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, DRCE CNRS,
with GenoScreen R&D
0000-0003-3690-3853
Deep sequencing for culture-free diagnosis of drug resistance in mycobacteria (Deeplex Myc-TB and Deeplex Myc-Lep)
Only 40% of the estimated ~400,000 new tuberculosis cases with rifampicin resistance or multidrug-resistance 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 the knowledge gained on the M. tuberculosis resistome, novel tools for rapid NGS-based, culture-free diagnostics are developed by GenoScreen (Lille) with our collaboration. This led to the development of the first commercial targeted NGS kit for prediction of susceptibility or resistance to 13 anti-tuberculosis drug classes, directly applicable on clinical samples, named Deeplex® Myc-TB. Based on results showing its high degree of accuracy, including in diagnostic trials conducted in Africa, Eastern Europe and Asia (DIAMA H2020 EDCTP; Seq&Treat UNITAID), this novel diagnostic has been endorsed by the WHO in 2023, and is used in >50 countries. We also used this assay to discover ancestral clades of tuberculosis bacilli in East Africa, supporting the East African origin of the pathogen (see Genomics and transcriptomics). We developed a similar first-of-its-kind NGS-based assay 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. Yenew B, Ghodousi A, Diriba G, Tesfaye E, Cabibbe AM, Amare M, Moga S, Alemu A, Dagne B, Sinshaw W, Mollalign H, Meaza A, Tadesse M, Gamtesa DF, Abebaw Y, Seid G, Zerihun B, Getu M, Chiacchiaretta M, Gaudin C, Marceau M, Didelot X, Tolera G, Abdella S, Kebede A, Getahun M, Mehammed Z, Supply P, Cirillo DM. A smooth tubercle bacillus from Ethiopia phylogenetically close to the Mycobacterium tuberculosis complex. Nat Commun. 2023 14(1):7519. doi: 10.1038/s41467-023-42755-9
2. Jouet A, Braet SM, Gaudin C, (…), Cambau E, de Jong BC, Suffys PN, Supply P. Hi-plex deep amplicon sequencing for identification, high-resolution genotyping and multidrug resistance prediction of Mycobacterium leprae directly from patient biopsies by using Deeplex Myc-Lep. EBioMedicine. 2023 93:104649. doi: 10.1016/j.ebiom.2023.1046493.
3. 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
4. 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
5. 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
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
Innovative Anti-TB Therapeutics
Alarmingly, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis have now spread worldwide. To address this global health threat, our team is developing innovative alternative therapeutics against this deadly disease.
Several key antituberculosis antibiotics are prodrugs, with resistance mechanisms primarily driven by mutations in the bacterial enzymatic pathways required for their bioactivation. Our approach focuses on developing molecules that stimulate alternative prodrug activation pathways, referred to as Small Molecules Aborting Resistance (SMARt). In collaboration with Team U1177 (ANR-IPL-Région HdF), we successfully identified SMARt molecules that counteract resistance to ethionamide. A first-in-human study (Clinical Phase 1) initiated by Bioversys and GSK in 2020 showed promising results, followed by a successful Phase 2a study in South Africa, which demonstrated that Alpibectir significantly enhances ethionamide efficacy and reverses resistance to the drug. We are now evaluating a second family of compounds aimed at overcoming resistance to Pretomanid and Delamanid.
Additionally, our group is actively seeking molecules to counteract antibiotic tolerance, a major factor contributing to the prolonged duration of tuberculosis treatment and the risk of relapse.
In partnership with key national collaborators within the PIA-funded Mustart consortium (coordinated by A. Baulard), we are exploring additional innovative therapeutic strategies. These include toxin-antitoxin disruptors, multitarget inhibitors, fluoroquinolone prodrugs, novel aerosol nanoparticle delivery systems, and host-pathogen interaction-modulating compounds.
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).
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.
