Translational research
BPZE1 vaccine against pertussis
Decades of research on the molecular pathogenesis of pertussis have allowed us to develop a novel, live attenuated nasal pertussis vaccine called BPZE1. In contrast to the currently available vaccines, this vaccine protects both against pertussis disease and infection by the causative agent Bordetella pertussis, as assessed in mice and non-human primates. It is now in clinical development and has successfully completed two phase I and two phase II clinical trials, showing safety and. These trials have shown that the vaccine is safe in humans, able to transiently colonize the human respiratory tract, to induce both humoral and T cell responses and to prevent subsequent colonization by a second dose of the vaccine strain. We also study the effect of current acellular vaccination on nasal carriage by B. pertussis and have found that acellular pertussis vaccination prolongs nasal carriage by inhibiting the natural recruitment of resident memory T cells in the nasal tissue. This was also observed in the offspring of acellular pertussis-vaccinated female mice indicating transgenerational effects of acellular pertussis vaccination. However, it was not observed after vaccination with BPZE1. Finally, immunogenicity and protective efficacy of BPZE1 were evaluated when co-administered with BCG in young mice.
- Dubois V; Chatagnon J; Thiriard A; Bauderlique-Le Roy H; Debrie AS; Coutte L; Locht C. Suppression of mucosal Th17 memory responses by acellar pertussis vaccines enhances nasal Bordetella pertussis carriage. NPJ Vaccines 2021; 6:6.
- Thalen M, Debrie AS, Coutte L, Raze D, Solovay K, Rubin K, Mielcarek N, Locht C. Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1. Vaccines (Basel). 2020 Sep 13;8(3):523.
- Jahnmatz M; Richert L; Al-Tawil N; Storsaeter J; Colin C; Bauduin C; Thalen M; Solovay K; Rubin K; Mielcarek N; Thorstensson R; Locht C; BPZE1 study team. Safety and immunogenicity of the live attenuated intranasal pertussis vaccine BPZE1: a phase 1b, double blind, randomized, placebo-controlled dose-escalation study. Lancet Infect Dis 2020; 20:1290-1301.
- Lin A, Apostolovic D, Jahnmatz M, Liang F, Ols S, Tecleab T, Wu C, van Hage M, Solovay K, Rubin K, Locht C, Thorstensson R, Thalen M, Loré K. Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans. J Clin Invest. 2020 May 1;130(5):2332-2346.
- Debrie AS, Mielcarek N, Lecher S, Roux X, Sirard JC, Locht C. Early Protection against Pertussis Induced by Live Attenuated Bordetella pertussis BPZE1 Depends on TLR4. J Immunol. 2019 Dec 15;203(12):3293-3300.
Anne-Sophie Debrie, Engineer
Dominique Raze, Engineer
Loïc Coutte, CRCN INSERM
Camille Locht, DRE INSERM
0000-0001-7859-8231
INFLAMMAVAX (Anti-inflammatory benefits of BPZE1)
During the development of the attenuated live pertussis vaccine (BPZE1) in our laboratory, we have observed non-specific anti-inflammatory properties that protect against morbidity and mortality associated with inflammation induced by heterologous viral or bacterial infections, as well as against non-infectious inflammatory disorders, such as allergic asthma. In our project, we plan to understand the molecular mechanisms behind these protective anti-inflammatory effects. The basic knowledge resulting from our project will open new avenues for the prevention of chronic inflammation, the common denominator of all age-related diseases. In the long term, our study may thus lead to novel anti-inflammatory therapies promoting healthy longevity.
Non-specific Effects of Live Attenuated Pertussis Vaccine Against Heterologous Infectious and Inflammatory Diseases.
Cauchi S, Locht C.
Front Immunol. 2018 Dec 7;9:2872. doi: 10.3389/fimmu.2018.02872. eCollection 2018.
Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice.
Belcher T, Kammoun H, Coutte L, Debrie AS, Mielcarek N, Sirard JC, Cauchi S, Locht C.
