BCG vaccination, while Phase B explores high-dose BCG effects over time. Both are very interesting, but need clarification about their relevance to Mtb infection and how much the immune response against high-dose BCG challenge could mimic Mtb infection. A recently conducted systematic review and workshop in Liverpool and Malawi highlighted the limitations of an intradermal BCG CHIM and the extent to which it can be used to model M.tb infection in TB vaccine evaluation. Firstly, the immune response to WT-\n<i>M.tb <\/i>is complex and can lead to a wide range of disease manifestations after initial primary infection. Furthermore, the immune response to BCG is variable according to age, geography and prior non-tuberculous Mycobacterium exposure and the correlates of protection are not fully known(4).  Finally, the compartmental skin response to intradermal BCG will likely differ to pulmonary \n<i>M.tb<\/i> given the variation in immune populations at these sites (5).  However, one study has shown concordance between the transcriptional profile of skin punch biopsy specimens from TST injection sites with human pulmonary granulomas suggesting correlation between the compartmental skin and pulmonary immune response to \n<i>M.tb<\/i>\n<i>(6)<\/i>\n<i>.<\/i>  This study aims to provide a detailed analysis of the immune response over time to BCG in skin, respiratory mucosa and systemically which has not previously been conducted and could be compared with emerging work analysing the host transcriptional response to WT-\n<i>M.tb<\/i> exposure (7).  Further detail has been added to the discussion in response to this comment.  ------------------------------------------------------------------------------------------------------------------  (II) \n<b>Reviewer Concern:<\/b> As the study is pilot in nature, I think it is better to also include people with a history of BCG vaccination, especially considering the future plans to extend this to Malawi. Adding individuals with a history of BCG vaccination might give early, valuable insights for TB-endemic regions. This way, at least you can be sure that BCG-CHIM is also safe in BCG-vaccinated adults, which most people in TB-endemic regions are.  \n<b>Author Response:&nbsp;<\/b>Many thanks for this valuable comment. We agree that it will be important to include people with a history of prior BCG vaccination. Of note, BCG CHIM has previously been safely undertaken in Oxford in participants with prior BCG vaccination(8). After completion of this pilot study, we plan to expand to include previously BCG vaccinated individuals and compare the immune response and mycobacterial recovery to those that have not previously received BCG. We have now added to the discussion explaining that this model in Malawi will include previously BCG vaccinated individuals.  ------------------------------------------------------------------------------------------------------------------ (III) \n<b>Reviewer Concern:&nbsp;<\/b>Using nasal samples to measure respiratory mucosa immune response is very interesting and exciting, but it's usability remains poorly understood. How well do these samples correlate with immune responses in the lower respiratory tract where Mtb resides?  \n<b>Author Response:&nbsp;<\/b>We agree that at present the correlation between nasal mucosa and lower respiratory tract mucosal immune responses to Mtb is not yet known. Our results of nasal mucosal immune responses can be compared with recently published literature describing the immune response to BCG in lower respiratory tract samples (9). Although it is beyond the scope of this current protocol, we plan on undertaking bronchoscopy in future work to compare nasal mucosal samples to lower respiratory samples in BCG CHIM participants (9).  1. Gordon SB, Sichone S, Chirwa AE, Hazenberg P, Kafuko Z, Ferreira DM, et al. Practical considerations for a TB controlled human infection model (TB-CHIM); the case for TB-CHIM in Africa, a systematic review of the literature and report of 2 workshop discussions in UK and Malawi. Wellcome Open Res. 2023;8:71.  2. Zelmer A, Carroll P, Andreu N, Hagens K, Mahlo J, Redinger N, et al. A new in vivo model to test anti-tuberculosis drugs using fluorescence imaging. J Antimicrob Chemother. 2012;67(8):1948-60.  3. Sabine Ehrt SF. Conditionally replicating Mycobacterium tuberculosis vaccines  4. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PE, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis. 2014;58(4):470-80.  5.Jarvela J, Moyer M, Leahy P, Bonfield T, Fletcher D, Mkono WN, et al. Mycobacterium tuberculosis-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4(+) T Cell-Dependent IFN-\u03b3 Production despite the Presence of Polyfunctional T Cells within the Airways. J Immunol. 2019;203(8):2194-209.  6. Bell LC, Pollara G, Pascoe M, Tomlinson GS, Lehloenya RJ, Roe J, et al. In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis. PLoS Pathog. 2016;12(3):e1005469.  7.Tabone O, Verma R, Singhania A, Chakravarty P, Branchett WJ, Graham CM, et al. Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis. J Exp Med. 2021;218(10).  8. Harris SA, Meyer J, Satti I, Marsay L, Poulton ID, Tanner R, et al. Evaluation of a Human BCG Challenge Model to Assess Antimycobacterial Immunity Induced by BCG and a Candidate Tuberculosis Vaccine, MVA85A, Alone and in Combination. Journal of Infectious Diseases. 2013;209(8):1259-68.  9. Davids M, Pooran A, Hermann C, Mottay L, Thompson F, Cardenas J, et al. A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Gu&eacute;rin. Am J Respir Crit Care Med. 2020;201(10):1277-91.  10. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006;10(11):1192-204.  11. Detjen AK, Keil T, Roll S, Hauer B, Mauch H, Wahn U, et al. Interferon-gamma release assays improve the diagnosis of tuberculosis and nontuberculous mycobacterial disease in children in a country with a low incidence of tuberculosis. Clin Infect Dis. 2007;45(3):322-8.  12. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PEM, et al. Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials. Clinical Infectious Diseases. 2013;58(4):470-80.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2#referee-comment-5688","order":1,"name":"referee-comment-5688","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.23582.r85854, Mangalakumari Jeyanathan, McMaster University, Hamilton, Ontario, 01 Jul 2024, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v2#referee-response-85854","order":2,"name":"referee-response-85854","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.21943.r73139, Paola Villanueva, The University of Melbourne, Melbourne, Victoria, 29 Aug 2024, version 1, 3 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/8-424\/v1#referee-response-73139","order":3,"name":"referee-response-73139","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [211433] and a UK Research and Innovation Strength in Places grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}