Vaccine. 2022 Mar 8;40(11):1555-1562. doi: 10.1016/j.vaccine.2021.01.025. Epub 2021 Jan 25.
Live attenuated pertussis vaccine for prevention and treatment of allergic airway inflammation in mice.
Belcher T, Ait-Yahia S, Solans L, Debrie AS, Cauchi S, Tsicopoulos A, Locht C.
NPJ Vaccines. 2022 Jun 23;7(1):66. doi: 10.1038/s41541-022-00494-w.
Philip Supply, Research Director CNRS,
with GenoScreen R&D
0000-0003-3690-3853
Development of deep sequencing kits for culture-free diagnosis of drug resistance in mycobacteria (Deeplex Myc-TB and Deeplex Myc-Lep)
Less than 40% of the estimated ~450,000 new tuberculosis (TB) cases with rifampicin or multi-drug resistance (MDR) occurring each year are diagnosed and treated, reflecting major limitations of conventional phenotypic and molecular tests. By building on the progress of next-generation sequencing (NGS) technologies and by extensively cataloguing resistance determinants in M. tuberculosis by whole genome sequencing (WGS), novel tools for rapid NGS-based, culture-free diagnostics are developed by GenoScreen (Lille) with our collaboration. This led to the development of the Deeplex® Myc-TB kit, based on deep amplicon sequencing for simultaneous prediction of susceptibility or (hetero)resistance to 13 anti-TB drugs/drug classes, mycobacterial identification (including the M. tuberculosis complex (MTBC) and non-tuberculous mycobacteria) and MTBC genotyping, directly on clinical samples. Among other unique features, this assay allows genotypic detection of recently re-defined extensively drug resistant (XDR) TB. We showed its high degree of accuracy versus phenotypic drug susceptibility testing and WGS done after culture. We used it e.g. to reveal an outbreak of MDR-TB in South Africa undetected by WHO-endorsed tests, and to discover a new sister clade of the MTBC in the African Great Lakes region, further supporting the East African origin of the MTBC. It is used by the WHO for surveillance of drug resistant TB and in >30 countries, and is being evaluated in several MDR-TB diagnostic trials, e.g. in Africa in the DIAMA H2020 EDCTP project and in India, South Africa and Georgia in the UNITAID-funded Seq&Treat project. We also developed a similar first-in-kind NGS-based test for culture-free diagnosis of the agent of leprosy, M. leprae, which is unculturable in vitro. We thereby performed the first nationwide NGS-based survey of leprosy drug resistance in the Comoros, revealing full susceptibility to anti-leprosy antibiotics of M. leprae strains in this country highly affected by this disease.
1. Marijke Braet S, Jouet A, Aubry A, Van Dyck-Lippens M, Lenoir E, Assoumani Y, Baco A, Mzembaba A, Cambau E, Vasconcellos SEG, Rigouts L, Suffys PN, Hasker E, Supply P, de Jong BC. Investigating drug resistance of Mycobacterium leprae in the Comoros: an observational deep-sequencing study. Lancet Microbe. 2022 3:e693-e700. doi: 10.1016/S2666-5247(22)00117-3
2. Walker TM, […], CRyPTIC Consortium (incl. P. Supply), Seq&Treat Consortium, Crook DW, Ismail N, Rodwell TC. The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis. Lancet Microbe. 2022 3:e265-e273. doi: 10.1016/S2666-5247(21)00301-3
3. Jouet A, Gaudin C, Badalato N, Allix-Béguec C, Duthoy S, Ferré A, Diels M, Laurent Y, Contreras S, Feuerriegel S, Niemann S, André E, Kaswa MK, Tagliani E, Cabibbe A, Mathys V, Cirillo D, de Jong BC, Rigouts L, Supply P. Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs. Eur Respir J. 2021 57:2002338. doi: 10.1183/13993003.02338-2020
4. Ngabonziza JCS, Loiseau C, Marceau M, Jouet A, Menardo F, Tzfadia O, Antoine R, Niyigena EB, Mulders W, Fissette K, Diels M, Gaudin C, Duthoy S, Ssengooba W, André E, Kaswa MK, Habimana YM, Brites D, Affolabi D, Mazarati JB, de Jong BC, Rigouts L, Gagneux S, Meehan CJ, Supply P. A sister lineage of the Mycobacterium tuberculosis complex discovered in the African Great Lakes region. Nat Commun. 2020 11:2917. doi: 10.1038/s41467-020-16626-6
5. Makhado NA, Matabane E, Faccin M, Pinçon C, Jouet A, Boutachkourt F, Goeminne L, Gaudin C, Maphalala G, Beckert P, Niemann S, Delvenne JC, Delmée M, Razwiedani L, Nchabeleng M, Supply P*, de Jong BC*, André E*. Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study. Lancet Infect Dis. 2018 18:1350-1359. doi: 10.1016/S1473-3099(18)30496-1. *Co-last authors
Romain Veyron-Churlet, CRCN CNRS
Rudy Antoine, CRCN INSERM
Kamel Djaout, Post-Doc
Jean Meneguello, Post-Doc
Sophie Lecher, Engineer
Stephanie Slupek, Technician
0000-0002-0150-5241
Small Molecules Aborting Resistance against Tuberculosis (SMARt-TB)
Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We are developing molecules that stimulates alternative prodrug activation pathway called Small Molecules Aborting Resistance (SMARt).
SMARt molecules aborting ethionamide resistance have been discovered in collaboration with team U1177 (ANR-IPL-Région HdF). First-in human study was initiated by Bioversys and GSK in 2020 with a molecule reverting Ethionamide resistance. A second family of compound aborting Pretomanid and Delamanid resistance is under evaluation with the support of ANR and SATT-Nord. The bioactivation of fluoroquinolone derivatives is also studied in collaboration with the team of Alexandra Aubry (Paris-CIMI), supported by the ANR project Detonator.
1. M. Flipo, R. Frita, M. Bourotte, M. S. Martinez-Martinez, M. Boesche, G. W. Boyle, G. Derimanov, G. Drewes, P. Gamallo, S. Ghidelli-Disse, S. Gresham, E. Jimenez, J. de Mercado, E. Perez-Herran, E. Porras-De Francisco, J. Rullas, P. Casado, F. Leroux, C. Piveteau, M. Kiass, V. Mathys, K. Soetaert, V. Megalizzi, A. Tanina, R. Wintjens, R. Antoine, P. Brodin, V. Delorme, M. Moune, K. Djaout, S. Slupek, C. Kemmer, M. Gitzinger, L. Ballell, A. Mendoza-Losana, S. Lociuro, B. Deprez, D. Barros-Aguirre, M. J. Remuinan, N. Willand, A. R. Baulard, The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis. Sci. Transl. Med. 14, eaaz6280 (2022).
2. B. Villemagne, A. Machelart, N. C. Tran, M. Flipo, M. Moune, F. Leroux, C. Piveteau, A. Wohlkonig, R. Wintjens, X. Li, R. Gref, P. Brodin, B. Deprez, A. R. Baulard, N. Willand, Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. ACS Infect. Dis. 6, 366-378 (2020).
3. L. Faion, K. Djaout, R. Frita, C. Pintiala, F. X. Cantrelle, M. Moune, A. Vandeputte, K. Bourbiaux, C. Piveteau, A. Herledan, A. Biela, F. Leroux, L. Kremer, M. Blaise, A. Tanina, R. Wintjens, X. Hanoulle, B. Deprez, N. Willand, A. R. Baulard, M. Flipo, Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening. Eur J Med Chem 200, 112440 (2020).
4. J. Costa-Gouveia, E. Pancani, S. Jouny, A. Machelart, V. Delorme, G. Salzano, R. Iantomasi, C. Piveteau, C. J. Queval, O. R. Song, M. Flipo, B. Deprez, J. P. Saint-Andre, J. Hureaux, L. Majlessi, N. Willand, A. Baulard, P. Brodin, R. Gref, Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. Sci. Rep. 7, 5390 (2017).
5. N. Blondiaux, M. Moune, M. Desroses, R. Frita, M. Flipo, V. Mathys, K. Soetaert, M. Kiass, V. Delorme, K. Djaout, V. Trebosc, C. Kemmer, R. Wintjens, A. Wohlkonig, R. Antoine, L. Huot, D. Hot, M. Coscolla, J. Feldmann, S. Gagneux, C. Locht, P. Brodin, M. Gitzinger, B. Deprez, N. Willand, A. R. Baulard, Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science 355, 1206-1211 (2017).
Lina Tawk, Post-Doc
Zainab Edoo, Post-Doc
Oriane Rivière, PhD student
0000-0002-0150-5241
Multiparametric Strategies against Antibiotic Resistance in Tuberculosis (Mustart)
Our team coordinates the “Mustart” project recently funded by the French initiative “Investments for the Future”(PIA3). Mustart associates 9 French academic experts to develop multifaceted regimens targeting the most coriaceous TB bacilli in their peculiar physiological niches, and to identify biomarkers of the treatment progress.
Associated partners :
1. CIIL, Lille 2. IPBS, Toulouse
3. Sorbonne Université, Paris 4. U1177, Lille
5. IP, Paris 6. TBI, Toulouse
7. LMGM, Toulouse 8. CEA, Saclay
9. CIRI-HCL, Lyon
Administrative coordinator : Institut Pasteur de Lille
Achilles’IL-BCG
Diabetic foot infection, the main complication of diabetes, is the result of infectious, neurological, vascular and immunological disorders. By maintaining an inflammatory process that is harmful to healing, these disorders promote the chronicity of the infection which is responsible for an amputation every 20 seconds worldwide, despite antibiotics use. In this setting, the aim of the Achilles'IL-BCG project is to evaluate BCG as a therapeutic adjuvant for: (1) skin repair by breaking the vicious cycle of inflammation, (2) improving the in-situ bioavailability of antibiotics, (3) evaluating new MALDI-MS imaging coupled to Spatialomics technology as prognostic and / or therapeutic monitoring tools.
Loïc Coutte, CRCN INSERM
Stéphane Cauchi, CRCN CNRS
Violaine Dubois, Post-Doc
Elena Santiesteban, Technician
Anne-Sophie Debrie, Engineer
Dominique Raze, Engineer
0000-0001-7295-7336
B-tech platform
The live attenuated nasal pertussis vaccine called BPZE1 has also shown protective off-target effects against influenza, lethal pneumococcal disease and allergic airway inflammation. In order to broaden the field of BPZE1 application, we are currently engineering the vaccine strain to present heterologous antigens to the respiratory tract, focusing on SARS-CoV2 and Mycobacterium tuberculosis antigens evaluated by 3 different expression/secretion systems. This work is performed under a collaborative agreement with the company ILIAD Biotechnologies which licensed BPZE1.
- Belcher T; Kammoun H; Coutte L; Debrie AS; Mielcarek N; Sirard JC; Cauchi S; Locht C. Live attenuated Bordetella pertussis vaccine candidate BPZE1 transiently protects against lethal pneumococcal disease in mice. Vaccine 2022; 40:1555-1562.
- Belcher T; Ait-Yahia S; Solans L; Debrie AS; Cauchi S; Tsicopoulos A; Locht C. Live attenuated pertussis vaccine for prevention and treatment of allergic airway inflammation in mice. NPJ Vaccines 2022; 7:66.
- Solans L; Debrie AS; Coutte L; Locht C. Construction and evaluation of a pertactin-deficient live attenuated pertussis vaccine candidate BPZE1 derivative. Vaccine 2021; 39:2843-2849.
